Guidelines on the management of. bipolar disorder in Catalunya

Transcription

1 Guidelines on the management of bipolar disorder in Catalunya Evidence base and Methods Pla Director de Salut Mental i Addiccions Departament de Salut Generalitat de Catalunya

2 INDEX 1. JUSTIFICATION 2. AUTHORS AND COLLABORATORS 3. METHODS AND QUESTIONS TO WHICH THE GUIDELINES ARE ADDRESSED 4. EPIDEMIOLOGY OF BIPOLAR DISORDER IN CATALUNYA 5. DIAGNOSIS OF BIPOLAR DISORDER 6. GENERAL ASPECTS ON THE TREATMENT OF BIPOLAR DISORDER 7. PHARMACOLOGIC TREATMENT 8. PSICHOLOGIC TREATMENT 9. OTHER TREATMENTS 10. SPECIALS POPULATIONS 11. COST-EFFECTIVENESS ANALYSIS 12. LEVELS OF INTERVENTIONS, FLOWS AND SETTINGS 13. MANAGEMENT OF BIPOLAR DISORDER FROM PRIMARY CARE 14. GUIDELINES IMPLEMENTATION 15. INFORMATION FOR PATIENTS, FAMILIES AND CAREGIVERS 16. CURRENT AND FUTURE RESEARCH 17. REFERENCES

3 01 - JUSTIFICATION Bipolar disorder (BD), formerly known as manic-depressive psychosis, is a severe, chronic and recurrent mental illness characterized by a cyclic and, most of the times, intense episodes of mood alteration, with manic (euphoria, feelings of elation, grandiosity, irritability, hypersexuality, increased speech, decreased need for sleep, sometimes psychotic symptoms, etc) an depressive episodes (sadness, anxiety, loss of interest, poor concentration sleep and eating alterations, suicidal ideation). According to the most recent epidemiological studies, lifetime prevalence is 4,4% in general population (Merikangas et al, 2007). Approximately 25% of bipolar patients try to commit suicide (APA, 2000), so it is very important to implement an adequate early intervention aimed at mood-stabilization (Vieta, 1997). Similarly, BD is associated, due to its chronic and recurrent course, to severe social, familiar, working burden. World Health Organization identified BD as the 4 th cause of neuropsychiatric incapacity in the general population aged years old (WHO, 2001), an age which should represent the peak of productivity in a person s life. BD patients have also been found to utilize health-care services more than do patients with depression or chronic medical conditions. In U.S.A. direct costs of BD have been evaluated in 1999 to an amount of $ billions. The great majority of this cost is due to hospitalization cost; other direct costs involve outpatients visits and expenses not directly related to treatment (i.e. costs due to legal consequences). Indirect costs (low productivity, los salaries, need for caregivers and specialized workers in hospitals, costs derived from patients who committed suicide) sum for up to million dollar (Vieta, 2007). At present day, there are no 100% effective treatments for BD. Current therapies may reduce morbidity and mortality associated with the disorder. Different options for treatment depend on the phase of the illness (short- or long-term treatment), polarity of current episode (manic, depressive, mixed state), polarity of past episodes (depressive or manic predominant polarity), cycles of the disorder (rapid or not). Factors like lack of adherence, substance use or comorbidity may negatively influence the course and outcome of the illness. The first objective of a clinician treating bipolar patients is to achieve the state of euthymia, which means full remission from mood symptoms. The availability of different drug options, combined with the complexity of the illness and the need of an early diagnosis and treatment to improve the outcome, brings to the need of maximum effectiveness in the first therapeutic choice. The growing bulk of knowledge on epidemiological, clinical, therapeutical aspects of BD underpin a need for up-to-date instruments which may help clinicians, namely mental health professionals in Catalunya, managing different aspects of the this complex illness. Moreover, an easy-to-use guide to BD may help choosing appropriate, evidence-based treatments, evaluating the role of specific pharmacological, psychological, physical interventions in the treatment and management of BD. Its spread use in clinical practice may thus: reduce the variability of clinical practice in the field of BD, increase the efficiency of local organization and resources available for the management of the illness in Catalunya according to health care levels, facilitate the knowledge of mental health care providers, identify gaps in the literature and ways to solve unanswered questions and, finally, point out actual directions in scientific research on BD

4 02- Authors and Collaborators Authors Eduard Vieta (Director UTB-Clínic, UB, IDIBAPS, CIBERSAM) Andrea Murru (psychiatrist UTB-Clínic) Maria Jesús Pueyo (Departament de Salut, Generalitat de Catalunya) Collaborators Alessandra Nivoli (psychiatrist UTB-Clínic) Francesc Colom (psychologist UTB-Clínic, IDIBAPS, CIBERSAM) Anabel Martínez-Arán (clinical neuropsychologist, Hospital Clínic, CIBERSAM) Brisa Solé (psychologist UTB, IDIBAPS) Nuria Cruz (clinical pharmacologist UTB-Clínic, IDIBAPS) Adriane R. Rosa (pharmacist UTB-Clínic, IDIBAPS) Mercè Comes (nurse Hospital Clínic) Lluïsa García-Esteve (Women Unit-Clínic) Anna Kotzeva (Catalan Agency for Health Information, Assessment and Quality CAHIAQ-) External reviewers Ana González-Pinto (Spain) Heinz Grunze (UK) Lakshmi Yatham (Canada) Societies and other entities Societat Catalana de Psiquiatria i Salut Mental Societat Catalana de Psicologia Clínica SEMFyC SEMERGEN CIBERSAM Acknowledgments Elena Calvo (Departament de Salut, Generalitat de Catalunya) Cristina Molina (Departament de Salut, Generalitat de Catalunya) Oriol de Solà-Morales (Catalan Agency for Health Information, Assessment and Quality CAHIAQ-)

5 03 METHODS AND QUESTIONS ANSWERED BY THE GUIDELINES 3.1. OBJECTIVE OF THE GUIDELINES At whom is this guideline aimed? Aims of this guideline 3.2. LEVELS OF EVIDENCE AND RECOMMENDATION GRADES GUIDELINES REVIEW COMPARISON OF CE AND RG ACROSS GUIDELINES CATALAN GUIDELINES LEVELS OF EVIDENCE AND RECOMMENDATION GRADES TREATMENT LEVELS OF EVIDENCE AND RECOMMENDATION GRADES FOR CATALAN GUIDELINES 3.3. LITERATURE REVIEW PROCESS EVALUATION OF THE SOURCES REVIEW PROCESS SEARCH FILTERS GENERAL CONSIDERATIONS ON THE METHODOLOGY OF DIAGNOSTIC AND EPIDEMIOLOGICAL SEARCH REVIEW ON THE TREATMENT FOR BIPOLAR DISORDER TREATMENTS COST-EFFECTIVENESS IN BIPOLAR DISORDER 3.4 RECOMMENDATIONS PROCESS 3.5. EXPERTS AND SCIENTIFIC SOCIETIES REVIEW 3.1. OBJECTIVE OF THE GUIDELINES AT WHOM IS THIS GUIDELINE AIMED? This guideline puts together and synthesizes the data on scientific research and clinical practice on the complex issue of bipolar disorder. It provides the tools for evidencebased diagnosis and treatment of bipolar disorder, and it may be of relevance to professionals in primary and secondary care who have to manage directly or indirectly patients suffering this illness. This guideline will briefly furnish data on the clinical presentation and epidemiological aspects of BD. It will address the issue of diagnosis and the unique problems that clinicians have to face in clinical practice. Some especially delicate aspects of the diagnostic features of BD will be discussed and suggestions made out of expert opinion will be furnished to ease BD diagnosis. The list of professionals who could benefit from these guidelines includes:

6 Professional groups who share in the treatment and care of people with bipolar disorder, including psychiatrists, clinical psychologists, mental health nurses, community psychiatric nurses, as well as other community nurses, social workers, counsellors, practice nurses, occupational therapists, pharmacists, general practitioners and others Professionals in other health and non-health sectors who may have direct contact with or are involved in the provision of health and other public services for those diagnosed with bipolar disorder. These may include medical staff, paramedical staff, prison doctors, the police and professionals who work in the criminal justice and education sectors Those with responsibility for planning services for people with bipolar disorder and their carers, including directors of public health, National Health System (NHS) trust managers and managers in primary care trusts AIMS OF THIS GUIDELINE Our goal was the integration of available research information and clinical consensus into a practical, ease to use compendium which considers the different stages of the management of bipolar illness, as well as the best treatment options. The guideline makes recommendations for pharmacological treatments and the use of psychological and service-level interventions. Specifically, it pretends answering the following questions concerning BD in clinical practice: Which are the specific pharmacological agents for the treatment and management of the disorder, in acute episodes and in the long-term? Which are the specific psychosocial interventions for the treatment and management of the disorder, in acute episodes and in the long-term? Which are the specific physical interventions for the treatment and management of the disorder, in acute episodes and in the long-term? What is the role of specific service delivery systems and service-level interventions in the management in acute episodes and maintenance treatment of BD? How to integrate the above to provide best practice advice on the care of individuals with BD through the different phases of illness, including the initiation of treatment, the treatment of acute episodes and the promotion of recovery? Do the various treatments for BD have economic aspects we should take into account? The content of the guidelines is relevant for all doctors who are treating patients with bipolar disorder. We expect that in most cases these will be doctors who are specialists in psychiatry, who pose as the natural recipients of this manuscript. However, we have written the guidelines with an eye also to informing general practitioners, patients and their families and health care providers with an interest in bipolar disorder, although the contents of these guidelines may have some technical features which could complicate the comprehension to untrained readers. We have emphasized our interest in scientific evidence. However, we could not review all the relevant literature in the detail required to give a fully comprehensive text. Even so, by distilling the evidence and summarising points of consensus, relating mainly to medical management of bipolar disorder, the

7 final version of the manuscript may not result in a format that is particularly brief, a fact which underpins the growing interest that bipolar illness has awaken in scientific research. The adoption of the present guidelines is not intended to substitute for clinical judgment, but instead is proposed to integrate it with a systematic guidance in the diagnostic, clinical management and therapeutic stages LEVELS OF EVIDENCE AND RECOMMENDATION GRADES A guideline represents a synthesis of current scientific knowledge developed by integration of the evidence-based data (from randomized clinical studies) with the rational clinical practice and experience regarding a specific topic. In general, the process by which a guideline is generated begins with a committee of experts who undertake an evaluation of the existing data ranking studies according to certain Levels or Categories of Evidence (LE). They represent the modality by which researchers categorize efficacy from evidence-based data. Depending on the methodology of study design, on the number of positive trials and on the absence or presence of negative evidence, a LE for efficacy is assigned to each compound. For instance a drug at the highest level (defined as level I or LE A and B) must have shown its efficacy in doubleblind placebo-controlled studies in order to be recommended with substantial confidence. Ideally the LE should guide researchers in making justified comparison of different studies findings, even if each level has its own strengths and weakness. For instance, the results of double-blind, placebo-controlled trials are supposed to be more valid than those of less rigorous observational studies. Practically, open randomized and large observational studies can be as accurate as level I studies while having the advantage to be more generalizable and near to every-day clinical practice (Goodwin & Jamison, 2007). In order to overcome these limitations, guideline developers have incorporated adjunctive clinical data from open trials, retrospective analyses, case reports and expert consensus in clinical experience. Deriving from the LE (efficacy) and from these additional clinical aspects (safety, tolerability and effectiveness) Clinical Recommendations (RG, Recommendation Grade) have been proposed for each compound GUIDELINES REVIEW A first, extensive search for recent published guidelines and systematic reviews was undertaken, to evaluate: 1. The levels of evidence (LE) used by other recent guidelines. 2. To find out the relevant and significant references in the development process. The majority of recently reviewed guidelines and algorithms on treatment of bipolar disorder were screened through a literature search in the National Guideline Clearinghouse, a public resource for evidence-based clinical practice guidelines. The results show different guidelines with differences in the staging methodology (Goodwin et al, 2008, 2009; Grunze et al, 2009; Kasper et al, 2008; Yatham et al, 2009; NICE, 2009). The earlier stages involve simpler treatments in terms of safety, tolerability, ease of use, side effect profiles whereas the later stages usually are supported by less evidence and involve more complicated regimens. Relevant recent guidelines, summarized in the table 3.1, were defined as published in the last 3 years.

8 Tab Guidelines considered for reviewing. Authors Year Guideline Goodwin et al ECNP Consensus Meeting. Bipolar depression, Nice, March 2007 Goodwin et al British Association for Psychopharmacology (BAP): Evidence-based guidelines for treating bipolar disorder: revised second editionrecommendation from the BAP Grunze et al World Federation of Societies of Biological Psychiatry WFSBP: update 2009 on the treatment of Acute Mania Grunze et al World Federation of Societies of Biological Psychiatry WFSBP: update 2009 on the treatment of Acute Bipolar Depression Kasper et al International Consensus Group on the Evidence-based Pharmacologic treatment of bipolar I and II depression NICE 2009 National Institute for Health and Clinical Excellence (NICE) The management of bipolar disorder in adults, children and adolescent, in primary and secondary care. Yatham et al Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) Collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update COMPARISON OF LE AND RG ACROSS GUIDELINES In World Federation of Societies of Biological Psychiatry Guidelines (Grunze et al. 2009) the scientific rigor is categorized into 6 categories of evidence for efficacy (CE, from A to F) and this scientific evidence is finally assigned to different grades of recommendation (RG, from 1 to 5) considering additional aspects as safety, tolerability and interaction potential (effectiveness). The British Association of psychopharmacology Guidelines (Goodwin 2009) refer for categories of evidence and clinical recommendation to the North of England Evidence-Based Guideline Development Project undertaken for the Services Research, University of Newcastle upon Tyne and the Centre for Health Economics, University of York (Shekelle et al, 1999). They use CE (form I to IV) and recommendation grading (form A to D). The NICE Guidelines (National Collaborating Centre Of Mental Health, 2009) does not furnish a similar ranking method, but the quality of the evidence is based on the quality assessment components (study design, limitations to study quality, consistency, directness and any other modifying factors) and graded using the following definitions: high, moderate, low, very low. The Canadian Network for Mood and Anxiety Treatments and International Society for Bipolar Disorders Guidelines (CANMAT and ISBD) (Yatham et al, 2009) furnish evidence criteria (from 1 to 4) and treatment recommendation (first line, second line, third line and not recommended). The International Consensus Group (ICG) on the Evidence-Based Pharmacologic Treatment of Bipolar I And II Depression (Kasper et al, 2008) defines CE by classifying treatments through Category 1, 2 and CATALAN GUIDELINES LEVELS OF EVIDENCE AND RECOMMENDATION GRADES None of the reviewed guidelines considered in the LE two methodological aspects deemed important by the authors of the present guidelines: 1. The epidemiologic and diagnostic features of BD are investigated by means of studies with a different methodology than the one used for treatment trials.

9 2. Longitudinal course of BD represents a nuclear aspect of the illness, which is by definition chronic. This element should be reflected in the LE by considering long-term treatment trials. Given these noteworthy aspects, authors decided to develop their own LE and RG, differentiating them for epidemiological-diagnostic features and for treatment. Following, LE and RG concerning epidemiologic and diagnostic aspects of BD are presented in tables 3.2. and 3.3. Tab.3.2. Levels of evidence for epidemiologic and clinic studies not aimed to interventions. Solid scientific evidence, based on epidemiologic/clinical studies characterized by highly 1 rigorous methods, highly representative, with wide sample sizes and independently replied results. Preliminary data from epidemiologic/clinical studies characterized by highly rigorous 2 methods, not replied with independent results or replied in samples with possible selection bias. 3 Expert consensus. Tab Degrees of recommendations for epidemiologic and clinical factors. A Level of evidence 1 B Level of evidence 2 C Level of evidence TREATMENT LEVELS OF EVIDENCE AND RECOMMENDATION GRADES FOR CATALAN GUIDELINES The group prioritized their recommendations on the basis of clinical evidence. The higher levels are supported by less evidence and involve more complicated regimens, whereas lower levels involve simpler treatments in terms of safety, tolerability and ease of use in practical clinic. To achieve an objective and evidence-based presentation of disposable treatments, we propose a classification of the levels of evidence which considers different aspects: 1. Data of efficacy: absolute efficacy (i.e. comparison to placebo), comparative efficacy (comparison to an active drug of known efficacy in bipolar disorder). Short- and long-term efficacy was considered. Magnitude of effect was taken into account when evaluating the trials. 2. Data of tolerability: absolute tolerability (i.e. comparison to placebo), comparative tolerability (comparison to an active drug of known efficacy and tolerability in bipolar disorder. Short- and long-term tolerability was considered. Magnitude of effect was taken into account when evaluating the trials. 3. Theoretical assumptions related to the illness construct (i.e.: efficacy and tolerability in the 2 poles of the illness, no treatment-emergent counter-polarity episodes). 4. Clinical experience. A particular conflict in these and other guidelines arise between existing practice and the interpretation of recent trials of new

10 compounds. Existing practice may be accepted as clinically effective on the basis of long standing experience and/or by extension of a related proven indication, while awaiting more robust evidences. 5. Expert consensus. Levels of evidence are summarized and described in the tables 3.4. and 3.5. Tab 3.4. Treatment Levels of evidence used in these guidelines. Level 1 Solid evidence of high efficacy and safety in short- and long-term treatment Level 2 Reasonable evidence of efficacy and safety in short- and long term treatment Level 3 Reasonable evidence of efficacy and safety in short term Level 4 Some evidence of effectiveness with wide experience Level 5 Some evidence of effectiveness without experience Level 6 Without evidence, but with some experience Level 7 Expert consensus Tab 3.5. Levels of evidence used in these guidelines - description. Level 1 At least two positive short-term* and one positive long-term* randomized controlled trials with superiority over placebo and non inferiority compared to a known standard treatment, with large effect size** and safety and tolerability not inferior to the standard treatment Level 2 At least one positive short-term and one positive long term randomized controlled trial with superiority compared to placebo, a moderate** effect Level 3 size, safety and tolerability comparable with standard treatment At least one positive short-term randomized controlled trial with superiority compared to placebo, a moderate effect size**, or a rate between efficacy and safety inferior to standard treatment Level 4 At least one randomized comparative trial with effectiveness, safety/tolerability comparable to current treatments, or small effect size** and experience based on high quality observational trials, case series and frequent use in clinical practice Level 5 Preliminary data on efficacy in a randomized controlled trial versus placebo, with limited sample size**, or as an add-on treatment, with little or no previous clinical experience Level 6 Observational studies, case series, acceptable safety and tolerability from experience in other illnesses Level 7 Experts opinion, theoretical fundaments for clinical use, single cases *Short term RCT follow-up < 6 months; long-term RCTs follow-up 6 months. **Effect size (ES) greater than 0.5 is large, is moderate, is small, and anything smaller than 0.1 is trivial (Cohen, J. (1988). Statistical power analysis for the behavioural sciences (2nd ed.). New Jersey: Lawrence Erlbaum) 3.3. LITERATURE REVIEW PROCESS The aim of the clinical literature review was to systematically identify and synthesise relevant evidence from the literature. Thus, clinical practice recommendations are

11 evidence-based, where possible and, if evidence was not available, consensus was achieved EVALUATION OF THE SOURCES. At present state, no studies that evaluate the presence and impact of BD on the Catalan population have been conducted. Even when considering the whole Spanish population, the lack of data on epidemiological, clinical and treatment aspects on the disorder is almost absolute. The only consistent sources of information on the epidemiology of BD are some European data and, mainly, U.S. data obtained from large population studies. This need for data extraction on BD epidemiology from studies involving not Catalan- Spanish samples and clinicians mainly bears three consequences. First, as genetic factor undoubtedly play an important factor on the aetiology of the BD, we cannot know if data extrapolation onto Catalan clinic practice may be influenced by the systematic bias of being essentially based on data coming from other populations, and how this may affect it. Second, the question if, and to what extent, clinical characteristics of bipolar disorder may be influenced by cultural aspects stays open and with no response, with an implicit bulk of consequences on our data discussion. Third and last, we may not exclude the possibility of cultural factors influencing clinicians towards a given diagnosis, so that a clinical tradition bias could be present. A search for indirect measures too did not produce an increase of knowledge on the burden of BD on the Catalan-Spanish population: we reviewed data on public health, referred to years , in the Spanish National Statistical Institute site ( which are of difficult interpretation. No mention on bipolar disorder is made. Depressive disorders, when considered, seem an over-inclusive category (unipolar-bipolar) combined with anxiety disorders. The Institute, even though potentially dividing useful data for each Spanish County, uses the too broad Mental and behavioural disorders definition when giving mortality and incapability rates, making it hard to extract data on affective, namely bipolar, disorders REVIEW PROCESS SEARCH FILTERS Search filters developed by the review team consisted of a combination of subject heading and free-text phrases. Specific filters were developed for the different guidelines chapters and subchapters, and are presented in Annex 1. In addition, the review team used filters developed for systematic reviews, RCTs and other appropriate research designs. Where possible, two independent reviewers extracted data from new studies. Where double data extraction was not possible, data extracted by one reviewer was checked by the second reviewer. Disagreements were resolved with discussion. Where consensus could not be reached, a third reviewer resolved the disagreement GENERAL CONSIDERATIONS ON THE METHODOLOGY OF DIAGNOSTIC AND EPIDEMIOLOGICAL SEARCH The topics of main interest concerning epidemiological and diagnostic aspects of BD have been set basing on the most comprehensive textbook on the topic of manicdepressive illness (Goodwin and Jameson, 2007) and a manuscript written by Ghaemi y colls on behalf of the International Society for Bipolar Disorder (Ghaemi et al, 2008). We only considered English- and Spanish-written sources for the draft of these guidelines.

12 Ideally, as justified in paragraph 3.2.1, some ethnical, cultural bias would require preferentially epidemiological studies on the Catalan population. We performed different PUBMED and ISI web of knowledge searches, trying to prioritize Catalan, Spanish and general samples respectively. Due to major diagnostic changes between DSM-III and DSM-IV, studies were considered if published in the last 10 years (since to ) to guarantee a minimum level of homogeneity in the data presented. However, 3 major population studies (5000+ individuals enrolled) have been included due to the importance and magnitude of the researches (CNCG, 1992; Weissman et al 1996, 1997). Case reports, editorials, letters, reviews were excluded from the results in the general sample search but not in the Catalan and Spanish samples search, this due to the paucity of literature on Catalan and Spanish samples. Studies were considered for inclusion in the epidemiology and diagnostic chapters according to the proper argument (i.e. misdiagnosis, etc.) if they presented samples of interest. Samples of interest were defined by counting at least 100 bipolar patients. The literature search results were evaluated independently by two reviewers, who evaluated the results by an abstract reading and, where in doubt, an article reading to sort material of interest, independently cross-checked and compared. Consensus was searched in case of discrepancies on results REVIEW ON THE TREATMENT FOR BIPOLAR DISORDER Apart from the guidelines considered, PUBMED was searched in order to locate papers with treatment guidelines and randomized controlled trials (RCTs) concerning the agents frequently used in the treatment of bipolar illness in all the populations of interest. The search was last performed on the 1 st of November Search strategies used in this review are reported in the Annexe I section TREATMENTS COST-EFFECTIVENESS IN BIPOLAR DISORDER The aim of the health economics review was to contribute to the guideline s development by providing evidence on the economic burden of BD as well as on the relative cost-effectiveness of different treatment options covered in the guideline. Where available, relevant evidence was collected and assessed in order to help the decision-making process. The following economic issues relating to the epidemiology and the management of BD were identified by the guidelines author group in collaboration with the health economist as primary key issues that should be considered in the guideline: - The global economic burden of BD with specific reference to the UK. - Comparative cost-effectiveness between pharmacological, psychological and physical interventions for the treatment of patients with BD either stabilised or experiencing an acute episode. - Comparative cost-effectiveness between different types of service provision appropriate for the management of patients with BD A systematic review of the published literature was conducted to identify studies that explored cost-effective treatments for bipolar disorder. Details on the literature search are reported in the Annexe 1 section RECOMMENDATIONS PROCESS The systematic review yielded the following number of documents, up to 30/09/2009:

13 Epidemiological studies results: 4423 total studies, 2839 after year filter, 1002 after publication filter. Diagnostic studies results: 13793, 7705 after year filter, 2117 after publication filters. Pharmacological treatment studies results: 17290, 1979 after publication filters. Psychological treatment studies results: 1196, 156 after publication filters. Physical treatment studies results: 941, 122 after publication filters. Paediatric studies results: 441, 53 after publication filters. Pregnancy studies results: 581, 15 after publication filters. Elderly studies results: 9672, 1634 after publication filters. Cost effectiveness studies results: 109, 25 after publication filters. A systematic review on the literature results has been written and ordered following the chapters and paragraphs previously decided. LE have been assigned to the studies considered for inclusion, and recommendations have been subsequently drafted. Most significant studies used for the literature review have been enclosed in Annexe I section EXPERTS AND SCIENTIFIC SOCIETIES REVIEW The resulting document was submitted to a critic review made by independent scientific evaluators (one Spanish and two foreign experts on clinical guidelines on BD), by the Catalan Agency for Health Information, Assessment and Quality CAHIAQ- and by the Scientific Societies involved, like the Catalan Society of Psychiatry and Mental Health, the Catalan Society of Clinical Psychology, the Catalan Society for Family and Community Medicine, the Spanish Society for Family and Community Medicine, the SEMERGEN and the Centre of Biomedic Research in the Mental Health Network (CIBERSAM).

14 04 - Epidemiology of Bipolar Disorder 4.1. GENERAL CONSIDERATIONS 4.2. LIFETIME AND 12-MONTH PREVALENCE 4.3. AGE AT ONSET 4.4. GENDER 4.5. GENETICS 4.6. PSYCHIATRIC COMORBIDITY 4.7. MISDIAGNOSIS 4.8. MORTALITY AND SUICIDE 4.9. SOCIAL VARIABLES Marital status Socioeconomic factors CONCLUSIONS In the following paragraphs, we will discuss the present state of epidemiologic research on bipolar disorders (BDs), their sometimes unique methodological problems and the weight of its issues on the clinical practice. We will then discuss briefly the first striking data, which is the lack of solid epidemiological data on BD in the Catalan-Spanish population despite its predictable social and medical burden. We will go on presenting data on lifetime prevalence and 12-month prevalence. Some general characteristics of Bipolar Disorder will be discussed, such as age at onset, gender differences, genetic aspects, social variables (marital status, socioeconomic factors), comorbidity, course of illness and prognostic factors, as well as more specific ones, such as misdiagnosis and mortality and suicide GENERAL CONSIDERATIONS Community epidemiological studies in the field of psychiatry provide important pieces of information on the prevalence and other characteristics of disorders that cannot be extrapolated from everyday clinical practice. So, when available, data on population studies will be presented: the advantage of general population samples is that they allow a representative description of any disorder without bias from severity, help-seeking and treatment effects. The increased interest in epidemiological aspects of psychiatric disorders in the last decades coincides with the development of research methodology. In the past, absence of a common format for diagnosis hampered cross-national syntheses in the first psychiatric epidemiological surveys. With the development of fully structured research diagnostic interviews (Robins et al, 1981) and the implementation of large-scale psychiatric epidemiological surveys in many countries (CNCG, 1992; Weissman et al 1996, 1997) this situation changed in the last thirty years. Epidemiological data are undoubtedly needed by policy planners to assess the societal burden of mental disorders, unmet need for treatment, and barriers to treatment. These data are especially important given evidence from the World Health Organization (WHO) Global Burden of Disease Study that mental disorders impose enormous

15 burdens worldwide, due to their combination of high prevalence and high disability (Murray and Lopez 1996), and evidence that, despite efficacious treatments, substantial unmet need for treatment exists throughout the world (Bijl et al, 2003). For what concerns BD, the Global burden of disease study places self-inflicted injuries, overwhelmingly attributable to psychiatric illnesses and especially to unipolar and bipolar disorders, are the sixth leading cause of death in adults of age 15-59, in low and middle-income countries and the second in high-income countries (Lopez et al 2006). BD has found to be a leading cause of premature mortality due to suicide and associated medical conditions, such as diabetes mellitus and cardiovascular disease. (Kupfer, 2005; Osby et al, 2001). Also, BD causes widespread role impairment (Calabrese et al, 2003; Dean et al, 2004). The recurrent nature of manic and depressive episodes often leads to high direct and indirect health care costs (Goetzel et al, 2003; Bauer and Pfenning 2005). The EMBLEM study, which enrolled 3536 patients of whom 312 were enrolled in Spain, confirms that bipolar patients suffer serious social and occupational dysfunction and generate a high degree of healthcare resource utilization (Montoya et al, 2007). When focused on BD, epidemiologic research has to face some unique features: 1. Bipolar disorder has a relatively low prevalence and thus requires large population samples for accurate estimates. 2. The findings are almost always based on structured interviews conducted by non-clinicians. When compared with studies conducted by clinicians only a small correspondence is found. 3. Diagnostic criteria have varied through the years (Goodwin and Jamison, 2007), and are possibly still varying. These features contribute to further complicating research on BD. Together, these features contribute to a further difficulty in extrapolating data onto clinical practice LIFETIME AND 12-MONTH PREVALENCE Data from the ESEMeD-Spain project, an epidemiological study about mental disorders in Spain, leave quite surprisingly Bipolar Disorder out of the considered disorders to be assessed (Haro et al, 2004). The WHO World Mental Health (WMH) Survey Initiative showed a lifetime prevalence of affective disorders of 10% in Spain, but no distinction between different mood disorders is operated (Kessler et al, 2007), so that the usefulness of the data is relative. Data from the UK, Germany, and Italy indicated that the prevalence of bipolar disorder in European countries was around 1% (Fajutrao et al, 2009). Prevalence ranged between 0.6% to 1% in Germany and 0.8% in Italy. In the UK, the first-episode incidence over 2 years was estimated at 4% to 4.6% in 3 cities and at 0.01% over 3 years in another area (Proctor et al, 2004). In the cities, the age-related incidence of bipolar disorder varied between 1.7% and 6.2% (Lloyd et al, 2005). Faravelli et al. (2006) found the prevalence of bipolar I and II disorder to be 0.5% and 0.4%, respectively. As said before, our knowledge of the burden of BD is based primarily on evidence from the United States, where the most influential epidemiological studies took place. The Epidemiological Catchment Area Sudy (ECA) in 1981 and the National Comorbidity Survey (NCS) in 1991 included respectively more than and more than 8000 subjects (Goodwin and Jamison, 2007; Kessler et al, 1994). They assessed the lifetime prevalence for BD at approximately 1%. The large discrepancy between rates of BP found these large-scale community surveys and those derived from prospective longitudinal studies suggests that lifetime

16 prevalence estimates from community surveys may underestimate the true prevalence of BD (Angst et al, 2003). The same author affirms that symptom inclusion criteria and the diagnostic thresholds for BP are too restrictive to detect BP in the general population, particularly in young adults, when the disorder is in evolution. Moreover, hypomania is frequently not recognized by the probands and recall bias can also affect the results, further complicating the possibility to diagnose BD type II particularly in normal populations. An underestimation of the true frequency of BDs seems possible and confirmed by some studies (Perälä et al, 2007). In a re-analysis of the ECA data (Judd and Akiskal, 2003), the addition of subthreshold bipolarity, mostly BD type II and subthreshold BD, increased the total lifetime prevalence up to 6.4%.Taken together, results from these last two studies, which both have included assessment of subthreshold mood disorders, suggest that bipolar spectrum disorder might affect up to 6% of the general population, having a social burden far greater than previously estimated. In the recent National Comorbidity Survey Replication (NCS-R), lifetime prevalence estimates in a sample of more than 9000 subjects is 1.0% for BD-I, 1.1% for BD-II, 2.4% for subthreshold BD, and 4.4% overall (Merikangas et al, 2007). In the end, as already pointed out, some authors stand for less strict diagnostic criteria: the broadening of these criteria and a more careful evaluation of the patients invariably leads to an increase in the prevalence of BD from the values obtained in past large-scale community surveys AGE AT ONSET Median average age of onset of BD is somewhat earlier for BD type I (18 years old) and BD type II (20 years old) than sub-threshold BD (22 years), with an interquartile range (i.e. the years between the twenty-fifth and seventy-fifth percentiles of the age-of-onset distribution) or roughly two decades for the whole bipolar spectrum (from the late teens through the late thirties (Kessler et al, 2007). Usually, BD type I starts at an earlier age then Major Depressive Disorder (Peselow et al, 1982), as well as BD type II. In most of the studies both types of BD start at a similar age (Angst, 1986; Benazzi, 1999), even if in a work from Hirschfeld y colls (2000) the age at onset for BD type II was found to be intermediate between that of BD type I and that of Major Depressive Disorder. Differently from Unipolar Depression, BDs usually show in adolescence and in early adulthood (Costello et al, 2002). Age at onset for the first symptoms would be between 15 and 19 years. Average age at onset in a sample of 2839 patients of the Register of Stanley Center Bipolar Disorder was 17.5 years (Kupfer et al, 2002). In a study 33% of the patients were less than 15 at illness onset, 27% between 15 and 19 and 39% at more than 20. First episode age at onset is at about 20 years of age (Vieta et al, 1994) and in BD type II patients could be later (Vieta et al 1997). Bipolar disorder may start before puberty but it is more difficult to differentiate it from other psychiatric disorders as ADHD (Attention Deficiency Hyperactivity Disorder), Major Depression or Schizophrenia (Geller et al 1998). Some investigators proposed three subgroups of onset early (child or early adolescent), intermediate or typical (late adolescent, young adult) and later life (after age 35). This trimodal distribution has been validated by Bellivier and coll. (2003), even if with 3 slightly delayed ages (16.9, 26.9 and 46.2 respectively). Similarly, a Sardinian group obtained a tri-modal distribution of age-at-onset in a sample of 181 patients: patients distributed around 18.1±2.3 (36%), 24.3±5.3 (39%) and 41±11.5 (25%) years (Manchia et al, 2008). It is also possible that bipolar symptoms may appear at a later age: a secondary peak of late onset is reported among women in the age range (Angst et al, 1978). These

17 patients are less likely to have a familiar history of the disorder, with a higher probability of being organically impaired or having neurological abnormalities of different aetiology (Tohen et al, 1994). In conclusion, three main peaks may be found in the age at onset of BD. Earlier onset of the illness normally tends to have worse outcomes. A secondary late peak may be possible in the age range 40-50, especially in women. Organic causes should be carefully investigated in this subgroup of patients GENDER The issue of clinical and epidemiological differences regarding gender amongst patients with BD is still quite controversial. Lifetime prevalence in bipolar disorders shows some gender-specific differences, namely: prevalence estimated for males and females are 0.8% and 1.1% respectively for BP I, 0.9% and 1.3% for BP II, 2.6% and 2.1% for subthreshold BPD (Merikangas et al., 2007). There is a contrast between the reported significant different course of illness between the two genders and the lack of agreement on which clinical variable may be influenced. A different tendency to depressive symptoms exists between bipolar men and women, as a solid bulk of evidences has been presented on the fact that women are more likely to present with an initial depressive episode (Goodwin & Jamison 2007, Viguera et al, 2001; Liebenluft 1996), to suffer from a greater number of depressive episodes (Roy-Byrne et al, 1985) and to suffer from more refractory depression, while male patients are at greater risk for manic episodes (Hendrick et al., 2000). Thus, apparently, there is a general trend amongst female patients to depression while male patients would be more prone to mania and psychosis. Results from STEP-BD showed a had higher rates of BD type II in women, which were most prone to comorbidities with bulimia, post-traumatic stress disorder and thyroid disease (Baldassano et al, 2005). Rapid cycling is reported to occur more frequently in bipolar women (Leibenluft et al, 1996; Tondo et al, 1998), age at onset of bipolar disorder is found to be significantly higher in women than in men in some studies (Kennedy et al, 2005), while other authors did not find any significant gender difference (Kawa et al, 2005). Proper treatment delay is also more frequent amongst women -3.2 years- (Viguera et al., 2001; Baldessarini et al., 1999). Axis I comorbidity specially with anxiety and eating disorders- is also more frequent in female patients (McElroy et al, 2001) whereas men were found to have more substance related disorders comorbidity (Frye et al, 2003). If we pay attention to the recently described and tested construct of predominant polarity, predominance of depressive episodes would characterize female patients, (hypo)manic predominant polarity male ones (Colom et al., 2006). Finally, even depressive features during a manic episode the so-called mixed mania - are more frequent amongst women (Arnold et al., 2003; Burt and Rasgon, 2004). Taken together, if we see these considerations at the light of the scientific literature, women seem to present features that may predict a poor prognosis of illness, such as atypical depressive symptoms and rapid cycling. However, further research on gender differences is needed to clarify conflicting results in previous studies GENETICS Familiar epidemiologic studies, especially those which study concordance on monozygotic and heterozygotic twins, show that genetic factors play an essential role in the etiopathogenesis of affective disorders. Adoption studies confirm this hypothesis

18 (Althoff et al 2005). Pounded risk of suffering an affective disorder in first-degree relatives of a bipolar patient is approximately of 20%, divided into an 8% for BD and 12% for unipolar depression (Fañanas y Gutierrez, 1997). This data reflects the fact that a significant percentage of unipolar and bipolar patients share the same vulnerability. It has not been possible to identify how this genetic burden may be inherited up until now, probably because of the extreme complex mechanism of the biologic heterogeneity. No linkage study has established in a clear way the inheritance pattern of bipolar illness, despite the fact that many have been proposed. Actually, many studies have been published on the possible role of genes with a minor effect, possibly related to normal physiologic functions, which expression, facilitated by environmental factors, could explain the variable penetrance and the phenotypical diversity of the illness (Craddock et al, 2006). An important study has recently pointed out the role of paternal age for the development of BD in the offspring. The study, conducted on a large sample of 13,428 patients, shows a stronger association for early onset BD offspring and no association with maternal age. Results seem coherent with the hypothesis of an increased risk for de novo mutations in susceptibility genes for neurodevelopmental disorders (Frans et al, 2008). In the end, a genetic basis for BD seems clear. A multitude of genes seem to play a role in a complex, non-mendelian inheritability. The identification of these genes, unluckily, has not short-range clinical implications PSYCHIATRIC COMORBIDITY Patients with bipolar disorder suffer from comorbidities. In particular, the evidence for concurrent mental disorders is strong compared with other conditions. In a sample of patients from the Stanley Foundation Bipolar Network, 65% of the patients with BD presented a comorbid condition. Of these patients, almost a quarter presented three or more diagnoses (McElroy et al, 2001). For what concerns Axis I comorbidities, in the ECA study, BD type I patients presented twice as high than unipolar depressed patient and than general population a lifetime history of substance use disorders (61%), panic disorders (21%) and obsessivecompulsive disorder (21%) (Regier et al, 1990). The vast majority of NCS-R respondents with a history of either threshold (i.e., BP-I or BP-II; 97.7%-95.8%) or subthreshold (88.4%) BD also met criteria for another lifetime DSM-IV/CIDI disorder (Merikangas et al. 2007). The extent of comorbidity is consistently somewhat higher for threshold than for subthreshold BD. Included here are 63.1% 86.7% of respondents with lifetime BD who have a history of at least one lifetime comorbid anxiety disorder, 56.1% 71.2% with at least one lifetime comorbid impulse control disorder, and 35.5% 60.3% with at least one lifetime comorbid substance use disorder (Kessler et al, 2007). Recently, Lunde and colleagues (2009) have found a significant comorbidity of BD with bulimia nervosa in a not blinded study on 201 bipolar patients. The finding that BD has extremely high comorbidity with other DSM-IV disorders is consistent with prior clinical (Strakowski and DelBello, 2000) and other population based (Grant et al. 2005, Keller 2006, Mitchell et al. 2004) studies, although comorbidity with substance use disorders was more prominently featured in previous studies. Recently, a research conducted on 591 bipolar patients of the Zurich cohort showed the specificity of the association between bipolar spectrum disorders and alcohol and benzodiazepines use (Merikangas et al, 2008)

19 For what concerns Axis II comorbidities, evidence from clinical studies usually reveals increased rates for personality disorders. Most studies indicate that both conditions have elevated rates of avoidant and dependent personality disorder (Akiskal, 1996; Battaglia et al., 1996). A small number suggest elevated risks for obsessive and/or borderline features are an unnoticed sign of bipolarity (Akiskal, 1996). Concluding, comorbidities are very frequent in BD. Anxiety disorders, impulse-control disorder and substance use disorders especially seem linked to the bipolar illness. Comorbidity is frequent among subthreshold BDs too, a fact that implies the possibility that they be undertreated MISDIAGNOSIS Patients with bipolar disorder are often misdiagnosed in clinical as well as research settings (Akiskal and Benazzi, 2005) and therefore fail to receive appropriate treatment (Hirschfeld, 2004). A study conducted by Hantouche et al. (1998) on a clinical sample has provided important and complete data about the prevalence of bipolar disorder II among patients with a diagnosis of major depression. The EPIDEP French study showed that the rate of bipolar II disorder nearly doubled from 22% at initial evaluation to nearly 40% in a month's time, after systematic search for hypomania according to DSM-IV criteria. A clinic-based study (Hirschfeld et al., 2005) of patients taking antidepressants for depressions found that 21.3% screened positive for bipolar disorder symptoms on the Mood Disorder Questionnaire (MDQ), a brief and easy-to-use instrument, especially designed for the detection of bipolar disorder (Hirschfeld et al., 2000; Sanchez-Moreno et al., 2008) which is available in Spanish too. Higher results were obtained in the EPIDEP study, where bipolar spectrum disorder the most prevalent and severe expression of the bipolar spectrum, and accounting for 33% of all major depressive episodes in a sample of 490 patients (Akiskal et al, 2006). A Spanish study (Baca-Garcia et al, 2007) found that only 30% of patients with bipolar disorder were given a bipolar diagnosis on their first evaluation (Fajutrao et al 2009) in a retrospective evaluation of a sample of 1153 patients. In a recent study, 905 patients diagnosed with unipolar depression were screened with MDQ for symptoms of hypomania. A positive screen rate for bipolar disorder in 24% of patients was found (Tafalla et al, 2009). Young patients with psychotic symptoms are frequently misdiagnosed as other psychotic disorders (Gonzalez-Pinto et al, 1998). Patients with BD can present incongruent psychotic symptoms that are age-related (Gonzalez-Pinto et al, 2003). In conclusion, misdiagnosis is not a mere diagnostic exercise: it involves negative clinical and therapeutic implications, such as an inadequate treatment, suicide, substance abuse comorbidity, mixed states or switch to mania, and rapid cycling, among others (Ghaemi et al., 1999;Ghaemi et al., 2000). In this regard, misdiagnosis may also have important negative consequences on the functional outcome of bipolar patients, so a reduction in the latency of diagnosis and proper treatment is crucial to avoid a significant worsening in the patient s course of illness and outcome (Martinez-Aran et al., 2007; Vieta and Phillips, 2007) MORTALITY AND SUICIDE Evidence for elevated suicide and premature mortality rates also adds to the economic burden of bipolar disease in Europe, primarily as a result of decreased productivity levels. The evidence for suicide is even worse (Fajutrao et al, 2009). Dutta and coll.

20 (2007) reported death rates of 18% for bipolar I disorder patients in the UK and 3 7% suicide rate (although this was only 8 individuals in total). Attempted suicide rates varied between 21% and 54%. An Italian study reported that 22% of males and 54% of females with bipolar I disorder had a history of suicide attempts (Benedetti et al, 2007). In a French study by Henry et al (2003), it was reported that 40% of bipolar patients had attempted suicide at least once. Vieta et al (2001) found that 38% of bipolar patients with comorbidity had attempted suicide compared with only 21% of patients without comorbidity. In the Basque Country 38% of bipolar patients attempted suicide at least once (López et al, 2001), being a risk factor the presence of more depressive episodes, younger age at onset, drug abuse and family history of affective disorders. In the same sample, ten years after, when the median age of patients was 52, almost half of the sample had attempted suicide at least once, without differences between men and women (Gonzalez-Pinto et al, 2006). The risk of suicide is greatly elevated during depressive episodes. Most suicide attempts and most completed suicides occur in the depressed phase of the illness and patients with bipolar II disorder are at especially high risk (Baldessarini et al., 2003). Annually around 0.4% of patients with bipolar disorder will die by suicide, which is vastly greater than the international population average of 0.017% (Baldessarini & Tondo, 2003). In a recent, large study, 8 factors were found to be positively associated with suicide in a sample of 1090 BD type I patients: multiple hospitalizations, depressive or mixed polarity of first episode, presence of stressful life events before illness onset, younger age at onset, no free intervals between episodes, female sex, higher number of previous episodes, and cyclothymic temperament (Azorin et al, 2009). Another recent finding relates positively atypical depression and suicide (Sánchez-Gistau et al, 2009). Familiar linkages of suicidal ideation and behavior has been found in the sample of the National Comorbidity Survey (Goodwin et al, 2004), and later confirmed in a Spanish sample (Romero et al, 2007). Clinicians should pay attention to the presence of these characteristics, which may help identify subjects at risk for suicide attempt throughout the course of bipolar disorder. Individuals with bipolar disorder possess a substantial burden of general medical comorbidity, and are occurring at an earlier age than in the general patient population, suggesting the need for earlier detection and treatment for patients with BD (Kilbourne et al 2004). A Spanish research group has assessed, in a cross-sectional study with 194 BD patients, a higher risk level for BD than the general population, and the high prevalence of associated risk factors such as age, body mass index, cigarette smoking and metabolic syndrome (Garcia-Portilla et al, 2009). Tobacco smoking has been found to be higher in the general population (Gonzalez-Pinto et al, 1998), and this association seems constant across countries (Leon et al, 2002). Overweight, obesity and extreme obesity are indeed quite common between bipolar patients, althought the extent of this association may be biased by a general trend to obesity in western countries and epseciallu in U.S. (McElroy et al, 2002). The increased cardio-vascular morbidity/mortality in bipolar patients may be explained by an increase in levels of hypertension in BP, which was actually found in a large sample of Danish bipolar patients (Johannessen et al 2006). This findings support the fact that clinicians should also closely monitor BD patients for cardiovascular risk factors, as part of the standard of care. A work by Thomson et al (2006) underlines the fact that the medical burden influences the psychiatric outcomes in patients with BD (i.e. symptomatic remission, degree of suicidality, levels of functioning) not to mention the influence on morbidity and mortality.

21 4.9. SOCIAL VARIABLES MARITAL STATUS There is a slightly increased prevalence of separated, divorced and single among bipolar patients. This may be related to and early onset of the bipolar illness from which interpersonal difficulties could derive (Serretti et al, 2002). The ECA revealed that individuals who are separated or divorced are more likely to suffer from BD as compared with married or never-married individuals. It has to be noted that the presence of affective episodes (mania, hypomania, depression) is a strong predictor for future separation or divorce, which can cause serious distress for the patients, their spouses and may generate negative life events for their children. These early negative life events are well known predisposing factors for adult mood disorders, particularly in the case of family loading (case of subjects with positive family history of mood disorder). Concluding, even if it seems assumed that persons with BD are more likely than those in the general population to be single, divorced or in a disrupted marriage, we know of no evidence to support a causal relationship between the disorder and the marital status. Although it is likely that symptoms of untreated mania are disruptive to forming or sustaining intimate relationships, this hypothesis is not supported by any data (Goodwin and Jamison, 2007) SOCIOECONOMIC FACTORS In both the ECA and the NCS, lower educational level was not found to be associated with an increased risk of BD. NCS found an association between rates of BD and lower family income, while a recent study (Tsuchiya et al, 2004) found a positive association between higher parental educational level, greater parental wealth and BD, but a negative association between patients unemployment and inferior education level. The associations of lower socio-economic indices of subjects may be explained as a consequence of the disease, while the association of higher socio-economic indices of parents may be explained by socio-economic achievement in the family of origin. Another interpretation may be that milder forms of the illness may lead to high achievement, but that fully, clinically developed BD usually bears severe consequences in the socioeconomic aspects of a patient s life. Dittmann and colleagues (2002) found that only 30% of patients with bipolar disorder in Germany were employed full-time at a level that was appropriate for their qualifications. Other studies showed that between 52% and 59% of bipolar patients had an occupation (Henry et al, 2003; Vieta et al, 2001), while an Italian study (Pini et al, 2003) found that 63% to 67% of patients with bipolar I disorder were unemployed. This data is coherent with a study by Brieger and colls (2007), who which found that 72% of bipolar I patients received disability payments. Absenteeism has been assessed at a rate of 8% (Das Gupta and Guest, 2002). A relationship between changes in mood symptoms and changes in functioning or disability in people treated for bipolar disorder has been found (Simon et al, 2007): modest changes in severity of depression are associated with statistically and clinically significant changes in functional impairment and disability. In contrast, changes in severity of mania or hypomania are not consistently associated with differences in functioning CONCLUSIONS Our knowledge of the burden of bipolar disorders is based primarily on evidence from the United States.

22 Results from NCS-R and from research on subthreshold bipolarity reinforce the argument that clinically significant subthreshold BPD is at least as common as threshold BP (Judd and Akiskal, 2003; Angst, 1998; Akiskal and Benazzi, 2005). Although most individuals with BP receive treatment owing to comorbid disorders, the lack of recognition of their underlying bipolarity leads to only a few receiving appropriate treatment. More comprehensive screening of bipolar symptoms is needed in people seen for treatment of other Axis I disorders. The failure to recognize subthreshold BD and pervasive comorbidity of BP can also reduce the precision of estimates and lead to bias in research on mood disorders (MacQueen et al, 2005). Epidemiologic studies point out that BD is an illness which may be identified in every culture, with possible variations due to cultural and personal differences. Given the differences between US and European health care systems, clinical practices, health research policymaking, and payer environments, specific studies focused on European, Spanish, Catalan samples are urged.

23 05 DIAGNOSIS OF BIPOLAR DISORDER 5.1. CURRENTLY USED CLASSIFICATIONS ICD ICD DSM-IV 5.2. ASSESSING THE CORRECT DIAGNOSIS 5.3. DIFFERENTIAL DIAGNOSIS Primary or secondary mood disorder Substance use disorders Schizophrenia Schizoaffective disorder Unipolar disorder Borderline personality disorder 5.4. COURSE OF ILLNESS 5.5. NUMBER OF EPISODES 5.6. COURSE SPECIFIERS Rapid cycling Seasonal pattern Age at onset Predominant polarity 5.7. IMPROVING THE DIAGNOSIS OF BIPOLAR DISORDER Limits and perspectives in the nosology of bipolar disorder Screening for bipolar disorder 5.8. MANAGEMENT OF BIPOLAR DISORDER FROM PRIMARY CARE 5.9. RECOMMENDATIONS To date, the diagnosis of BD is purely clinical and based on the past or actual presence of a manic or hypomanic episode. When making a diagnosis, the clinician should assess presenting signs and symptoms, and weight them together with the patient s history and eventual prior response to treatment. A transversal evaluation of the symptoms often lacks diagnostic specificity, so careful attention must often be paid to the patients history to detect time episodes associated with manic symptoms, as patients rarely provide this type of information spontaneously CURRENTLY USED CLASSIFICATIONS ICD-9 The ICD is used to provide a standard classification of diseases for the purpose of health records. The World Health Organization (WHO) assigns, publishes, and uses the ICD to classify diseases, to track mortality rates based on death certificates and other vital health records by the use of a single format with the use of ICD codes. ICD-9 is still

24 used in Catalunya to encode BD, so that a scheme of the ICD-9 diagnoses is presented in tables and 5.2. Tab ICD-9 diagnoses for Bipolar Disorder 296.x Episodic Mood Disorder Include Episodic affective disorders Exclude Neurotic depression (300.4) Reactive depressive psychosis (298.0) Reactive excitation (298.1) The following fifth-digit subclassification is for use with categories : 0 unspecified 1 mild 2 moderate 3 severe, without mention of psychotic behaviour 4 severe, specified as with psychotic behaviour 5 in partial or unspecified remission 6 in full remission 296.0x [0-6] Bipolar disorder, single manic episode Include Hypomania (mild) NOS single episode or unspecified Hypomanic psychosis single episode or unspecified Mania (monopolar) NOS single episode or unspecified Manic-depressive psychosis or reaction, single episode or unspecified: hypomanic, single episode or unspecified Manic-depressive psychosis or reaction, single episode or unspecified: manic, single episode or unspecified Exclude Circular type, if there was a previous attack of depression (296.4) 296.1x [0-6] Manic disorder, recurrent episode Includes Any condition classifiable to 296.0, stated to be recurrent Excludes Circular type, if there was a previous attack of depression (296.4) 296.2x [0-6] Major depressive disorder, single episode Include Depressive psychosis, single episode or unspecified Endogenous depression, single episode or unspecified Involutional melancholia, single episode or unspecified Manic-depressive psychosis or reaction, depressed type, single episode or unspecified Monopolar depression, single episode or unspecified Psychotic depression, single episode or unspecified Exclude Circular type, if previous attack was of manic type (296.5) Depression NOS (311) Reactive depression (neurotic) (300.4) psychotic (298.0) 296.3x [0-6] Major depressive disorder, recurrent episode Include Any condition classifiable to 296.2, stated to be recurrent Exclude circular type, if previous attack was of manic type (296.5) depression NOS (311) reactive depression (neurotic) (300.4) psychotic (298.0) 296.4x [0-6] Bipolar I disorder, most recent episode (or current) manic Include Bipolar disorder, now manic Manic-depressive psychosis, circular type but currently manic Exclude Excludes: brief compensatory or rebound mood swings (296.99)

25 Tab (follows) ICD-9 diagnoses for Bipolar Disorder 296.5x [0-6] Bipolar I disorder, most recent episode (or current) depressed Include Bipolar disorder, now depressed Manic-depressive psychosis, circular type but currently depressed Exclude Brief compensatory or rebound mood swings (296.99) 296.6x [0-6] Bipolar I disorder, most recent episode (or current) mixed Include Manic-depressive psychosis, circular type, mixed Bipolar I disorder, most recent episode (or current) unspecified Atypical bipolar affective disorder NOS Manic-depressive psychosis, circular type, current condition not specified as either manic or depressive Include Manic-depressive psychosis, circular type, mixed Other and unspecified bipolar disorders Bipolar disorder, unspecified Include Bipolar disorder NOS Manic-depressive: reaction NOS Manic-depressive: syndrome NOS Atypical manic disorder Atypical depressive disorder Other Include Bipolar II disorder Manic-depressive psychosis, mixed type ICD-10 The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) was first introduced in Spain in 1999 (INE, 1998). This new edition represents the most important update since sixth edition and brings new major changes and complexity, with an increase in the number of codes. The WHO classification for mental and behavioural disorders (WHO, 1992) faces the diagnosis of bipolar disorder in section F30 to F31.9 and F34.0. BD is described as the presence of recurrent (at least two) episodes with a strong alteration of mood and activity levels. Alterations consist in mood exaltation, increase in vitality and activity levels (mania or hypomania), or decrease of mood levels, vitality and activity (depression). A total inter-episodic recovery is possible. Unlike other mood disorders, incidence in sexes is approximately the same. Tables 5.3. to 5.9 present codes and diagnostic criteria for BD.

26 Tab 5.3. Main classification of bipolar disorders in ICD-10 F30 Manic episode F30.0 Hypomania F30.1 Mania without psychotic symptoms F30.2 Mania with psychotic symptoms F30.8 Other manic episodes F30.9 Manic episode, unspecified F31 Bipolar affective disorder F31.0 Bipolar affective disorder, current episode hypomanic F31.1 Bipolar affective disorder, current episode manic without psychotic symptoms F31.2 Bipolar affective disorder, current episode manic with psychotic symptoms.20 With mood-congruent psychotic symptoms.21 With mood-incongruent psychotic symptoms F31.3 Bipolar affective disorder, current episode mild or moderate depression.30 Without somatic syndrome.31 With somatic syndrome F31.4 Bipolar affective disorder, current episode severe depression without psychotic symptoms F31.5 Bipolar affective disorder, current episode severe depression with psychotic symptoms.50 With mood-congruent psychotic symptoms.51 With mood-incongruent psychotic symptoms F31.6 Bipolar affective disorder, current episode mixed F31.7 Bipolar affective disorder, currently in remission F31.8 Other bipolar affective disorders F31.9 Bipolar affective disorder, F34 Persistent mood [affective] disorders F34.0 Cyclothymia Tab F Hypomania A. The mood is elevated or irritable to a degree that is definitely abnormal for the individual concerned and sustained for at least four consecutive days. B. At least three of the following must be present, leading to some interference with personal functioning in daily living: (1) (2) (3) (4) (5) (6) increased activity or physical restlessness; increased talkativeness; difficulty in concentration or distractibility; decreased need for sleep; increased sexual energy; mild spending sprees, or other types of reckless or irresponsible behaviour; increased sociability or over-familiarity. (7) C. The episode does not meet the criteria for mania (F30.1 and F30.2), bipolar affective disorder (F31.-), depressive episode (F32.-), cyclothymia (F34.0) or anorexia nervosa (F50.0). D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0.

27 Tab F Mania without psychotic symptoms A. A mood which is predominantly elevated, expansive or irritable and definitely abnormal for the individual concerned. This mood change must be prominent and sustained for at least a week (unless it is severe enough to require hospital admission). B. At least three of the following must be present (four if the mood is merely irritable), leading to severe interference with personal functioning in daily living: (1) (2) (3) (4) (5) (6) (7) (8) Increased activity or physical restlessness; Increased talkativeness ('pressure of speech'); Flight of ideas or the subjective experience of thoughts racing; Loss of normal social inhibitions resulting in behaviour which is inappropriate to the circumstances; Decreased need for sleep; Inflated self-esteem or grandiosity; Distractibility or constant changes in activity or plans; Behaviour which is foolhardy or reckless and whose risks the subject does not recognize e.g. spending sprees, foolish enterprises, reckless driving; Marked sexual energy or sexual indiscretions. (9) C. The absence of hallucinations or delusions, although perceptual disorders may occur (e.g. subjective hyperacusis, appreciation of colours as specially vivid, etc.). D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0. Tab 5.6. F Mania with psychotic symptoms A. The episode meets the criteria for mania without psychotic symptoms (F30.1) with exception of criterion C. B. The episode does not simultaneously meet the criteria for schizophrenia (F20) or schizoaffective disorder, manic type (F25.0). C. Delusions or hallucinations are present, other than those listed as typical schizophrenic in F20 G1.1b, c and d (i.e. delusions other than those that are completely impossible or culturally inappropriate and hallucinations, that are not in the third person or giving a running commentary). The commonest examples are those with grandiose, selfreferential, erotic or persecutory content. D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0. A fifth character may be used to specify whether the hallucinations or delusions are congruent or incongruent with the mood: F30.20 mania with mood congruent psychotic symptoms (such as grandiose delusions or voices telling the subject that he has superhuman powers) F30.21 mania with mood incongruent psychotic symptoms (such as voices speaking to the subject about affectively neutral topics, or delusions of reference or persecution).

28 Tab 5.7. F31 Bipolar Affective Disorder Diagnostic criteria Note: Episodes are demarcated by a switch to an episode of opposite or mixed polarity or by a remission. F31.0 Bipolar affective disorder, current episode hypomanic A. The current episode meets the criteria for hypomania (F30.0). B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-) or mixed affective episode (F38.00). F31.1 Bipolar affective disorder, current episode manic without psychotic symptoms A. The current episode meets the criteria for mania without psychotic symptoms (F30.1). B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-) or mixed affective episode (F38.00). F31.2 Bipolar affective disorder, current episode manic with psychotic symptoms A. The current episode meets the criteria for mania with psychotic symptoms (F30.2). B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-) or mixed affective episode (F38.00). A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood: F31.20 with mood congruent psychotic symptoms F31.21 with mood incongruent psychotic symptoms F31.3 Bipolar affective disorder, current episode moderate or mild depression A. The current episode meets the criteria for a depressive episode of either mild (F32.0) or moderate severity (F32.1). B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), or mixed affective episode (F38.00). A fifth character may be used to specify the presence of the somatic syndrome as defined in F32, in the current episode of depression: F31.30 without somatic syndrome F31.31 with somatic syndrome F31.4 Bipolar affective disorder, current episode severe depression without psychotic symptoms A. The current episode meets the criteria for a severe depressive episode without psychotic symptoms (F32.2). B. There has been at least one well authenticated hypomanic or manic episode (F30.-) or mixed affective episode (F38.00) in the past. F31.5 Bipolar affective disorder, current episode severe depression with psychotic symptoms A. The current episode meets the criteria for a severe depressive episode with psychotic symptoms (F32.3). B. There has been at least one well authenticated hypomanic or manic episode (F30.-) or mixed affective episode (F38.00) in the past. A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood. F31.50 with mood congruent psychotic symptoms F31.51 with mood incongruent psychotic symptoms

29 Tab 5.8. F31 Bipolar Affective Disorder Diagnostic criteria (following) F31.6 Bipolar affective disorder, current episode mixed A. The current episode is characterized by either a mixture or a rapid alternation (i.e. within a few hours) of hypomanic, manic and depressive symptoms. B. Both manic and depressive symptoms must be prominent most of the time during a period of at least two weeks. C. There has been at least one well authenticated hypomanic or manic episode (F30.-), depressive (F32.-) or mixed affective episode (F38.00) in the past. F31.7 Bipolar affective disorder, currently in remission A. The current state does not meet the criteria for depressive or manic episode in any severity, or for any other mood disorder in F3 (possibly because of treatment to reduce the risk of future episodes). B. There has been at least one well authenticated hypomanic or manic episode (F30.-) in the past and in addition at least one other affective episode (hypomanic or manic (F30.-), depressive (F32.-), or mixed (F38.00)). F31.8 Other bipolar affective disorders F31.9 Bipolar affective disorders, unspecified Tab 5.9. F Diagnostic Criteria for cyclothymia (ICD-10) A. A period of at least two years of instability of mood involving several periods of both depression and hypomania, with or without intervening periods of normal mood. B. None of the manifestations of depression or hypomania during such a two- year period should be sufficiently severe or long lasting to meet criteria for manic episode or depressive episode (moderate or severe); however, manic or depressive episode(s) may have occurred before, or may develop after, such a period of persistent mood instability. C. During at least some of the periods of depression at least three of the following should be present: (1) A reduction in energy or activity; (2) Insomnia; (3) Loss of self confidence or feelings of inadequacy; (4) Difficulty concentrating; (5) Social withdrawal; (6) Loss of interest or enjoyment in sex and other pleasurable activities; (7) Less talkative than normal; (8) Pessimistic about the future or brooding over the past. D. During at least some of the periods of mood elevation at least three of the following should be present: (1) (2) (3) (4) (5) (6) (7) (8) Increased energy or activity; Decreased need for sleep; Inflated self esteem; Sharpened or unusually creative thinking; More gregarious than normal; More talkative or witty than normal; Increased interest and involvement in sexual and other pleasurable activities; Over-optimism or exaggeration of past achievements. Note: If desired, specify whether onset is early (in late teenage or the twenties) or late (usually between age 30 to 50 subsequent to an affective episode).

30 DSM-IV-TR The American Psychiatric Association (APA) classification proposed in 1994 the most widely used classification for bipolar disorders (APA, 1994, 2000). It first defines criteria for manic, hypomanic, depressive and mixed episodes (tables 5.10 to 5.13). The presence of a BD is defined by the presence of a manic/mixed (BD type I) or hypomanic episode (BD type II) (tabs to 5.17). Type II BD requires a present/past depressive episode. Cyclothymic disorder is defined as the presence of sub-threshold hypomanic and depressive episodes for at least two years (tables 5.14). Tab DSM-IV-TR Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. 1. depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g. appears tearful). Note: In children and adolescents, can be irritable mood. 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3. significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4. insomnia or hypersomnia nearly every day 5. psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. fatigue or loss of energy nearly every day 7. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

31 Tab DSM-IV-TR Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar I Disorder. Tab DSM-IV-TR Criteria for Mixed Episode A. The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. B.. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, or light therapy) should not count toward a diagnosis of bipolar disorder.

32 Tab DSM-IV-TR Criteria for Hypomanic Episode A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar II Disorder. Tab DSM-IV-TR Cyclothymic Disorder A. For at least 2 years, the presence of numerous periods with hypomanic symptoms and numerous periods with depressive symptoms that do not meet criteria for a Major Depressive Episode. Note: In children and adolescents, the duration must be at least 1 year. B. During the above 2-year period (1 year in children and adolescents), the person has not been without the symptoms in Criterion A for more than 2 months at a time. C. No Major Depressive Episode, Manic Episode, or Mixed Episode has been present during the first 2 years of the disturbance. Note: After the initial 2 years (1 year in children and adolescents) of Cyclothymic Disorder, there may be superimposed Manic or Mixed Episodes (in which case both Bipolar I Disorder and Cyclothymic Disorder may be diagnosed) or Major Depressive Episodes (in which case both Bipolar II Disorder and Cyclothymic Disorder may be diagnosed). D. The symptoms in Criterion A are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism). F. The symptoms cause clinically significant distress or impairment in social, occupational,

33 or other important areas of functioning. Tab DSM-IV-TR Bipolar I Disorder 296.0x Single Manic Episode A. Presence of only one Manic Episode and no past Major Depressive Episodes. Note: Recurrence is defined as either a change in polarity from depression or an interval of at least 2 months without manic symptoms. B. The Manic Episode is not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified Most Recent Episode Hypomanic A. Currently (or most recently) in a Hypomanic Episode. B. There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified x Most Recent Episode Manic A. Currently (or most recently) in a Manic Episode. B. There has previously been at least one Major Depressive Episode, Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified 296.5x Most Recent Episode Depressed A. Currently (or most recently) in a Major Depressive Episode. B. There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified x Most Recent Episode Mixed A. Currently (or most recently) in a Mixed Episode. B. There has previously been at least one Major Depressive Episode, Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified Most Recent Episode Unspecified A. Criteria, except for duration, are currently (or most recently) met for a Manic, a Hypomanic, a Mixed, or a Major Depressive Episode. B There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The mood symptoms in Criteria A and B are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).

34 Tab DSM-IV-TR Bipolar II Disorder A. Presence (or history) of one or more Major Depressive Episodes. B. Presence (or history) of at least one Hypomanic Episode. C. There has never been a Manic Episode or a Mixed Episode. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Hypomanic. This specifier is used if the current (or most recent) episode is a Hypomanic Episode. Depressed. This specifier is used if the current (or most recent) episode is a Major Depressive Episode. Tab DSM-IV-TR Bipolar Disorder Not Otherwise Specified The bipolar disorder not otherwise specified category includes disorders with bipolar features that do not meet criteria for any specific bipolar disorder. Examples include the following: A. Rapid alternation (over days) between manic symptoms that meet symptom threshold criteria but not minimal duration criteria for manic, hypomanic, or major depressive episodes B. Recurrent hypomanic episodes without intercurrent depressive symptoms. C. A manic or mixed episode superimposed on delusional disorder, residual schizophrenia, or psychotic disorder not otherwise specified. D. Hypomanic episodes, along with chronic depressive symptoms, that are too infrequent to qualify for a diagnosis of cyclothymic disorder E. Situations in which the clinician has concluded that a bipolar disorder is present but is unable to determine whether it is primary, due to a general medical condition, or substance induced ASSESSING THE CORRECT DIAGNOSIS To achieve a diagnosis of bipolar disorder in adults, ICD-10 requires at least two episodes (one of which must be mania or hypomania) in which the person s mood and activity levels are significantly disturbed. By contrast, DSM-IV-TR requires only a single manic or mixed episode. The disturbance consists of either an elevation of mood and increased energy and activity (mania or hypomania), or a lowering of mood (depression). Episodes can be further classified as hypomanic, manic without psychotic symptoms, manic with psychotic symptoms, mild or moderate depression, severe depression without psychotic symptoms, and severe depression with psychotic symptoms or mixed. Manic episodes usually begin abruptly and last for between 2 weeks and 4 5 months (median duration about 4 months). Depressions tend to last longer (median duration about 6 months). Recovery may or may not be complete between episodes. The pattern of remissions and relapses is very variable, although

35 remissions tend to get shorter as time goes on and depressions to become commoner and longer lasting. BD type I is distinguished from unipolar depressive disorder and by the lifetime history of at least one manic or mixed episode. The presence of a manic or mixed episode also distinguishes BD type I from BD type II, so that when an individual previously diagnosed with BD type II develops a manic or mixed episode, the diagnosis has to be changed to BD type I. BD type I disorder has proven to be a stable diagnosis in a recent study, conducted on 500 first-episode psychotic patients. BD type I diagnosis remained stable in 96.5% of cases (Salvatore et al, 2009). On the contrary, some first psychotic episodes changed the diagnosis to BD type I or schizoaffective disorder. This lack of recognition of BD type I patients in the first stages of illness has been reported previously (Gonzalez-Pinto et al, 1998), so that a diagnostic shift from other diagnoses to BD is not uncommon (Baca-Garcia et al, 2007). In cyclothymic disorder, the numerous periods of hypomanic symptoms do not meet criteria for a full manic episode and, similarly, periods of depressive symptoms do not reach symptom or duration criteria for a major depressive episode. BD type I is distinguished from cyclothymic disorder by the presence of one or more manic or mixed episodes. If a manic or mixed episode occurs after the first 2 years of cyclothymic disorder, then BD type I and cyclothymic disorder diagnosis may both be used. APA classification is by far the most used in research, so that in the following paragraphs we will refer to DSM-IV categories for BD. Different diagnostic interviews are disposable, as the Mini International Neuropsychiatric Interview (Sheehan et al, 1998). These tools may help clinicians in Primary Care to rule out a diagnosis of Major Depressive Disorder or (hypo)mania, ans so of BD, following DSM-IV or ICD-10 criteria DIFFERENTIAL DIAGNOSIS Primary or secondary mood disorder Major depressive, (hypo)manic and mixed episodes in BD must be distinguished from episodes of a mood disorder due to a general medical condition, as the etiologic aspect bears important therapeutic implications. The diagnosis for episodes that are judged to be the direct physiological consequence of a specific general medical condition (e.g., multiple sclerosis, stroke, hyper- and hypothyroidism) is Mood disorder due to a general medical condition. This determination is based on the history, laboratory findings, or physical examination. Symptom control may require the standard treatment for a mood disorder, but treatment of the underlying medical condition remains mandatory Substance use disorders A substance-induced mood disorder is distinguished from major depressive, manic, or mixed episodes that occur in BD by the fact that a substance (e.g., a drug of abuse or a medication) is judged to be etiologically related to the mood disturbance. Symptoms like those seen in a (hypo)manic, mixed, or episode may be part of an intoxication with or withdrawal from a drug of abuse and should be diagnosed as a substance-induced mood disorder (e.g., euphoric mood that occurs only in the context of intoxication with cocaine would be diagnosed as cocaine-induced mood disorder, with manic features, with onset during intoxication). Symptoms like those seen in a manic or mixed episode may also be precipitated by antidepressant treatment such as medication,

36 electroconvulsive therapy, or light therapy. Such episodes may be diagnosed as a substance-induced mood disorder (e.g., fluoxetine-induced mood disorder, with manic features) and would not count toward a diagnosis of BD type I. However, when the substance use or medication is judged not to fully account for the episode a diagnosis of BD has to be considered, as in the case of symptoms of a mood disorder continuing for a considerable period after the substance is discontinued. There is a difficulty in assessing patients with antidepressant-induced (hypo)mania, who represent a consistent part of the patients affected by recurrent depressions. It seems worth resizing the basis of a distinction between spontaneous and induced hypomania. Patients with spontaneous hypomania do not seem to have mayor clinical differences when compared to patients with antidepressant induced hypomania: the two groups did not differ in clinical manifestation or in duration of hypomania (Akiskal et al, 2003).. Similarly, familiar history for BD did not show differences between the two groups, confirming a large study conducted in Italy (Cassano et al 1992). A statistically significant difference between the groups was found when evaluating temperaments: patients with spontaneous hypomania presented more cyclothymic and hyperthymic temperament while patients with drug-induced hypomania presented more depressive temperament. A different age at onset of the disorder was found, being younger the patients with spontaneous hypomania Schizophrenia The discussion on the genetic overlap between schizophrenia and bipolar disorder goes beyond the purposes of the present guidelines. In clinical practice, these two disorders present themselves as mainly separate. However, cross-sectionally, some bipolar patients, especially young ones, may present with psychotic symptoms and be disorganized, posing the problem of a differential diagnosis with schizophrenia. It is widely accepted that there are not pathognomonic symptoms for BD or schizophrenia. Despite this, it is usually possible to distinguish BD from schizophrenia by the careful application of diagnostic criteria combined with a longitudinal retrospective evaluation: a special attention to the patient s history (pre-morbid functioning, age at onset, previous episodes) and familiar history for affective disorders (Goodwin and Jamison, 2007). Even so, there may be some difficulty in making a differential diagnosis between the two disorders. Longitudinal, perspective evaluation may rule out the correct diagnostic category Schizoaffective disorder DSM-IV criteria rule out the differential diagnosis by allowing a diagnosis of schizoaffective disorder only if psychotic symptoms are present in a period of at least 2 weeks free of affective symptoms, thus introducing a longitudinal evaluation. ICD-10 classification keeps a somewhat blurry distinction, as affective and psychotic symptoms have to be present in the same moment. At present state, the differential diagnosis between BD and schizoaffective disorder may seem somewhat less important, as therapeutic decisions for this disorder frequently overlap Unipolar disorder The misdiagnosis of BD as unipolar depression is a major clinical issue that has been highlighted in the past (Akiskal et al, 2000). Correct diagnosis is essential, because the treatment for BD differs significantly from the treatment of major depressive disorder. Clinical implications of a BD misdiagnosed as unipolar detection are disastrous, as antidepressant monotherapy in bipolar patients brings as consequences secondary

37 (hypo)manic and mixed episodes (Boerlin et al, 1998; Koukopoulos et al, 2007) and could be related to rapid cycling (Schneck et al, 2008), significantly worsening the prognosis of the patient. The main problem in correctly diagnosing BD is hypomania detection. A way to improve efficiency and increase sensitivity in detecting bipolar disorder is to screen for it, particularly in patients with depression, irritability, or impulsivity. The Hypomania Checklist -32, HCL-32, is a screening instrument developed to self-assess hypomania symptoms (Angst, 2005). It has been validated in Spanish (Vieta et al, 2007). The Mood Disorder Questionnaire is a 13-item, self-report screening instrument for bipolar disorder that has been used successfully in and in the general population (Hirschfeld et al. 2000). A Spanish version of MDQ has been validated (Gonzalez et al, 2009). Temporal threshold for hypomania in DSM-IV was arbitrarily set to four days. There have been many critics to this cut-off: a threshold of 2 days could be more appropriate, as judged on the basis of external validating strategies as age at onset, depressive recurrence and family bipolarity (Akiskal et al, 1977, 1979, 2000; Coryell et al, 1995; Akiskal 1996; Angst, 1998; Dunner, 1998).. The use of diagnostic criteria softer than those proposed from this nosologic classification and the systematic use of tools with specifically designed to detect hypomania broadens the diagnoses of hypomania (and thus BD type II) in previously diagnosed unipolar depressed patients, pointing out the presence of hypomanic symptoms in depressed patients too (Cassano et al, 2004). Apart from a reduction in duration cut-off for hypomania, a bipolar family history showed the highest positive predictive value in reducing the misdiagnosis of BD type II (Benazzi, 2007). A greater care for manic symptoms and the systematic presence of caregivers during visits may help to rule out hypomanic episodes which would otherwise pass undiagnosed (Akiskal and Benazzi, 2005) Borderline personality disorder Even if in some cases patients presents with both disorders (Vieta, 1999), a trend toward excessively diagnosing personality disorders has been found, especially cluster B disorders (antisocial, borderline, histrionic and narcisistic) and a trend toward infradiagnosing BD (Akiskal, 1987). Almost a 20% of BD type II patients are misdiagnosed as having personality disorders (Vieta et al, 1994). Differential diagnosis with bipolar depression and borderline disorder should consider the overall symptom cluster, reactivity to environment and mood lability. A day-to-day or even hour-to-hour variability of depressive mood in borderline disorder is frequent, whereas in BD the depressive mood is generally experienced as an episode with a clear onset and termination, with a pattern of alteration in the sleep and appetite domains (Goodwin and Jamison, 2007). Differential diagnosis with mania and borderline disorder may not only be based on duration, as mood elation in borderline disorder could overlap with hypomania or Cyclothymia. The lack of precipitating events could point for BD, as well as sleep reduction and racing thoughts (Goodwin and Jamison, 2007). In general, careful application of the criteria for (hypo)mania distinguishes quite clearly between patients with BD and patients with borderline disorder (Benazzi, 2000) COURSE OF ILLNESS BD is a severe, chronic and recurrent illness, with a variable course (Goodwin and Jameson, 2007). The first episode may be of (hypo)manic, mixed or depressive type.

38 Manic onset is more common in male patients, while there is no gender-prevalence for depressive onset. Duration of episodes differs: manic ones may start abruptly and last for as short as two weeks up to five months, with an average duration of 4 months. Depressive episodes tend to last longer, with an average duration of six months. There is evidence that polarity of first episode may predict following recurrences (Calabrese et al, 2004). The diagnosis and recognition of bipolar disorder in adults, particularly in those first presenting to services, can be difficult. Many people have periods of considerable psychological and social disturbance before diagnosis. The literature is consistent in finding a significant time gap between onset of the illness and first treatment. A delay of 5-10 years between the onset of the first episode of the BD and the age of the first adequate treatment or hospitalization is quite common (APA, 1994). Some studies indicate that a correct diagnostic of the BD is usually made with a delay of 8-10 years (Ghaemi et al, 2000). This may be in part due to the fact that onset episode may be a depressive one: in a 5-years, naturalistic follow up on 269 patients affected by major depressive disorder, 8.9% switched to a diagnosis of BD type II and 8.9% to a diagnosis of BD type I (Holma et al, 2009). According to a recent report earlier age at onset predicts a longer latency to a proper diagnosis and proper treatment (Morken et al, 2009) NUMBER OF EPISODES Bipolar disorder is a recurrent illness, and the likelihood of its recurrence is near total (resumed in Goodwin and Jamison, 2007). A recent study has shown that medication strategies are influenced to a larger extent by the previous course of illness and history of poor response to treatment rather than by treatment severity. In fact, although first-episode patients presented higher levels of psychopathology compared with multiepisode patients, the majority were prescribed with monotherapy, but were able to achieve remission and recovery more often than multiepisode patients (Tohen et al, 2009). This finding reinforces the notion that patients with a longer course of illness become progressively less responsive to pharmacological treatment (Goldberg et al, 2005). There is evidence from Scott e Colom (2005) that individuals receiving CBT who had a past history of multiple relapses (>12 episodes) did not do well with adjunctive therapy. It was not possible to explore this hypothesis in all studies, but a secondary analysis of data from Colom et al. (2003) confirms that in their study, individuals with more than 12 previous BD episodes also appeared to show no additional benefit from adjunctive therapy compared with usual treatment. The extent to which the number of episodes may influence response to treatment is still not clear, but clinicians should always keep in mind the importance of an early start of therapy COURSE SPECIFIERS A recent article from Colom and Vieta (2009) analyzes DSM-IV specifiers for bipolar disorder, weighting their importance in clinical practice for their relevance for course and outcome. Specifiers as Rapid Cycles, as well as Catatonic, Melancholic and Atypical Features have shown a good clinical, evidence-based usefulness and should be maintained. A re-conceptualization in Seasonal Pattern specifier is proposed, as well as

39 the introduction of two others specifiers which have demonstrated relevance in the clinical outcome, Age at Onset and Predominant Polarity. In the following paragraphs we consider three specifiers which clinical relevance bears important therapeutic consequences Rapid cycling Dunner and Fieve (1974) first coined the term rapid cycling when describing clinical factors associated with lithium prophylaxis failure in bipolar disorder. The concept was later incorporated into DSM-IV as a course modifier. It can be conceptualized as either a high frequency (4 or more within a year) of episodes of any polarity or as a temporal sequence of episodes of opposite polarity. Despite the fact that this was initially quite an arbitrary definition, many studies support it nowadays, as its presence is definitely associated to poor outcome (Calabrese et al, 2001; Dubovsky, 2001; Coryell et al, 2003; Kupka et al, 2005; Cruz et al, 2008; Schneck et al, 2008). Same authors outline that rapid cycling is quite common amongst bipolar patients, with rates ranging around 12 24%, and it has been described to be more common in women, bipolar II patients, juvenile cases and patients, with an early age of onset of bipolar disorder. Rapid cycling has been positively linked to higher suicide attempts (Garcia-Amador et al 2009), a history of more frequent and longer hospital admissions, more outpatient consultations, more alcohol use problems and more severe impairment in work functioning (Cruz et al, 2008). It has been associated also with the length and number of episodes suffered from the start until the first psychiatric treatment and comorbid substance abuse (Vieta et al, 2004; Vieta et al, 2008); moreover, it has been associated with mixed episodes, and there is some evidence that those patients could respond to the association of atypical antispcyhotics (Gonzalez-Pinto et al, 2002). There is consisting evidence that antidepressant use in patients with BD could to precipitate manic or mixed reactions and inducing rapid cycling. Suggested early estimates for antidepressant-induced rapid cycling are 20-50% were cases (Wehr et al, 1988; Bauer et al, 1994). New data from the large (n = 1,742) STEP-BD prospective study found that among the patients with rapid cycling, who approximately constitute one-third of the total sample, antidepressant use was the major predictor of worse outcome (Schneck et al, 2008). A French study on a sample of 1090 bipolar patients found instead a much lower prevalence of rapid cycling (9%), which was found to be associated with longer duration of illness, antidepressant treatment, episodes with no free intervals, cyclothymic temperament and thyroid disorder (Azorin et al, 2008). On the other hand, there is now some controlled evidence that long-term treatment with antidepressants may stabilize acute antidepressant responders (Altshuler et al, 2009), a result which does not clarify the possible role of antidepressants in the therapy of BD. Nonetheless, rapid cycling represents a longitudinally severe form of bipolar disorder, with poorly evidence-based diagnostic and therapeutic tools (Azorin et al, 2009) Seasonal pattern Seasonal pattern is described by DSM-IV as the pattern of depressive episodes featured by onset and remission at characteristic times of the year; in most cases, the beginning would be in fall or winter. Apart from historical observations, it has been shown that approximately 10% of all affective disorders present a seasonal pattern of recurrence (Faedda et al. 1993) and it seems to be more frequent among bipolar patients (Shin et al, 2005). No conclusive data on the pattern of seasonality have been found. A study conducted at both hemispheres found a peak for depressive episodes in the fall, but no seasonality for

40 mania (Silverstone et al, 1995). Another study found a peak for pure mania in early spring and for mixed mania in late summer, while mixed manic admissions were found to have a peak in late summer and a decrease in November (Cassidy and Carroll, 2002). The most consistent findings in literature (Frangos et al, 1980; Parker and Walter, 1982; Carney et al, 1988) are a relative decrease in manic episodes during winter months and a peak in the spring. A large retrospective study on admissions for bipolar disorder showed that admission peaks were noted during spring/summer, early winter and early spring, for manic, depressive and mixed/unspecified episodes, respectively (lee et al, 2007). However, DSM-IV does not permit to use the Seasonal Pattern specifier for recurrent seasonal (hipo)manic episodes, as it is possible to apply it only for the depressive pole. A patient with recurrent manic episodes in a specific season, but suffering non-seasonal depressions, is thus not classified as seasonal, according to the DSM. Criteria should be broadened to include seasonality for manic episodes too (Goikolea et al, 2007; Cassidy et al, 2008). Dimensional approaches to measuring the severity of seasonality, using tools such as the Seasonal Pattern Assessment Questionnaire (SPAQ), a questionnaire translated and validated into Spanish (Goikolea et al. 2003), could be more sensitive, as non-seasonal (seasonal episodes are <50% of total episodes) patients still experience significant seasonal fluctuations (Shin et al, 2005). Data relating to gender differences regarding SP are inconclusive, as some studies support their involvement (Arnold, 2003) but others do not (Goikolea et al, 2007). Twin studies suggest that there is a genetic component behind susceptibility to seasonal changes (Hakkarainen et al. 2003), but environmental stimuli, such as exposure to light, may also play a major role, as shown by the fact that seasonality is much more frequent in northern European countries, where light variations are extreme (Goikolea et al, 2007). The study from Goikolea et al. (2007) links the presence of seasonal pattern to BD type II and predominant depressive polarity, being the latter more frequent in seasonal pattern bipolar patients. Quite interestingly, patients with seasonal pattern do not show higher rates of suicidality, more hospitalizations or worse functional outcome, suggesting milder severity of episodes. A large study on a sample of 1000 bipolar patients confirms that seasonal effects upon bipolar patients vary by region and bipolar subtype, being more common in northern sites and BD type II patients (Friedman et al, 2006). In conclusion, a close link between seasonality and depressive predominant polarity and bipolar II disorder seems established. When treating bipolar patients and particularly bipolar II, close attention to seasonality is advised, because patients with SP are more predictable in terms of recurrence, and therefore treatment efforts should be more easily directed towards preventing recurrence, and particularly depressive recurrence, in this subpopulation Age at onset The average age at onset in bipolar disorder has been evaluated to be 22.2 years, basing on pooled data from 15 published studies (Goodwin and Jameson, 2007). There were no gender and type I-type II differences. Although some authors have defined two primary groups of age at onset (Suppes et al, 2001, Carlson et al, 2000), further analyses have found a trimodal (early-intermediate, late model) distribution, with average onsets at age 16.9, 26.9, 46.2 (Bellivier et al, 2001). This model was tested and confirmed in a subsequent study by the same group (Bellivier et al, 2003) and by researchers of the Basque Country (Gonzalez-Pinto et al, 2009). In the latter, major differences were

41 found between the early and intermediate group and the late-onset group: this one presented with less suicide risk, less psychotic symptoms and less family vulnerability. Early age at onset (<19 years old) is present in about one third of bipolar subjects (Suominen et al, 2007), associated to a worse outcome than later onset on a variety of measures as recurrence, chronicity of mood symptoms, and functional impairment during prospective observation (Perlis et al, 2009), as well as comorbidity with other Axis I disorders, psychotic symptoms (Perlis et al, 2004), lithium resistance (Carlson et al, 2002) and poor treatment response in general (Engstrom et al, 2003). Approximately one third of bipolar subjects presents early age at onset (Suominem et al, 2007). There is a considerable evidence-based consensus in existing literature on considering years as a valid cut-off for considering early onset (Schneck et al, 2008; Suominem et al, 2007). This is associated with greater illness severity and poorer outcome (Geller et al, 2004; Carlson et al, 2002; Carter et al, 2003; Ernst and Goldberg, 2004). There is evidence that early age at onset may be linked with higher rates of psychotic symptoms (Schurhoff et al, 2000), greater Axis I comorbidity (Suominem et al, 2007), cannabis use (Gonzalez-Pinto et al, 2008) and suicidality (Perlis et al, 2004), although there is no concordance over these poorer outcomes (McElroy et al, 1997). The appearance of manic-like symptoms in patients aged 60 years or more is less likely to have a genetic substrate and seems associated more with some underlying organic condition such as a stroke or a central nervous system lesion (McDonald and Nemeroff, 1996) Predominant polarity The importance of the concept predominant polarity, based on an early proposal by Angst (1978), comes from the direct experience in everyday clinical practice. Predominant polarity is a construct defined by the existence of 2/3 of a patients lifetime mood episode of the same pole (depression vs. mania/hypomania), as defined in the two main studies on the issue (Colom et al, 2006; Rosa et al, 2008). Up to 50% of bipolar patients present a specific predominant polarity and, as expected from clinical practice, depressive polarity is more frequent than manic/hypomanic polarity (about 60% of depressive predominant polarity versus 40% of manic one). Depressive predominant polarity appears to be more common in bipolar II disorder (Colom et al, 2006, Vieta and Suppes, 2008), but, evaluating the number of days spent on a certain episode, depressive predominant polarity is more common both for bipolar I and II patients (Judd et al, 2003b; Kupka et al, 2001; Judd et al, 2003). There is a link between polarity of first episode and subsequent ones (Calabrese et al, 2004; Perlis et al, 2005): depressive predominant polarity is associated with depressive onset (Daban et al, 2006). No differences between groups regarding socio-demographic variables and global social functioning have been reported yet by the literature. On the other hand, suicidality, lifetime history of attempted suicide and number of attempts are strongly linked to depressive polarity, but suicidal ideation is not. Triggering factors may also differ between these groups, with predominantly depressive patients being more prone to have life events as a trigger, and predominantly (hypo)manic patients being more likely to have substance misuse (Colom et al, 2006). Depressive polarity has been found to be associated with difficulties in ceasing alcohol and drug abuse in the long-term (Gonzalez-Pinto et al, 2010). Predominant polarity represents the formalization of a concept widely used by clinicians in medical practice: they do pay attention to this fact when choosing a maintenance treatment. Actually, it has been shown to have major therapeutic and clinical implications (Judd et al, 2003; Calabrese et al, 2004). For instance, as expected, acute

42 and maintenance use of atypical antipsychotics and conventional neuroleptics is far more common amongst predominantly (hypo)manic patients, whilst the use of antidepressants and lamotrigine is more frequent amongst predominantly depressive patients, but no differences are found regarding lithium, valproate and carbamazepine use (Colom et al., 2006); Daban et al., 2006; Goikolea et al., 2007; Rosa et al., 2008). Predominant polarity has recently been suggested as a potentially useful new course specifier by a International Society for Bipolar Disorder s Committee on Nomenclature consensus statement (Tohen et al., 2009) IMPROVING THE DIAGNOSIS OF BIPOLAR DISORDER Limits and perspectives in the nosology of bipolar disorder Critics against actual nosologic systems have been moved. There is general agreement that DSM-IV and ICD-10 require major improvements in format and content to make them more valid, evidence-based and clinically useful. The Task Force of the International Society for Bipolar Disorder (ISBD) published in 2008 a discussion of possible revision of the definitions used (Ghaemi et al, 2008). Seven sub-groups focused on different diagnostic subtypes for more intensive analysis, namely the seven diagnostic groups covering the most relevant diagnostic material, lastly producing suggestions are here provided for each diagnostic subgroup (with the exception of schizoaffective disorder), and summarized in tables 5.21 to Tab DSM-IV revision: Bipolar Depression (from Ghaemi et al, 2008). (Modified criteria or sentences are in bold) A A past Manic or Hypomanic Episode B A Major Depressive Episode characterized by five (or more) of the following symptoms has been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (i) depressed mood or (ii) loss of interest or pleasure: 1 Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. 2 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others). 3 Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. 4 Insomnia or hypersomnia nearly every day. 5 Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6 Fatigue or loss of energy nearly every day. 7 Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely selfreproach or guilt about being sick). 8 Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

43 C D E F G The symptoms do not meet criteria for a Mixed Episode. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation. Special consideration should be given to presence of (i) atypical depressive symptoms (hypersomnia, hyperphagia, or leaden paralysis), (ii) psychomotor disturbance, (iii) psychotic features or pathological guilt, and (iv) a positive family history of bipolar disorder. Tab DSM-IV revision: Rapid Cycling (from Ghaemi et al, 2008) (Modified criteria or sentences are in bold) Specify if: With Rapid Cycling [can be applied to Bipolar I Disorder, Bipolar II Disorder, or Bipolar Disorder not otherwise specified (NOS)]. At least four episodes of a mood disturbance in the previous 12 months that meet criteria for a Major Depressive, Manic, Mixed, or Hypomanic Episode. Specify episode criteria (full duration or briefer) and duration of interepisodic interval. Note: Episodes are demarcated either by partial or full remission for a least 2 months (and in brief mood episodes a full remission for at least 2 weeks) or a switch to an episode of opposite polarity (e.g., Major Depressive Episode to Manic Episode). Tab DSM-IV revision: Hypomanic Episode (from Ghaemi et al, 2008) (Modified criteria or sentences are in bold) A A distinct period of persistently elevated, expansive, depressed, or irritable mood, lasting throughout at least 2 days, that is clearly different from the usual non-depressed mood. B During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1 Inflated self-esteem or grandiosity. 2 Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 3 More talkative than usual or pressure to keep talking. 4 Flight of ideas or subjective experience that thoughts are racing. 5 Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli). 6 Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation. 7 Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., the person engages in unrestrained buying sprees, sexual indiscretions, or foolish business

44 investments). C The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D The disturbance in mood and the change in functioning are observable by others. E The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features, although mild-to-moderate depressive symptoms may be present (mixed hypomania). F The symptoms are not because of the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism), but may happen in the context of medication, substance intake, or physical illness as far as the symptoms are not clearly etiologically related to those. Tab DSM-IV revision: Bipolar II Disorder (from Ghaemi et al, 2008) (Modified criteria or sentences are in bold) (Modified criteria or sentences are in bold) A Presence (or history) of one or more Major Depressive Episodes. B Presence (or history) of at least one Hypomanic Episode. C There has never been a Manic Episode or a Mixed Manic Episode. D The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder NOS. E The depressive symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; the hypomanic symptoms do not necessarily cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Course specifiers: With hypomanic or depressive predominant polarity Tab DSM-IV revision: Bipolar Disorder NOS (from Ghaemi et al, 2008) (Modified criteria or sentences are in bold) The Bipolar Disorder NOS category includes disorders with bipolar features that do not meet criteria for any specific bipolar disorder. Examples include: 1. Very rapid alternation (over days) between manic symptoms and depressive symptoms that do not meet minimal duration criteria for a Manic Episode or a Major Depressive Episode. 2. Recurrent Hypomanic Episodes without intercurrent depressive symptoms. 3. A Manic or Mixed Episode superimposed on a Delusional Disorder, Residual Schizophrenia, or Psychotic Disorder NOS. 4. Situations in which the clinician has concluded that a Bipolar Disorder is present but is unable to determine whether it is primary, due to a general medical condition, or substance induced. 5. Subthreshold Hypomanic Episodes in the context of multiple other signs of bipolarity.* 6. Multiple signs of bipolarity without Hypomanic or Manic Episodes (also known as Bipolar Spectrum Disorder).* *Clinicians should specify precisely which such signs are present and include this list in their assessment statement, as follows:

45 a. Family history (bipolar diagnoses; multi-generational mental illness; alcohol and other substance use; suicides). b. Depressive symptom phenomenology (atypical, seasonal, psychomotor slowing, psychosis). c. Course of illness (early age of onset, short duration of episodes, greater number of episodes). Tab DSM-IV revision: Paediatric Bipolar Disorder (from Ghaemi et al, 2008) (Modified criteria or sentences are in bold) A. Presence of an acute manic or mixed or hypomanic plus depressed episode prior to age 18. B. The definition of the acute manic or hypomanic or mixed episode meets adult criteria. If only irritable mood is present, and not euphoria, documented spontaneously episodic fluctuations in the presence absence of symptoms of mania are required for the diagnosis of an acute manic, hypomanic, or mixed episode. The mania task force subgroup did not suggest any revision of DSM-IV acute mania criteria. The bipolar depression subgroup suggested focusing more on atypical depressive symptoms, psychomotor disturbances, psychotic features or pathological guilt and positive family history for BD. The rapid cycling subgroup proposed to apply this specifier to BD NOS, considers specifying episodes criteria (full duration or briefer) and the duration of the interepisodic interval (it accepts 2 weeks in between brief mood episodes). The BD type II subgroup first proposed a re-conceptualization of hypomania: a temporal threshold of 2 days, and the possibility of mixed hypomania and secondary hypomania. A newly suggested criterion for BD type II considers the presence of significant distress or impairment in social, occupational or other important areas of functioning, but their possible absence during hypomania. The bipolar spectrum subgroup proposes considering subthreshold hypomanic episodes in the context of other signs of bipolarity such as familiarity, depressive symptom phenomenology, course of illness such as early age at onset, episode recurrence. The paediatric BD subgroup (in cap. 10 a wider description of paediatric BD is presented) proposes the presence of a full (hypo)mania or mixed episode (following adult criteria) plus at least one depressive episode, or documented fluctuations in the presence/absence of symptoms of mania if only irritable mood is present, and not euphoria Screening for bipolar disorder The problem of misdiagnosis and underdiagnosis of bipolar spectrum disorder has been long debated (Akiskal et al, 2000; Hirschfeld et al, 2000). Correct diagnosis is essential, since the treatment of BD greatly differs from that of unipolar depression. The problem of patients classified as unipolar that subsequently experience a (hypo)manic episode is a serious one, as these false unipolars (Goodwin and Jameson, 2007) need a different treatment. Hypomania is perhaps the most difficult psychiatric syndrome to rule out retrospectively (Vieta et al., 2005). However, the retrospective detection of hypomania is crucial for a correct diagnosis of bipolar disorder, and particularly for BDII, and for treatment accuracy. The APA guidelines on the management of BD state that BD type II is frequently misdiagnosed as unipolar major depressive disorder and as a result may receive inadequate or inappropriate treatment (APA, 2002). An expert group concluded

46 that the current diagnostic criteria have high specificity but might have too low a sensitivity and that a greater focus on certain symptoms (such as activation levels) or less emphasis on symptom duration may improve recognition of those at risk of BP episodes (Angst et al, 2003). One method of increasing recognition of an illness is to screen for it. In the last 10 years, two screening instruments have been developed for this purpose. The Mood Disorder Questionnaire is a self-report, single-page, paper-and-pencil inventory that can be quickly and easily scored by a physician, nurse, or any trained medical staff assistant. The Mood Disorder Questionnaire screens for a lifetime history of a manic or hypomanic syndrome by including 13 yes/no items derived from both the DSM-IV criteria and clinical experience. The Mood Disorder Questionnaire was tested first in a tertiary care clinical sample and showed a sensitivity of 73% and a specificity of 90% (two thirds of the sample had BP-I) with a cut-off score of 7 or more (Hirschfeld et al, 2000). In a population sample (Hirschfeld et al., 2003) the sensitivity was 28% and the specificity was 97% for BP. Moreover, it seems to be sensitive to identify BP-I disorder but probably less so for BP-II disorder (Benazzi and Akiskal, 2003; Zimmermann et al, 2004). A Spanish version of the Mood Disorder Questionnaire is available (Sanchez-Moreno et al, 2008). The Hypomania Checklist-32 is a self-applied questionnaire being internationally developed, which purpose is to identify hypomanic symptoms in patients with major depressive disorder, so that it may help to rule out a diagnosis of BD type II or other BDs in the bipolar spectrum (Angst et al, 2005). As this group of patients is frequently diagnosed and treated in Primary Care, the use of this questionnaire is of great use with depressed patients in this setting to improve diagnosis and treatment in bipolar patients and thus their outcome, functioning and quality of life. The Hypomania Checklist -32 comprises a checklist of possible symptoms of hypomania that are rated yes (present or typical of me) or no (not present or not typical) by the subject. A Spanish Version of the Hypomania Checklist -32 is available (Vieta et al, 2007): this version exhibits good psychometric properties in relation to sensitivity and specificity. The psychometric study of the development of the HCL-32 scale in Spain exhibits high internal consistency and similar stability over time, in comparison with other instruments such as the MDQ and suggests that this scale may be very useful for the detection of bipolar disorder and past hypomania. A cut-off point of 14 affirmative responses indicates good sensitivity (0.85) and specificity (0.79). Compared with the MDQ, the HCL-32 presents greater sensitivity for the detection of bipolar disorder. Furthermore, a cut-off point of 15 affirmative responses increases the questionnaire's specificity (0.83 versus 0.79), with its sensitivity remaining unaltered (0.85). Moreover, the HCL-32 was useful to discriminate between BDII and unipolar patients, and also between BDII and controls, and therefore may be used in clinical practice for this purpose (Vieta et al, 2007). Interestingly enough, though, 26% of unipolar patients had a HCL-32 score of 14 or above, indicating either some false positives or, alternatively, that soft hypomania may be present even in clinically undisputable unipolar patients (Akiskal et al. 2003). Given the difficulties involved in both the retrospective and cross-sectional diagnosis of hypomania, which represent key aspects of appropriate management of bipolar disorders, this questionnaire represents a potential improvement in clinicians ability to detect and correctly treat bipolar disorder MANAGEMENT OF BIPOLAR DISORDER FROM PRIMARY CARE

47 Bipolar disorder is no longer an illness limited to diagnosis and management by the psychiatric profession. Only a third of all patients with mental illness are treated in the mental health sector, while approximately half of all patients with mental illness are seen by primary care physicians (Regier et al, 1993). The introduction of atypical antipsychotic drugs in BD clinical management has led to the need of a careful metabolic watch for their risk of weight gain, cardiovascualar diseases, metabolic syndrome and type 2 diabetes mellitus, all conditions which may emerge when treating BD with this class of drugs. Primary care clinicians may thus play a role in careful monitoring these somatic aspects in the multi-professional management of this complex illness. This role will be deeply discussed in ch RECOMMENDATIONS Screening for Bipolar Disorder * The most frequent reason for consult for people with BD is depression, so the most effective form of screening is the identification of bipolarity in depressed patients, according to following risk factors: - Family history of BD - Severe depression in adolescent or young adult - Score of 14 or more in HCL-32 (Angst i cols., 2005; Vieta i cols., 2007) A * Patients with incipient psychosis or recurrent psychotic pictures may or evolve into a bipolar disorder. Following DSM-IV-TR, affective manic or depressive symptoms have to be excluded before diagnosis schizophrenia * To make a good screening for BD a clinician should have, whenever possible, additional sources of information to the patient, and preferably from those who live with him. A Suicide risk evaluation * Clinicians should probe suicidal ideation and plan in every unipolar or bipolar major depressive episode.

48 * When recollecting information from a patient, a clinician should always ask for previous suicide attempts. All cases of depressive episode which, among its symptoms, include recurrent thoughts of death, or suicide, or suicidal behaviour should be considered at least moderate or severe depressive episodes and have a specialist intervention to implement the recommendations of Levels 3 to 5. All bipolar depression require at least Level 3 care and, in some cases, higher. * In patients at high risk of suicide it is often recommended additional support. The urgent referral to a specialist in mental health has to be evaluated. * Hospitalization should be considered in patients with high risk of suicide

49 06 GENERAL ASPECTS OF THE TREATMENT OF BIPOLAR DISORDER 6.1. DIAGNOSTIC EVALUATION 6.2. EVALUATE FUNCTIONAL IMPAIRMENT 6.3. SAFETY 6.4. THERAPEUTIC ALLIANCE 6.5. EDUCATION FOR THE PATIENT AND THE CAREGIVERS 6.6. TREATMENT ADHERENCE 6.7. CHOICE OF TREATMENT AND MANAGEMENT 6.8. FOLLOW-UP 6.9. RECOMMENDATIONS Consensus exists on the general recommendations for the assessment and management of patients with bipolar disorder (Suppes et al, 2005; Yatham et al, 2007; Goodwin et al, 2009; Grunze et al, 2009). The use of clinical guidelines does not substitute the judgment derived by clinical practice and experience, but may guide in the choice of the most adequate treatment from an evidence-based point of view. Clinicians should keep in mind the main objectives of the treatment of bipolar disorder, which are listed in Tab.6.1. Tab 6.1. The 10 objectives in the treatment of Bipolar Disorder (Vieta, 2007) 1. To ensure safety for the patients and other people 2. To treat and reduce the severity of acute episodes, if they occur 3. To treat psychotic symptoms, if they occur 4. To avoid switching from an episode into another 5. To avoid suicidal behaviours 6. To reduce the frequency of affective episodes 7. To treat subclinical symptoms 8. To treat comorbidities, general health and cognitive symptoms 9. To improve patients and caregivers knowledge on the disorder, and improve patients adherence to treatment 10. To help patients in achieving a good inter-episodic functioning.

50 These goals may be resumed in the following: 1) Symptomatic and functional remission 2) Full return of psychological functioning 3) Prevention of relapses and recurrences The treatments choice in the care of patients with bipolar disorder should be guided by cross-sectional (i.e., current clinical status) and longitudinal (i.e., frequency, severity, and consequences of past episodes) evaluation, and should be guided by the principle of weighing evidence regarding effectiveness, tolerability and safety. In addition, treatment decisions should be continually reassessed as new information becomes available, the patient s clinical status changes, or both DIAGNOSTIC EVALUATION. As presented in chapter 5, clinicians should perform a diagnostic evaluation of psychiatric condition with attention to clinical history of patient and family too. The use of screening tools as HCL-32 (Angst et al, 2005) or MDQ (Hirschfeld et al, 2000) may improve efficiency and sensitivity in detecting bipolar disorder, given the difficulty to retrospectively assess hypomania. General principles for diagnostic evaluation have widely been discussed in chapter 5 of the present guidelines, as well as aspects of screening for BD. Considerations on the screening for BD in primary care are made in chapter EVALUATE FUNCTIONAL IMPAIRMENT Functional impairment in bipolar disorder can be associated to manic and depressive episodes, but persists also during euthymia (Zarate et al, 2000; Depp et al, 2006). The majority of the available instruments used to assess functioning have focused on global measures of functional recovery rather than specific domains of psychosocial functioning. Clinicians should instead evaluate the presence, type and severity of functional impairment, such as deficit in cognition, interpersonal relationship, work, living conditions, and other medical and health-related needs. The FAST scale (Rosa et al, 2007), a quick and easy-to-use interview-administered tool, may help clinicians in the assessment of the functioning of patients with BD, both acute or euthymic SAFETY A careful assessment of the patient s suicide risk is critical and recommendable, throughout the evaluation of the current presentation and severity of this cluster of symptoms (i.e. thoughts, plans, behaviours), psychiatric illness (comorbidity with substance and anxiety disorders, actual acute episode), history (previous attempts and family history), psychosocial situation (stressors, life-events), individual strengths and vulnerabilities (cooping skills, personality traits, etc) (APA, 2003). It is important to discuss with women in treatment the risks of pregnancy (including the risks of relapse, damage to the fetus, and the risks associated with stopping or changing medication), as

51 some of the treatments available have teratogenic effects. These aspects should be discussed with all women of child-bearing potential, regardless of whether they are planning a pregnancy. They should be encouraged to discuss pregnancy plans with their doctor. These aspects will be more widely treated in chapter THERAPEUTIC ALLIANCE BD is a long-term illness that may manifest itself in different ways in different patients and at different moments during its course. After the assessment, another goal of psychiatric management includes establishing and maintaining a therapeutic alliance, monitoring the patient s psychiatric status, enhancing treatment adherence. Establishing and maintaining therapeutic alliance is critical to the proper management of an individual patients and to favour and enhance adherence of patients to treatments, often complicated and chronic and to remain vigilant to changes on mood status, which may herald to onset of an acute episode. Reported non-adherence rates for long-term prophylaxis in BD range from 20% 66% (Bech et al, 1976; Adams and Scott, 2000). Doctors must take responsibility for diagnosis, physical examination, investigations and explanation of the medical plan of management. They must communicate clearly and effectively. A therapeutic alliance between doctor and patient is essential for the management of any complex chronic condition, which bipolar disorder certainly is (Goodwin, 2009). The psychiatrist should remain vigilant for changes in the patient s psychiatric status. This element is certainly true for every psychiatric disorder, but it is especially important in the case of BD because of the intrinsic nature of the illness: limited insight on the part of the patients is frequent, especially during manic episodes. Moreover, small changes in mood or behaviour may well be prodromal symptoms of a recurring episode, with potentially severe consequences. A progressive knowledge on the particular characteristics of a patient s illness may enhance and support the clinician EDUCATION FOR THE PATIENT AND THE CAREGIVERS Clinicians are strongly recommended to provide education regarding bipolar disorder to the patient and family regarding their illness, treatment and prognosis, as it allows reinforcing the patient s collaborative and active role in treating BD. A collaborative, therapeutic relationship with the patient and his/her family and carers (within the normal bounds of confidentiality) has to be established. Clinicians have to be respectful of the patient s knowledge and experience of the illness, and provide relevant information (including written information) at every stage of assessment, diagnosis and treatment. An understanding of the pharmacological and psychological options available is fundamental as well. These active roles of the patient and adequate lifestyle changes need to be discussed, (including the proper use and likely side-effect profile of medication). (Goodwin and Jamison, 2007). Healthcare professionals should encourage patients to involve their families and carers in assessment and treatment plans if appropriate and make themselves accessible to family members and carers in time of crisis. The needs of patients family members or carers should be also taken into account, including: 1. the impact of the disorder on relationships 2. the welfare of dependent children, siblings and vulnerable adults 3. the regular assessment of carers physical, social and mental health needs (NICE, 2009).

52 Education should be an ongoing process in which the psychiatrist gradually introduces facts about the illness. The information about the nature, course and treatment of bipolar disorder is fundamental in promoting access to services, and understanding and collaboration between patients, close family members, paid and unpaid carers and healthcare professionals. Careful and regular self-monitoring of symptoms (including triggers and early warning signs), lifestyle (including sleep hygiene and work patterns) and coping strategies should be discussed. (NICE, 2009). Printed material on crosssectional as well as longitudinal aspects of bipolar illness and its treatment may be useful, including information available on the internet (such as that found in Associationism may be useful and constitute a further support to patients. Patients may be addressed to the local patients associations (such as the Catalunyian Bipolar Patients Association, ). Similar educational approaches are also important for family members and significant others. They too may have difficulty accepting and managing their beloved s illness and the patient s need for continuing treatment (Rosenfarb et al, 2001; Mino et al, 2001) TREATMENT ADHERENCE Adherence to treatment plays a major role in BD, as it may improve the patients course of illness (see ch.7). However, bipolar patients are frequently ambivalent with their need for treatment (Jamison et al, 1979). This ambivalence often may take the form of noncompliance with medication and other treatments (Gutheil, 1982; Goodwin and Jameson, 2007), which usually ends in a relapse (Jamison and Akiskal, 1983; Pardes et al, 1989). Ambivalence about treatments is consequence to many factors, one of which is the lack of insight. The difficulty in believing that they have a serious mental illness takes some patients to leaving medication, minimizing or denying the reality of an episode, or their own behaviour and its consequences. This aspect is normally extremely pronounced during manic episodes. Another factor that may play a role in scarce acceptance of the treatment is that some patients are reluctant to renounce to hypomania or mania (Jamison and Akiskal, 1983). The exciting sensation of increased energy, euphoria, heightened self-esteem, ability to focus on multiple tasks may be very desirable and enjoyable. This aspect is often recalled by patients, and they often minimize or deny entirely the subsequent devastating effects of full-blown mania or the extended demoralization and lack of energy of a depressive episode. Other important elements are medication side effects, which need to be discussed realistically with patients and care-givers. Some of the side effects may be corrected with careful dose-adjusting. Those which cannot be corrected must be discussed in the context of an informed consent to treatment, after having weighted the benefits and the risks of actual or potential treatments 6.7. CHOICE OF TREATMENT AND MANAGEMENT The treatment of bipolar disorder is based primarily on psychotropic medication to reduce the severity of symptoms, stabilise mood and prevent relapse. Individual variation in response to medication will often determine the choice of drug, as will the side effects and potential harms associated with each drug (NICE, 2009).

53 Actual guidelines (Suppes et al, 2005; Yatham et al, 2007; Goodwin et al, 2009; Grunze et al, 2009) agree on treatment choice criteria: the treatment for a patient should be determined by the clinician based on a review of: 1) Relevant psychiatric factors (i.e. symptoms severity, suicidal ideation, comorbidity); 2) Side effect profile; 3) General medical factors (i.e. age, gender, general medical comorbidities); 4) Prior treatment history and response; 5) Evidence for efficacy as maintenance treatment, if appropriated; 6) Route and ease of administration; Treatment of bipolar disorder is chronic and needs to be considered separately for manic, hypomanic, mixed and depressive acute episodes, as well as for continuation and maintenance phase. Acute treatment is the treatment administered during the period from the beginning of the manic or depressive episode to a clinical response, ideally, remission. This phase usually lasts from 6 to 12 weeks, and the clinician should closely monitor the patient. Continuation treatment is the ongoing treatment of a depressive or manic episode from the point of clinical response to the point of at which spontaneous recovery would be expected to occur in untreated patients. The duration of continuation treatment is determined by natural course of the illness. In bipolar patients antidepressant treatment is recommended for a period of 6 months. For mania the continuation treatment is suggested to last 4 months or longer, involving the management of a post-mania depression or a sometimes protracted period of mood instability dominated by dysphoria. Maintenance treatment (long-term prophylactic treatment), is intended to prevent or attenuate future episodes in patients with bipolar or recurrent mood episodes in bipolar patients. For patients experiencing a manic or mixed episode, the primary goals of treatment, should be: 1) the control of symptoms to allow a return to normal levels of psychosocial functioning; 2) the rapid control of agitation, aggression and impulsivity; 3) Prevent or diminish subsequent episodes (maintenance treatment). The primary goals of the treatment of a depressive episode should be: 1) Remission of the depressive symptoms with return to normal level of psychosocial functioning; 2) Avoid precipitation of a manic, mixed, hypomanic episode or mood cycling; 3) Prevent or diminish subsequent episodes (maintenance treatment); 4) prevent suicide. The goals of maintenance treatment should be: 1) To prevent mood episodes, including manic, hypomanic, mixed and depressive ones; 2) To decrease cycle frequency; 3) To diminish the amplitude of mood episodes (1i.e. hypomania instead of mania); 4) To reduce inter-episode subthreshold symptoms; 5) To reduce suicidality. These are the classical definitions of the treatment phases in BD (resumed in Goodwin and Jameson, 2007). It is true that the distinction between acute and maintenance phase gives a sense to an operative perspective, but the new trend in the treatment of BD is more on the integrated approach, as it permits the management of acute aspects, but keeps in mind the need of a long-term prognosis, including functional outcome (Martinez-Aran et al, 2006; Martinez-Aran et al, 2009) and reduction of morbility and metabolic complications (Bobes et al, 2008). For this reason, the treatment of an acute phase always has to consider a longitudinal aspect, including not only the cross-sectional presence (or absence) of symptoms, but the predominant

54 polarity of past episodes too (Colom et al, 2006), plus the general principles listed on table 6.2. Tab Some general principles for the managing of manic-depressive illness (Goodwin & Jamison, 2007) 1. Include a family member in the initial evaluation and (on occasion and when appropriate) in the ongoing evaluation of treatment 2. Use a life-chart to record the patient s history and to monitor the course of the illness 3. Aim for balanced effectiveness ; that is, given equal weight to a drug s tolerability, efficacy and safety. Among agent with evidence of efficacy, it is generally better to start with the better tolerate one. The side effects of most concern to patients are weight gain, neurocognitive impairment, and sedation 4. Treat breakthrough symptoms, substance abuse, comorbid anxiety and side effects vigorously. Bipolar II patients may be more sensitive to side effects than bipolar-i patients 5. Focus psychotherapy on adherence, psychoeducation and circadian integrity. 6. Watch for suicidal behaviour and persistent suicidal ideation, especially if the patient has a specific plan. 7. If antidepressants are needed for the acute treatment of bipolar depression, include a mood stabilizer. Do not maintain antidepressants in bipolar patients unless attempts to taper off repeatedly fail; watch for early signs of a hypomanic/manic switch and/or increased cycling 8. When mood stabilizer monotherapy proves inadequate, use combinations in modest doses. Lithium may interact sinergically with some anticonvulsants FOLLOW-UP Clinicians have access to a wide variety of rating scales designed to help identify, assess, and quantify symptoms of different illnesses. Although many of these scales measure the presence and severity of discrete illness variables, rating scales of global illness conditions can contribute with valuable information to the overall clinical picture of each patient and can be helpful in assessing the efficacy of a given intervention. Moreover, they are more compatible with the often restricted quantity of time clinicians may dedicate to patients in everyday practice. Hence, global judgments of illness severity and change during the course of treatment may usefully inform clinicians of whether to continue or alter treatment strategies (i.e. decisions regarding whether or not a treatment is effective) (Rush and Kupfer, 1995). Given the need for an evaluation of the overall clinical condition of a patients affected by BD and the need to use a quick and intuitive tool, we propose the use of Clinical Global Impression Scale Bipolar (CGI-BP), a scale which represents the adaptation of the original CGI scale by Guy and cols (1976), to be included in the follow-up evaluation of bipolar patients.

55 The CGI scale (Guy, 1976) is a standard measure for making global assessments of illness. The CGI-BP scale allows for separate assessments of each phase of the illness (i.e. mania, depression, and overall illness). Also, the scale can be used to assess either the acute (single episode) or prophylactic (long-term prevention of episodes) effects of treatments. For prophylactic assessments, the scale allows clinicians to integrate severity, duration, and frequency of episodes in evaluating a treatment. A copy of the scale is included in Annexes III RECOMMENDATIONS RECOMMENDATIONS ON GENERAL ASPECTS * * Patients diagnosed with BD type I or type II should be referred for psychiatric evaluation by a specialist for diagnosis confirmation and the assessing of a therapeutic plan. It is recommended to schedule the appointment with a specialist within 30 days. Regardless of their referral to the Mental Health Centre, patients with BD should be monitored in their physical health, in coordination with Specialized Care * Patients with BD who are currently not in a manic, hypomanic or mixed episode should undergo structured and supervised physical exercise programs of moderate intensity, in frequency of minutes-session per week during weeks. The management of bipolar disorder mainly corresponds to level 3, ie, the mental health centers (CSM). The main reason is the complexity of treatment, both pharmacological and psychoeducational, and the potencial severity of the disease. The mental health Team will coordinate with the Primary Care and the Levels 4 and 5 if the patient is being assisted also in those levels. GENERAL ASPECTS OF THE TREATMENT TREATMENT OF MILD-MODERATE MANIA AND HYPOMANIA * Treatment of acute mania often requires hospitalization, since in many cases it is accompanied by significant behavioural alterations, little insight or even psychotic symptoms. Mild to moderate mania and hypomania, especially when they occur in patients who received psychoeducation, may be managed in the CSM. * Mild manic episodes may increase in severity if an effective treatment is not introduced quickly or if the patients does not assume the prescribed treatment, In cases where treatment adherence is questionable, family members should be involved in monitoring the treatment, otherwise the patient should be hospitalized. A A

56 * Hypomanic episodes may worsen or switch to a depressive episode. It is fundamental to treat hypomania, since its very start, to avoid the development of a full manic or depressive episode. * Assuming it is possible, a mild-moderate manic or hypomanic episode will be treated by a drug with a level of evidence of 1 or 2, in monotherapy or in combination to another according to the personal history of the patient. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * Even though mania or hypomania do not respond to psychosocial interventions, a good therapeutic alliance between the clinician and the patient is recommended that may be supported by psychoeducative elements since the very beginning of the treatment in the effort to improve a good adherence to treatment * The presence of depressive symptoms during mania contistutes a mixed episode and brings a higher risk for suicide and a need for hospitalization. The treatment of a mixed episode is similar to that for a manic one. A B Follow-up * All patients presenting with mild manic, hipomaniac, or mixed episodes, for whom hospitalization is not indicated, will be evaluated again within 8 days after the introduction of treatment. * At least one family member or care-giver should be envolved in the monitoring of the patient, so that it is possibile to evaluate effectiveness and tolerability to drug treatment and the patient s adherence * Befote beginning with pharmacological treatment the Mental Health professional has to adequately inform the patient on the benefits, expected from the treatment, as well as frequent and infrequent short- and long-term side effects and the duration of the treatment. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels anda n adjustment in the doses used A depending on the side effects and the efficacy of the treatment. * Follow up of the patients with pharmacologic treatment must be close, at least in

57 the first 8 weeks. Duration of the treatment * Pharmacologic treatment of a manic episode has to be continued until symptom remission, to pass then to maintenance treatment. * In patients presenting a switch to depression drug therapy should be adjusted according to the recommendations for the treatment of bipolar depression. A B TREATMENT OF BIPOLAR DEPRESSION Bipolar depression is characterized by being preceded, at some point in the life of the patient, by a manic, mixed or hypomanic episode. Depressed patients that cannot recall reliable information about such previous episodes maght have bipolar depression, especially if they refer a family history for BD, symptoms like emocional lability, psicomotor inhibition, hypersomnia, overeating psychotic symptoms in childhood or adolescent. * Depressive episodes in the context of a BD do not require, in most cases, to be treated in a psychiatric ward, and can be manager in the CSM, except for tose cases in which a risk for suicide, agitation or catatonia is assessed. * Depressive episodes may prolong in time i fan appropriate treatment is not introduced, or the patient fails to take prescribed drugs. In cases where treatment adherence is questionable the clinician should involve family members in the monitoring of treatment or, in serious cases, proceed the patient to a hospital. * Depressive episode may switch to mania or hypomania spontaneously or secundarily to an antidepressant treatment. Clinicians must set psychoeducational and pharmacological measures to minimize this risk. * If possible, clinicians have to treat a bipolar depressive episode with a drug of level of evidence 1 or 2, in monotherapy or combination with another one, depending on the patient s history. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * The efficacy of psychological interventions in bipolar depression if not B A A B

58 accompanied by an appropriate drug treatment, has not been demonstrated. * Subclinical, persistent or residual symptoms of depression are associated with cognitive dysfunction, poor psychosocial functioning, and increased risk of relapse. Clinicians should treat bipolar depression with the objective to achieve a full remission, if possible. B Follow-up * All patients with BD who present a depressive episode should be evaluated again within 15 days after the introduction of the treatment. * At least one family member or caregiver should be envolved in the monitoring of the patients, so that clinician can compare the effectiveness and tolerability of the treatment as well as patient s adherente. * Befote beginning with pharmacological treatment the Mental Health professional has to adequately inform the patient on the benefits, expected from the treatment, as well as frequent and infrequent short- and long-term side effects and the duration of the treatment. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels anda n adjustment in the doses used depending on the side effects and the efficacy of the treatment. * Follow up of the patients with pharmacologic treatment must be close, at least in the first 8 weeks. A Duration of the treatment * Pharmacologic treatment of a depressive episode has to be continued until symptom remission, to pass then to maintenance treatment. * In patients presenting a switch to manic, hipomanic, or mixed episode drug therapy should be adjusted according to the recommendations for the treatment of bipolar depression. A B

59 MAINTENANCE TREATMENT The maintenance treatment of BD corresponds mainly to the CSM, except in cases of high complexity, which will be attended at level 4 until they can be derived to level 3. During maintenance treatment it is especially important to work with the patient and, if possible, with the family or caregivers, to ensure that they understand the need for longterm treatment in preventing future relapses. * Euthymia or remission from an acute episode may lead the patient to think that the disease has passed and there is no need for treatment, but as this is a highly recurrent disease it is essential to establish a therapeutic relationship which allows establishing a proper treatment indefinitely. * Psychoeducational interventions are essential complements to medical treatment as they improve adherente to therapy and a good psychosocial adaptation. When adherence is questionable family members and caregivers should be envolved in monitoring the treatment. * Relapses may arise spontaneously, as well as induced by treatment. Clinician should avoid "bargaining" the medication with the patient, as it may lead to a subtherapeutic use of the prophylactic treatment. * If possible, clinicians have to treat a bipolar depressive episode with a drug of level of evidence 1 or 2, in monotherapy or combination with another one, depending on the patient s history. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * The efficacy of psychological interventions, if not accompanied by an appropriate drug treatment, has not been demonstrated, but, as adjunctive treatment, group or individual psychoeducative interventions (on patients or caregivers) and cognitive behavioural therapy have demonstrated an efficacy in preventing manic, as well as depressive, recurrences. * It is not recommended the withdrawal of an effective prophylactic drug treatment if there are no tolerability problems or special situations (pregnancy, B contraindications) to do so. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels with a minimum annual frequency, A A B A

60 which have to be increased in special situations or whenever the clinician values it as adequate. HOSPITALIZATION AND EMERGENCY CARE The following cases correspond to this level: a large proportion of cases of acute mania and severe cases of bipolar depression, mixed episodes, resistance to acute treatment, or special situations involving a risk for the patient and/or those who are near. Patients who require urgent medical assessment, those who have medical or psychiatric comorbidity, severe behavior disorders (such as large economic costs, megalomaniac projects, etc.), psychotic symptoms, high risk of suicide, pregnant with acute symptoms, acute neuropsychiatric disorders, multiple medicalconditions associated to elderly age, or difficulty in self care, frequently require urgent interventions in acute care units of hospitals, where treatments can be implemented in safe conditions and with the support of other specialists. Objectives of the treatment in the Acute Unit The main goal of the treatment at level 4 is to bring the patient back to lower levels, so that he can gain autonomy and self-management skills to make unnecessary hospital treatment. Short-term objectives are included: to treat emergency and the most debilitating symptoms. Long term objectives are also given: they have to be fulfilled in other levels, but require some attention from the time of hospitalization: the decision to choose which treatment can have a major impact on intermediate targets syuch as achieving clinical and functional remission, ensure a good tolerability and a good adherence to treatment. Objectives * To treat the most severe symptoms Agitation Psychotic symptoms Behavioural alterations Catatonia * To obtain clinical remission Subclinical residual symptoms favour recurrences and a worse psychosocial adaptation * To prevent recurrences and switches * To prevent suicide attempts * To ensure a good adherence to treatment * To minimize treatment adverse effects * To comply with a mandatory injuction (judicial admission)

61 DERIVATION TO SPECIALIZED CARE TEAMS For those patients who meet criteria for high complexity CSM Team and Tertiary Care Team have to coordinate in order to confirm the complexity of the case, plan a suitable therapeutic approach until the patient is able to continue his treatment at the CSM. The patient care centre or specialized program will not involve a temporary separation from the CSM, but a co-operation between the two centres to optimize the treatment. Geographical and accessibility/mobility criteria have to be considered in the management of the specific situation. Criteria for complexity * Acute manic or mixed episode unresponsive to 3 different grade A recommendation therapeutic strategies, in full dose. * Resistant bipolar depression according to modern criteria for lack of response to three therapeutic strategies. * Rapid cycling unresponsive to long-term treatment. * Severe somatic comorbidity which requires a Level 3 treatment for the medical condition (i.e. transplant) in a patient with instable BD. * Severe psychiatric comorbidity which brings problems in treatment adherence and therapeutic response and high suicide risk. * Patients who require maintenance electroconvulsive therapy or other biophysical therapies. * Patients who require highly complex or specialized (i.e. neurocognitive rehabilitation) psychotherapeutic interventions. * Patients who require exhaustive monitoring of psychotropic drugs * Patients resistant to electroconvulsive therapy

62 07 - PHARMACOLOGIC TREATMENT 7.1. INTRODUCTION 7.2. ACUTE MANIA INTRODUCTION FIRST STEPS PHARMACOLOGIC TREATMENT OF ACUTE MANIA LITHIUM ANTICONVULSANTS Valproate Carbamazepine Lamotrigine Gabapentin Topiramate Other anticonvulsants ANTIPSYCHOTICS Amisulpride Aripiprazole Asenapine Chlorpromazine Clozapine Haloperidol Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone TAMOXIFEN RECOMMENDATIONS 7.3. ACUTE DEPRESSION INTRODUCTION ANTIDEPRESSANTS Lithium ANTICONVULSANTS Valproate Carbamazepine Lamotrigine Other anticonvulsants ANTIPSYCHOTICS Amisulpride Aripiprazole Asenapine

63 Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Typical antipsychotics AUGMENTATION STRATEGIES RECOMMENDATIONS 7.4. MAINTENANCE PHASE INTRODUCTION Lithium ANTICONVULSANTS Valproate Carbamazepine Lamotrigine Other anticonvulsants ANTIPSYCHOTICS Amisulpride Aripiprazole Asenapine Clozapine Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone RECOMMENDATIONS 7.1 INTRODUCTION Pharmacologic treatment is the first and fundamental therapeutic step in the treatment of BD, aimed at fulfilling the goals previously illustrated (see chap. 6): to reduce the severity of symptoms, stabilise mood and prevent relapse. In some occasions, forced hospitalization and treatment are needed for a period of time. Manic patients with psychotic symptoms or mixed states may be more difficult to treat. In clinical practice, combined treatment is the most common form of treatment, despite the fact that most of the cited drugs have evidence only on monotherapy. The reason is that treatment of acute mania is not easily achievable and needs a long-term perspective frequently not evidence based for every disposable treatment. When there is the need to choose an appropriate treatment, tolerability is one of the most important worries, as differences in safety and tolerability may exceed those in efficacy for most of the available drugs. Combined treatments may cause more or less adverse effects, depending on the efficient doses used. Following, we present a review on the scientific literature concerning pharmacological treatments in Acute Mania, Bipolar Depression and Maintenance Treatment, with relative recommendations at the end of the paragraphs.

64 7.2 ACUTE MANIA INTRODUCTION Lithium represents conventional therapeutic option, but most of the patients do not respond to a lithium monotherapy and other drugs which have been introduced in past decades, as anticonvulsant carbamazepine and valproate, while newest anticonvulsants did not show efficacy in acute mania (Vieta and Rosa, 2007). Anticonvulsants appear to possess a broad spectrum of activity on BD, including mixed dysphoric and rapidcycling forms. Despite the evidence for valproate and carbamazepine, newer anticonvulsants as lamotrigine, gabapentin and topiramate, as well as eslicarbazepine, were not superior to placebo in randomized controlled trials for mania. Therefore, not all anticonvulsants have antimanic properties. Antipsychotics have been used since their introduction in clinical practice for the treatment of acute mania. Despite this, for years the evidence of their efficacy in acute mania was limited. Antipsychotics were the main treatment in schizophrenia and have traditionally been used to treat mania too, but recent, growing literature redefined their role in the treatment of BD, as substitutes or add-on treatment as well to traditional mood stabilizers (Berk and Dodd, 2005; Vieta and Goikolea, 2005). Second generation antipsychotics have been extensively studied in mania, but solid evidence of the possible role of some of these compounds in bipolar maintenance treatment and depression exists. Moreover, secondary analyses of randomized controlled trials suggest that some antipsychotics may be effective in the treatment of mixed states and rapid cycling. Most of the patients in acute mania need to be treated with combination treatment in clinical practice, as shown by naturalistic studies (Vieta et al, 2008e). As an alternative to lithium, to anticonvulsants and antipsychotics, or their combination, the use of electroconvulsive therapy is based primarily on clinical practice and on some limited evidence (Fink, 2006, Valenti et al, 2008). The treatment of hypomania has not been extensively studied even though is widely assumed that drugs proving to be effective for mania are effective for hypomania too. Nonetheless, as clinical decisions are made basing on a cost-benefit evaluation, comparative trials on this specific subpopulation are needed. Psychotic mania has instead been studied: most of the trials offer separate analyses for psychotic versus no-psychotic patients, although the usefulness of this course specifier has been questioned (Colom and Vieta, 2009). Last, mixed mania has been studied in some trial. Is seems to better respond to valproate, some atypical antipsychotics or their combination than to other classical treatments (Vieta, 2005a), but is still stands as a challenge for clinicians, especially for the risk of a switch to depression (Vieta, 2005b). Although diagnostic criteria permit to define affective episodes as manic, hypomanic or mixed, it may be different to tell them at times. The level of mood inflation plays not a decisive role in such a differential diagnosis, whereas the level of deterioration and behavioural alterations, starting from symptoms such as aggressiveness, agitation, psychosis, working or social dysfunction, poses as the typical precipitating factor in clinical practice and thus one of the main objectives of the intervention. In practical terms, bipolar I patients who present a manic, hypomanic, mixed episode may be grouped as suffering from acute mood inflation. Despite the fact that a distinction between acute and maintenance treatment makes sense in an operative perspective, in the last years is getting clearer that the best approach to the treatment of BD considers acute aspects with an eye to the long term treatment which includes functional outcomes too. For this reason, a clinician willing to treat mania has to always keep in mind longitudinal aspects, comprehending cross-sectional aspects as well as

65 predominant polarity of the episodes (Colom et al, 2006) and the general principles already listed in tab FIRST STEPS The objectives of the treatment of an acute manic (or mixed) episode are to reduce the most disabling symptoms (agitation, inappropriate behaviour, and aggressiveness) and to permit functional recovery. To help reduce the negative consequences of manic symptoms, healthcare professionals should consider advising patients to avoid excessive stimulation, to engage in calming activities, to delay important decisions, and to establish a structured routine (including a regular sleep pattern) in which the level of activity is reduced. If a patient is taking an antidepressant at the onset of an acute manic episode, the antidepressant should be stopped. This may be done abruptly or gradually, depending on the patient s current clinical need and previous experience of discontinuation/withdrawal symptoms, and the risk of discontinuation/withdrawal symptoms of the antidepressant in question. Achieving a rapid control of aggressiveness, agitation and impulsivity is especially important to ensure safety for patients and caregivers and permits to establish a therapeutic alliance. Sometimes, forced hospitalization is needed to ensure an effective treatment PHARMACOLOGIC TREATMENT OF ACUTE MANIA At present state, solid evidence supports the use of lithium, anticonvulsants like valproate and carbamazepine, and antipsychotics like chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone aripiprazole paliperidone and asenapine in acute mania, with some evidence in favour of clozapine and tamoxifen, and, as adjuvant, benzodiazepines (i.e.: clonazepam, lorazepam). The choice of initial treatment depends on the past and actual response to drug treatment (Tohen et al, 2009), the need to quickly solve agitation and aggressiveness, characteristics of the manic episode and the presence of rapid cycling as well as the willingness of the patient in taking the medication. When possible, oral treatment should be preferred, but intra-muscular injections may be an alternative if oral treatment represents an unreliable way. Published consensus clinical guidelines and treatment algorithms show some differences in their recommendations on first- and second-line treatments for acute mania (Fountoulakis et al, 2005). Despite the fact that most of them support the use of monotherapy with lithium, valproate and, in some case, olanzapine and other antipsychotics in acute, mild or moderate mania, there s a progressive admission that a significant part of the patients will end up receiving two or more drugs, usually a mood stabilizer as lithium or valproate (carbamazepine has less evidence in combination and possible significant interactions) and an antipsychotic (Baldessarini et al, 2008). Two meta-analyses confirm the efficacy of antipsychotics, lithium and valproate in the treatment of acute mania (Scherk et al, 2007; Smith et al, 2007). The first one included 24 studies (n=6187 and found atypical antipsychotics to be more effective than placebo (12 studies) and as effective as lithium/valproate (5 studies). The other meta-analysis included randomized controlled trials and showed a significant reduction on mania scores for aripiprazole, carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone and valproate compared to placebo. Rates of response were 1.7 superior for all antipsychotics grouped together and twice as much for lithium and valproate grouped together and compared to placebo LITHIUM

66 During last 60 years lithium has been used in the treatment of mania and showed superiority compared to placebo in several randomized controlled trials (Bowden, 1998). In these studies, percentage of patients showing at least a moderate improvement after two or three weeks of treatment is 40% to 80%. Lithium seems to be the most effective treatment in patients with classic, euphoric mania, while the response rate is poorer in mixed as well as rapid cycling patients (Swann et al, 1997). There are two placebocontrolled studies (Bowden et al, 1994, 2005) suggesting that the percentage of acutely manic patients that responded (at least 50% reduction of symptoms) is around 49% for lithium vs. 25% for placebo. Lithium has been evaluated in comparison to other antimanic agents. Head-to-head comparisons with antipsychotics (usually chlorpromazine) have usually found lithium to be superior in general symptom improvement but inferior in hyperactivity control and in onset of effect. Lithium showed to be as effective as quetiapine in a 12-weeks doubleblind randomized controlled trial (Bowden et al, 2005). In a randomized, three-arm trial which compared placebo, lithium and valproate, lithium and valproate showed similar efficacy in controlling manic symptoms (Bowden et al, 1994). Two other studies comparing lithium to topiramate confirmed the efficacy of lithium (Kushner et al, 2006). Another study comparing lithium to aripiprazole suggests that although they were equal at endpoint, aripiprazole acted faster (Keck et al, 2006). An earlier small study on 23 patients comparing lithium vs. chlorpromazine reported that lithium was superior against acute mania at week 3 but the difference was not significant (Platman, 1970). More recent studies suggest that lithium is as effective as olanzapine (Berk et al, 1999) but may be less effective in specific populations like those with mixed features. A recent, trial (Niufan et al, 2008), suggests olanzapine is more effective than lithium but with more adverse effects. It is reported to be equivalent to lamotrigine (Ichim et al, 2000) and risperidone, chlorpromazine and haloperidol (Segal et al, 1998; Shopsin et al, 1975). Two studies suggest it is equivalent to carbamazepine (Okuma et al, 1990; Small et al, 1991) but another one suggests it is superior to it (Lerer et al, 1987), while a further study suggests it is superior to valproate (Freeman et al, 1992). Disadvantages of a treatment with lithium are the need to control plasmatic levels of the drug (recommended levels are mmol/l), tolerability, especially at high doses, and the risk of rebound mania at treatment suspension (Goodwin, 1994). Drawbacks of lithium therapy include its narrow therapeutic index (recommended plasma level mmol/l), poor tolerability, especially at higher doses, and risk of rebound mania on withdrawal (Goodwin, 1994). Common side-effects of lithium are tremor, polydipsia, polyuria, and in the long-term, hypothyroidism. However, in spite of these shortcomings, lithium still remains the gold standard of anti-manic treatment (Nivoli et al, in press) with the possibility of also possessing an antisuicidal effect (Baldessarini et al, 2006; Gonzalez-Pinto et al, 2006). Randomized comparisons of a mood stabilizer (lithium or valproate) alone or in combination with antipsychotics are usually superior to monotherapy in the rapid control of manic symptoms (Vieta, 2003). On the contrary, two double blind trials (Garfinkel et al, 1980; Johnstone et al, 1988) did not produced evidence of superiority for the combination for lithium and haloperidol or pimozide compared to haloperidol or pimozide alone in the treatment of acute mania. Lithium is well tolerated in combination with antipsychotic or anticonvulsants (Freeman and Stoll, 1998). In a double blind study manic patients were randomized to three arms: aripiprazole (15-30 mg/d; n= 155), placebo (n=165) or lithium ( mg/d; n=160) during 3 weeks and those on active drug were maintained in double blind 9 weeks more. Response rate at third week was significantly superior for aripiprazole (46.8%) and lithium (45.8%) arms

67 than for the placebo one (34.4%, both p<0.005, LOCF), increasing at week 12 for aripiprazole (56.5%) and lithium (49%) too (Keck et al, 2009). In a multicentric double blind trial conducted in China (Niufan et al, 2008) acute manic or mixed patients were randomized to one lithium ( mg/d, n=69) and one olanzapine (5-20 mg/d, n=71) arm. Significant statistical differences were found, favouring response to olanzapine at CGI-BP (global severity, p=0.009), YMRS (p=0.013), BPRS (p=0.032), CGI-BP (severity of mania, p=0.012) scales. Lithium may be used combined to antipsychotics in short- and long-term treatment of mania. Lithium is mainly eliminated through renal filtration (95%), but 80% of this filtration is re-absorbed in the proximal tubule. This re-absorption is antagonist to that of the sodium ion (Na+), so that an over-concentration of Na+ will determine a higher excretion of lithium, while a lower concentration of Na+ will have a decreased excretion of lithium as a consequence. For this reason, the use of thiazide diuretics, ACE-inhibitors, Non steroid anti-inflammatory agents or cyclooxygenase -2 inhibitors may induce an increase in lithium serum levels by favouring its tubular re-absorption (Schatzberg and Nemeroff, 2009). Lithium may cause a polyuria-polydipsia syndrome, insipid neurogenic diabetes due to inhibition of the sensibility of the adenilcyclase to antidiuretic hormone. If it happens, lithium serum levels should be maintanined lower than 0.8mEq/l with reintegration of liquids. If it is severe, diuretcs as tiazides or amiloride may be added (indometacine in resistant cases) (Schatzberg and Nemeroff, ANTICONVULSANTS VALPROATE Some galenic forms of valproic acid, which represents the active drug, are available worldwide and have been used since the 1960s in Europe to treat bipolar disorder. There are two double blind randomized controlled trials in which valproate showed to be superior to placebo and as effective as lithium in acute mania (Bowden et al, 1994; Pope et al, 1991). The first study reported a robust 54% decrease in scores on the YMRS of patients under valproate vs. 5% of patients under placebo (Pope et al, 1991). Subsequent studies report that valproate at doses leading to serum levels of 150 mg/ml produced a 48% response compared to 49% for lithium and 25% for placebo, with valproate being as effective in rapid cycling manic patients as in other patients (Bowden et al, 1994). A pooled analysis of these studies showed that a 54% of the patients treated with valproate showed at least a 50% reduction of manic symptoms. Differently from lithium, valproate shows a quick starting effect, which may explain the significant difference at first week and the global similar efficacy in the treatment of acute mixed and euphoric mania (Swann et al, 1997). At the dose leading to serum levels of mg/ml, the improvement from baseline was significantly greater among patients under valproate compared with placebo by day 5. Responders were 48% vs. 34% with placebo (Bowden et al., 2006). Earlier studies with very small study samples and a very different study design (ABA design) were also positive but also difficult to interpret (Emrich et al, 1980, 1981). An earlier study suggested mg/d valproate was inferior to lithium at serum levels of 1.5 mmol/l but unlike the case with lithium, favourable response to valproate was associated with high pre-treatment depression scores, suggesting that treatment with valproate alone may be particularly effective in manic patients with mixed affective states (Freeman et al, 1992). A different result was reported by another study suggesting that valproate oral loading (20 mg/kg per day) may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with

68 minimal side-effects in the initial treatment of acute psychotic mania in a subset of bipolar patients (McElroy et al, 1996). Valproate loading is reported to be safe and well tolerated (Hirschfeld et al, 1999). Valproate was reported to be more effective and faster acting than carbamazepine (Vasudev et al., 2000). It is possible that valproate is not as effective as antipsychotics as olanzapine (Vieta 2003) The comparison of olanzapine (5 20 mg/d) with valproate ( mg/d in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes, suggested that 47.2% of olanzapine-treated patients had remission of mania symptoms vs. 34.1% of valproatetreated patients (Tohen et al, 2002a), but it is better tolerated, even when compared to other compounds (Zajecka et al, 2002). Slow release valproate is disposable too, and it has proved to be effective in acute mania (Bowden et al, 2006) with the advantage of a single daily dose. Recent data suggest that quetiapine mg/d and valproate at serum levels of mg/ml could be equally effective in monotherapy to improve impulsivity and aggressiveness in adolescents in a manic state with comorbid behavioural disorders, but quetiapine might act faster (Delbello et al, 2006; Barzman et al, 2006). The risk of valproate use in women is widely known for its teratogenic effect: for this reason, clinical guidelines as NICE warn on the use of valproate in women due to the high frequency of unplanned pregnancies in women with or without BD. Despite it, this recommendation may not be very practical and realistic (Curtis and Kerr, 2005). Other potential adverse effects are weight gain and alopecia CARBAMAZEPINE Since its introduction in psychiatry (Okuma, 1993), carbamazepine has been evaluated in different controlled clinical trials, although most of them had some methodological limits as small samples or concurring treatment. A placebo controlled trial with drugfree patients found that 63% of the patients showed a significant improvement in maniac, depressive and psychotic symptoms, with a loss of effect when switching to placebo (Ballenger and Post, 1978). However, the effect sized was not calculated to validate these results. Several patients also showed relapses when placebo was substituted and improvement when carbamazepine was reinstituted at mg/d at blood levels of 8 12 mg/ml (Ballenger and Post, 1980). Recently, three randomized double-blind trials evaluated slow release carbamazepine in monotherapy for acute treatment of manic or mixed episodes at the dose of 800 mg/d with a mean plasma drug level of 8.9 mg/ml produces a significant improvement at week 2 (Weisler et al, 2004, 2005, 2006). The three trials showed the superiority of carbamazepine towards placebo (41.5% vs. 22.4% respectively), with nausea, somnolence, vertigos, vomit, ataxia, blurry vision, dyspepsia, xerophthalmia, dysarthria as most common side-effects. The literature suggests that carbamazepine is generally equivalent to lithium, although somewhat more suitable for specific but difficult-to-define populations (Lerer et al, 1987; Okuma et al., 1990; Small et al, 1991). It is also suggested that it is equivalent to chlorpromazine (Okuma et al., 1979) and inferior and with slower onset of action than valproate (Vasudev et al, 2000). Carbamazepine is not suitable for combined treatments due to its feature of inducing the metabolism of other drugs. Moreover, evidence in favour of combination treatment with carbamazepine and antipsychotics is scarce, lacking substantial advantages LAMOTRIGINE

69 There are two unpublished negative trials of 3-wk and 6-wk treatment of acute manic episodes (SCAA2008 and SCAA2009). There is one pilot study reporting that lamotrigine to be as effective as lithium in the treatment of patients with BD hospitalized for acute mania (Ichim et al, 2000). The most significant drawback of lamotrigine treatment is the need to initiate it slowly with a rate of 25 mg at 2-wk intervals in order to avoid a moderately high incidence of rash. Carbamazepine decreases lamotrigine concentrations by 50%, and during combination therapy, lamotrigine can start with higher doses and faster titration GABAPENTIN Placebo-controlled data concerning the acute phase are negative (Frye et al, 2000) and gabapentin can be considered only as an add-on therapy (Pande et al, 2000; Vieta et al, 2006a; Wang et al, 2002) TOPIRAMATE Recently, the negative results of four controlled trials concerning the use of topiramate against acute mania were published (Kushner et al, 2006). Data as an adjunctive therapy are also negative, in spite of some positive reports (Roy Chengappa et al, 2006). What is unique with topiramate is its ability to cause weight loss at doses of mg/d. It is reported that more than 70% of patients taking topiramate for a mean duration of 5 months lost a mean of 5 6 kg OTHER ANTICONVULSANTS There are no reliable data concerning the other anticonvulsant agents, although there are open studies and case reports including complicated cases (Oulis et al, 2007). Oxcarbazepine, structurally similar to carbamazepine, may have antimanic effects (Popova et al, 2007). A recent placebo-controlled trial reports some advantages in secondary measures of adjunctive oxcarbazepine versus placebo in highly relapsing patients (Vieta et al, 2008). There is some limited evidence for the use of phenytoin in acute mania (Mishory et al, 2000) ANTIPSYCHOTICS AMISULPRIDE There are no double-blind, placebo-controlled trials with amisulpride as monotherapy for the treatment in mania. There are only open-label studies (Carta et al, 2006; Vieta et al, 2005d) and one multicenter, open-label, randomized, comparative trial of amisulpride with haloperidol as combination treatment with valproate (Thomas et al, 2008). The rate of response was 72,6% for the amisulpride/valproate group and 65,5% for the other arm, but no significant differences were obtained. A better tolerability was recorded for the amisulpride/valproate combination. These studies support the use of amisulpride in acute mania, but in the absence of stronger evidence, this conclusion should be viewed with caution. Hyperprolactinaemia and extrapyramidal symptoms (EPS) are the most usual adverse effects with amisulpride ARIPIPRAZOLE There are seven monotherapy, placebo-controlled studies. Two of them suggest that mg aripiprazole treatment produces a 10 20% greater response than placebo against manic and mixed episodes (Keck et al, 2003a, 2007a; Sachs et al, 2006). The fourth unpublished study is negative (Garcia-Amador et al, 2006). Three recent studies

70 compared aripiprazole with placebo and an active comparator, haloperidol (Young et al, unpublished observations), and lithium (Keck et al, 2007a, Keck et al, 2009). Aripiprazole provides statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. Meta-analytical studies confirmed that aripiprazole is effective against acute mania (Suppes et al, 2008a). The effect of aripiprazole is considered to be specific and not attributed to sedation alone (Sachs et al, 2007a). In a 12-wk comparison to haloperidol, aripiprazole showed superior levels of response and tolerability to haloperidol in the treatment of an acute manic episode (Vieta et al, 2005a). Another 12-week trial showed similar efficacy for aripiprazole and haloperidol, but aripiprazole was better tolerated (Young et al, 2009) There is one placebo-controlled trial with aripiprazole as adjunctive treatment to mood stabilizers, which showed significantly better efficacy on the primary outcome for the combination vs. lithium or valproate alone (Vieta et al, 2008b). Aripiprazole seems to be effective in patients with no regard to gender, age, type of episode (manic or mixed), different degrees of severity, presence or absence of psychotic symptoms, presence of rapid cycling, as observed in a controlled study in which 516 patients were enrolled and stratified for these variables (Suppes et al, 2008). Akathisia and EPS are the adverse effects most often reported with aripiprazole, as well as nausea, headache, constipation and trembling (Lyseng-Williamson and Perry, 2004) ASENAPINE Asenapine is not disposable in clinical practice, but it is investigated for a possible use in acute mania. A number of completed trials now exist, most of which are not yet published. So far only the results of one randomized, 3-wk double-blind, placebocontrolled trial on 960 adult bipolar I patients with moderate-to-severe mania (McIntyre et al, 2009a) has been published. Mean daily dosages of asenapine 18.2 mg and olanzapine 15.8 mg significantly differentiated from placebo at day 2. A similar study (Ares ) has been announced. Asenapine patients received asenapine (5 10 mg twice daily), olanzapine (5 20 mg once daily) or placebo, and at day 21 in both studies, both asenapine and olanzapine produced significant mean improvements in the Young Mania Rating Scale (YMRS) versus placebo. The results of a 9-wk trial of asenapine versus olanzapine have been published. Asenapine showed noninferiority to olanzapine and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder (McIntyre et al, 2009b). Currently two 12-weeks trials (NCT and NCT ) on the safety and efficacy of asenapine add-on to mood stabilizers (lithium or valproate) are expected. Asenapine seems to have a modest impact on weight and metabolic measures, although the incidence of extrapyramidal effects has been found to be significantly superior than that with olanzapine (Bishara and Taylor, 2009) CHLORPROMAZINE Chlorpromazine is a first generation antipsychotic. It has been studied in a small placebo-controlled trial (Klein, 1967) and in some randomized trials in comparison to lithium (Prien et al, 1972; Shopsin et al, 1975; Cookson et al, 1981). Chlorpromazine is the antipsychotic which launched the modern psychopharmacological era, and probably many of the agitated patients it was initially tried on, were suffering from acute mania. However, until the present, there is only one early, small, placebo-controlled study (Klein, 1967), plus three randomized comparative studies: versus lithium, haloperidol, and pimozide (Cookson et al, 1981; Prien et al,

71 1972; Shopsin et al, 1975). The results from these studies suggest chlorpromazine is more efficacious in the treatment of acute mania compared to placebo and equivalent to lithium and the other antipsychotics. The most frequent side-effects of chlorpromazine are EPS, tardive dyskinesia (in long term), postural hypotension and hepatotoxicity (Prien et al, 1972) CLOZAPINE Clozapine is the prototype atypical antipsychotic but it is not as widely used and studied as the others, mainly due to its risks of agranulocytosis and convulsions. No randomized, double blind, placebo-controlled assessing clozapine in acute mania exist, although there are a few, small-sample, open-label studies, suggesting that clozapine may be effective in the treatment of acute mania (Barbini et al, 1997; Calabrese et al, 1996; McElroy et al, 1991), especially in the treatment of dysphoric mania (McElroy et al, 1991). In an open study, 27 patients were enrolled and were divided in two groups treated with clozapine (n = 15) and chlorpromazine (n = 12). The group treated with clozapine had a significant reduction in the YMRS score in the second week of treatment but not in the third, thus suggesting a more rapid symptom control with clozapine (Barbini et al, 1997). An open, prospective study with bipolar and schizoaffective patients not responsive to first-line treatments (lithium, anticonvulsants, other antipsychotics), clozapine showed efficacy, profiling as a treatment for resistant patients (Calabrese et al, 1996). Besides the potential risk for agranulocytosis and seizures, other potential side-effects of acute use of clozapine include clinically significant weight gain, the induction of a metabolic syndrome and sialorrhea HALOPERIDOL Placebo-controlled trials with haloperidol have been conducted only recently. Evidence from trials made in the past suggested a possible efficacy for mania and recent results have outlined very strong antimanic properties (Smulevich et al 2005, McIntyre et al, 2005), but important side-effects as well, among which are extrapyramidal effects and tardive dyskinesia. The results of the first placebo-controlled study of haloperidol versus lithium, chlorpromazine and pimozide suggest that haloperidol is more efficacious in the treatment of acute mania compared to placebo and equivalent to lithium and chlorpromazine (Shopsin et al, 1975). It is worth to notice that haloperidol shows a very rapid onset of action but shortens the occurrence of a depressive episode too (Tohen et al 2003a). More recent studies suggest that haloperidol (up to 8 mg/d) is superior to quetiapine (up to 800 mg/d) at week 3 but not at week 12 against acute mania (McIntyre et al, 2005) and that 2 12 mg/d haloperidol is equivalent to 1 6 mg/d risperidone (Smulevich et al, 2005). High doses of haloperidol were superior to placebo and ziprasidone in another trial (Dunn et al, 2006; Vieta et al, 2008c). Haloperidol monotherapy has been compared to placebo, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and added to placebo and risperidone (Smulevich et al, 2005; McIntyre et al, 2005; Sachs et al, 2002; Tohen et al, 2003a; Muller- Oerlinghausen et al, 2000; Vieta et al, 2005a, Vieta et al, 2008b). Comparative studies suggest haloperidol is equivalent to risperidone and lithium (Segal et al, 1998), and olanzapine (Tohen et al., 2003a). It has been reported that 25 mg/d is superior to 5 mg/d against acute mania but with more side-effects (Chou et al., 1999). Two 12-wk comparisons to aripiprazole were made (Vieta et al, 2005a; Young et al, 2009). In the first one 15 mg/d haloperidol was less effective compared to mg/d aripiprazole in

72 the treatment of acute manic/mixed patients and less well tolerated. In the second haloperidol showed similar efficacy to aripiprazole, but confirmed an inferior tolerability. Moreover, intramuscular (i.m.) haloperidol was equal in efficacy but faster acting compared to i.m. clonazepam in agitated mania (Chouinard et al, 1993). Valproate oral loading (20 mg/kg per day) was equivalent to 0.2 mg/kg per day haloperidol for the treatment of exited manic patients in a single-blind study (McElroy et al, 1996). One study suggests that mg/d haloperidol was equivalent to olanzapine (Tohen et al, 2003a). Small earlier comparison studies do not permit a valid interpretation (Brown et al, 1989). It has also been reported that haloperidol could decrease the time to switch into depression compared with atypical antipsychotics (Tohen et al, 2003a). In a comparison of haloperidol (8-30 mg/d) to ziprasidone (80/160 mg/d) and to placebo, haloperidol showed superior efficacy to placebo and to the active comparator (96% response at 12 week versus 88% in the ziprasidone group), but inferior tolerability (Vieta et al, 2008c) Add-on studies reported that adding haloperidol to lithium was similar to adding lorazepam (Lenox et al, 1992) or carbamazepine (Small et al, 1995). In another study, it was the low dose (5 mg/d) not the high dose (25 mg/d) which could be augmented by adding lithium but not lorazepam (Chou et al, 1999). Another study reported that haloperidol+valproate was more effective against acute mania than valproate+placebo (Muller-Oerlinghausen et al, 2000) and that haloperidol+valproate or lithium was also more effective than valproate or lithium+placebo and equivalent to risperidone+valproate or lithium (Garfinkel et al, 1980; Sachs et al, 2002). These results suggest that the antimanic effect of haloperidol may be enhanced by a combination treatment with valproate, without a significant worsening of its tolerability. Haloperidol adverse effects include EPS, tardive dyskinesia (in long-term) and hyperprolactinaemia OLANZAPINE Olanzapine is the most studied atypical antipsychotic in bipolar disorder (Vieta, 2004). It has been studied as monotherapy of acute mania with positive results in different trials. Two double blind studies evaluated during 3 and 4 weeks patients randomized to olanzapine or placebo (Tohen et al, 1999, 2000). In the first trial, at 10 mg/d it has been reported that 48.6% of patients under olanzapine responded compared to 24.2% under placebo. In the second one, a dose of 5 20 mg/d produced a 65% response vs. 43% of placebo and 61% of patients achieved full remission vs. 36% under placebo. In adolescents it produced a 44.8% response vs. 18.5% of placebo and 35.2% remission versus 11.1% of placebo (Tohen et al, 2007). Meta-analytical studies suggest that olanzapine is effective against dysphoric mania concerning both manic and depressive symptoms (Baker et al, 2003) and irrespective of factors like sex, age at onset, rapid cycling or psychotic features (Baldessarini et al, 2003a) or prior history of good or poor response to lithium or anticonvulsants (Baker et al, 2002). The overall response rate is superior to placebo (55% vs. 29.5%) (Chengappa et al, 2003). A double blind, 12-week olanzapine comparison to haloperidol in acute mania failed to demonstrate olanzapine superiority in improving manic symptoms, although patients in the haloperidol arm switched more rapidly to a depressive episode (Tohen 2003a). One study suggested that olanzapine was superior to valproate against manic or mixed episodes in a sample patients not responding to mood stabilizer for 2 weeks (Tohen et al, 2002a), but another one suggests they are equivalent with valproate having a more favourable adverse-effects profile (Zajecka et al, 2002). A more recent study evaluated the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-

73 blind trial in mild to moderate mania: after 3 weeks of treatment, the olanzapine arm showed significant improvements compared to placebo but not to valproate, whereas valproate arm did not show difference to placebo arm. At 12 weeks, both olanzapine and valproate differed from placebo. When compared to valproate, olanzapine showed a significant higher incidence of metabolic side effects (Tohen et al, 2008). When compared to lithium, olanzapine has not univocal performance: in a published study they show similar efficacy, although olanzapine is better tolerated than lithium (Berk et al, 1999), while in an unpublished study (F1D-GH-LOBV), as well as a published one, olanzapine is more effective than lithium but also less well tolerated in acutely manic and mixed patients (Niufan et al, 2008). Recently, a 12 week double blind, placebo controlled study shows a superior efficacy of olanzapine than valproate in the treatment of mild-moderate manic patients. Other studies report olanzapine as equivalent to risperidone (Perlis et al, 2006) and haloperidol (Tohen et al, 2003a). Intramuscular olanzapine is reported to be superior to benzodiazepines or placebo for controlling agitation in manic patients (Meehan et al, 2001). A post-hoc analysis suggests olanzapine is superior to valproate in rapid cycling and equivalent in classic manic patients (Suppes et al, 2005). A combination study shows that the addition of olanzapine to lithium or valproate is efficient in treating dysphoric mania (Baker et al, 2004). The combination of olanzapine and carbamazepine seems to lack substantial benefits in acute mania (Tohen et al, 2006; Tohen et al, 2008). Common side effects include weight gain, increase of appetite and somnolence (Tohen et al, 2002a). Weight gain and the tendency to increase blood glucose and lipid levels in long term treatment represent the most important side effect, and it could be more prevalent in bipolar adolescents (Kryzhanovskaya et al, 2009) PALIPERIDONE Double blind, placebo-controlled trials with paliperidone are currently in progress. As it is the active metabolite of risperidone, its use in acute mania has a theoretical basis. In a randomized, double-blind, placebo- and active-controlled (quetiapine) study which included a 3-week acute treatment phase and a 9-week maintenance phase (to assess noninferiority of paliperidone Extended Release relative to quetiapine) paliperidone Extended Release (3-12 mg/day, flexibly dosed) was efficacious and well-tolerated in the treatment of 493 acute manic and mixed episodes in patients with bipolar I disorder (Vieta et al, 2008f). A recently presented multicenter, double blind placebo controlled study (Berwaerts et al, 2009) shows the efficacy of paliperidone ER in acute mania. The incidence of mood-switch to depression was double in the placebo-arm. Add-on studies with add-on treatment of paliperidone to a mood stabilizer (lithium or valproate) in manic or mixed patients were negative. This could partially be explained by the doses used, inferior to those recommended (8mg/d instead of 12mg/d). Most common side effects reported are mild to moderate extrapyramidal effects and prolactin elevation (Berwaerts et al, 2009) QUETIAPINE In a double blind trial 302 acutely manic patients were randomized to a quetiapine, haloperidol or placebo arm, haloperidol (up to 8 mg/d) was superior to quetiapine (up to 800 mg/d) at week 3 but not at week 12 (McIntyre et al, 2005). Quetiapine was also studied in acute mania in a randomized, double blind trial in comparison with lithium and placebo. It reduced YMRS score significantly better than placebo and similarly to lithium. However lithium was proven superior concerning the YMRS score which was

74 the primary efficacy measure (Bowden et al, 2005). A pooled analysis of these two studies confirmed efficacy, rapid onset of efficacy and better tolerability for quetiapine (Vieta et al, 2005b). A 4-week multicenter, randomized, double-blind, lithiumcontrolled, parallel-group study was conducted on a Chinese sample. It showed quetiapine to be clinically effective in patients with acute bipolar mania (Li et al, 2008). Add-on treatment with quetiapine has been evaluated. Two double blind placebocontrolled trials probed efficacy and tolerability of quetiapine added to lithium or valproate in acute mania (Sachs et al, 2004, Yatham et al, 2007). In the first one the combination of quetiapine and mood stabilizer proved to be superior to mood stabilizer monotherapy in terms of YMRS decrease, response rate and clinical remission. In the second trial quetiapine did not reached significant difference from placebo. Quetiapine is superior to valproate in adolescents with manic or mixed episodes (DelBello et al, 2006) (Delbello et al 2002, 2006) with comorbid behavioural disorders (Barzman et al, 2006). The adverse events included somnolence, dry mouth, weight gain and dizziness (Vieta et al, 2005b, 2008f) RISPERIDONE There are a number of studies on the efficacy of risperidone monotherapy in acute mania. In a multicentric double blind placebo-controlled study (Hirschfeld et al, 2004) 259 patients showed significant improvements versus placebo (p<0,001) since day 3 of the treatment. Another randomized, placebo-controlled trial enrolled 290 acutely manic bipolar I patients: those in the active treatment arm showed significant improvement since day 3 (Khanna et al, 2005). Risperidone at doses of 1 6 mg/d manifest a remission rate of 42% vs. 13% of placebo (Gopal et al, 2005) and the improvement is evident from day 3 (Hirschfeld et al, 2004; Khanna et al, 2005). Risperidone (1 6 mg/d) has similar efficacy than haloperidol (2 12 mg/d) although its use seems safer (Smulevich et al, 2005). Some studies included patients with mixed states (Hirschfeld et al, 2004; Khanna et al, 2005; Smulevich et al, 2005). The Indian study (Khanna et al, 2005) sparked a debate concerning the extent of the use of placebo in similar studies (Mudur, 2006; Patel, 2006). Risperidone was reported to be equivalent to olanzapine (Perlis et al, 2006), and to lithium and haloperidol (Segal et al, 1998). The efficacy of risperidone as add-on treatment with lithium, valproate and carbamazepine has been evaluated. In a randomized, double blind study mood stabilizers were evaluated in add-on with risperidone or placebo in acute mania. The combination was reported to be more effective than a mood stabilizer alone (Yatham et al, 2003), and as effective as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms (mixed patients were included in the study, although no sub-analysis is given) and was also well tolerated (Sachs et al, 2002). The main disadvantages are dose-related extrapyramidal symptoms, weight gain, sedation and hyperprolactinaemia (Khanna et al, 2005; Rendell et al, 2006). Some authors suggested that risperidone could induce or worsen mania, maybe due to some antidepressant effect (Dwight et al, 1994), but following trials (Vieta et al, 2001a, 2001b, 2002) confirmed a very low risk ZIPRASIDONE In four studies published in two papers, mg/d ziprasidone was reported to be rapidly (by day 2) effective against acute manic or mixed episodes (Keck et al, 2003b;

75 Potkin et al, 2005), with significant improvements in all primary and secondary outcome measures. A third monotherapy, placebo-controlled trial (Vieta et al, 2008c) also had a haloperidol arm and showed significant superiority over placebo but significantly lower efficacy vs. haloperidol (up to 30 mg/d) at the 3-wk and 12-wk endpoints, even if haloperidol was worse tolerated. An add-on, unpublished double blind randomized trial of mg/d ziprasidone vs. placebo on top of lithium was negative concerning the primary outcome, which was the YMRS (Weisler et al, 2003). A pooled analysis on two previous studies suggests that a partial response in the first 2 days may predict positively the complete response (Vieta et al, 2008d). Recent studies suggest that ziprasidone can me efficient as monotherapy in child and adolescents, without affecting metabolic parameters and blood glucose and lipids levels (Delbello et al, 2008). Similar results were obtained in an open study in a child-adolescent population (Biederman et al, 2007). Somnolence, akathisia and EPS, as well as a QTc prolongation are the main adverse effects of ziprasidone treatment. Another potential secondary effect may be excessive activation: akathisia and anxiety (Potkin et al, 2005) TAMOXIFEN Tamoxifen is a selective estrogen receptor modulator which is used in the treatment of breast cancer. It is cited along with anticonvulsants in the current review under the framework that it acts against acute mania by inhibiting protein kinase C (PKC) (Einat et al, 2007; Manji and Chen, 2002). Two pilot, placebo-controlled studies suggest it is more effective against acute mania than placebo (Kulkarni et al, 2006; Zarate et al, 2007). A NIMH sponsored clinical trial commenced in 2001 (Clinical- Trials.gov Identifier: NCT ) but the results are yet to be announced. A second trial sponsored by the Stanley Medical Research Institute (ClinicalTrials.gov Identifier: NCT ) led to one 3-wk, small (66 patients), placebo- controlled trial suggesting that mg/d tamoxifen is effective against acute mania at doses and remarkably well tolerated (Yildiz et al, 2008). The safety of tamoxifen has to be fully evaluated, especially for its association with a 2-7-fold increased risk of endometrial carcinomas, noted as early as three months after the in initiation of the therapy (Singh et al, 2009; Shen et al, 2009) RECOMMENDATIONS Drugs with level of recommendation A (in alphabetical order): Aripiprazole Carbamazepine Lithium Olanzapine Quetiapine Risperidone Ziprasidone A A A A A A A Drugs with level of recommendation B (in alphabetical order):

76 Amisulpride Clorpromazine Clozapine Haloperidol Paliperidone Valproate B B B B B B

77 Drugs with level of recommendation C (in alphabetical order): Asenapine Oxcarbazepine Tamoxifen C C C Negative evidence (evidence of lack of efficacy) in acute mania: Gabapentin, Lamotrigine, Licarbazepine, Topiramate ACUTE DEPRESSION INTRODUCTION Much more attention has traditionally been paid to acute mania than to acute bipolar depression, despite the fact that bipolar patients are used to turn to the psychiatrist when they are depressed, they spend more time on depression than in (hypo)mania, they present a higher suicide risk in depression and depressive symptoms seem to play a major role in functional impairment (Judd et al, 2002) ANTIDEPRESSANTS Although antidepressants have an established efficacy against unipolar depression, this fact does not unequivocally concern bipolar depression. As we said in chapter 5, a problem with antidepressant use in BD is the potential risk to induce the opposite pole, mixed episodes and rapid cycling. The earlier placebo-controlled studies suggested that amitriptiline was equivalent to lithium (Glen et al, 1984) but imipramine was inferior to it during all phases of bipolar illness, while adding imipramine does not improve the outcome (Kane et al, 1982; Prien et al, 1973b, 1984). Later randomized, placebo-controlled studies reported that 86% of the fluoxetine-treated patients improved compared with 57% of the imipramine-treated and 38% of the placebo-treated (Cohn et al, 1989) patients. Another study suggested that fluoxetine is effective both during the acute and the maintenance phase for bipolar II patients (Amsterdam et al, 1998; Amsterdam and Shults, 2005a) and after 6 months treatment 43% of fluoxetine-treated patients and 100% of placebo-treated bipolar II patients relapsed (Amsterdam and Shults, 2005b). In a three-arm double blind placebocontrolled trial (Tohen et al, 2003c), fluoxetine, when combined to olanzapine (OFC), has shown to fulfil remission criteria in 48.8% of patients, compared to 32.8% of patients treated with olanzapine alone and 24.5% of patients treated with placebo. Treatment-emergent mania did not differ between the two treatment groups. The combination of fluoxetine and olanzapine may be somewhat superior to lamotrigine (Brown et al, 2006). Only a small, placebo-controlled, crossover study suggests that SSRIs might be superior to placebo as monotherapy (Parker et al, 2006). Conversely, one of the quetiapine bipolar depression trials had a paroxetine monotherapy arm which failed to separate from placebo (McElroy et al, 2008). Studies without a placebo arm suggested both paroxetine and venlafaxine are effective (Vieta et al, 2002), and that adding paroxetine (Young et al, 2000) or citalopram (Schaffer et al, 2006) to a mood stabilizer might improve the outcome without a significant rate of switch to mania or hypomania, however, placebo-controlled studies have not confirmed these findings.

78 Studies comparing the response rates of bipolar versus unipolar depression report the rates to be similar (Amsterdam and Garcia-Espana, 2000; Amsterdam et al, 1998). As previously said (see chap. 5) problem with the use of antidepressants is the possibility of a mood-switch towards mania. A meta-analysis suggests a higher switch rate for venlafaxine compared to SSRIs, however, the studies included were randomized trials of adjunctive treatment, possibly including more refractory patients (Leverich et al, 2006). It seems that without the concomitant use of an antimanic agent the switch rate is around 25% (Bottlender et al, 2001). In a recent double-blind, placebo-controlled study, 179 bipolar depressed patients were randomly assigned to receive up to 26 week treatment with a mood stabilizer with adjunctive antidepressant therapy or a mood stabilizer with placebo. Recovery rates were similar (23.5% in the antidepressant group vs. 27.3% in the placebo group). Switch rates were also similar. Thus, this study does not support the usefulness of adjunctive antidepressant therapy (Sachs et al, 2007b), and it is in accord with earlier reports (Nemeroff et al, 2001). Recent placebo-controlled studies suggests no increase in switch rates after fluoxetine monotherapy and report that rates for patients under fluoxetine, olanzapine, OFC and placebo ranged from 0 to 6.7% but were not significantly different. A randomized comparison study without a placebo arm suggested both paroxetine and venlafaxine are effective adjunctive treatments to mood stabilizers (Vieta et al, 2002b) Adjunctive studies report that around 14% of bipolar depressed patients under both an antidepressant and a mood stabilizer switch to mania or hypomania (Post et al, 2001, 2006) Lithium Lithium has demonstrated efficacy en acute bipolar depression. Even if studies used small sample sizes, it is one of the most studied drugs. Controlled trials show a significant improvement in 68% of depressed patients (Goodwin et al, 1972; Mendels, 1975), similar to the response obtained with antidepressant in unipolar depression and higher than the 51% response obtained by lithium in unipolar depression (El-Mallak, 1996). Lithium monotherapy studies (Gelenberg et al, 1989; Keller et al, 1992), as well as studies on its combination with antidepressant (Nemeroff et al, 2001), show that high doses of lithium are more effective in treating depressive symptoms than lower doses. Apparent superiority of lithium + antidepressant combination happened when lithium serum levels were below 9,8mEq/l, while when doses were higher lithium monotherapy was efficacious. Slow velocity of action, combined with the narrow therapeutic window and subsequent security issue, and secondary effects represent main lithium drawbacks, combined with the fact that many patients keep experiencing depressive episodes while on therapy with lithium. Comparative studies are generally powered for the studied drug, while lithium is used as active comparator. Comparison of lithium efficacy to that of antidepressant has been evaluated in 4 randomized, parallel design studies where lithium was faced to tricyclics which did not provide conclusive data (Yatham et al, 2003b). There are no comparative studies in acute bipolar depression apart from the previously mentioned quetiapine vs. lithium study, which had a placebo arm (Young et al, 2008). An add-on study on the use of lithium with imipramine showed the lack of a response but the absence of significant treatment-emergent affective switches (Quitkin, 1981a, 1981b)

79 ANTICONVULSANTS Valproate There are only two small studies (25 and 18 patients) suggesting that valproate may be effective in reducing the symptoms of depression and anxiety in bipolar I patients during the acute depressed phase (Davis et al, 2005; Ghaemi et al, 2007) Carbamazepine There is only one small withdrawal study mentioned (Ballenger and Post, 1980) Lamotrigine Five trials concerning the treatment of acute depression (SCA100223, SCA30924, SCA40910, SCAA2010 and SCAB2001) (Goldsmith et al, 2003) were negative concerning the primary outcomes but showed some benefit on the basis of secondary outcomes. On the basis of these secondary outcomes, the response rates against depression are reported to be 50% and are double than those observed under placebo (Calabrese et al, 1999). A recent meta-analysis of these trials suggests that there could be a trend to weak positive signal in the data, and thus this agent could be effective during the acute depressive phase also (Geddes 2009). Another study, comparing lamotrigine, gabapentin and placebo in treatment-resistant, rapid cycling patients, lamotrigine was better than placebo, but not gabapentin (Frye et al, 2000). Response rate was 52% in lamotrigine group, statistically superior to that of gabapentin (26%) and placebo (23%). A double blind, randomized study (Schaffer et al, 2006) compared lamotrigine to citalopram in a sample of bipolar depressed patients (n=20) treated with a mood-stabilizer, but no differences were found. One study suggests that OFC is somewhat superior to lamotrigine although the response rates did not differ between groups (OFC 68.8% vs. lamotrigine 59.7%). The time to response was significantly shorter for OFC-treated patients (OFC 17 days vs. lamotrigine 23 days) and there were lesser suicidal and self-injurious behaviour among OFC-treated patients (OFC 0.5% versus lamotrigine 3.4%) (Brown et al, 2006). Lamotrigine may be combined with other compounds, be it lithium, other anticonvulsants, antidepressants or antipsychotics. One study (van der Loos et al, 2009) reported that adding lamotrigine to lithium was better than placebo in patients with bipolar depression. Combination with benzodiazepines is also possible. Other anticonvulsants such as valproate and carbamazepine represent the most important interactions that have to be considered. Valproate partially inhibits lamotrigine metabolism and may raise its plasma levels, an issue that has special importance at treatment initiation. Lamotrigine thus needs to be titrated more slowly when combined to valproate, normally at half the pace by starting with 12,5 mg/d and raising it to 25mg/d to 50mg/d in 2 weeks and then adding 50mg/dia every 2 weeks. Carbamazepine bears the opposite problem, as it is an enzymatic inducer and may down regulate lamotrigine plasma levels, so that its titration has to start directly with 50mg/d and be raised with 50mg/d every 2 weeks. Combination with lithium is safe, often preferable to achieve a safe combination in depressive, as well as (hypo)manic prophylaxis. No problems in combination therapy with antipsychotics or benzodiazepines are reported. Stevens-Johnson syndrome or exanthemas are extremely rare, near to 0,1%, but a quick interruption of the treatment with lamotrigine is sufficient to reverse them. Lamotrigine is generally well tolerated and with the correct titration risks of side effects are minimized Other anticonvulsants

80 Solid evidences (double blind, controlled trials) on the efficacy of other anticonvulsants in the treatment of bipolar depression lack. Valproate could be useful in bipolar depression if combined to lithium, reaching a response similar to that of lithium or valproate combined with antidepressants (Young et al, 2000). Recently, a small double blind controlled trial has evaluated valproate in bipolar depression (Davis et al, 2005). Some open studies suggest the use of carbamazepine, but no double blind, controlled trial with adequate sample sizes exist. One of the main problems with oldest studies is that depressed patients were included regardless of having a unipolar o bipolar depression, so that it is difficult to extrapolate data. Nevertheless, when combining data from 4 controlled trials and 8 open-label studies, response rate of carbamazepine was found to be 55% (Post et al, 1996) ANTIPSYCHOTICS Amisulpride No evidence on the treatment of bipolar depression with amisulpride is available, despite studies demonstrating its efficacy in dysthymia (Boyer et al, 1999) and unipolar depression (Lecrubier et al, 1997) Aripiprazole Despite a first open, not randomized study on the use of aripiprazole in bipolar depression was positive (McElroy et al, 2007), two 8-wk placebo-controlled trials were negative at study endpoint (Thase et al, 2008). Unpublished data suggest that aripiprazole could also be effective during the acute depressive phase, as the combined data from the two negative studies show a significant effect at week 8 (pooled MADRS score change _11.03 vs. _12.15, P<0.04) (Fountoulakis KN, Vieta E, Schmidt F, unpublished observation) Asenapine No evidence on the treatment of bipolar depression with asenapine is available Clozapine Clozapine has not been studied in bipolar depression. Apart from its limited safety (Vieta, 2005c), clozapine seems to have an antisuicidal action, well demonstrated in schizophrenic patients (Meltzer et al, 2003) Olanzapine A meta-analysis of the effect of atypical antipsychotics on bipolar depression confirmed that only quetiapine and olanzapine have demonstrated efficacy in patients with bipolar depressive from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression (Cruz et al, 2009). The recent metaanalysis (Cipriani et al, 2009) of olanzapine data indicated that, although based on a limited amount of information, there is evidence that olanzapine may prevent further mood episodes in patients who have responded to olanzapine during an index manic or mixed episode and who have not previously had a satisfactory response to lithium or valproate. A double blind, placebo-controlled study (Tohen et al, 2003b) conducted on depressed bipolar patients showed that olanzapine is superior to placebo, but the best outcome was obtained by an olanzapine-fluoxetine (OFC) combination, superior to placebo and to olanzapine-only treatment: the remission criteria were met by 24.5% of the placebo

81 group, 32.8% of the olanzapine group, and 48.8% of the olanzapine fluoxetine combination (OFC) group. Treatment-emergent mania did not differ among groups. Thus, olanzapine is more effective than placebo, and OFC is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms. However, the study sample was small concerning the OFC arm and there are some concerns about the effect treatment had on the depressive core of symptoms, that is, those symptoms representing the core concept of depression (e.g. depressed mood, suicidality, anhedonia. etc.). In contrast, the patients manifested a significant improvement in symptoms peripheral to the definition of depression such as insomnia, anxiety, loss of appetite and so on (Bech, 2001; Lecrubier and Bech, 2007). When compared to haloperidol, olanzapine showed less antimanic efficacy, but it did show a superior antidepressant effect (Tohen et al, 2003a). A double blind controlled trial was done to compare OFC with lamotrigine: outcomes at week 7 and month 6 were considered. OFC showed a more rapid onset of action, with no statistical differences at endpoints (Brown et al, 2006). OFC had a significantly shorter time to response than lamotrigine (17 days versus 23 days) but was significantly less tolerated, especially producing a higher weight gain. The extension of this study to 25 weeks confirmed equal prophylactic efficacy but a better tolerability and safety profile for lamotrigine (Brown et al, 2009). The meta-analysis suggests that OFC is superior to olanzapine alone, has improved many secondary indices (Shi et al, 2004) and shown a beneficial effect from day 7 (Dube et al, 2007). Add-on studies of olanzapine show that adding olanzapine to lithium or valproate improves outcome (Tohen et al, 2002b; Tohen et al, 2004) and may reduce suicidal behaviour (Houston et al, 2006; Tohen et al, 2008) Quetiapine The recent meta-analysis from Cruz and cols (2009) confirmed the role of quetiapine in the treatment of acute bipolar depression. Quetiapine is the antipsychotic which use can rely on the hardest data. Quetiapine use has been tested in 2 trials, BOLDER I (Calabrese et al, 2005) and BOLDER II (Thase et al, 2006). The first one demonstrated that quetiapine monotherapy of 300mg/d as well as 600mg/d was more efficacious than placebo in depressed bipolar patients. The second one confirmed the efficacy for BD type I as well as BD type II patients. A problem with quetiapine may be to determine the optimal dose and the quickness in titration. Manic patients could require faster titration and higher doses in acute phase, and keep quetiapine in maintenance at lower doses, whereas depressed patients could need lower doses as BOLDER I and II showed a similar efficacy for 300mg/d and 600mg/d. The use of 600 and 300 mg/d of quetiapine produced response rates of 58.2% and 57.6%, respectively, versus 36.1% for placebo. Remission rates were 52.9% in the groups taking 600 and 300 mg/d quetiapine versus 28.4% for placebo. Quetiapine significantly improved the Montgomery Asberg Depression Rating Scale (MADRS) items corresponding to the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% versus 3.9%, respectively) (Calabrese et al, 2005a; Thase et al, 2006). Similar results were obtained from a recent study which was simultaneously negative for lithium (Young et al, 2008) and another study which was negative for paroxetine (McElroy et al, 2008). Post-hoc analysis suggests that the dose of 300 mg is not inferior to 600 mg in spite of a different effect size, and both are superior to placebo (Cookson et al, 2007) and improved secondary measures including quality-of-life indices (Endicott et al, 2007). It also

82 suggests that quetiapine is effective against depression in rapid cycling bipolar I or II patients (Vieta et al, 2007a). In a small-sized study on rapid cycling bipolar patients quetiapine was successfully used as add-on treatment to mood stabilizers, at different doses basing on the polarity of the episode and the length of treatment (Vieta et al, 2002b). Similar results were obtained from a recent study (Young et al, 2008) that was simultaneously negative for lithium and another one that was negative for paroxetine (McElroy et al, 2008). A recent study suggests that quetiapine monotherapy is no more effective than placebo for the treatment of depression in adolescents with bipolar disorder (DelBello et al 2009) Risperidone No evidence on the treatment of bipolar depression with risperidone is available Ziprasidone Ziprasidone failed to demonstrate efficacy in the treatment of bipolar I depression in a recent, 6-week randomized controlled trial (Saches et al, 2009) Typical antipsychotics Typical antipsychotic have been widely used in clinical practice to treat affective disorders. Their use found place in the treatment of psychotic bipolar depression, but always in combination therapy with lithium, antidepressants or both (Vieta, 2003). There is general agreement on the fact that typical antipsychotics present valid antimanic properties but have not antidepressant properties and they could even worsen or precipitate the apparition of depressive symptoms (Keck et al, 1996; Vieta, 2005c) AUGMENTATION STRATEGIES A placebo-controlled trial on the combination of modafinil ( mg/day) with lithium, valproate or ongoing antidepressants was supported by one. No increased rate of treatment-emergent affective switches has been observed (Frye et al, 2007). A multicenter double blind placebo-controlled trial on the use of armodafinil as adjunctive treatment to bipolar depression showed a statistically significant improvement of depressive symptoms in the armodafinil arm (study NCT ). Some add- on treatments have been examined in bipolar depression including pramipexole (Zarate et al, 2004b; Goldberg et al, 2004) supported by a metaanalytic review of the single studies with insufficient sample sizes, (Aiken, 2007), inositol (Eden Evins et al 2006; Nierenberg et al 2006), zonisamide (Baldassano et al, 2004; Ghaemi et al, 2006; McElroy et al, 2005; Wilson and Findling 200), topiramate (McIntyre et al, 2002), omega-3 fatty acids (Frangou et al, 2006; Keck et al, 2006b) and N-acetyl cysteine (Berk et al, 2008). Several open studies suggest antidepressant properties of adjunctive gabapentin (Young et al, 1997; Altshuler et al, 1999; Vieta et al, 2000; Yasmin et al, 2001), but the so far methodologically best study for gabapentin could not find a separation from placebo in treatment resistant unipolar or bipolar depression. There is some suggestion that adjunctive gabapentin may be effective in patients with alcohol or anxiety comorbidity (Perugi et al, 2002). If no sufficient treatment response is observed despite the trial of different welldocumented compunds, alone ore in combination high dose thyroxin may also be an augmentative treatment of choice, although somatic side effects have to be closely and carefully monitored, especially cardiovascular (Bauer et al, 2002, 2005).

83 RECOMMENTATIONS Acute Bipolar Depression Treatment Drugs with level of recommendation A (in alphabetical order): Quetiapine Lamotrigine A A Drugs with level of recommendation B (in alphabetical order): Fluoxetine Lithium Olanzapine B B B Drugs with level of recommendation C (in alphabetical order): Armodafinil Carbamazepine Modafinil Pramipexole C C C C Negative evidence (evidence of lack of efficacy) in Acute Bipolar Depression: aripiprazole, paroxetine, risperidone, ziprasidone MAINTENANCE PHASE INTRODUCTION Long-term treatment is primarily aimed at the prevention of manic and depressive episodes. There is certainly more evidence in maintenance treatment of patients whose first episode has been manic. A long-term treatment is strongly recommended because, even after 1 episode, the percentage of lifetime recurrence is 95%. Maintenance treatment is also recommended in those patients whose clinical history is characterized by lack of full recovery from acute symptoms (Goodwin and Jameson, 2007) Lithium Prophylactic effect of lithium in BD has been observed during many decades and is now confirmed by a recent Cochrane review (Burgess et al, 2001) and two meta-analyses

84 (Davis et al, 1999; Geddes et al, 2004). According to the work from Burgess and cols, this supposed selectivity of lithium against mania could be a biased result caused by the discontinuation design of many studies, since discontinuation seems to predispose more to mania than depression. The overall efficacy during the maintenance phase appears to be rather weak, since the average risk of relapse in the placebo group was 60% compared with 40% for lithium. Concerning manic episodes alone, the average risk of relapse in the placebo group was 24% compared with 14% for lithium. This difference was significant in contrast to the risk concerning depressive episodes which for the placebo group was 32% compared with 25% for lithium and was marginally nonsignificant (Geddes et al, 2004). At optimum doses, lithium reduces to 50% recurrences and seems to be more effective to prevent manic than depressive recurrences (Calabrese et al, 2003; Bowden et al, 2003). Moreover, lithium has shown anti-suicide properties, independently from its relapse-prevention properties (Baldessarini et al, 2006; Gonzalez-Pinto et al, 2006; Goodwin et al, 2003). Undoubtedly, lithium efficacy in clinical practice may be inferior to that extrapolated by clinical trials due to the problem of patients comorbidities and to problems of therapeutic adherence. It is thus desirable to keep in mind known predictors of response to lithium as familiar history of BD, absence of rapid cycling, interepisodic full recovery, no substance abuse, good adherence (Abou-Saleh and Coppen, 1986). Actually, relapse risks at lithium discontinuation, combined with the risk of a lack of response at lithium re-introduction, have leaded some experts not to recommend lithium in patients whose probability of treatment adherence seems low (Goodwin, 1994). Data from a 6-month maintenance, double blind comparison trial of lithium alone or combined with valproate have shown that patients (n = 149 BD type I or II, rapid cyclers or not) who received the combination had a no-significant delay in response, a similar response rate, showing thus no benefit for the patients (Kemp et al, 2009). In another pilot study, a double blind randomized trial using carbamazepine or oxcarbazepine as adjutant to a lithium therapy in a sample of 52 patients, oxcarbazepine showed higher efficacy in different outcomes as YMRS, HDRS-21, MADRS-21; CGI-S and CGI-I, with a better tolerability profile(juruena et al, 2009). This suggests the possible role of oxcarbazepine as adjutant treatment to maintenance with lithium, although placebo-controlled trials are needed to support this finding. Although there was an earlier study (Goodwin et al, 1969), the first real placebocontrolled study was a discontinuation one. It included 50 stabilized bipolar patients (Baastrup et al, 1970). Later, Prien studied 205 and 31 patients immediately after the resolution of the acute episode (Prien et al, 1973a). A similar study sample was used by Pokorny (Pokorny and Prien, 1974). Kane studied 22 bipolar II patients in remission for at least 6 months and randomly assigned them to lithium, imipramine, lithium+imipramine, or placebo. Lithium was found to help prevent relapse of any type among those with bipolar II disease. No effect or interaction of imipramine was found in either group (Kane et al, 1982). Several other small studies exist with samples of 15 (Melia, 1970), 18 (Fyro and Petterson, 1977), 53 (Fieve et al, 1976) and 24 patients (Cundall et al, 1972). Although all the above studies report positive results for lithium, the generally small size does not permit a formal analysis. Although earlier maintenance placebo-controlled studies suggested lithium was effective for the prophylaxis against both mania and bipolar depression (Dunner et al, 1976; Glen et al, 1984; Prien, 1984; Prien et al, 1973a,b, 1984), later studies suggest, as previously cited, that lithium is effective in the prevention of manic episodes but possibly not for depressive episodes

85 (Bowden et al, 2000a, 2003; Calabrese et al, 2003a, 2006; Goodwin et al, 2004; Kane et al, 1982). Studies with mixed and small samples (Fieve et al, 1976; Hullin et al, 1972; Klein et al, 1981; Prien et al, 1973b), small non-randomized case-control studies with placebo (Margo and McMahon, 1982; Persson, 1972), small crossover studies (Mander and Loudon, 1988) and discontinuation studies (Baastrup et al, 1970; Christodoulou and Lykouras, 1982; Cundall et al, 1972; Hullin et al, 1972; Kafantaris et al, 2004; Melia, 1970; Small et al, 1971) are all difficult to interpret. Discontinuation studies are more difficult to interpret for a variety of reasons including shorter duration of the study and a lithium-discontinuation related refractoriness (in up to 15% of patients) (Post et al, 1992). Conclusively, the literature is supportive concerning the efficacy of lithium against mania both during the acute phase and as a prophylactic agent, but possibly not against bipolar depression. However it seems that lithium is also effective against subsyndromal symptoms of both polarities during the maintenance phase (Frye et al, 2006) as well as for the treatment of concomitant substance abuse (Geller et al, 1998, 1992). One study reported that olanzapine was superior to lithium in the prophylaxis against manic and mixed episodes and with similar efficacy against depressive episodes (Tohen et al, 2005) while another one found them to be equivalent (Houston et al, 2005). Lithium appears to be as effective as valproate in the prophylaxis of rapid-cycling patients (Calabrese et al, 2005b) and paediatric patients (Findling et al, 2005). Several studies suggest it is not superior to carbamazepine although there is a trend for lithium to perform slightly but not significantly better (Coxhead et al, 1992; Denicoff et al, 1997; Greil and Kleindienst, 1999a,b; Greil et al, 1997; Kleindienst and Greil, 2002; Lusznat et al, 1988; Placidi et al, 1986; Simhandl et al, 1993; Small et al, 1991; Stoll et al, 1989; Watkins et al, 1987). A post-hoc analysis suggests that using olanzapine early in the course of the disorder is possibly more beneficial than lithium during the maintenance phase (Ketter et al, 2006). Adding lithium to low doses but not to high doses of haloperidol increases efficacy against acute mania (Chou et al, 1999) while the combination with imipramine produced no advantage but also no switches to the opposite pole (Quitkin et al, 1981a,b). An interesting although with a problematically low-dose study contrasted lithium vs. placebo in patients receiving cognitive behaviour treatment and found no difference between lithium and placebo (Wilson et al, 1995). Another study reported that lithium was less effective than valproate when added on antidepressants for the prevention of bipolar depression (Gyulai et al, 2003) ANTICONVULSANTS Valproate Despite the high expectations on the supposed efficacy of valproate, it didn t achieved demonstrating its superiority to placebo in relapse prevention in a randomized trial in which lithium proved to be superior to placebo with the outcome time to any mood episode. In this study, however, lithium also produced negative results, thus a possible explanation could be that the study sample was problematic. Valproate was superior concerning some of the secondary outcomes, e.g. less deterioration in depressive symptoms and Global Assessment Scale (GAS) scores (Bowden et al, 2000a). Secondary sub-analyses indicated that valproate was superior to placebo in preventing depressive relapses in severe patients. In randomized studies with active comparator, valproate proved to be similar to lithium (Calabrese et al, 2005b; Lambert and Venaud, 1992) and to olanzapine (Tohen et al, 2003c) in recurrence prevention. Redden and cols

86 (2009) recently outlined the efficacy of slow release valproate in child and adolescents, but the same group failed to see a difference from placebo (Wagner et al, 2009). The good tolerability profile showed side effects similar to those found in adult samples (nausea, weight and appetite gain). Maintenance studies suggest valproate is equivalent to lithium concerning any mood episode (Calabrese et al, 2005b), not superior to lithium as maintenance treatment in youths who were stabilized on a combination of lithium and valproate (Findling et al, 2005) and that the overall per-patient treatment costs are similar for olanzapine and valproate (Zhu et al, 2005). One study reported that adding valproate to neuroleptics improves outcome (70% vs. 46%) (Muller-Oerlinghausen et al, 2000). Another study reported that valproate was superior to lithium or placebo when added on antidepressants for the prevention of bipolar depression (Gyulai et al, 2003). There is concern whether valproate should be used in women at childbearing age, due to the high frequency of unplanned pregnancies in bipolar females, and the relatively high teratogenicity of the compound. Other potential acute side-effects of valproate are weight gain and hair loss. Moreover, valproate has controversially been reported to induce polycystic ovarian syndrome Carbamazepine Carbamazepine has a tradition of second-line treatment in patients not responsive to lithium. It showed to be superior to placebo in a small trial on 32 patients, as 60% of the carbamazepine group had a good response compared to 22.2% of the placebo group (Okuma et al, 1981). Carbamazepine was equivalent to lithium in a meta-analysis (Dardennes et al, 1995). Several studies suggest carbamazepine is equivalent to lithium although in some of them there is a trend for lithium to perform slightly but not significantly better (Coxhead et al, 1992; Denicoff et al, 1997; Greil and Kleindienst, 1999a, b; Greil et al, 1997; Kleindienst and Greil, 2002; Lusznat et al, 1988; Placidi et al, 1986; Simhandl et al, 1993; Small et al, 1991; Stoll et al, 1989; Watkins et al, 1987). However, the studies were too much heterogeneous to reach conclusive results. However, the most important studies comparing carbamazepine with lithium were the MAP study in 1997 (Greil et al, 1997; Kleindienst and Greil, 2000) and a replication in 2003 (Hartong et al, 2003). They were both open studies on mixed populations and they both showed a superiority of lithium over carbamazepine for the treatment of classic mania. In a randomized trial of lithium versus carbamazepine which lasted 2,5 years lithium was associated to a better outcome in terms of relapses (27% relapses versus 47%) and less side effects (Greil et al, 1997). Nevertheless, carbamazepine showed to be more effective than lithium in patients with atypical symptoms, as, for instance, mixed states and delusions (Greil et al, 1998). A 2 years study with naïve patients showed lithium to be more effective than carbamazepine, despite this last compound was superior in the first 6 months (Hartong et al, 2003). More recently, oxcarbazepine has showed a profile of higher tolerability as adjutant to lithium compared to carbamazepine. A secondary analysis of the MAP data showed that patients unresponsive to lithium could have a favourable response to carbamazepine (Greil et al, 1998) although its true long-term efficacy is questioned. Combination of lithium+carbamazepine might not produce further improvement for patients although rapid-cycling patients do better under combination than under monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine and 56.3% to their combination) (Denicoff et al, 1997). Moreover, adding carbamazepine to

87 lithium could further improve agitation in manic patients (Klein et al, 1984). Adding haloperidol to lithium was similar to adding carbamazepine (Small et al, 1995). A potentially life-threatening side-effect of carbamazepine may be the Steven Johnson syndrome and related dermatological effects Lamotrigine Evidences are in support of the prophylactic effect of lamotrigine, especially in the prevention of depressive episodes, but its role in the prevention of manic episodes is, at best, not clear. Two randomized, double blind placebo-controlled trials on maintenance treatment with lamotrigine in recently depressed (Calabrese et al, 2003a) or recently (hypo)manic (Bowden et al, 2003) patients. Three placebo-controlled studies suggest that at doses of mg/d, lamotrigine was equivalent to lithium and superior to placebo at prolonging the time to intervention for any mood episode in bipolar I patients who had recently experienced a manic or hypomanic episode. Lamotrigine was found to be superior to placebo at prolonging the time to a depressive episode, while lithium was superior at prolonging the time to a manic, hypomanic, or mixed episode (Bowden et al, 2003). The proportions of patients who were free of depression after 1 yr are reported to be 57% of those on lamotrigine, 46% for those on lithium and 45% for those on placebo. The respective proportions of patients free of mania after 1 yr were 77% for lamotrigine, 86% for lithium, and 72% for placebo. Thus the conclusion is that lamotrigine is predominantly effective against depression, and lithium predominantly effective against mania (Calabrese et al, 2003a). These studies suggest the superiority of lamotrigine to placebo in preventing depressive episodes and delaying new recurrences. Moreover, a pooled analysis found out the superiority of lamotrigine to placebo in preventing manic, hypomanic, mixed episode (Goodwin et al, 2004). Lamotrigine is also effective against rapid cycling (Calabrese et al, 2000). The post-hoc analysis confirmed that both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode in bipolar I disorder (Calabrese et al, 2006). One study reports that adding lamotrigine to lithium was superior to placebo in patients with bipolar depression (Van der Loos et al, 2009). Lamotrigine does not induce mania/hypomania/mixed states, episode acceleration, or destabilize the overall course of illness (Calabrese et al, 2003b; Goodwin et al, 2004) Other anticonvulsants The topic of oxcarbazepine in the maintenance treatment of BD bears little evidence (Vieta, 2004b; Popova et al, 2007; Juruena et al, 2009). In a 1-year double blind placebo-controlled trial 55 BD type I and II patients were randomized to lithium only or lithium and oxcarbazepine arm, but the difference was not significant (Vieta et al, 2008). In another, small trial, phenytoin showed some mood stabilizing effect (Mishory et al, 2003). Another randomized, placebo-controlled pilot study suggested some prophylactic effect of gabapentin combined to lithium in euthymic rapid cyclers (Vieta et al, 2006a) ANTIPSYCHOTICS Long-term management of BD with low doses of antipsychotics is a well established practice (Sernyak and Woods, 1993). First generation antipsychotics were not effective in the prevention of depressive episodes, which they could even cause (Kukopulos et al, 1980), so that they did not constitute a valid tool in maintenance treatment. A number of studies are posing second generation antipsychotics as a useful tool in mood stabilization (Vieta and Goikolea, 2005).

88 Amisulpride A small study suggests the possible role of this antipsychotic in maintenance treatment. Carta and colls (2006) used amisulpride as adjutant treatment to other mood stabilizers in 14 BD type I patients who showed a reduction in manic or mixed recurrences Aripiprazole It has obtained the approval for maintenance treatment from FDA and EDA. A double blind, 26-weeks trial euthymic patients were included and randomized to an aripiprazole (n = 78) or placebo (n =83) arm. Aripiprazole reduced significantly the risk of a manic relapse but it did not show any difference from placebo as per depression prevention (Keck et al, 2006). This study was later extended to 74 weeks more, to achieve 100 weeks: aripiprazole confirmed the prevention of relapses in patients previously stabilized with this drug, showing a good safety and tolerability profile (Keck et al, 2007b). Aripiprazole is reported to protect from manic relapses but there were no statistical differences in depressive relapses compared to placebo (Keck et al, 2006, 2007b) Asenapine A 40-wk placebo-controlled study of the safety and efficacy of asenapine when added to lithium or valproate (NCT and NCT ) and a 40-wk extension study of asenapine vs. olanzapine (Ares ) are expected to be announced Clozapine One randomized add-on study suggesting clozapine is superior to treatment as usual in the prevention of mania in refractory patients (Suppes et al, 1999). A case series of clozapine augmentation showed clozapine to be beneficial in 2 BD type I and 1 schizoaffective patients. Most common side effects are weight gain and fatigue (hummel et al, 2002). Atypical antipsychotics may reduce the percentages of emergencies, and this effect is probably stronger with clozapine (Brown et al, 2001) Olanzapine Olanzapine has been one of the most studied atypical antipsychotics, approved by FDA and EDA for long-term treatment of BD in patients responsive in acute mania. A number of trials support its use as adjutant and monotherapy. A 12-month, double blind placebo-controlled trial of olanzapine monotherapy showed its superiority versus placebo in the prevention of relapses to manic, depressive and even mixed episodes (Tohen et al, 2006). In another double blind trial 251 manic or mixed patients were randomized to a valproate or olanzapine arm for 47 weeks. Patients improved significantly and olanzapine treatment was comparable to valproate in terms of efficacy (Tohen et al, 2003c). Olanzapine was compared to lithium in a double blind trial which lasted 52 weeks. Both drugs showed similar efficacy in the prevention of depressive episodes, but olanzapine was superior in the prevention of manic and mixed recurrences (Tohen et al, 2005). This study suggested the efficacy of olanzapine in the prevention of recurrences, and another double blind, placebo-controlled trial confirmed it (Tohen et al, 2005). Patients with a manic or mixed episode received olanzapine for 6-12 weeks: those who achieved euthymia were randomized to a 52 trial of olanzapine or placebo treatment. Olanzapine was superior to placebo in the prevention of any, manic, depressive episodes.

89 Olanzapine combination treatments with other mood stabilizers have been studied. In a 18-months, placebo controlled double blind study, 99 patients were randomized to a mood-stabilizer-only (lithium or valproate) arm or mood stabilizer with olanzapine arm (Tohen et al, 2004). No differences in any or depressive recurrences were found, but the olanzapine-treated arm lasted longer without manic recurrences. More recently, olanzapine proved to be superior to placebo in maintenance treatment of patients who presented a mixed first episode (Tohen et al, 2009b). One study suggests that after 48 wk the relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%) and this was true concerning manic, depressive and mixed episodes (Tohen et al, 2006). Olanzapine was found to be superior to lithium in the prophylaxis against manic and mixed episodes and with similar efficacy against depressive episodes (Tohen et al, 2005). It is also reported to be similar concerning the prevention of manic episodes but did slightly better than valproate concerning YMRS (Tohen et al, 2003c). A post-hoc analysis suggests that using olanzapine early in the course of the disorder is possibly more beneficial than lithium during the maintenance phase (Ketter et al, 2006). Adding olanzapine to lithium or valproate improves outcome (Tohen et al, 2002b, 2004) and may reduce suicidality (Houston et al, 2006). Overall, there are strong data supporting the usefulness of olanzapine during all phases of BD (Rendell et al, 2003), although it may be particularly useful in patients with manic predominant polarity (Colom et al., 2006; Rosa et al, 2008). The most frequent adverse effects include dry mouth, weight gain, increased appetite and somnolence (Tohen et al, 2002a). Another problem with olanzapine is that it is believed to carry some risk of developing metabolic syndrome and diabetes mellitus (Vieta, 2004). Other common side effects are somnolence, xerostomia, increase of appetite and weight gain, akathisia and increase in alanine-aminotransferase (Tohen et al, 2003c) Perphenazine There is only one 6-month maintenance study with a placebo-controlled double-blind design of a mood stabilizer (lithium, carbamazepine, or valproate) and perphenazine or a mood stabilizer and placebo in patients just remitted from an acute manic episode. The results suggested that patients receiving perphenazine did not have a better course compared to those receiving placebo, but on the contrary they had a shorter time to depressive relapse, more drop-outs, and increased rates of dysphoria and depressive symptoms (Zarate and Tohen, 2004) Quetiapine There are no monotherapy trials published yet, but there are two positive, add-on placebo-controlled trials (Suppes et al, 2009; Vieta et al, 2008h). Two recent placebo-controlled add-on trials of quetiapine and mood stabilizer during maintenance treatment, suggest that quetiapine is superior to placebo in the prevention of manic and depressive recurrences in either manic, depressive, or mixed index episode over a period of 2 years (Vieta et al, 2008h). These add-on studies appear to be the first to report prevention on both depression and mania regardless of the type of index episode. Placebo-controlled trials show the efficacy of quetiapine with rapid cyclers in preventing depressive and manic episodes, independently from first episode (Vieta et al, 2007).

90 Normally, quetiapine is well tolerated due to its scarce extrapyramidal effects, but sedation and weight gain may pose as relevant problems in maintenance treatment, even if their magnitude is inferior to that of clozapine or olanzapine Risperidone There are not controlled trials on the use of risperidone for more than 12 weeks. In 2001 a multicentric, open, observational 6-months-study was published on the use of risperidone combined to mood stabilizers in 541 bipolar and schizoaffective patients: after the introduction of risperidone, patients were found to clinically improve, suggesting a use of risperidone in the maintenance treatment of BD (Vieta et al, 2001a). Similar results were obtained by Yatham et al (2003). He same group compared risperidone combination with lithium or valproate, founding the combinations to be similar in terms of efficacy and tolerability (Yatham et al, 2004). Risperidone plus a mood stabilizer was reported to be more effective than a mood stabilizer alone (Yatham et al., 2003), and as effective as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was also well tolerated (Sachs et al, 2002). A long-acting release injectable formulation of risperidone is disposable. Only a recent 1 year randomized, double-blind, placebo-controlled multi-phase study (Kujawa et al, 2008) assessed augmentation of treatment as usual (TAU) with risperidone long-acting injectable (RLAI) in patients with frequently relapsing bipolar disorder ( 4 mood episodes in the past 12 months). In this study, the addition of long-acting injectable risperidone to treatment as usual improves the outcome of the disease in highly relapsing patients, in a placebo-controlled design. Nevertheless open, observational trials confirm its efficacy and its generally well-tolerated profile (Han et al, 2007; Benabarre et al, 2009). An open, mirror-design study suggests that risperidone longacting may be useful in preventing hospitalizations due to mania and helps improving therapeutic adherence (Vieta et al, 2008g). One of the main problems associated with long-term use of risperidone is hyperprolactinaemia (Yatham et al, 2004) Ziprasidone Preliminary data on the open extension of some trial suggest that ziprasidone may be an option in maintenance treatment, but controlled trials are needed to confirm it (Weisler et al, 2004b). Ziprasidone seems to be well tolerated and does not induce weight gain. Recently, a randomized placebo-controlled trial on the efficacy of ziprasidone in a sample of BD type I patients have been presented: it showed a longer time to recurrence compared to placebo (Vieta et al, 2009) RECOMMENDATIONS Drugs with level of recommendation A (in alphabetical order): Aripiprazole Lamotrigine Lithium A A A

91 Olanzapine Quetiapine Long-acting injectable risperidone Ziprasidone A A A A Drugs with level of recommendation B (in alphabetical order): Carbamazepine Clozapine Valproate B B B Valproate, despite having a degree of recommendation B in monotherapy, has positive data on maintenance when associated with other drugs (lithium, quetiapine and ziprasidone) Drugs with level of recommendation C (in alphabetical order): Asenapine Oxcarbazepine C C Negative evidence (evidence of lack of efficacy) in Maintenance Treatment: imipramine.

92 008 - PSYCHOLOGICAL TREATMENT 8.1. INTRODUCTION 8.2. ACUTE MANIA RECOMMENDATIONS 8.3. ACUTE DEPRESSION Cognitive behavioural therapy Interpersonal social rhythm therapy Recommendations 8.4. MAINTENACE TREATMENT Brief technique-driven interventions Cognitive-behavioural therapy Interpersonal social rhythm therapy Patients psychoeducation Caregivers psychoeducation Group psychoeducation within systematic care models Recommendations 8.1. INTRODUCTION Until few years ago, the introduction of psychological interventions in the treatment of BD was a controversial theme due to the genetic, biological, biochemical nature of the illness. Moreover, psychological interventions have traditionally been evaluated with a substantial lack of strict and precise methods until very recently, in an area in which psychopharmacology occupies a central place. With a comprehensible scepticism, researchers have started to look at the possibility that psychological interventions can play an adjutant role in the treatment of BD. A consensus on the opportunity of some type on psychological intervention in bipolar depression has always existed between professionals. The problem with psychological interventions is that their clinical use is not always based on evidence, which is scarce. More trials are needed. The use of psychotherapy must take into account individuality. Patient s intelligence, cultural level, actitude toward introspection are undoubtedly factors that have to be considered, but these factors should not mask the need for concrete outcomes in BD. Psychological treatment should follow the same rules that make the evaluation of other interventions. Outcome measures need to be, just as in the case of drug trials, objective parameters which may measure the impact of the treatment over the course of the illness. In the case of BD, the best measure is represented by hospitalizations and recurrences prevention. Psychotherapy finds place in BD, especially during euthymia as an adjuvant maintenance treatment. Its efficacy in acute phases of the illness is still discussed, although some type of intervention could have a role in the treatment of bipolar

93 depression, for instance cognitive or interpersonal and social rhythm therapy, even though data on their efficacy are not strong and sometimes are contradictory. It is obvious that not every type of psychological intervention may be useful in the treatment of BD. There is not doubt that the indication for psychotherapy should consider individual parameters as basic intelligence, motivation, attitude to introspection. But these parameters cannot substitute more objective considerations or justify the integration of interventions which are not evidence based (Vieta, 2009). Recommendations are given at the end of the three paragraphs (acute mania, acute depression, maintenance treatment) ACUTE MANIA In mania or hypomania there seems not to be space for psychotherapy. Psychological treatments for acute mania are not useful and there are not data supporting their use. Psychosocial intervention may be useful if applied to patients in remission or with mild symptoms. During acute mania it is possible to give basic information (Colom and Vieta, 2007) but with no doubt acute mania should be treated with pharmacotherapy RECOMMENDATIONS None. There is no evidence of efficacy of psychosocial treatment in the acute phase of mania 8.3. ACUTE DEPRESSION Despite the fact that BD is a condition with a strong genetic, biochemical, biological basis, mental health professionals traditionally agreed on the usefulness of psychological intervention in acute bipolar depression, basing on very little, if any, evidence (Sharma et al, 1997) Cognitive behavioural therapy CBT demonstrated its efficacy in unipolar depression, in combination therapy with antidepressants or in monotherapy (Scott et al, 2000; Keller et al, 2000; Ward et al, 2000). These results may not lightly be applied to bipolar depression. Cognitive distortions, which are the basis of CBT, have not proven to drive affective changes in bipolar depression, as atypical, behavioural symptoms are more common (i.e.: inhibition, apathy, hypersomnia and hyperphagia) and do not seem explained by the classical Beck s model (Leahy and Beck, 1988). Solid trials with CBT in bipolar acute depression substantially lack. A factibily study on CBT has been done (Palmer et al, 1995; Patelis-Siotis et al, 2001), but no hard data have been produced, despite the presence of high quality structured handbooks (Lam et al, 1999). An open study with small sample size (n=11) showed good results (Zaretsky et al, 1999). More conductual data as those on sleep deprivation have been reported in ch. 9, in Chronobiological interventions paragraphs. CBT may find a place in improving treatment adherence (Cochran, 1984). Some andecdotic report outlines the risk of a treatment-emerging affective switch with the use of CBT (Kingdon, 1986), but there is no solid evidence in favour of considering it as a certain risk.

94 Interpersonal social rhythm therapy Interpersonal social rhythm therapy (IPSRT) represents an adaptation to BD of interpersonal therapy, which proved its efficacy in the therapy of unipolar depression (Elkin et al, 1989, 1995) and unipolar recurrent depression (Frank et al, 1990, 1991). IPSRT main features are a special enphasis on habits and on circadian rhythms: it focuses on helping the patient in understanding and managing the social background associated with his/her affective symptoms and helping the patient in detecting life events which could influence his/her circadian rhythms. Solid data for the use of IPSRT have not yet been produced (Colom and Vieta, 2004). Some studies on the use of IPSRT as adjuntant treatment to mood stabilizers (Frank, 1999; Frank et al, 1999). An element of interest is that patients who have received IPSRT in acute phase and follow it in maintenance treatment have a better outcome than thos who received two different psychological treatments (Frank et al, 1999). IPSRT could be especially useful in bipolar patients with medical comorbidities (Frank et al, 2005) Recommendations There is limited evidence for the effectiveness of certain treatments. None of them exceed level C (listed in alphabetical order). Familiar Intervention Cognitive behavioural therapy Interpersonal and Social Rhythm Therapy C C C 8.4. MAINTENACE TREATMENT Accumulated data have shown that psychoeducation, family-focused psychoeducation, and cognitive behavioural therapy seem to be the most efficacious interventions in the prophylaxis from recurrences in medicated bipolar patients and can help the patient and family members to learn to identify early warnings of evolving episodes so that earlier treatment can occur and triggering factors can be identified (Colom et al, 2003a,b, 2004, 2005; Reinares et al, 2004; Scott et al, 2007). More data are available concerning psychoeducation which seems to emerge as the first line of psychosocial intervention. The hypothesis that the number of previous episodes may modulate the response to treatment has been proposed: a post-hoc analysis by Scott and cols (2006b) detected a threshold of 12 episodes as the cutoff between response and no-response to CBT. A post-hoc analysis on family psychoeducation was conducted: patients were divided into those who had no functional or clinically relevant impairment and lack of symptoms confined to psychiatric comorbidity and those with functional or clinically relevant impairment and/or symptoms confined to psychiatric comorbidity in the inter-epipsode period (Reinares et al, 2009). The intervention was found to be especially useful for those patients who presented well established periods of euthymia and absence of overt psychiatric morbidity alongside impairment between episodes. This adds to the idea developed by Scott et al. (2006b) that patients with a high number of previous affective episodes at study entry are less likely to respond to psychological treatment. However, results from Reinares and cols suggest that the main factor conditioning response to psychological treatments may not only be the number of prior episodes but also the

95 degree of functional impairment in the inter-episodic period, as proposed by Kapczinski and cols (2009). A recent meta-analysis from Lam and cols focused on the overall efficacy of bipolar disorder-specific psychological therapies, considering family interventions, complex psychoeducation, psychoeducation, CBT, IPSRT, and CBT modified for medication adherence (Lam et al, 2009). These interventions globally proved to be is effective in preventing or delaying relapses in bipolar disorders. no clear evidence that the number of previous episodes moderated the effect have been found, although this aspect is biased by the exclusion of an important study (Scott et al, 2006b) in favour of this hypothesis, which should thus be further and specifically tested. A randomized controlled trial on 293 patients concerning the effectiveness of familyfocused therapy, interpersonal and social rhythm therapy, and cognitive behaviour therapy on bipolar depression suggested that patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% versuss 51.5%) and shorter times to recovery than patients in collaborative care. No statistically significant differences were observed in the outcomes of the three intensive psychotherapies (Miklowitz et al, 2007) Brief technique-driven interventions Results from 2 randomized, controlled 1-year trials have been presented comparing an experimental intervention (add-on) with treatment as usual. In the first one, 28 stable bipolar subjects were randomly allocated to standard treatment (lithium alone) or to standard treatment plus six sessions using cognitive and behavioural strategies to enhance treatment adherence. At the end of the sessions and during the six-month follow-up the psychotherapy group had significantly fewer relapses, less tendency to discontinue lithium (21% vs 57%) and overall better medication adherence (Cochran, 1984). In the second one, 69 bipolar patients who had experienced a relapse within the previous 12 months were enrolled and randomized to receive either routine care alone or routine care and 7-12 individual treatment sessions aimed at teaching them to identify early symptoms of relapse (Perry et al, 1999). Patients that had received the psychological intervention had a significant increase in time to first manic relapse and a 30% decrease in the number of manic, but not depressive, episodes over 18 months. Moreover, this group of patients had reduced hospital stay, and showed higher level of social functioning and better work performance Cognitive-behavioral therapy To date, several well-designed studies testing CBT in bipolar disorders there have been performed. Data on CBT are controversial. Lam and cols (2003) showed the efficacy of CBT focuses on educational aspects in 1-year recurrence prevention. Unfortunately, when evaluated in a 2-years-follow up, it showed to have lost its efficacy This could mean that as therapy became more distant, the beneficial effects became weaker. Further investigations should explore the opportunity of booster sessions or maintenance therapy (Lam et al, 2005). Scott and colleagues (2006), in a large trial conducted in the UK, involving 253 difficult-to-treat BP I and II patients, showed that, over 18 months, patients receiving individual CBT (22 sessions over 26-weeks) did not differ from those treated as usual as regards time to recurrence, duration of illness episodes or mean symptom severity scores. A post-hoc analysis revealed some efficacy of CBT in patients with a small number of episodes. The same approach, used with veteran patients (from twelve episodes on), who may have psychiatric comorbidities and bear the presence of acute symptoms, has proven useless and may even worsen the

96 outcome (Scott et al, 2006b). In an 18-month, randomized, long-term, controlled trial testing the efficacy of individual CBT in bipolar patients (euthymic, mildly depressed or hypomanic at the time of initial assessment) a number of positive trends towards better overall outcome even at 12 months were also reported, but the same authors recognize that benefits from CBT were gradually lost upon withdrawal, suggesting the importance of maintaining psychological strategies, although this aspect has not been tested (Ball et al, 2006). It seems likely that CBT in BD needs a new design which better reflects the specific needs of bipolar patients. In a pilot Canadian study (Zaretsky et al, 2008), BP patients in full or partial remission from an index episode (n=79) were randomized to receive either 7 sessions of individual psychoeducation, or 7 sessions of psychoeducation followed by 13 additional individual sessions of CBT as maintenance therapy. Patients on CBT had 50% fewer days of depressed mood and fewer antidepressant dosage increases over one year. It should be noted that psychoeducation alone was shorter than CBT (only 7 sessions for PE vs. 13 sessions for CBT) Interpersonal social rhythm therapy A two-stage randomized controlled trial (n=175) was conducted by Frank and cols (2005). In the acute phase, BP-I patients with a current episode were randomly assigned to IPSRT or an intensive clinical management. After patients were stabilized, they entered phase two, where they were re-allocated to IPSRT or intensive management for a 2-year maintenance period. The results of this study showed no differences between the IPSRT and ICM in time to stabilization. Patients allocated to IPSRT in the acute treatment phase survived longer without a new mood episode, independently from their assignment to maintenance treatment (p=0.01). Patients in the IPSRT groups had more regular social rhythms at the end of the acute phase, and the ability to increase the regularity of daily routine during the acute treatment was associated with reduced likelihood of recurrence during the maintenance phase, supporting its inclusion in bipolar treatment routines Patients psychoeducation Psychoeducation goes beyond mere delivery of information, since information alone shows no therapeutic effect (Miklowitz, 2008); it is rather an information-based behavioural training aimed at providing bipolar patients with a theoretical and practical approach towards understanding and coping with the consequences of their illness, allowing them to change attitudes and beliefs towards the illness and providing specific coping strategies. Active patients collaboration in some aspects of the treatment may be achieved my means of a psychoeducative intervention Psychosocial interventions should be focused on relapse/recurrence prevention. Among the existing possible interventions, group psychoeducation poses many practical advantages: its demonstrated efficacy (Colom et al, 2003a,b) and its perfect integration in the model of BD (Colom et al, 1998), its low cost due to its time-limited and group targeted structure, its high applicability and its generalizability (it does not need to take into account patients subtyped for preferences, IQ or other characteristics, Scott et al, 2007). On the other hand, psychoeducation integrates in one treatment the most relevant aspects of other psychological treatments tested in BD: early symptom detection (Perry et al, 1999), habit regularization (Frank et al, 2005), improvement of therapeutic adherence (Scott and Tacchi, 2002) and symptom management with problem solving (Lam et al, 2003). Moreover, psychoeducative model has shown its applicability with

97 caregivers (Miklowitz et al, 2003, Reinares et al, 2004, 2006, 2008), a fundamental issue in BD. Pioneering studies by Peet and Harvey showed some changes in patients' attitudes towards lithium, but provided no clinical outcome measures. In Europe, the studies by Eduard van Gent and coworkers showed a significant decrease of non-compliant behaviour and hospitalizations amongst psychoeducated patients (Beynon et al, 2008). Today, psychoeducation is part of a good therapeutic practice in BD (Colom and Vieta, 2004; Fountoulakis et al, 2005; Goodwin, 2009), as it showed its prophylactic efficacy in recurrence and hospitalization prevention in euthymic bipolar patients (Colom et al, 2003a; Colom and Vieta, 2003; Colom et al, 2009). Clinic guidelines already recognize the need to implement psychoeducation as a part of therapeutic routine, but, despite this, professionals attitude and knowledge towards this technique is not as solid as it should be, due to a number of series (scarce tradition, short duration of visits, lack of clinical psychologists and active resistance of some mental health professionals who handle obsolete and not-evidence-based approaches to psychiatric patients). One of the advantages of psychoeducation is that it does not require a complex specific training as other psychotherapeutic approaches: knowledge on the basic aspects of BD, of the psychoeducative program and experience on group management are needed. General objective of psychoeducation is to reduce the number of recurrences and to ease the management of the disorder. For this reason, acceptance of the diagnosis, early detection of new episode, management of the symptoms and adherence to pharmacological treatment are worked on. The prophylactic efficacy of psychoeducation has been demonstrated at a 5-years follow-up without refresh sessions (Colom et al, 2009): patients who beneficiated from a psychoeducative intervention and a pharmacological treatment had suffered half of the affective episodes suffered from patients treated with pharmacological treatment and a placebo psychointervention (3,86 versus 8,37, p<0,0001). Differences were significant for any affective episode, depressive, mixed, manic or hypomanic episodes. Time spent acutely ill was greatly affected by psychoeducative intervention, as patients fulfilled episode criteria during 154 days out of 5 years, while not-psychoeducated 586 days (p=0,0001) Caregivers psychoeducation The illness of the patient has an impact on families and caregivers in general. The important of environmental stress onto the course of BD, the load experienced from the familiars who live with the patients, the families need of having more information on the disorder, the subjective load of some patients symptomatic behaviours (Reinares et al, 2006) and the need for strategies on how to handle bipolar illness are some of the reasons which justify the introduction of psychoeducative interventions aimed at the family of a bipolar patients (Reinares et al, 2002). A familiar intervention, together with pharmacological treatment, constitutes an efficient tool to improve the patients course of illness. Family psychoeducation provides the families with some knowledge on the illness: this may help understand better the disorder, modulate changes in attitude and behaviour, optimizing the way families faces the illness. Some studies have outlined the usefulness of family psychoeducation in relapse (Miklowitz and Goldstein, 1990; Miklowitz et al, 2000) or hospitalizations (Davenport et al, 1977) prevention. The study from Miklowitz and cols (Miklowitz et al, 2000, 2003) seems the most rigorous in methods: bipolar patients, after an acute episode, were randomized to a familiar psychoeducation, communication skill training, and problem solving arm or treatment as usual: familiar intervention, realized with the patient, could reduce the number of

98 relapses and improved depressive symptoms, but not manic. A Catalonian group conducted a randomized, placebo-controlled trial with more than 100 patients on the use of family group psychoeducation without patients: this intervention reduced the recurrence of acute episodes in the following year, with a very strong effect in preventing mania, but not depression (Reinares et al, 2008). It seems clear that both interventions are complementary, but they could be also chosen according to the predominant polarity of the patient (Colom et al, 2006, Rosa et al, 2008) Familiar intervention has been found to be efficacious in improving social and working functioning of the patients (Clarkin et al 1990; Glick et al, 1993), as well as the overall functioning and treatment adherence (Clarkin et al, 1998), maybe due to the family attitude towards pharmacotherapy during intervention (Clarkin et al, 1990) Group psychoeducation within systematic care models Two large studies have considered a psychoeducative program in the context of of overall systems of care. The first one (Bauer et al, 2006) was structured so that patients in the Veteran Affair program received, besides a drug treatment, an individual nurse care coordinator, regular telephon monitoring of prodromal mood symptoms, a life goals program organized in 5 weekly followed by twice monthly group sessions for up to 3 years (Bauer et al, 2006). Sample consisted of 306 bipolar I patients, 87% of whom began as inpatients. Over 3 years, patients in the collaborative care intervention had 6.2 fewer weeks in affective episodes, 4.5 weeks of which were attributable to reductions in the length of manic episodes. There were no differences between the collaborative care and the treatment-as-usual groups in the length of depressive episodes. Broad effects of the care intervention were found on social and work functioning, quality of life, and treatment satisfaction. Most interestingly, the group differences were not statistically reliable until 2 years, suggesting a delayed effect of psychoeducation and facilitated collaboration with care providers. A similar design was used to conduct to largest psychosocial study to date, carried out in the Group Health Cooperative organization of Washington State, U.S. (Simon et al, 2005). The sample of 441 bipolar patients was randomly divided in two groups: a 2-year systematic collaborative care program or treatment as usual (typically medication management visits). The probability of a new manic episode was significantly lower in the systematic care group over the eight assessment points of the study. Patients spent an average of 5.5 fewer weeks with clinically significant symptoms of mania than those in treatment as usual. There were no effects of systematic care on depression severity, weeks depressed, or depressive recurrences Maintenance treatment recommendations In this phase of the illness more evidence of efficacy of psychological interventions has been produced. Psychological treatments are always complementary medication and never replace pharmacological treatment. Familiar intervention Group psychoeducation B B

99 Family psychoeducation Cognitive behavioural therapy Interpersonal and Social Rhythm Therapy B B C

100 09 OTHER TREATMENTS 9.1. INTRODUCTION 9.2. ACUTE MANIA Electroconvulsive therapy Chronobiological intervention Magnetic transcranial stimulation Recommendations 9.3. BIPOLAR DEPRESSION Electroconvulsive therapy Chronobiological intervention Magnetic transcranial stimulation Vagal stimulation Recommendations 9.4. MAINTENACE THERAPY Electroconvulsive therapy Vagal stimulation Recommendations 9.1. INTRODUCTION Besides pharmacological and psychotherapeutic interventions, other types of interventions are possible in BD: these are mainly represented by electroconvulsive therapy, which despite some cultural and historical resistances has found a place in the clinical practice, and newer interventions such as chronobiological interventions, magnetic transcranial stimulation and vagal nerve stimulation. Recommendations are given at the end of the three paragraphs ACUTE MANIA Electroconvulsive therapy Electroconvulsive therapy (ECT) keeps being an effective option to treat resistant manic, depressive states as well as mixed states, which are not infrequent and generally hard to treat (Rasmussen, 2002; Fink, 2006; Valenti et al, 2007; Tess and Smetana, 2009). Its role as an effective treatment has been traditionally neglected, due to the fact that it does not produce economic benefits and it generates social and cultural resistances. This is reflected by a paucity of studies producing evidence on its efficacy. Despite clinical trials show lithium, anticonvulsants or antipsychotic as being partially effective, a considerable part of the patients do not respond to these pharmacologic options. A systematic review suggests ECT to be an effective treatment, safe and generally underutilized (Valenti et al, 2007).

101 Clinical features and the response to electroconvulsive therapy were compared between 41 treatment-resistant patients with mixed mania and 23 treatment-resistant patients with bipolar depression consecutively assigned to ECT treatment. ECT was associated with improvement in symptoms in treatment-resistant patients with mixed mania or bipolar depression. Patients with mixed mania exhibited a greater reduction in depressive symptoms (Ciapparelli et al, 2001). In this study, the percentage of response in patients with bipolar depression was lower than the 50% reported in literature (Thiery, 1965; Prudic et al, 1996). A case series from Gruber and cols (2000) reports the good outcome for 7 patients who showed poor response to pharmacological treatment. The presence of delusional symptoms has been traditionally reported to be a predictor of favourable response to ECT (Abrams, 1992), but in the study from Ciapparelli and cols (2001) this fact was not confirmed. Bilateral, twice-weekly ECT delivered at stimulus intensities just above individually titrated seizure threshold demonstrated as effective and safe as ECT administered at stimulus intensities 2.5 times seizure threshold in rapidly resolving the symptoms of acute mania in a recently published study (Mohan et al, 2009). Moderate-dose bifrontal has proven to be as effective as low-dose bitemporal ECT in the treatment of patients with severe mania, but was associated with fewer cognitive side effects in a recent study (Barekatain et al, 2008; Hiremani et al 2008). A comparison study between 38 depressed, 5 manic and 10 mixed bipolar patients showed no differences in the response of the three groups. Mixed patients responded very well to ECT sessions, although they needed a longer hospitalization period (Devanand et al, 2000) Chronobiological intervention A case-control study on the add-on use of dark therapy and enforced rest in 32 bipolar I patients showed a faster improvement in the patients who received the dark therapy. Responders to dark therapy had shorter hospitalization duration (Barbini et al, 2005) Magnetic transcranial stimulation Data on bipolar patients with potential therapeutic alternatives, as vagal nerve stimulation (VNS) or magnetic transcranial stimulation, substantially lack. Suprathreshold repetitive transcranial magnetic stimulation in acute mania was evaluated in an add-on study on 41 patients, and it was found to be efficacious and well tolerated (Praharaj et al, 2009). A previous sham-controlled, study from Kaptsan and cols (2003) found out that right pre-frontal rtms was not effective as add-on treatment in 25 acutely manic patients. An add-on, open study conducted on 9 BD type I patients found right prefrontal rtms to be a useful treatment to reduce manic symptoms (Michael and Erfurth, 2004) Recommendations ECT has a grade B recommendation BIPOLAR DEPRESSION Electroconvulsive therapy Although controlled data are limited ECT is an effective non-pharmacologic treatment for bipolar depression, actually the most effective non-pharmacological treatment (Silverstone and Silverstone, 2004; Macedo-Soares et al, 2005) and may achieve higher response rates than some pharmacologic options (Zornberg and Pope, 1993; Kalin

102 1997). Its rapid onset of action makes it a possible, valuable alternative in the treatment of severely (including psychotic), treatment-resistant depressed patients (Prudic et al, 1990; Srisurapanont et al, 1995; Russell et al, 2003; Prudic et al, 2004), pregnant women (APA, 1994) and patients with drug intolerance (Prudic et al, 1990). When possible, bilateral ECT should be preferred to unilateral due to its higher efficacy (UK ECT group, 2003). Although there are no definite data in favour, some older clinical observations and some more recent clinical trials support the efficacy of ECT (Daly et al, 2001). A recent randomized study considered 13 bipolar depressed patients in a total sample of 64 depressed patients (Sienaert et al, 2009): Patients with bipolar and unipolar depression did not differ in rates of response or remission following the ECT course or in response to unilateral or bifrontal ECT. Patients with bipolar depression, however, showed a more rapid response than patients with unipolar depression. Another recent trial concluded that ECT turns out to be a viable option for the treatment of bipolar depressive (and unipolar) patients resistant to pharmacological treatment (Medda et al, 2009). Nevertheless, while the unipolar group showed the best response and clinical outcomes, the BD type I patients tended to exhibit residual manic and psychotic symptomatology. The switch risk is around 7 % (Angst 1985). Protective lithium co-administration may be considered but could increase the risk and duration of a transient postect delirium. Despite its high efficacy, ECT is usually used after the failure of 1 or more first-line treatments, due to its side effects (Prudic, 1990) or, as said before, to the burden of the heritage from its past misuse (Freeman and Kendell, 1986; Freeman and Cheshire, 1986). For this reason, the possibility of using ECT is quite different in different countries and mainly reflects public opinion and not its usefulness. Thus, ECT may be used in some countries at an early stage of treatment, whereas in others it is usually only applied in selected, mostly treatment refractory patients. Nonetheless, further investigation should be conducted on this highly effective technique, as it may still play a fundamental role in the management of bipolar depression Chronobiological intervention The efficacy of chronobiological intervention has been evaluated in bipolar depression. In open condition, 115 patients in maintenance treatment with lithium were randomized in total sleep deprivation arm and light therapy or total sleep deprivation alone. Total sleep deprivation confirmed its efficacy in association with long-term lithium-treated bipolar depression, while light therapy showed efficacy in short term prevention of depressive relapses (Colombo et al, 2000). An open-label, combination study on the use of lithium with light therapy and sleep deprivation in 19 depressed non-psychotic bipolar I patients showed significant improvement in depressive symptoms (Benedetti et al, 2009). Rapid-cycler depressed patients with not satisfactory response to lithium could benefit from a combination therapy with sleep deprivation on the basis of an open, observational study (Papadimitriou et al, 1993). A case series on 9 bipolar depressed women reports a high sensibility to morning bright light treatment, less to midday light treatment: 3 of the women underwent a mixed state, 3 achieved full remission, 1 was non responsive and 2 partially responsive. (Sit et al, 2007) Magnetic transcranial stimulation

103 Scarce data have been produced on bipolar depression too. A recent 3-weeks, open study on 11 bipolar depressed patients resistant to pharmacologic treatment showed a significant improvement at HAM-D, with a stimulation response (an improvement of more than 50% at HAM-D) of 6 out 11 patients, a partial response in 3 patients (Dell Osso et al, 2009). A double blind sham-controlled study on the efficacy of rtms in bipolar depression on a sample of 20 patients found out a significant result in patients treated with rtms (Dolberg et al, 2002), while another sham-controlled study on 25 depressed and mixed BD type I and II patients found no significant improvement in depressive symptoms (Nahas et al, 2003). An add-on, double blind sham-controlled was conducted on a sample of 5 acutely depressed bipolar patients, showing efficacy for rtms treatment, but only since week 4 (Tamas et al, 2007). The problem of treatment-emergent mania with rtms has been targeted by a recent review in literature, which concludes that rtms carries a slight risk of inducing a treatment-emergent mania when compared to sham treatment, although this represents another critical issue which needs further data (Xia et al, 2008) Vagal stimulation Although VNS is a recent treatment, a systematic review of the published studies and reports has been conducted (Daban et al, 2008). As for acute depression, only a pivotal trial with negative results has been published on the use of VNS (Rush et al, 2005a). Naturalistic studies have been published. In a study from Rush (2000) conducted on 30 patients, 40% were considered as responders on the basis of the HDRS, while 17% were in remission. It appeared that more than half of the total reduction in depressive symptoms occurred after 6 weeks of VNS. Results from the study published by Sackeim and cols (2001) are slightly disappointing. Only 30.5% of the patients met the criteria for response and 15.3% the criteria for remission. No difference was found between unipolar and bipolar patients. Another study (Armitage et al, 2003) showed that VNS significantly improved depressive symptoms after 10 weeks of treatment (p < ). Unfortunately, it was conducted on a very small group (N = 7). Another small naturalistic study (O'Keane et al, 2005) evaluated 11 treatment-resistant bipolar patients receiving VNS therapy. The clinical measures of depression decreased significantly, but only one patient reached the status of responder. Neuhaus and cols. (2007) showed that almost 40% of patients became responders after 10 weeks of treatment Recommendations ECT has a grade B recommendation MAINTENACE THERAPY Electroconvulsive therapy The use of ECT in maintenance treatment of BD is based more on clinical, anecdotic experience than in scientific evidence. Few published studies support the use of this treatment in patients who are refractory to pharmacologic treatment, although some studies suggest that it may be considered as a useful and safe intervention in the treatment of treatment-resistant patients (Tsao et al, 2004; Sienaert and Peuskens 2006). As ECT is a treatment which does not produce economical benefits and, as previously said, generates some social and cultural resistances, it is usually under-utilized. The use of ECT is problematic for its complexity of administration, the implicit risks of

104 anaesthesia and potential adverse effects on cognitive function, especially memory (Valenti et al, 2007) Vagal stimulation Marangell and cols (2002) presented a follow-up of patients evaluated by Rush et al. (2000) at short term. The response rate was sustained after 9 months of VNS: 40% to 46%. At 12 months, the remission rate significantly increased from 17% to 29%. The responders at 3 months (n = 12) largely maintained their response, with 91% (10/11) of the patients still being responders to VNS at 12 months. Among the non-responders at 3 months (n = 18), 18% were considered as responders at 12 months. A long-term opentreatment phase that showed a statistically significant improvement in depressive symptoms compared with baseline has been conducted (Rush et al, 2005b). It is a naturalistic follow-up study, including 205 patients, showing improvement of depressive symptoms: the greatest increase was seen in the first four months. However, during the 12-month study, 30 patients had worsening of depression requiring hospitalization. A 12-month (George et al, 2005) and subsequent 24-months (Nahas et al, 2005) comparison of those who received VNS and treatment as usual with a similar group of patients with treatment-resistant depression who received only treatment as usual showed that VNS patients did significantly better than the nonrandomized comparison group. Bipolar patients were included in the trial (n=25), but their outcomes have been reported in detail only in a subsequent post-hoc analysis, showing that the 1- year and 2-year outcomes were similar to that of the other unipolar depressed patients (Nierenberg et al, 2008). Another study (Burke and Husain 2006) reporting comparisons between patients receiving VNS plus ECT and patients receiving VNS alone. The results show that both groups had comparable improvements on their HDRS scores, suggesting that ECT does not affect the VNS therapy and vice versa. Corcoran and cols (2006) have also showed significant improvements of depressive scores, especially after a year of treatment. Very impressive results have been presented by Schlaepfer and cols. (2008), with higher rates of response (58%) and remission (36%) at the end of the study, after one year of VNS therapy. Patients who did not respond also showed improvement in their depressive symptoms, as shown by a 27% decrease of the HDRS score after a year of VNS therapy. The role of VNS should be further, specifically tested in BD. A 1- year open study on 9 treatment-resistant rapid cycling bipolar patients supports the use of VNS in treatment resistant patients, but bigger sample size, comparison studies are needed (Marangell et al, 2008) Recommendations ECT has a grade B recommendation.

105 10 SPECIAL POPULATIONS SOMATIC COMORBIDITIES CHRONIC RENAL INSUFFICIENCY HYPOTHYROIDISM ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE HEPATIC INSUFFICIENCY WOMEN OF CHILDBEARING AGE PREGNANCY AND TERATOGENIC EFFECTS Lithium ANTICONVULSANTS Valproate Lamotrigine Carbamazepine Oxcarbazepine Other antiepileptics ANTIPSYCHOTICS Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone BREASTFEEDING Lithium ANTICONVULSANTS Carbamazepine Lamotrigine Oxcarbazepine Valproate ANTIPSYHOTICS Olanzapine Quetiapine Risperidone CHILDREN AND ADOLESCENTS DIAGNOSIS COMORBIDITY TREATMENT PHARMACOLOGICAL TREATMENT LITHIUM ANTICONVULSANTS Valproate Carbamazepine

106 Lamotrigine Oxcarbazepine ANTIPSYCHOTICS Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone PSYCHOSOCIAL INTERVENTIONS PHYSICAL INTERVENTIONS BIPOLAR DISORDER IN THE ELDERLY EPIDEMIOLOGY AND CLINICAL FEATURES TREATMENT Lithium ANTIEPILEPTIC DRUGS Carbamazepine Lamotrigine Oxcarbazepine Valproate ANTIPSYCHOTICS Clozapine Risperidone Other antipsychotics ANTIDEPRESSANT BENZODIAZEPINES PSYCHOTHERAPY ELECTROCONVULSIVE THERAPY SOMATIC COMORBIDITIES CHRONIC RENAL INSUFFICIENCY Chronic renal insufficiency is a progressive and irreversible loss of renal function. Its more causes are diabetes, hypertension and glomerulonephritis. A decrease of up to 75% of renal filtering function may not produce evident symptoms, as remaining glomeruli may adapt with hyperfiltration. Plasmatic creatinine levels may be reliable and very sensible indicators of a renal insufficiency. The risk of chronic renal insufficiency seems increased in patients with BD respect to no psychiatric patients (Bobes et al 2008). When managing bipolar patients with chronic renal insufficiency a special attention must be paid to drug treatment, as renal elimination will be decreased. The renal side effects already listed in chapter 7 pose an absolute contraindication on the use of lithium in patients with renal failure or chronic tubular illnesses. Lithium may be started in patients with an elevation of serum creatinine and urea who are not on renal failure: lower doses and titration should be used, i.e. starting from mg/d. Some patients on renal dialysis may be stabilized with a dose of 300mg/d in a single dose after every dialysis session (Schatzberg and Nemeroff, 2009).

107 Lower doses of anticonvulsants, antipsychotics antidepressants and benzodiazepines, and longer titrations, should also be used to avoid intoxications in patients with chronic renal insufficiency. Sertraline has to be viewed as first-line antidepressant in nephropathic patients, as its pharmacokinetic is not altered by renal insufficiency and it is well tolerated in a mild to moderate insufficiency. Between antipsychotics, aripiprazole has showed a safer profile in patients with no severe renal insufficiency (Schatzberg and Nemeroff, 2009). Urinary retention may be difficult to handle in the elderly, especially in elder men with prostatic pathology. For this reason, most anticholinergic agents, as tricyclic antidepressant with a tertiary amine structure (amitriptiline, imipramine), should be avoided in the elderly (Florez et al, 2004) HYPOTHYROIDISM Hypothyroidism is a clinical condition which results of below-average thyroid hormones levels. It recognizes different causes, which usually permit a classification into primary (lesions or insufficiency of the thyroid, i.e. Hashimoto s thyroiditis, lithium side effects), secondary (lesions or insufficiency of the hypophysis) or tertiary (lesions or insufficiency of the hypothalamus) hypothyroidism. The association between hypothyroidism and BD has been questioned. A comparative study between BD patients and general populations showed that the prevalence of hypothyroidism in bipolar patients was 9.6% in comparison to 2.5% in the general population (p<0.0001), and rapid cycling patients seemed to have higher risk for this condition (Carney and Jones, 2006). Hypothyroidism occurs in about 10-15% of the patients treated with lithium, with a slight prevalence in women, and appears to be related to a decrease in the synthesis and release of thyroxine. This condition is normally subclinical (normal thyroid hormone levels with a compensatory increase in TSH serum levels) and does not need to be managed with a specific treatment. The onset of a clinical hypothyroidism requires treatment with levothyroxine (Álvarez et al, 2000) ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE An increased risk of asthma has been found to be positively related to DB compared to general population, with prevalence of 3-17% vs. 2-10% (Calabrese et al, 2003). Bipolar patients also show an increased risk for chronic obstructive pulmonary disease (COPD) with respect to general population (2.7% vs. 1.1%) (Bobes et al, 2008). It has to be outlined that the recurrence of an affective episode may be triggered by the intermittent or regular assumptions of steroid drugs, as it is the case of asthma or COPD (Camara teruel et al, 2006). Benzodiazepines have a limited use in patients with COPD because of their potential effect in depressing the respiratory centre. Special care must then be paid to BD patients with comorbid COPD and anxiety disorders (Yellowless and Alpers, 1987; Calabrese et al, 2003), which seems not a rare situation as almost 40% of patients with COPD presents panic attacks (Porzelius et al, 1992). Zolpidem seems a better alternative in these patients. Drugs with anticholinergic effects may reduce bronchial secretion and exacerbate pulmonary diseases, so that caution must be used when dealing with such compounds. (Salazar et al, 2004). Antipsychotics have not a direct action on respiration, but precautions must be used because of their sedative effect: this may interfere with normal oxygenation (Vieta and Goikolea, 2005).

108 HEPATIC INSUFFICIENCY Bipolar patients present an almost fourfold increased risk of suffering from hepatopathy (Bobes et al, 2008). Most of the drugs are metabolized in the liver after absorption in the intestine. A hepatic insufficiency supposes higher drugs serum level. Normally, even in presence of hepatic damage, glucuronidation is preserved, while methylation and other metabolic processes show earlier signs of impairment. Drugs which need to be dysmethylated, (i.e. diazepam) may reach high serum levels if administered in patients with hepatic insufficiency, while those which only need to be glucuronidated (i.e. lorazepam) present a safer profile (6-15). Lithium represents the first-line mood stabilizer for patients with hepatic insufficiency. Olanzapine greatly eludes hepatic metabolism, so that it may be an option in the treatment of patients with advanced hepatic insufficiency. Aripiprazole may be used in mild hepatic insufficiency (Schatzbergh et al, 2008). Carbamazepine has hepatic metabolism through cytochrome P450 and this may generate drug interactions (see ch.7). Patients with hepatic insufficiency need ½ to 1/3 of the usual dose (Cámara teruel et al, 2006). Of the SSRIs, citalopram is the safest in patients with hepatic insufficiency or in polypharmacy for its few interactions and its capability to weakly inhibit CYP450 subunits. Same consideration for escitalopram, as it represents a citalopram enantiomer. Despite its long half-life, fluoxetine is a safe option. The decrease of proteins blood-levels is frequent in hepatic diseases. It may increase the free (not bound to proteins) drug levels, relatively increasing the action of drugs without altering the blood levels. This problem is less frequent with venlafaxine, which binds less with blood proteins (Crone and Gabriel, 2004) Classic tricyclic antidepressants as amitriptiline and imipramine convert less easily to their dysmethylated metabolites (respectively nortriptiline and desipramine). Some side effects, especially anticholinergic ones, may be worsened as a consequence, so that when possible drugs blood levels should be carefully monitored. (Cole and Bodkin, 1990) WOMEN OF CHILDBEARING AGE The clinician should explicitly ask his patients about reproductive desire, giving out information on drug teratogenic effects and encouraging a planned pregnancy. Female patients needs for family planning and prevention of sexually transmitted diseases should be routinely addressed. Women with BD who are of childbearing age should be counselled regarding effective contraceptive practice, the possible effects of pregnancy and parturition on the course of their illness, treatment options during pregnancy and lactation, the stress of pregnancy and child-bearing, and genetic transmisión of BD so that they can make informed decisions (Packer, 1992; Cohen et al, 1994). Patients who consider the risks of pregnancy unacceptable should be encouraged to use effective contraception (Cohen et al, 1994), recommending the use of condoms if there are risky sexual behaviours. In case the patient assumes cytochrome P450 inducers (i.e.: carbamazepine, topiramate, oxcarbazepine) higher doses of estrogens or alternative contraceptive methods should be decided, as well as an adjustment of lamotrigine doses (basing on the drug serum levels). Drugs with the least teratogenic effect should be used (Bobes et al, 2008) PREGNANCY AND TERATOGENIC EFFECTS

109 Clinicians should provide the patients with education about teratogenic and other adverse effects of all drugs being used as a standard of care. In addition, the current status of the patient planning to continue a pregnancy should be carefully evaluated. It is a fundamental step in the management of the bipolar pregnant patients because of the intrinsic high risks of untreated mania and depression, as the likelihood of risky behaviour and substance use, which may have consequences for the patient and the foetus (Viguera and Cohen, 1998; Altshuler et al 2003). Moreover, clinicians should as well evaluate the patient s illness history and disease course during eventual previous pregnancies and postpartum periods (Viguera et al, 2002; Altshuler et al, 2003). Data on BD during pregnancy are contradictory. Pregnancy has been associated with reduced risk for psychiatric admission overall (Kendell et al, 1987) and a lower risk for suicide (Appleby, 1991, Markuz et al, 1997). The few published specific findings on pregnancy in patients with bipolar disorder are contradictory. A small (n = 28) retrospective study of patients with lithium-responsive BD type I found that the clinical course of he illness improved during pregnancy (Grof et al, 2000), In contrast, a prospective study of recurrence risk among pregnant bipolar women who continued or discontinued mood stabilizer treatment reported a recurrence risk was 2.3 times greater after discontinuation of mood stabilizer treatment (53 of 62, 85.5%) than with continued treatment (10 of 27, 37.0%). In addition, subjects who discontinued the mood stabilizer spent over 40% of pregnancy in an illness episode, versus only 8.8% of pregnancy among subjects who maintained the mood stabilizer (Viguera et al, 2007). A retrospective study including 30 bipolar mothers found that while half of these patients reported fewer mood symptoms or no change in symptoms during pregnancy, affective symptoms were said to worsen during pregnancy among the other half (Freeman et al, 2002). Another retrospective study observed that 45.3% of 139 patients with bipolar disorder told of severe emotional problems during pregnancy through the first month postpartum (Blehar et al, 1998). In case of pregnancy, an individualized assessment of risks-benefits regarding the opportunity of continuing the psychopharmacological treatment during the first trimester of pregnancy (reporting of maternal and foetal risks) should be done. Information on maternal and foetal risks should be given to the patients (Bobes et al, 2008). More frequent contact by specialist mental health services (including, where appropriate, specialist perinatal mental health services), working closely with maternity services, should be considered for pregnant women with bipolar disorder, because of the increased risk of relapse during pregnancy and the postnatal period (NICE, 2009). A pregnancy in a bipolar woman should be considered of high risk: serum levels of drug treatment should be measured in case of lithium, valproate and carbamazepine. Hepatic and renal toxicity should be evaluated, gestational diabetes should be avoided and eventually managed and thyroid function should be monitored. In case of a therapy with anticonvulsants or lithium foetal morphology should be evaluated to detect malformations, especially in the neural tube and cardiac ones (Bobes et al, 2008). When considering the risks to the foetus from individual agents it must be recognised that agents are not of equal importance for the treatment of bipolar disorder (Dodd and Berk, 2006). As a general rule, treatment during pregnancy should be reduced to the minimum in terms of compounds and dosages used: a dose adjustment for maternal hemodilution during the second and third trimesters of pregnancy has to be taken into account. If the patient is treated with valproate/carbamazepine, an adjunctive therapy with folic acid should be provided (Bobes et al, 2008). In the Viguera and cols study (2007), predictors of illness recurrence during pregnancy, besides the most robust risk factor of discontinuing mood stabilizer treatment, included

110 characteristics associated with illness severity. Such factors were younger onset, more years of illness and more recurrences, a history of rapid cycling, suicide attempts, presence of comorbid disorders, and antidepressant use, so that clinicians should consider element when considering how to manage drug treatment in pregnant bipolar patients LITHIUM The use of lithium during the first trimester of pregnancy has been associated with an increased risk for cardiovascular defects, including Ebstein s anomaly, which involves right ventricular hypoplasia and displacement of the tricuspid valve into the right ventricle. Data on the teratogenic effects of lithium were first collected on a large scale in the 1970s in the International Register of Lithium Babies. Since then, the Register data have been revealed to be biased in favor of reporting adverse events, and more recent data indicate a lower risk for congenital defects from exposure during the first trimester (Llewellyn et al, 1998; Ernst and Goldberg, 2002), so that lithium-related teratogenicity may have been overestimated in the past (Yonkers et al, 2004, Kotzma, 2005). The incidence of major malformations in infants exposed to lithium during their foetal life ranges from 4% to 12%, while the rate in unexposed infants ranges from 2% to 4% (Cohen et al, 1994). The risk of Ebstein's anomaly (20 times more common with lithium) exists especially if the drug is taken during weeks 2 6 post conception (Bazire, 2003). However, the overall risk remains very low because of the rarity of the anomaly. In a recent report, Kozma (2005) concludes that the use of lithium during pregnancy was associated with no significant increase of congenital anomalies. Other types of lithium-related foetal and neonatal complications include: premature delivery, floppy infant syndrome, transient neurodevelopmental deficits, nephrogenic diabetes insipidus, thyroid dysfunctions, and rarely, polyhydramnios. However, the frequency of these events remains unknown (Llewellyn et al, 1998; Frassetto et al, 2002; Kotzma, 2005). Recently, one case of lithium-associated anencephaly was described (Grover and Gupta, 2005). In addition, higher lithium concentrations in maternal serum at delivery have recently been associated with increased risk of perinatal complications (Newport et al, 2005). For patients with relatively mild and stable bipolar disorder, lithium should be discontinued gradually (over a period of 10 days), preferably prior to pregnancy (Cohen et al, 1994). Patients with severe bipolar disorder who have a moderate risk for relapse should continue lithium until the first menstrual period is missed, then temporarily discontinue its use by decreasing the dose over 10 days. Lithium use should be avoided during embryogenesis (4 12 weeks after the last menstrual period). All patients who use lithium during the first trimester should receive appropriate support and high resolution ultrasound and fetal echocardiography at weeks of gestation. Reintroduction of lithium, if clinically necessary, may be undertaken during the second or third trimester, during which its use is not expected to increase risk of congenital abnormalities. Patients with severe bipolar disorder whose risk for relapse during discontinuation outweighs the risk for lithium teratogenicity should maintain lithium throughout the pregnancy (Cohen et al, 1994). Williams & Oke (2000) recommended the following treatment plan: (a) stop lithium prior to conception, (b) restart the compound during trimester 2 or 3, (c) discontinue lithium prenatally, and (d) restore the treatment postnatally. In any case, fetal cardiac ultrasonography is recommended at weeks 18 and 20 of gestation when the maternal clinical conditions require lithium therapy (AAP, 2000). The increase of renal lithium

111 excretion during pregnancy may require an increase of the lithium dosage, whereas it has been suggested that the drug-dosage should be decreased at the beginning of labor, in order to reduce the risk of toxicity related to the abrupt reduction of vascular volume after parturition (Weinstein, 1980). In case of prolonged labor, adequate hydration of the mother should also be maintained (Yonkers et al, 2004). Discontinuation of lithium therapy is not risk free for the pregnant patient. Cessation of lithium therapy for bipolar disorder has been associated with relapse in pregnant and non-pregnant patients (Faedda et al, 1993; Baldessarini et al, 1999; Viguera et al, 2000). Data indicate that abrupt discontinuation of lithium was associated with a greater risk for rebound relapse than gradual discontinuation, so tapering off may be advisable for patients who need to discontinue lithium therapy (Faedda et al, 1993; Cohen et al, 1994) ANTICONVULSANTS VALPROATE Valproate has been associated with teratogenic and toxic outcomes from foetal exposure. Its utilization in pregnant women confers an approximately fivefold increased risk of major malformations and other serious pregnancy complications, especially if the compound is administered in the first trimester of pregnancy (Ernst and Goldberg, 2002; Wyszynski et al, 2005). The overall incidence of major malformations is 11% (Kaneko et al, 1999). Neural tube malformations represent a side effect of major concern and may derive from first trimester exposure. Increased teratogenic outcomes with increased maternal dose have been demonstrated in a primate model (Mast et al, 1986). Reported neural tube defects have included; spina-bifida (1 2%, which is 50 times the spontaneous rate) and developmental retardation (up to 71%) (Lindhout and Meinardi, 1984; Ardinger et al, 1988; Iqbal et al, 2001; Adab et al, 2004), hydrocephalus and meningomyelocele (Robert and Guibaud, 1982). Other severe malformations have been reported from in utero valproate exposure and include skeletal abnormalities and microcephaly (Koch et al, 1983), septo-optic dysplasia (McMahon and Braddock, 1998), and congenital heart defects (Thisted and Ebbesen, 1993; Sodhi et al, 2001). Risk of limb defects due to valproate exposure was calculated as 0.42% using data from 22,294 consecutive malformed infants from the Spanish Collaborative Study of Congenital Malformations (Rodriguez-Pinilla et al, 2000). In a survey of 149 births from the North American Antiepileptic Drug Pregnancy Registry, 16 cases of malformations were identified (10.7%), whereas the prevalence of malformations in a control group of neonates not exposed in utero to anticonvulsant medication was 1.62% (Wyszynski et al, 2005). In an Australian study of 307 first trimester exposures to antiepileptic medications, the incidence of birth defects was 16.7% for valproate exposure (n=103 exposures), 7.7% for lamotrigine exposure (n=68 exposures) and 3.3% for carbamazepine exposure (n=144 exposures), suggesting that valproate is associated with a greater risk to the foetus than other anticonvulsant medications or lithium (Vajda et al, 2003). Also of note is that in utero valproate exposure, termed foetal valproate syndrome, has been proposed well documented (DiLiberti et al, 1984; Thisted et al, 1993) to produce a consistent facial appearance, heart defects and withdrawal syndrome (irritability, jitteriness, hypotonia, and difficulty eating) several other characteristic anomalies and dysfunction of the central nervous system (Kuller et al, 1996). Facial features can include epicanthic folds, a flat nasal bridge, small nose and anteverted nostrils, a long thin upper lip and thickened lower lip (DiLiberti et al, 1984). Gum hypertrophy and hypertrichosis (Stoll et al, 2003) and ocular abnormalities (Glover et al, 2002) have also

112 been associated with valproate exposure. Limb defects such as club feet and club hands may occur (Stoll et al, 2003). Coagulopathies, neonatal hypoglycaemia, and hepatotoxicity have also been reported (Kenedy et al, 1998; Marcus et al, 2003). Case reports of foetal intoxication from valproate exposure have included afibrinogenemia (Majer and Green, 1987), hypoglycaemia (Thisted and Ebbesen, 1993) and two fatal cases of liver atrophy and cholestasis in siblings (Legius et al, 1987). Intrauterine haemorrhage has also been reported (Bason et al, 1998). Long-term neurodevelopmental effects on the offspring of women treated with anticonvulsants have been studied. In a study, 249 children from mothers with epilepsy aged between 6 and 16 and their mothers (n=163) underwent a battery of neuropsychological tests. Forty-one children had been exposed in utero to sodium valproate monotherapy, 52 to carbamazepine monotherapy, 76 to other anticonvulsants or polytherapy and 80 were not exposed to any anticonvulsant. Valproate exposure was associated with a lower verbal IQ in these children. The odds ratio for a verbal IQ score less than 69 was 1.00 in non-exposed children, 1.03 in carbamazepine exposed children and 3.47 in valproate exposed children suggesting that the harmful effects of valproate exposure in utero may extend into childhood neurodevelopment (Vinten et al, 2005). Eadie and Morrow et al. found that the rate of major malformations in foetuses exposed to valproate alone or in combination with other epileptic drugs ranges between 15.2% and 17.1%, and between 6.2% and 9.0%, respectively. In addition, the authors also found that valproate doses higher than mg/day were associated with an even greater increase in malformation rate and a peculiar pattern of anomalies (Kaneko et al, 1999; Vajda et Eadie, LAMOTRIGINE Rapid transplacental passage of lamotrigine has been demonstrated by human placental perfusion studies. Analyses of paired samples showed a cord to maternal lamotrigine plasma concentration ratio of 1.02 and 1.55 in two pairs of samples (Myllynen et al, 2003). An observational study of 16 pregnancies in 14 women treated with lamotrigine demonstrated that mean lamotrigine clearance increases by > 50% during pregnancy and quickly returns to pre-pregnancy rates post-partum; considerable variation in changes in apparent clearance of lamotrigine was measured between individuals and throughout the course of the pregnancy within the same individual (Tran et al, 2002). Another lamotrigine monotherapy study of twelve pregnancies confirmed the considerable inter and intra-individual variation and calculated that lamotrigine plasma level to dose ratios may decrease to 47% of levels measured prior to pregnancy (de Haan et al, 2004). A further study of 14 pregnant women treated with lamotrigine monotherapy found that lamotrigine apparent clearance progressively increased during pregnancy, peaking at 361.2% of pre-pregnancy levels at 32 weeks of gestational age, then slowly declining but remaining high until delivery. Three recent studies reported decrease in lamotrigine levels (from 60% to 65%) between preconception and the second and third trimester of pregnancy in 35 epileptic women; 11 pregnancies required a higher dose of lamotrigine to maintain a therapeutic effect (Tran et al 2002; de Haan et al, 2004; Petrenaite et al, 2005). Toxicity due to high plasma concentrations of lamotrigine in the first two weeks postpartum, as clearance returned to pre-pregnancy rates, was reported by several study participants (Pennell et al, 2004). De Haan and cols reported some toxic effects in women after delivery (2004). Clinicians should measure lamotrigine plasma levels prior

113 to conception and monitor throughout pregnancy and postpartum until clearance rates return to pre-pregnancy levels. Dose adjustments required to maintain the lamotrigine plasma concentration at steady-state should be calculated on a per individual basis. Lamotrigine has not been documented to cause teratogenic outcomes. The International Lamotrigine Pregnancy Registry, mainly focusing on epileptic women, was initiated in 1992 to identify any additional risks of drug-related birth defects (Tennis et al, 2002, Cunnington, 2004). Data from the registry show that major birth defects can be observed in 2.9% of pregnant women exposed to lamotrigine monotherapy (Cunnington et al, 2005). Morrow estimated this percentage at % (Morrow, 2003; Morrow et al, 2006), while Vajda reported it to be 7.7% (Vajda et al, 2004). Percentages of malformations, apart from that reported by Vajda, were within the expected range for malformations from pregnancies in the general population not exposed to anticonvulsant medication (2-3%). There was no distinctive pattern amongst the birth defects recorded. However, the percentage substantially decreased (to 0 2.4%) in the most recent updates of the Australian Registry of Antiepileptic Drugs (Vajda and Eadie, 2005; Vajda et al, 2004). In contrast, the percentage reaches significantly higher values in cases of polytherapy involving valproate. There were 88 first trimester exposures to lamotrigine in combination with valproate with 11 major malformations reported (12.5%) and 182 first trimester exposures to lamotrigine in combination with medications other than valproate with 5 major malformations reported (2.7%) (Cunnington and Tennis, 2005). The observed proportion of major defects after lamotrigine polytherapy without valproate during the first trimester varies from 2.4% to 4.3% (Morro, 2003; Vajda et al, 2003; Cissoko et al, 2002; Vajda and Eadie, 2005). In any case, no specific patterns of abnormalities in any subgroups or within the registry as a whole were observed. The Swedish Medical Birth Registry showed analogous results (Wide et al, 2004). However, lamotrigine was associated with increased risks of poor neonatal adaptation and thrombocytopenia. In a Danish study of 51 pregnancies exposed to lamotrigine in utero, 1 minor malformation was reported (2%) (Sabers et al, 2004). In a UK study of 476 pregnancies exposed to lamotrigine in utero the rate of major congenital malformations was 2.9% (Russell et al, 2004). A study prospectively identified 51 epileptic women exposed to lamotrigine monotherapy during the first trimester of pregnancy (Sabers et al, 2004). No major malformations were recorded in the infants; one minor malformation (a small defect of the left auricle) was observed but it was not regarded as significant. A correlation between lamotrigine-dose greater than 200 mg/day and increased risk of major malformations has been recently suggested (Morrow et al, 2006). Only one report analyzed the safety of lamotrigine for bipolar pregnant women; of the two pregnancies examined, one resulted in the birth of a healthy infant and the other was electively terminated (Bowden et al, 2004). Lamotrigine clearance in the neonate may be slow and lamotrigine levels in the neonate have been reported to remain high when an infant is re-exposed through breast-feeding (Rambeck et al, 1997). A study of 62 children exposed in utero to lamotrigine and assessed at birth and at 1, 3 and 6 months and 1 year after birth measured Apgar score, weight, size, cranial parameters and psychomotor development. All findings were within the expected range for the general population (Dominguez Salgado et al, 2004) CARBAMAZEPINE

114 Both valproate and carbamazepine are associated with increased rates of major malformations, although the association is less strong for carbamazepine (Perucca, 2005). Carbamazepine has been shown not to induce CYP3A4 in the human placenta (Pienimaki et al, 1997). Transplacental exposure to carbamazepine has been associated with an decrease in vitamin K (Kaaja et al, 2002) and folate (Pippinger, 2003) in the foetus, presumably due to enzyme induction. Carbamazepine and three metabolites have been measured in cord blood and compared to maternal serum concentrations. Results showed no evidence of foetal accumulation for carbamazepine or its metabolites (Pienimaki et al, 1997). Carbamazepine has been associated with teratogenic and toxic outcomes associated with foetal exposure. Pooled data from 984 births with in utero exposure to carbamazepine, with no exposures to combined valproate and carbamazepine included, identified nine cases of spina bifida. This suggests a risk of approximately 1%, which is higher than the expected population prevalence of spina bifida of 0.07% (Rosa, 1991). The overall incidence of foetal malformations with carbamazepine is 5.7%. Foetal malformations include microcephaly, other craniofacial skeletal defects, growth retardation, and cardiac defects. Jones and cols (1989) have reported a high rate of major malformations and developmental delay in cases of prenatal exposure to this anticonvulsant (craniofacial anomalies: 11%; fingernail hypoplasia: 26%; developmental retardation: 20%). An increased risk of coagulopathies in infants was also reported (Kaneko et al, 1999). Other malformations reported with carbamazepine exposure have included congenital rib abnormalities (Legido et al, 1991), minor craniofacial defects and fingernail hypoplasia (Jones et al, 1989) and cardiovascular and urinary tract anomalies and cleft palate (Matalon et al, 2002). Other reports of outcomes of carbamazepine exposure have included transient cholestatic hepatitis in a neonate (Frey et al, 1990) and reduced gestational age at delivery (Matalon et al, 2002). The association between neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate in neonates exposed to the compound through the placenta is known as 'carbamazepine syndrome' (Ornoy and Cohen, 1996). However, in a recent observational study the rate of foetal malformations in infants exposed in utero to the compound has been estimated at 2.2% (Morrow et al, 2006). Possible carcinogenicity of carbamazepine, suggested in a case report of congenital neuroblastoma (Baptista et al, 1998), is not supported by substantial data. A study of 80 children exposed in utero to anticonvulsant found an association between deficits in IQ and minor malformations, suggesting that infants with minor malformations due to anticonvulsant exposure, including carbamazepine, may be at increased risk of below average neuropsychological development (Holmes et al, 2005). Further work is needed to clarify the cognitive effects of in utero exposure to carbamazepine as studies have produced mixed findings (Gaily et al, 2004; Adams et al, 2006). Periconceptional folic acid supplementation has been recommended as a means to reduce the risk of neural tube defects, largely based on population data rather than data from women on valproate or carbamazepine, although there is preliminary evidence for prophylactic efficacy in the setting of carbamazepine exposure (Hernandez-Diaz et al, 2001) OXCARBAZEPINE An insufficient number of in utero exposures to oxcarbazepine have been reported to determine its risk during pregnancy. In a report of 12 exposures there were 3 spontaneous abortions and 9 normal outcomes (Morrell, 1996). A larger study reported

115 55 in utero exposures to oxcarbazepine, 35 as monotherapy and 25 as combination therapy. A cardiac malformation was reported in one neonate exposed to oxcarbazepine in combination with phenobarbital (Meischenguiser et al, 2004). In pregnant epileptic women, available teratogenic information is reassuring (Friis et al, 1993; Lindhout and Omtzigt, 1994; Rabinowicz et al, 2002; Meischenguiser et al, 2004; Kaplan, 2004; Wide et al, 2004, de Haan et al, 2004). Nevertheless, three spontaneous abortions, one neonate with amniotic bands and a case of urogenital anomaly were reported after exposure to oxcarbazepine monotherapy (Andermann, 1994; Bulau et al, 1998; Artama et al, 2005). Paediatric examination of a newborn whose epileptic mother took 300 mg three times a day of oxcarbazepine monotherapy throughout the pregnancy showed mild facial dysmorphism, with a discrete epicanthus and a somewhat broad bridge of the nose, but no typical signs of embriopathy (Bulau et al, 1998) OTHER ANTIEPILEPTICS There are no well-controlled studies in humans on topiramate and gabapentin (Iqbal et al, 2001) ANTIPSYCHOTICS There is a substantial lack of data regarding exposure to the second-generation antipsychotics during pregnancy. One prospective comparative reported 60 cases of exposure to olanzapine, 49 cases of exposure to risperidone, 36 cases of exposure to quetiapine, and 6 cases of exposure to clozapine during pregnancy (McKenna et al, 2005). Women who had been exposed to these medications during pregnancy were matched with a comparison group of pregnant women who had not been exposed to antipsychotic medications. No statistically significant differences were found between the exposed and comparison groups in any of the pregnancy outcomes of interest, with the exception of rate of low birth weight, which was fivefold in babies in the group whose mothers were exposed to antipsychotics. These results suggest that secondgeneration antipsychotics do not appear to be associated with an increased risk for major malformations. A significant higher tendency in weight gain was found for atypical antipsychotic-treated women. The largest and most recently published study involved cases in a database from the Swedish Medical Birth Register, in which all citizens are enrolled at birth. All of the women in the country (population approximately 10 million) are enrolled in this database on their first obstetrical visit, so that this was a population-based study. The authors identified 2,908 women who had reported the use of antipsychotic drugs or lithium in early pregnancy between 1994 when the register was established and 2005 (n = 958,729 total pregnancies) (Reis and Källén, 2008). There were 570 women who had taken antipsychotic medications during pregnancy for treatment of various psychiatric disorders: 460 had taken first-generation antipsychotics and 101 had taken second-generation agents. An overall, slightly significant increased risk of major birth defects, mostly cardiovascular defects, especially atrium or septal defects was found. However, these cardiovascular defects occurred only in the group treated with first-generation antipsychotics, while there were no reports of cardiovascular defects in the group who received second-generation agents. In general, atypical antipsychotic agents have a better safety record when used during pregnancy than the conventional mood stabilisers. In a study of 151 pregnancies exposed to monotherapies or combination therapies with olanzapine (n=60), risperidone (n=49), quetiapine (n=36) and clozapine (n=6) there were 110 live births, 22 spontaneous abortions, 15 therapeutic abortions and 4 stillbirths. Major malformations were reported in a neonate exposed to olanzapine and included cleft lip, encephalocele

116 and aqueductal stenosis. A rate of 1 malformation in 151 exposures suggests that these agents are not associated with an increased risk for major malformations. Mean gestational age at birth and birth weight was not effected by drug exposure (Weinstock et al, 2001). Antipsychotic agents are often used in combination with conventional mood stabilisers. Polytherapy is associated with increased risks of adverse outcomes with pregnancy (Morrell et al, 1996). Before safety in the use of atypical antipsychotics can be stated, more and clear data are required for each drug ARIPIPRAZOLE Only 2 case reports involving human pregnancies have been published. In the first one the woman used aripiprazole intermittently during her pregnancy. The newborn infant was born normal and healthy and developed normally during 6 months of follow up (Mendhekar et al, 2006). The second report involved a woman who took aripiprazole from 10 weeks (29 to 39) of pregnancy. This infant had no neonatal complications and was developing normally at 6-month follow-up (Mendhekar et al, 2006) OLANZAPINE Several reports of healthy newborn without complications despite intrauterine exposure to olanzapine have been published (Nagy et al, 2001; Malek-Ahmady, 2001; Lim, 2001; Mendhekar et al, 2002). Some data reported a total of 144 prospectively and 98 retrospectively identified pregnant women treated with olanzapine treated with a daily dosage of 5 25 mg (Goldstein et al, 2000; Ernst et al, 2001). The rates of spontaneous abortions (8.3%), stillbirths (2.1%), pre- and postnatal complications (9.0%), and prematurity (4.2%) were within the range of normal recorded control rates (Kerly, 1991). Data on the outcome of 60 additional pregnancies exposed to olanzapine are also available (McKenna et al, 2005). This study supports the hypothesis that olanzapine, as well as other atypical antipsychotics, is not associated with increased rates of major structural malformations despite a recent communication suggesting that olanzapine may interfere with human embryonic development (Burt and Rasgon, 2004). However, olanzapine appears to be associated with higher risk of lower birth weight and perinatal and gestational metabolic complications, (Kirchheiner et al, 2000; Ernst and Goldberg, 2002; McKenna et al, 2005; Morrow, 2003; Friedman and Rosenthal, 2003) QUETIAPINE Quetiapine in pregnancy: to date, 487 reports have examined prenatal exposure to quetiapine at maternal daily doses ranging from 50 to 600 mg; eight cases of congenital anomalies have been described (Tenyi et al, 2002; Taylor et al, 2003; Yaris et al, 2004; McKenna et al, 2005) RISPERIDONE Approximately 300 cases of pregnancies exposed to risperidone have been reported; in most the outcomes remain unknown. Eight cases of major malformations (with no recurrent patterns of anomalies) have been described (Ratnayake and Libretto, 2002: McKenna et al, 2005). In a report, the rates of major malformation and spontaneous abortions were within expected rates in the general population (Coppola et al, 2007). A case of the use of long-acting injectable risperidone in pregnancy has been reported in the literature, in which the baby was born normal and healthy and continued to be so at 8 months of age when the report was done (Kim et al, 2007). No data concerning the

117 use of paliperidone (which by the way is the active metabolite of risperidone) in pregnancy are yet available. Two other foetuses exposed in utero to maternal daily doses of 4 and 6 mg/day, respectively, showed normal neurodevelopment during the first year of life (Ratnayake and Libretto, 2002) ZIPRASIDONE No published data are available concerning exposure to ziprasidone in human pregnancy BREASTFEEDING The treatment of BD in pregnancy needs to be balanced between the achievement of optimal illness control and the potential iatrogenic risks of medications, which include teratogenicity (morphological and possibly neurobehavioural), neonatal toxicity, and withdrawal syndromes. Similarly, the desirability of breastfeeding during moodstabilising treatment is dependent on maternal BD factors, the overall benefits of breastfeeding (nutritional, psychological and financial), the feasibility of formula feeding, and the potential medication adverse effects for the baby. These decisions are therefore highly contextual, and further complicated by the paucity of inconclusive safety data for most medications in pregnancy and breastfeeding. Randomized controlled studies in these groups are unethical and unfeasible, so that references depend on less scientifically rigorous studies. Clinicians should advice women with BD who are taking psychotropic medication and wish to breastfeed should be informed on the risks and benefits of breastfeeding. Data are lacking regarding use during breastfeeding of many of the drugs currently used to treat BD. While there are many advantages for infant health and maternal infant bonding, breastfeeding almost guarantees sleep deprivation, a condition that does not bode well for psychiatric stability in bipolar patients (Burt and Rasgon, 2004). Antipsychotic, but not clozapine, should be the first choice on these patients. Women should avoid breastfeeding if on treatment with lithium, benzodiazepines or lamotrigine Antidepressant therapy in women on breastfeeding should be done with an SSRI, but not fluoxetine or citalopram (NICE, 2009). The American Academy of Paediatrics Committee on Drugs (2001) published breastfeeding guidelines, which include some data regarding agents commonly used to treat bipolar disorder. These guidelines are based on very limited data, and recommendations for carbamazepine and valproate are based on epileptic populations and generally involve the use of combination medications. These guidelines support the emphasis of the American Academy of Paediatrics in increasing the breastfeeding among women in the USA. The Academy recommends a determination of whether medication is truly necessary, consultation between the paediatrician and the mother s physician, and choice of the safest drug. If there is a risk of harm to the infant, the physician should consider measuring blood levels. It is recommended that the mother take the medication just after she has breastfed the infant or just before the infant is due to have a lengthy sleep period to minimize risk of exposure There are no published controlled studies on the role of psychotherapy in the management of bipolar women during the postpartum. There is one study on the use of interpersonal psychotherapy to treat postpartum depression (O Hara et al, 2000). Many of the psychotropic agents that are used in treating bipolar disorder, such as the benzodiazepines, SSRIs, older antipsychotic agents, clozapine, and lamotrigine are classified by the American Academy of Paediatrics Committee on Drugs as Drugs for

118 Which the Effect on Nursing Infants is Unknown but May Be of Concern. While they appear in low concentrations in milk after maternal ingestion, their long half-lives or those of their metabolites may result in accumulation in plasma and tissues such as the brain. This may have significant consequences during the first few months of life, when infants have immature hepatic and renal function. Carbamazepine and valproate are classified as Maternal Drugs Usually Compatible with Breastfeeding, while lithium is classified among Drugs That Have Been Associated With Significant Effects on Some Nursing Infants and Should Be Given to Nursing Mothers With Caution, and infant serum lithium levels may be indicated. Gabapentin, topiramate, olanzapine, and risperidone are not mentioned in the guidelines (Burt and Rasgon, 2004). Choice of treatment should be based on the mother s clinical state and history of response to medication, regardless of breastfeeding status; whenever possible, polypharmacy should be avoided, and the lowest possible dose of medication to maintain psychiatric stability should be used. Formula supplementation is one way to reduce infant exposure while providing some breast-feeding benefits (Burt et al, 2001). Close monitoring of the infant and a low threshold for cessation or suspension of breastfeeding are recommended (Llewellyn et al, 1998). As breastfeeding does not always prevent conception, it is important to educate patients about birth control options (Newport et al, 2002) LITHIUM High concentrations of lithium have been reported in infant serum, breast milk, and maternal serum, with ranges of 5 200% both in infant serum and breast milk, and of 24 72% in maternal serum (Bazire, 2003; Skausig and Schou, 1977; Kaneko et al, 1999; Chaudron and Jefferson, 2000). One study estimated neonatal lithium levels to be about 25% of the corresponding maternal levels, with none of the 10 infants showing obvious side effects, although transient increases in blood urea nitrogen, creatinine, and TSH were found in some (Viguera et al, 2007b). There are not many reports describing detrimental effects in newborns whose mothers continued to take the compound during the postpartum period. Such effects include lethargy, hypothermia, hypotonia, and T-wave modifications on ECG (Woody et al, 1971; Tunnessen et al, 1972; Skausig and Schou, 1977). The monitoring of lithium levels in breast milk and infant blood has been suggested (Moretti et al, 2003), but it seems not highly feasible ANTICONVULSANTS CARBAMAZEPINE Its concentrations range from 7% to 95% in breast milk and from 6% to 65% in infant serum (Chaudron and Jefferson, 2000). Nonetheless, there is only one case report describing minor adverse effects (poor suckling) in newborns exposed to carbamazepine via breast milk (Froescher et al, 1984). Carbamazepine is metabolized rapidly in newborns, which may explain a relatively low risk of adverse effects (Ebherard-Gran et al, 2205). With regard to carbamazepine, there have been two reported cases of cholestatic jaundice and one case of liver dysfunction in exposed breastfed infants, all of which resolved over time (Frey et al, 2002), and four reports of poor feeding (Chaudron and Jefferson, 2000). Prophylactic administration of antenatal vitamin K to carbamazepine-treated pregnant women has been suggested (Crawford, 2005), but there is evidence that contradicts the usefulness of this practice (Kaaja et al, 2002).

119 LAMOTRIGINE There are reports of breastfeeding during lamotrigine treatment without short-term adverse effects on the infant (Rubin et al, 2004), and although there are theoretical concerns over Stevens-Johnson syndrome, there are no reports of this in breastfed infants exposed to lamotrigine to date. Six studies evaluated the neonatal consequences of Lamotrigine exposure throughout breastfeeding (Rambeck et al, 1997; Tomson et al, 1997; Ohman et al, 1998; Ohman et al, 2000; Liporace et al, 2004; Gentile, 2005). The mean milk/plasma ratio was 0.6 (range: ). A considerable amount of lamotrigine (2 5 mg/day) is excreted in breast milk; the drug-levels in infant serum actually range from 23% to 33% of maternal levels. Nonetheless, no unusual events were observed in the newborns, although in some cases lamotrigine concentration in breastfed children reaches 'therapeutic ranges' (Liporace et al, 2004) OXCARBAZEPINE The milk/plasma ratio of oxcarbazepine was 0.5 (Bulau et al, 1998). From day 3 after delivery, the child was also exposed to the drug throughout breastfeeding. No adverse effects were noted in a short-term follow-up; the baby's re-examination at age 13 months showed normal development, with no sign of mental retardation or neurological deficit. A second infant whose epileptic mother was on 600 mg two times a day of oxcarbazepine during pregnancy and breastfeeding showed a normal evolution during the first 12 months of life (Gentile, 2003) VALPROATE Concentrations range from less than 1% to 10% in breast milk and infant serum, and from undetectable levels to 40% in maternal serum (Chaudron and Jefferson, 2000, Kuller et al, 1996). Thrombocytopenic purpura and anaemia were attributed to valproate exposure through placenta and breast milk (Stahl et al, 1997), but these effects have subsequently been suggested to be unrelated to valproate (Piontek et al, 2000) ANTIPSYHOTICS Data on infant outcomes with atypical antipsychotic exposure via breastfeeding are limited. These medications are excreted in breast milk, but there have been no reported adverse events that can be attributed to these drugs (Wisner et al, 2007). A review highlighted the difficulties of determining the safety profiles of atypical antipsychotics in breastfeeding (Gentile et al, 2008), recommending the avoidance of breastfeeding during clozapine treatment because of potentially life-threatening. A cautious approach is suggested in the absence of solid data (Stowe, 2007). Clinical monitoring for side effects in the infant, additional precautions in premature infants given the relative immaturity of their drug-metabolising capacity, minimising drug exposure, and monitoring of laboratory parameters are suggested (Ng et al, 2009) OLANZAPINE Thirty infants subjected to olanzapine have been evaluated, the majority of whom were exposed in utero to the compound (Ornoy et al, 1996; Kirchheiner et al, 2000; Patton et al, 2002; Ambresin et al, 2004). Five (16.7%) showed adverse effects, which included cardiac problems, jaundice, lethargy, poor suckling, shaking, sleep disturbances, rash, gastrointestinal and extrapyramidal symptoms, and transient neurodevelopmental delay. Olanzapine appears to be excreted into breast-milk in relatively small amounts; the

120 milk/plasma ratio ranges from 0.1 to 0.84 and the relative infant dose from 0.22% to 2.5% (based on the weight-adjusted maternal daily dosage), at maternal day dosages of 5 25 mg (Croke et al, 2002; Gardiner et al, 2003) QUETIAPINE Recently, the amount of quetiapine ingested by an exclusively breast-fed infant whose mother took 200 mg/day of the compound was estimated to be between 0.09% and 0.43% of the weight-adjusted maternal dose. This study also concludes that the level of infant exposure to quetiapine in breast milk appears to be low for significant drugrelated effects (Lee et al, 2004). A recent report (Ritz, 2005) also suggested the safety of paroxetine-quetiapine association (20 and 200 mg/day, respectively) for the nursing infant. The mother was diagnosed with bipolar disorder type I at post partum onset, moderate severity-mixed mood state. Another woman treated with quetiapine fluvoxamine compound while pregnant and also while breastfeeding experienced neither gestational complication nor was her baby adversely effected (Gentile, 2006) RISPERIDONE Hill et al. (2000) calculated risperidone and its active metabolite milk/plasma ratios, and the estimated infant dose exposure during breastfeeding; however, this value was well below the attention critical level of many medications during lactation. To determine the amount of risperidone and its active metabolite transferred into breast milk, Ilett et al. (2004) recently evaluated three mothers treated with this medication. Two patients breastfed their babies, whereas the third mother experienced risperidone-induced galactorrhea. The drug and its metabolite were not detected in the plasma of the two breastfed infants, and no adverse effects were noted. By contrast, risperidone and its metabolite were detected in another infant whose mother took the compound while breastfeeding and drug-levels in breast milk were 10-fold lower than maternal serum levels (Aichhorn et al, 2005) CHILDREN AND ADOLESCENTS The prevalence of paediatric BD in large community samples has been found to range between 0.1% and 2% (Lewinsohn et al, 1995; Costello et al, 1996; Johnson et al, 2000). Bipolar adolescents showed twice the rate of suicide attempts and significantly lower levels of functioning compared with adolescents with major depressive disorder (Lewinsohn et al, 1995). Estimates of the lifetime prevalence of BD (including bipolar II disorder) in adults generally range from 1% to 2%, although some recent estimates have been as high as 3.9%.6-9. In 2 large samples (Lish et al 1994; Chengappa et al, 2003) 50% to 60% of bipolar adults recalled the initial onset of mania or depression to be 19 years or younger. The onset of BD in childhood or adolescence may be associated with a more severe course compared with onset in adulthood (Carter et al, 2003; Perlis et al, 2004). Children of bipolar parents have been well established to be at higher risk than the general population for development of BD. A meta-analysis of studies conducted before 1997 found bipolar offspring to be at 2.7 times higher risk for development of any psychiatric disorder and 4 times higher risk for developing a mood disorder than children of parents without psychiatric illness (Lapalme et al, 1997). Approximately 50% of bipolar offspring meet criteria for at least one DSM-IV psychiatric disorder in cross-sectional studies conducted after 1997 (Duffy et al, 1998; Chang et al, 2000). Bipolar spectrum disorders (BD type I, type II and cyclothymia) were ranged from 14%

121 to 50%, with the exception of a study which found BD in only 4 out of 140 (2.8%) bipolar offspring (Wals et al, 2001). The authors tried to explain this discrepancy by citing much less use of antidepressants and stimulants in the Netherlands and European countries in general compared to the United States, which might lead to fewer cases of BD caused by pharmacologically induced mania; however, there was still a 27% incidence of mood disorders in these offspring, raising the possibility that offspring with prodromal BD forms were included in this category. Little data is available on gender differences in paediatric bipolar disorder. A large study (Biederman et al, 2004) compared the clinical features of bipolar disorder in a large sample of 301 youth with BD. There were no gender differences either in the prevalence of BD, or in the polarity of the disorder at onset. Males were less likely to have a chronic course and more likely to have an earlier onset. They were more likely to have had a decreased need for sleep, a history of tutoring and Attention Deficit Hyperactivity Disorder (ADHD), but less likely to have had anxiety disorders or anorexia. The diagnosis and pharmacological treatment of bipolar disorder in children and adolescents are topical issues in psychiatry DIAGNOSIS Making an accurate diagnosis of bipolar disorder in children is often a difficult clinical task. Boundaries of paediatric BD are still widely discussed, and a specific expression in children has been suggested. Most common mood disturbance in this developmental period seems marked irritability, with affective instability and prolonged bursts of rage reported as most common. It is still debated if children with a prepubertal and earlyadolescent BD phenotype have the same illness as their adult counterparts (Geller et al, 2003; Geller and Tillman, 2004). Severe, persistent, and often violent irritability may lead to the incorrect diagnosis of many cases as conduct disorder (Wozniak et al, 1995). Clinical course also seems to differ from that of adults, tending to be more chronic and continuous than acute and episodic (Davis, 1979; Carlson, 1984), and with more frequent rapid cycles and mixed mania (Carlson, 1984; Geller and Luby, 1997). Differences in clinical presentation and course between youth and adult BD generated considerable controversy among professionals in the field. A possible interpretation is that a broader definition of mania, with less clear-cut episodes and more childhood psychopathology in addition to concurrent comorbidity, could represent a developmental condition with an earlier onset and thus a more severe clinical course with a worse prognosis (Carlson 2005). Many studies report greater severity, longer current episode, preponderance of mania, and high rates of ultra-rapid cycling and comorbid attention-deficit/hyperactivity disorder in child mania in prospective and retrospective studies (Schurhoff et al, 2000; Geller et al, 2000; Findling et al, 2001; Mick et al, 2003; Bellivier et al, 2003; Tillman and Geller, 2003; Tillman et al, 2003; McClure et al, 2005). In most but not all (McClure et al, 2005) studies, children with BD type I resemble the most severely ill adults with BD type I, of whom approximately 20% also have long episodes and rapid cycling (Schneck et al, 2004; Goodwin and Jamison, 2007). Modified diagnostic criteria and assessment techniques should be used in youths (Leibenluft and Rich, 2008). The two primary developmental differences that have been suggested are (a) a distinction between discrete mood episodes separated by periods of euthymia or subsyndromal symptoms in adults, in contrast to chronic symptoms and/or rapid mood cycles in youths, and (b) the prominence of severe irritability over euphoria

122 in paediatric mania. Diagnostic guidelines for youths, different form those for adults, have been developed and used (Geller et al, 1995; Wozniak et al, 1995). Increasing trends in diagnosing youth BD over years could be interpreted as a reconceptualization of youth previously diagnosed with conduct-related disorders (Blader and Carlson, 2007). In a Spanish study (Lazaro et al, 2007) two early-onset BD patients groups were created, prepubertal and adolescent onset, on the basis of data published by a number of authors (Geller et al, 1995; Wozniak et al, 1995). There was a notable prevalence of prior psychopathology and consultations with mental health professionals among patients with childhood onset of BD compared to the adolescent onset group. In spite of the behavioural symptoms, it was not until pre-adolescence that symptoms characteristic of BD were first detected. The mean time between onset of symptoms and diagnosis was one year in both groups, although in more than half of the adolescent onset group, the emergence of symptoms coincided with the time of diagnosis, as is frequently the case among adults. Onset could thus be more insidious in childhood and more acute in adolescence and adulthood. The difference from DSM-IV clinical features may partially explain the delay in diagnosis COMORBIDITY In a recent study (Evans-Lacko et al, 2009), youth diagnosed with BD showed to be significantly more likely to be treated with 1 to 7 chronic medical conditions. In the multivariate model proposed, following comorbidities showed to be significantly more prevalent: cardiologic (OR=1.95; 95 CI, ), gastrointestinal/hepatic (OR=1.46; 95 CI, ), neurological (OR=1.55; 95 CI, ), musculoskeletal (OR=1.21; 95 CI, ), female reproductive (OR=1.94; 95 CI, ) and respiratory (OR=1.24; 95 CI, ). Most importantly, toxic effects and adverse events due to drug therapies were higher in youth diagnosed with BD (OR=3.45; 95 CI, ), compared to youth with other psychiatric disorders (Evans-Lacko et al, 2009). Comorbid psychopathology is common in paediatric BD (Biederman et al, 1999). For example, ADHD is thought to co-occur in approximately 70% of BD youths (Axelson et al. 2006, Dickstein et al. 2005b, Geller et al. 2004). Some authors report ADHD comorbidity at a rate of approximately 90% in prepubertal children and 30% 40% in adolescents with bipolar disorder (Kowatch et al, 2005). Differentiating between bipolar disorder and ADHD can sometimes be a challenge, due to the presence of overlapping symptoms. In fact, some researchers have raised the question whether these are actually two distinct disorders. However, studies of familial aggregation patterns and clinical correlates indicate that pediatric bipolar disorder is distinct from ADHD (Wozniak et al, 1995; Faraone et al, 1997; Findling et al, 2005; Birmaher et al, 2006) Euphoria, grandiosity, hypersexuality, decreased need for sleep, and racing thoughts, which are core symptoms of mania, are not seen in ADHD. Co-occurring ADHD and bipolar disorder may represent a distinct subtype of bipolar disorder with distinct neurobiological alterations (Faraone et al, 1997, 2001). Reported rates of Oppositional Defiant Disorder range from 46% to over 80% (Axelson et al. 2006, Biederman et al. 2005), Conduct Disorder ranges from 12% to 41% (Axelson et al. 2006, Biederman et al. 1999), and high rates of comorbid anxiety, ranging from 45% to 78%, are also reported (Dickstein et al. 2005b, Harpold et al. 2005). In attempting to differentiate the symptoms of BD from those of comorbid illnesses, the clinician must determine if a symptom is present solely during a mood episode or

123 worsens significantly during a mood episode, as opposed to being present only when the child is otherwise euthymic or subsyndromally ill. A symptom isolated to a particular mood episode, or one that becomes markedly more impairing during an episode, could be counted toward the diagnosis of mania (Leibenluft et al, 2008). Conversely, a symptom present between episodes would be considered to be a symptom of another psychological disorder. For example, to a certain degree, diagnostic confusion between ADHD and paediatric BD reflects the overlap between the symptoms of ADHD and the B criteria of mania (e.g., distractibility, decreased need for sleep, talkativeness, increased goal-directed activity and excessive involvement in pleasurable activities). The critical distinction is that ADHD symptoms are constant (i.e., nonepisodic) and reflect the youth s typical behaviour. In contrast, these symptoms reflect mania only if they are inconsistent with the child s baseline behaviour. Thus, for certain symptoms, the DSM uses qualifying words such as decreased need for sleep, more talkative than usual, and increase in goal-directed activity. With regard to Oppositional Defiant Disorder, although negativistic and defiant behaviour may occur in youths with BD, it is critical to distinguish episodic, mood-related behavioural changes consistent with mania from the unremitting behaviour problems of ODD. A child or adolescent with BD is more likely to have an additional disorder, either psychiatric or somatic, than not TREATMENT PHARMACOLOGICAL TREATMENT Clinicians wishing to implement evidence-based pharmacological or psychotherapeutic treatment for their paediatric BD patients face a scarcity of data. The lack of replicated findings from randomized placebo-controlled trials, or trials comparing different psychotherapeutic approaches, prevents strong evidence-based support for treating paediatric BD at the moment (Leibenluft et al, 2008). Medication is often the first intervention with a BD child, with the goal to provide an immediate reduction in symptom severity. Stabilization via medication may also better prepare the child to benefit from psychotherapeutic interventions (Fristad et al. 2003, Miklowitz et al. 2003a, Pavuluri et al. 2004). Despite the widespread use of medication in youths with BD, there are few double-blind, placebo-controlled studies. Different pharmacokinetics and pharmacodynamics of mood stabilizers have to be considered when used in children as these influence drug effects, dosages, toxicity, and adverse effects (Kearns et al, 2003; Martin et al, 2007). It is broadly accepted that the actions of drugs may alter with developmental stages (Kearns et al, 2003). Drug absorption, distribution, metabolism, and excretion processes all show age-dependent changes (Gilman et al, 2006). Children also have comparatively greater total body water, which increases the volume of distribution for water-soluble medications. Lithium s pharmacokinetics in children is similar to those in adults except for a shorter half-life of 18 h (Vitiello et al, 1988), which may result from higher weight-adjusted glomerular filtration rates. So, in children, steady-state blood levels of lithium can be obtained after approximately four days, and higher dosages may be required because of this, and also because of the greater volume of distribution and lower brain-to-serum-lithium ratios (Martin et al, 2007; Scahill et al, 2007). Greater cytochrome P450 activity and higher liver-to-body-weight ratios (Martin et al, 2007) could be the basis for the observed higher plasma clearance of hepatically metabolised drugs, consistently observed in children under 10 years of age compared with adults, which may justify the use of

124 higher weight-adjusted dosages in children (Kearns et al, 2003). The need for higher dosages per unit of body weight in children relative to adults may be mistaken for treatment nonadherence, and vice versa (Gilman et al, 2006). The use of low starting dosages and gradual dose titration are recommended for children and adolescents in order to minimise adverse effects (Birmaer and Axelson, 2007). Scahill and col (2007) proposed some doses adjustments in the use of psychotropic medications in children and adolescents, and recently the International Society for Bipolar Disorder has adopted the same suggestions: lithium: mg/kg/day with serum level mmol/l; valproate: mg/kg/day with serum level μg/l; carbamazepine: mg/kg/day with serum level 4 14 μg/l; lamotrigine: mg/day; risperidone: mg/day; olanzapine: mg/day; quetiapine: mg/day; aripiprazole: 5 40 mg/day; and ziprasidone: mg/day (Ng et al, 2009). The topic of treating a patient with comorbid BD and ADHD is of extreme interest, given the forementioned high prevalence of both conditions and the fact that the latter disorder is treated with stimulant drugs. A randomized, controlled trial of 40 children and adolescents with BD and comorbid ADHD demonstrated that treatment with lowdose mixed amphetamine salts was safe and effective for the treatment of comorbid ADHD once the child s mood symptoms were stabilized with divalproex (Scheffer et al, 2005). Safety data for psychotropic medications in children and adolescents are limited (Greenhill et al, 2003), but preschool-aged children are at higher risk of adverse effects than older children and adolescents (Gleason et al, 2007). The risks for adverse effects seen in children and adolescents compared with their adult counterparts are similar for lithium, lamotrigine, carbamazepine (Scahill and Martin, 2007), valproate (Azorin and Findling, 2007), and atypical antipsychotics (Correll 2008), but special concern related to this group are cognitive adverse effects and sedation that may affect school performance (Gilman et al, 2003), disturbance of bone growth due to anticonvulsants or hyperprolactinaemia (Correll et al, 2008) the long-term sequelae of Polycystic Ovarian Síndrome (PCOS) and the metabolic syndrome in the young, and the unknown potential effects of these medications on physical growth and brain development (Greenhill et al, 2003; Correll, 2006). Clinicians should also be aware of the concerns regarding the efficacy and safety (included suicidality) of antidepressants in youths (Vitiello and Swedo, 2004) LITHIUM Available data on lithium treatment in paediatric BD consist of case reports, chart reviews and a small number of prospective studies. Most of the first lithium reports lacked methodological rigor and included small sample sizes, thereby making it difficult to reach definitive conclusion based on these publications. More recent studies provide better insight into the effectiveness and tolerability of lithium in the treatment of acute mixed and manic states in young people. The few double-blind, placebo-controlled studies of lithium specifically addressed to child-adolescent population are positive, but they are limited by small sample sizes and diagnostic variability (Gram and Rafaelsen, 1972; McKnew et al, 1981; Delong and Aldershof, 1987; Carlson et al, 1992; Geller et al, 1998). However, one controlled discontinuation trial randomized adolescents acutely stabilized on lithium to either ongoing lithium therapy or placebo showed high rates of relapse in both groups. (Kafantaris et al, 2004). Other studies include a positive, large, open-label trial (Kafantaris et al, 2003) and a trial demonstrating benefit for comorbid substance abuse (Geller et al., 1998). Lower rates of relapse for adolescents with acute

125 psychotic mania were reported when antipsychotic medication was maintained for at least 4 weeks in combination with lithium (Kafantaris et al., 2001). A randomized-controlled trial of 91 patients between the ages of 5 and 13, new-onset enuresis has been reported as a unique adverse effect. Fatigue, ataxia, vomiting, headache, and stomach ache were common adverse effect (Silva et al, 1992). The use of lithium in the treatment of bipolar acute depression has been studied in a recently published 6-weeks open trial which examined the effectiveness of lithium for the treatment of acute depression in adolescents with bipolar disorder (Patel et al, 2006). Lithium was well-tolerated in this study with the most commonly reported side effects being headache, nausea, vomiting and stomach ache ANTICONVULSANTS Few studies document the efficacy of the anticonvulsants for BD in youths. The effectiveness of valproate has been described in open-label trials, case reports, and retrospective chart reviews describe (West et al, 1994; Papatheodorou et al, 1995; Wagner et al, 2002; Davanzo et al, 2003; State et al, 2004). Carbamazepine has very limited evidence of efficacy (Hsu, 1986). Limited evidence exists also for the use of lamotrigine in adolescents with bipolar depression (Chang et al, 2006). In a randomized open trial Kowatch and cols (2000) found valproate, lithium, and carbamazepine helpful for mania and mixed episodes in 40 children and adolescents, with response rates of 53%, 38%, and 38%, respectively. Combinations of mood stabilizers in youths with bipolar disorder have also been found to be beneficial and safely tolerated for mania and hypomania (Findling et al, 2003; Kowatch et al, 2003; Findling et al, 2006) VALPROATE A 7-weeks open study on 17 acutely manic youths affected by BD reported the efficacy of divalproex in improving manic symptoms (Papatheodorou et al, 1995). Mean final serum valproic acid level was ± mmol/l at the end of the study; 62% of the subjects were reported to experience marked improvement of symptoms, while 31% of the subjects showed moderate improvement. Valproate was well-tolerated with the most common side effects reported being drowsiness and sedation. However, one of the subjects was reported to have developed transient elevation of liver enzymes that resolved within 1 week medication discontinuation. Another developed abnormal thyroid and cortisol values that were corrected by dose reduction. In an 8-week open multisite study on divalproex 40 bipolar youths were treated with divalproex, and showed a good percentage of favourable responses to the treatment (Wagner et al. 2002). Divalproex was relatively well-tolerated with the most commonly reported side effects being headache, nausea, vomiting, diarrhoea and somnolence. Hepatitis has been found to be a more common side effect in young children, especially those under two years of age and receiving valproate as part of polytherapy, while developmental delay and coexisting metabolic disorders are also risk factors (Bryant and Dreyfuss, 1996) CARBAMAZEPINE Carbamazepine has often been used and was studied in adults, but there is very little evidence from studies to support its use in the treatment of youths with BD. Moreover, there were some reports of carbamazepine-induced mania in some children (Reiss and O Donnell, 1984; Myers and Carrera, 1989).

126 Little data exist from published clinical trials about the use of carbamazepine in the treatment of acute mania. Available data in children and adolescents with acute mixed and manic states consists mainly of case reports (Woolston 1999; Craven and Murphy 2000; Davanzo et al, 2003) and one open clinical trial reported by Kowatch et al, 2000, which observed a similar effectiveness for carbamazepine, lithium and divalproex in the treatment of manic and mixed episodes in paediatric BD. The paucity of data highlights the need for prospective clinical trials (especially randomized placebo-controlled studies) to better define the role of this drug in the treatment of paediatric BD LAMOTRIGINE Data from one open study that suggest that lamotrigine may be beneficial for adolescents with bipolar depression, but no data from randomized, controlled studies. Published prospective studies in adults suggest that lamotrigine may be beneficial for the treatment of mood (especially depressive) symptoms in bipolar disorder. The data particularly supports its role in both the acute and long-term treatment of bipolar depression (Calabrese et al, 1999; Ichim et al, 2000; Calabrese et al. 2000, 2003a; Bowden et al, 2003; Goodwin et al, 2004; McElroy et al, 2004). However, data in paediatric BD basically consists of case reports (Carandang et al, 2003; Thakur et al, 2005) and one recently published open trial with lamotrigine as monotherapy or combination therapy to mood stabilizers, antipsychotics or stimulants, which suggests a role for lamotrigine as monotherapy or adjunctive therapy in paediatric bipolar depression (Chang et al, 2006). Incidence of rash may be increased in paediatric populations, with high initial dose, rapid dose titration, and concomitant use of valproate (Messenheimer, 1998). The increased risk for skin eruptions and Stevens-Johnson syndrome in association with lamotrigine has been reported in young patients (Guberman et al, 1999; Culy and Goa, 2000). However, this increased risk has not been confirmed, as its estimation was based on only 14 possible cases of Stevens-Johnson syndrome or toxic epidermal necrolysis in clinical trials, the diagnosis of which had not been agreed upon by an expert panel of dermatologists. Furthermore, the influences of concomitant valproate use and rapid dose titration were not excluded (Culy and Goa, 2000) OXCARBAZEPINE Wagner and cols. (2006) reported the results of a multi-centered randomized doubleblind, placebo-controlled study. The difference in mean scores at YMRS (which constituted the primary aim of the study) between the treatment groups was not statistically significant.. Oxcarbazepine was well-tolerated with the most commonly reported side effects being dizziness, nausea, somnolence, diplopia, fatigue and rash. Although safe, oxcarbazepine proved not to be more beneficial than placebo in the treatment of paediatric BD. In summary, there is very little evidence to support the use of this drug in the treatment of acute mixed and manic states in children and adolescents ANTIPSYCHOTICS When used as mood stabilizers, the atypical antipsychotic agents are prescribed with the same dose ranges and seem to have the same spectrum of side effects as when used for psychotic illnesses.

127 Results form the Child and Adolescent First-Episode Psychosis Study (CAFEPS), a naturalistic longitudinal study of early-onset first psychotic episodes, show that atypical antipsychotic are commonly and equally used in clinical practice especially risperidone, quetiapine, and olanzapine, are the most used in our context in first psychotic episodes in children and adolescents. These three obtain similar clinical improvement, but differ in their side effects (Castro-Fornieles et al, 2008). Weight gain has been a particular concern for this class of agents, especially in youths (McClellan et al 2007). Hyperprolactinaemia, an issue of concern in adult patients, seems not frequent in prepubertal children, making detection more difficult, but has to be investigated by clinicians as chronic hyperprolactinaemia may impair bone growth and possibly increase risks of osteoporosis, pituitary tumour, and breast cancer (Correll et al, 2008) ARIPIPRAZOLE A recent double blind, placebo-controlled trial on 296 acutely manic bipolar I subjects of 10 to 17 years of age assessed the efficacy of 10mg- and 30mg- aripiprazole monotherapy in reducing significantly YMRS score at the 4 th week of treatment, with a significant improvement from week 1. No significant occurrence of depression in the aripiprazole arms was observed. Aripiprazole was generally well tolerated. In the 10-mg arm adverse effects resulting in study discontinuation were fatigue, sedation, akathisia, aggression and suicidal ideation. In the 30mg- arm adverse effects resulting in study discontinuation were extrapyramidal disorders, exacerbation of BD, vomiting, dystonia and somnolence. Results from this study confirmed data reported in previous open label studies (Barzman et al, 2004; Biederman et al, 2005, 2007) CLOZAPINE There are limited available data regarding the use of clozapine in the treatment of children and adolescents with BD. Results of the only prospective study to date suggest that it may be beneficial in youths with treatment-refractory mania, but there is a need for controlled studies to help define its in paediatric BD. Data regarding clozapine use in children and adolescents with BD consist of case reports (Fuchs, 1994; Kowatch et al, 1995; Masi and Milone, 1998), chart reviews (Kant et al, 2004) and one open clinical trial. Masi et al. (2002) reported A 4-weeks open trial of clozapine in 10 acutely manic or mixed patients refractory to previous pharmacological treatment with a mood stabilizer or a typical/atypical antipsychotic was published (Masi et al, 2002), showing a good response to clozapine monotherapy, with an average dose of 142.5±73.6 mg/day. Clozapine was relatively well-tolerated by the subjects in this study with the most commonly reported side effect being weight gain. Other reported side effects include sedation, enuresis and sialorrhea. There was no reported incidence of agranulocytosis or seizures. Clozapine could thus be effective and safe for treatment-refractory mania in adolescents OLANZAPINE Olanzapine might be beneficial for the acute treatment of mixed and manic states in paediatric BD. A positive multicenter double blind, placebo-controlled trial of olanzapine monotherapy in 161 youths with acute mixed or manic episode (with or without psychosis) has been published (Tohen et al, 2007). Appetite increase and

128 weight gain were the two most commonly reported side effects with mean weight gain at the end of the study being 3.66±2.18 kg. Two open prospective clinical trials have also examined the safety and effectiveness of olanzapine monotherapy in children and adolescents with acute mixed and manic states. In the first study (Frazier et al. 2001), 23 subjects were treated in monotherapy for 8 weeks duration. The most commonly reported side effects were increased appetite, somnolence, abdominal pain and weight gain. The mean weight increase was 5.0±2.3 kg at study end. The second open clinical trial (Biederman et al. 2005a-c) examined the use risperidone or olanzapine in the monotherapy for preschoolers with acute mixed or manic states. Based on the results, the authors noted that olanzapine appeared to be equally effective as risperidone in the treatment of mania in preschoolers with BD, but that further studies were needed to clarify its tolerability. Apart from these studies, some reports on the use of olanzapine in paediatric BD have been published (Krishnamoorthy and King, 1998; Soutullo et al, 1999). Although weight gain may be a potential problem, olanzapine might be beneficial for the treatment of acute mixed and manic states in children and adolescents QUETIAPINE There is evidence that quetiapine may be effective for the treatment of adolescent mania. In a double blind, placebo-controlled trial conducted on a paediatric BD sample, 32 depressed bipolar adolescents were randomized to a quetiapine arm ( mg/d) or placebo (DelBello et al, 2008). Differences between the 2 arms were not statistically different. The placebo arm showed a high placebo response rate. Another double blind placebo-controlled trial compared the efficacy of quetiapine and divalproex in a paediatric sample of 50 acutely manic patients (DelBello et al, 2006). The mean quetiapine dose used at the end of the study was 412±83 mg/day while the mean serum valproic acid level at the end of the study was 101 μg/ml. A statistically significant improvement was observed for both treatment groups with no statistically significant between-group differences found. An open study on the use of quetiapine considered its effectiveness during 48 weeks in a sample of 28 adolescent bipolar patients (Duffy et al, 2009). The study concluded that quetiapine may successfully be used in the maintenance treatment of paediatric BD, and it was generally well tolerated. Some case reports (Schaller and Behar, 1999; Catapano- Friedman, 2001), and a retrospective chart review (Marchand et al, 2004) report the efficacy of quetiapine in the treatment of paediatric BD. Adjunctive treatment with quetiapine has been evaluated in a double-blind, controlled trial, in which the combination of this drug to valproate was more effective than valproate alone in the treatment of acute mania in adolescents (DelBello et al, 2002) RISPERIDONE A recent randomized double blind, placebo-controlled trial on the use of risperidone in acutely manic or mixed adolescents with BD has been published, showing a significant improvement on the YMRS, which was the primary outcome (Haas et al, 2009). Most common side effects were somnolence, headache, and fatigue. Risperidone in combination with either lithium or valproate appeared to be effective in an open-label, prospective trial (Pavuluri et al, 2004, 2006). Previous open trials found risperidone to be effective in the treatment of acute mania in paediatric BD (Frazier et al, 1999; Biederman et al, 2005b), even among pre-school children (Biederman et al, 2005c).

129 Some case reports (Schreier, 1998; Cesena et al, 2002; Duval, 2005), retrospective chart review (Frazier et al. 1999) have been also published on the efficacy of risperidone as a treatment for acute manic or mixed episodes in paediatric BD. Risperidone long-acting injection has been also positively tested in paediatric BD patients; results have been published in a recent case-series (Fu-I et al, 2009). In conclusion, there are some evidence from prospective data that suggest that risperidone may be effective in the monotherapy for acute mixed and manic states in children and adolescents. However, weight gain is a potential concern ZIPRASIDONE An open study on mixed sample (acutely manic BD, schizophrenia, schizoaffective disorder patients) lasted 24 weeks and assessed the efficacy and safety of ziprasidone used in flexible doses (DelBello et al, 2008). It was well tolerated and produced a symptom remission. Adverse effects were more likely to occur at high doses (160mg/d) and were sedation, somnolence, nausea and headache. Significant (>7%) weight gain was assessed in approximately one third of the patients. Available data in children and adolescents consist of a case report of four bipolar youths who had been switched to ziprasidone after a failed trial of lithium, anticonvulsants or other second generation antipsychotic (Barnett 2004). All four patients were reported to have responded favourably to ziprasidone without any serious adverse effects. Prospective studies are therefore needed to further explore the potential benefits of ziprasidone in the treatment of children and adolescents with bipolar disorder PSYCHOSOCIAL INTERVENTIONS The development and research on psychosocial interventions for paediatric BD are in their early stages. Few controlled studies of psychotherapy in BD youths exist. The American Association of Children and Adolescent Psychiatry (AACAP) practice parameters (McClellan et al, 2007) and a prior report (Goldberg-Arnold and Fristad, 2002) suggest that psychotherapeutic interventions with BD youths should aim to improve (a) the child and parent s understanding of the causes, symptoms, and treatment options of BD (psychoeducation); (b) symptom management; (c) coping skills; (d) social and family relationships; (e) academic and occupational functioning; and (f) the prevention of relapse. It still remains to be assessed how exactly psychosocial intervention may enhance medication treatment and contribute to sustained remission and improved quality of life for children and adolescents with BD (West and Pavuluri, 2009). Limited evidence on psychointervention in paediatric BD has been produced for familyfocused psychoeducational therapy (FFT) (Miklowitz et al, 2000), child- and familyfocused cognitive-behavioural therapy (CFFCBT) (Pavuluri et al, 2004b) and multifamily psychoeducation groups (MFPG) (Fristad et al, 2002), which share many of the therapeutic strategies used. Other research groups are working on the paediatric adaptation of interventions which proved some efficacy in the adjunctive treatment of BD (Hlastala and Frank, 2006; Goldstein et al, 2007). Miklowitz and colleagues (2006) adapted their adult BD family-focused therapy for adolescents. Family-focused treatment for adolescents has the goal of reducing symptoms through increased awareness of how to cope with the disorder, decreased levels of expressed emotion from caregivers, and improvement in family problemsolving and communication skills. A 2-year randomized clinical trial in adolescents with BD demonstrated that compared with adolescents who received the control treatment (psychopharmacology plus three sessions of this type of psychoeducation),

130 adolescents who received the adolescent family-focused therapy intervention had shorter times to recovery from depression, less time in depressive episodes, and lower depression severity scores for 2 years (Miklowitz et al, 2008). Child- and family-focused cognitive-behavioural therapy was adapted from the familyfocused therapy (Miklowitz et al, 2004) and was developed as an adjunctive psychosocial intervention for children 8 12 years old with bipolar spectrum disorders and their families (Pavuluri et al, 2004b). This preliminary open trial was conducted to assess its feasibility, patient adherence to the treatment (including dropouts), therapist adherence to the treatment protocol, and parent satisfaction with the treatment experience. This model was designed to meet the specific developmental needs of children 8 12 years old with a spectrum BD. In addition, outcome measures were administered to explore the effect of the treatment on symptom severity and overall functioning. Results on the simple of 34 paediatric BD patients enrolled indicated that the child-family-focused cognitive behavioural therapy was feasible to deliver and that patients were very satisfied with their experience. In addition, preliminary evidence demonstrated a reduction in symptoms of attention problems, aggression, mania, psychosis, depression, and sleep disturbance, and increased global functioning alter the intervention. A maintenance study testing this model, comprising psychosocial booster sessions and optimized pharmacotherapy, was conducted after (West et al, 2007). The 34 patients who underwent the initial 12-session treatment were followed up over a 3- year period and assessed for symptom experience and global functioning at years 1, 2, and 3 during the maintenance phase. During these 3 years, maintenance treatment consisted of ongoing medication management with psychosocial booster sessions using the child-family-focused cognitive-behavioural therapy components. Results indicated that patients were able to maintain the initial positive effects of the treatment over the 3- year follow-up period with continued booster treatment. Finally, this model has also been adapted to group format, comprising 12 weeks of parallel parent and child groups. A preliminary open trial of the child-family-focused CBT group treatment was completed to test feasibility. Results indicated that the group adaptation is feasible to deliver and resulted in a significant increase in parents report of their child s coping skills, a decrease in parenting stress, an increase parents knowledge and self-efficacy in coping with the disorder, and a decrease in parentreported symptoms of mania after treatment (West et al, 2009). Multifamily psychoeducation group showed, in the initial randomized clinical trial of 35 children indicated that families demonstrated increased knowledge about mood disorders, improved family interactions, improved ability to access services, and increased perceived social support from parents, compared with those of a wait-list control group (Fristad et al, 2002). Children s mood symptom severity did not decrease significantly following treatment. A larger-scale randomized controlled trial was recently completed on a sample of 165 paediatric BD patients, showing the efficacy of this brief, adjunctive psychoeducational group psychotherapy, which proved to be associated with improved outcome for children aged 8 to 12 years with BD and major depression (Fristad et al, 2009). The same group also developed an individual form of multifamily psychoeducation called individual family psychoeducation, incorporating similar concepts, but delivered across 24 child, parent, and family sessions. The individual family psychoeducation protocol delivers content similar to that of multifamily model, with the addition of a healthy habits component to address sleep hygiene, nutrition, and exercise. An initial randomized placebo-controlled trial of 20 children suggested that this intervention had a

131 positive impact on children s mood symptoms, family climate, and treatment use (Fristad et al, 2006). An adapted version of interpersonal and social rhythm therapy for adolescents (IPSRT) for adolescents with BD is being developed. IPSRT (Frank, 2005) is focused on the theory that one aspect of vulnerability to BD is instability in circadian rhythms and neurotransmitter systems involved in regulation. In this model, psychosocial stressors are hypothesized to precipitate and/or exacerbate bipolar episodes through their ability to disrupt social and sleep routines. A pilot study of this adapted IPSRT model is underway, but no results have been published yet (Hlastala and Frank, 2006). Goldstein and colleagues (2007) are adapting dialectical behaviour therapy for adolescents affected by BD. This therapy was originally developed for adults with borderline personality disorder (Linehan, 1993). The adapted intervention is delivered over the course of 1 year. The acute treatment period is 6 months and includes 24 weekly sessions that alternate between individual and family therapy. Continuation treatment consists of 12 additional sessions tapering in frequency over the rest of the 1 year. A small, preliminary open trial of dialectical behaviour therapy in 10 adolescents with BD found decreases in suicidality, non-suicidal self-injurious behaviour, emotional dysregulation, and depression symptoms after the intervention (Goldstein et al, 2007) PHYSICAL INTERVENTIONS ECT may be an effective treatment for adolescents with severe BD when more conservative treatments have been unsuccessful. ECT may be considered when there is a lack of response to two or more trials of pharmacotherapy or when the severity of symptoms precludes waiting for a response to pharmacological treatment (Ghaziuddin et al, 2004). There is paucity of data on the use of ECT in paediatric BD populations (Rey and Walter, 1997; Walter and Rey, 2003). Most of the evidence produced is based on case reports and case series. One retrospective study considered the use of ECT in a population of 42 Australian paediatric BD patients, who showed a good response to the treatment in half of the cases (Walter and Rey, 1997). Comorbidity with Axis II disorders was predictor of poorer response. One study considered a mixed ample of bipolar and unipolar patients evaluated 5 years after they had undergone ECT for psychotic depression or mania, matching them with psychiatric controls (Taieb et al, 2002). The two groups showed similar social and school functioning. Data on prepubertal children are even scarce, showing the efficacy of ECT in treating a case of refractory mania (Hill et al, 1997) and depression with catatonic features (Russell et al, 2002) BIPOLAR DISORDER IN THE ELDERLY EPIDEMIOLOGY AND CLINICAL FEATURES There is considerable confusion in the literature concerning the age cut-off for "elderly." Most studies consider as elderly patients being aged 60 years. However some studies consider as older adults patients aged 50 or 55 years or more. Bipolar affective disorder is not uncommon in the elderly. Prevalence rates in the United States range from 0.1% to 0.4% (Sajatovic and Kales, 2006). However, it accounts for 10% to 25% of all geriatric patients with mood disorders and 5% of all patients admitted to gero-psychiatric inpatient units (Yassa et al, 1988). Major risk factors for the development of late-life bipolar disorder are neurologic illness,

132 cerebrovascular disease, and a family history of affective disorders (Ahearn et al, 1998; Hays et al, 1998; Krishnan, 2002). Several studies (Schürhoff et al, 2000; Bellivier et al, 2001; Bellivier et al, 2003; Moorhead and Young, 2003) suggest the existence of subgroups with early and late onset, which may represent different subtypes of bipolar disorder. Incidence and distribution of first-episode mania by age among 246 cases peaked in those aged years, declined steadily until another smaller peak in mid-life followed by a slower decline in incidence in late life (Kennedy et al, 2005). Although there remains controversy (Almeida and Fenner, 2002; Depp et al, 2004), it seems relevant to discriminate between early-onset BD compared to late-onset BD. Late-onset BD is likely to be associated with a lower familial rate of BD, and with more medical and neurological comorbidity (Depp and Jeste, 2004). Late-onset BD mania is generally associated with fewer manic symptoms which are milder than those seen in younger manic patients (Cassano et al, 2000). Symptoms and disease outcome may also differ. Patients with late-onset BD are more likely to have irritable behavioural characteristics, a tendency toward treatment resistance, and a higher mortality rate (Sajatovic, 2002). There is some evidence that the prognosis for the elderly with bipolar disorder is worse than in their younger counterparts (Cutler and Post, 1982). Elderly bipolar patients often have incomplete response to treatment, recurrent episodes of illness, and higher mortality rates than the younger population. Suicide rates are the highest of all age groups in the elderly, and bipolar disorder is also associated with a high risk of suicide. Unfortunately, there continues to be limited data on the treatment for late-life bipolar disorder (Young et al, 2004). The data that are available suffer from a lack of adequate randomized, placebo-controlled studies. It is difficult, therefore, to arrive at any definitive conclusions regarding the management of this disorder. Given this substantial lack of data, clinicians tend to depend on anecdotal evidence, case reports, and expert opinion rather than on reliable, more solid data. This may partially explain the inadequate treatment response, the high adverse-effect rates, and the subsequent frustration in dealing with these patients TREATMENT LITHIUM There are no published, randomized, placebo-controlled trials of lithium in the elderly. Recommendations for clinical use have been based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed-age populations, and clinical experience in geriatric psychiatry (Sproule et al, 2000). Although there has been some suggestion that lithium may be less effective in geriatric patients, supportive evidence for this assumption is lacking. Most studies appear to indicate that lithium is equally efficacious in all age groups (Eastham et al, 1998). Despite this, a recent study showed that prescription patterns are shifting in favour of valproic acid over lithium for elderly patients with bipolar disorder (Shulman et al, 2003). In terms of acute therapeutic outcomes with lithium, Young and cols (2004) reviewed 4 studies each involving >10 elderly patients. The total number of older adult (aged years) and elderly (age _>60 years) patients in the trials was 137. Overall, 66% of patients improved on lithium within a 2- to 10-week time frame. Lithium dosages were not reported. In 3 of the studies, the lithium levels ranged between 0.3 and 2.0 meq/l. It is well established that lithium's pharmacokinetics are substantially altered by age. Although the absorption of lithium is generally unchanged in the elderly (Foster, 1992), its kinetics may be influenced by a number of factors, including reduced volume of distribution and reduced renal clearance. These

133 changes can cause an increase in the concentration-dose ratios. The volume of distribution is decreased in the elderly due to increased adipose tissue, decreased skeletal muscle mass, and decreased total body water (Sproule et al, 2000). Furthermore, lithium is eliminated renally. Because renal clearance is reduced in older adults, its elimination half-life is longer than in younger adults (28-36 vs 24 hours) (Chapron et al, 1982; Shulman et al, 1987). Therefore, it has been suggested that the elderly may require lower dosages and serum levels (Foster, 1992) Controversy exists regarding the optimal serum lithium levels in older adults. A target serum lithium level in the range of 0.4 to 0.7 meq/l for older adults with BD has been recommended (Foster, 1992). Several studies have indicated that elderly patients require 25% to 50% lower dosages than younger patients (Eastham et al, 1998). However, the determination of appropriate serum levels should be influenced by age, medical status, tolerability, and fragility (Sajatovic et al, 2005). The therapeutic benefits of lithium may be modified in the elderly. The adverse effects observed in younger adults are also seen in older patients. According to a retrospective chart review, there was no significant difference between elderly and adult patients with regard to the overall incidence of adverse effects, but there was a significantly greater incidence (p < 0.02) of moderate to severe adverse effects in the elderly. (Smith and Helms, 1982). Typical adverse events associated with lithium include gastrointestinal distress, nausea, vomiting, weight gain, cognitive impairment, ataxia, fine hand tremor, cerebellar dysfunction, renal impairment, polyuria, polydipsia, diabetes insipidus, hypothyroidism, electrocardiogram (ECG) changes, rash, acne, and psoriasis (Sajatovic et al, 2005). The neurotoxic effects of lithium are characterized by confusion, disorientation, memory loss, ataxia, and akathisia. Neurotoxicity may occur in the elderly at levels considered therapeutic in the adult population (Sproule et al, 2000). Lithium can cause ECG alterations in geriatric patients. Specifically, reports have indicated a high frequency of ECG T-wave morphologic changes (Mitchell and Mackenzie, 1982). Therapeutic and toxic levels of lithium have occasionally been associated with serious cardiac dysfunction. The incidence of cardiac complications may increase with age (Mitchell and Mackenzie, 1982). Lithium also affects several other organ systems. It antagonizes thyroid function. In a survey of 148 elderly outpatients, 32% were on thyroxine or had elevated thyroid-stimulating hormone levels) (Goldstein et al, 2006). In another study of 46 psychiatric outpatients aged 50 to 84 years, polyuria, polydipsia, weight gain, and edema occurred in 46% (Hewick et al, 1977). Lithium toxicity can be life-threatening. Its most dramatic manifestations involve the central nervous system and the kidneys. Some of the effects can be permanent. In a case-control study involving elderly patients continuously treated with lithium, 4% were admitted at least once over 10 years for lithium toxicity (Juurlink et al, 2004). Interestingly, the risk of lithium toxicity was dramatically increased when a loop diuretic or an ACE inhibitor had been started within the previous month ANTIEPILEPTIC DRUGS There do not appear to be any published, controlled studies with these medications that focus on late-life bipolar disorder. Recommendations for clinical use have been based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed-age populations, and clinical experience in geriatric psychiatry. Valproate and carbamazepine reportedly arc the most widely prescribed agents for bipolar disorder in the elderly (Sajatovic et al, 2005).

134 CARBAMAZEPINE Basing on our literature review there are no published, controlled trials of carbamazepine that focus on late-life BD. Studies in mixed-aged populations have proposed that carbamazepine is inferior to lithium in the long-term treatment of bipolar disorder (Greil et al, 1998). However, it has also been suggested that patients with nonclassical features may profit more from prophylaxis with carbamazepine. Carbamazepine appears to be inferior to valproate in the treatment of acute mania in a mixed-age population (Vasudev er al, 2000). Carbamazepine induces the metabolism of drugs that are metabolized by the liver (Sajatovic et al, 2005). It is highly protein bound. Carbamazepine metabolism is auto-induced in the elderly, as in younger patients. Because of the auto-induction process, it may become necessary to increase carbamazepine dosages over the first 3 to 6 weeks of treatment to maintain a steady drug level. Targeted serum levels are generally 4 to 12 pg/l. Possible drug-drug interactions with carbamazepine include calcium channel antagonists, cimetidine, terfenadine, and erythromycin (Sajatovic et al, 2005). The most common adverse effects of carbamazepine are neurologic in origin. They include dizziness, sedation, vertigo, ataxia, diplopia, nystagmus, blurred vision, and cognitive impairment. These effects are dosage related, transient, and often reversible with dosage reduction (Eastham et al, 1998). Cognitive adverse effects may be particularly problematic in the elderly (Hirsch et al 2003). Other adverse effects include alteration of the normal regulation of antidiuretic hormone (vasopressin), leading to hyponatremia (Eastham et al, 1998). Carbamazepine has quinidine-like properties. It has been associated with bradycardia and atrioventricular conduction delays. Kasarskis and cols (1992) observed these potentially life-threatening bradyarrhythmias or atrioventricular conduction delays mainly in elderly women. The patients had either therapeutic or modestly elevated carbamazepine serum levels. Rashes are common with carbamazepine therapy, as are mild blood dyscrasias such as mild leucopoenia (Cates and Powers, 1998). Carbamazepine-induced rashes have been shown to occur in 12% of adult psychiatric patients, while leucopoenia has occurred in 7% of adults. Severe rashes and blood dyscrasias, such as aplastic anaemia and agranulocytosis, arc rare, however. The incidence of drug induced blood dyscrasias increases with advanced age. It has been suggested that elderly psychiatric patients treated with carbamazepine that develop skin rashes should receive vigilant monitoring of blood counts, as there may be an association with carbamazepine-induced rashes and blood dyscrasias (Cates and Powers, 1998) LAMOTRIGINE Lamotrigine has not been well studied in the geriatric population. A small, open-label, uncontrolled case series involving 5 women with bipolar disorder reported that 3 of the 5 improved after 6 weeks when lamotrigine was added to either lithium or valproate (Robillard and Conn, 2002). The mean age of the patients was 71.5 years. The 3 patients who improved had rapid cycling bipolar disorder. The drug was well tolerated, and no rashes were noted. Another case report suggested that lamotrigine may have a role in the replacement of ECT in treatment-refractory bipolar depression (Rhodes, 2000). Sajatovic and cols (2005b) retrospectively examined the response to lamotrigine, lithium, and placebo in older (aged >55 years) adults with bipolar I disorder who participated in 2 mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. The data from 98 older adults (lamotrigine, n = 33; lithium, n = 34; placebo, n = 31) were examined. The authors found that lamotrigine, but not lithium, significantly

135 delayed the time to intervention for any mood episode, compared with placebo (lamotrigine vs. placebo, p = 0.011; lithium vs. placebo, p = 0.122; lamotrigine vs. lithium, p = 0.245). The median time to intervention for a mood episode was 201 days for lamotrigine, 138 days for lithium, and 98 days for placebo. Mean total daily doses were lamotrigine 240 mg and lithium 750 mg. When analyses were adjusted for index mood, no significant differences were found (lamotrigine vs. placebo, p = 0.084; lithium vs. placebo, p = 0.184; lithium vs. lamotrigine, p = 0.210). Lamotrigine, but not lithium, significantly delayed time to intervention for a depressive episode (lamotrigine vs. placebo, p = 0.011; lithium vs. placebo, P = 0.779; lamotrigine vs. lithium, p = 0.011). Median time to intervention for depression was 149 days for lithium and 182 days for placebo but was not calculable for lamotrigine because <50% of patients relapsed to depression. Analyses adjusted for index mood showed that results for the lamotrigine group reached statistical significance (lamotrigine vs. placebo, p = 0.021). Lithium, but not lamotrigine, significantly delayed the time to intervention for mania/hypomania/mixed symptoms compared with placebo (lithium vs. placebo, p = 0.034; lamotrigine vs. placebo, p = 0.233; lamotrigine vs. lithium, p = 0.350). Median time to intervention for mania was 236 days (34 weeks) for placebo but was not calculable for the lithium and lamotrigine groups. When analyses were adjusted for index mood, no significant differences were found. A disproportionate number of patients in the analysis came from the study with an index episode of depression (lamotrigine, n = 24; lithium, n = 26; placebo, n = 21) compared with an index episode of manic/hypomanic/mixed symptoms (lamotrigine, n = 9; lithium, n = 8; placebo, n = 10). When older adults judged currently or recently depressed were examined separately, a significantly longer time to intervention for a mood episode was observed with lamotrigine, but not lithium, compared with placebo (lamotrigine vs. placebo, p = 0.029; lithium vs. placebo, p = 0.319; lamotrigine vs. lithium, p = 0.113). Lamotrigine was also superior to placebo and lithium for time to intervention for depression in the depressed subgroup, but no significant treatment effect was observed for time to intervention for mania. When older adults entered the study recently manic/ hypomanic/mixed, no significant effect was observed for any treatment on any efficacy measure. Overall, these older adults reported more adverse events with lithium treatment (85%) than with lamotrigine (82%) (Sajatovic et al, 2005). Of adverse events occurring in >10% of patients, those more common with lithium than lamotrigine included diarrhoea, headache, nausea, infection, amnesia, dizziness, dyspraxia, xerostomia, tremor, fatigue, and influence. Only back pain was more common with lamotrigine. The overall incidence of rash was similar between treatment groups: lamotrigine, n = 1 (3%); lithium, n = 2 (6%); placebo, n = 0 (0%). In the randomized phase, no cases of serious rash were reported. The overall incidence of weight loss (<4%), weight gain (<6%), mania (<9%), and depression (<4%) reported as adverse events was similar between treatment groups. Most adverse events were mild to moderate in intensity and resolved without sequelae. No serious adverse events with an incidence of >10% were reported in any treatment group. The proportion of patients that withdrew from the study because of adverse events was highest in the lithium group. Adverse events leading to premature withdrawal were reported in 18% of lamotrigine-treated patients, 29% of lithium-treated patients, and 13% of patients in the placebo group (Sajatovic et al, 2005). Lamotrigine appears to be well tolerated in the long term. It is metabolized in the liver and has little influence on the pharmacokinetics of other agents, although it may increase plasma concentrations of the active metabolite of carbamazepine during concomitant administration (Goa et al, 1993). Carbamazepine also lowers the

136 concentrations of lamotrigine in the blood. Lamotrigine and valproate should be used cautiously when administered together, since valproate doubles the plasma level of lamotrigine, and lamotrigine decreases the concentration of valproate by 25% (Robillard and Conn, 2002). The most common adverse effects in 1 study of 463 mixed-age adults were headache, insomnia, non-serious rash, tremor, and somnolence. Non-serious rash presented in 7% of the lamotrigine group compared with 2% of the placebo group (p < 0.05) (Calabrese et al, 2003). In another study, the incidence of rash associated with hospitalization among adults treated with lamotrigine was 0.3%. The incidence of cases reported as possible Stevens-Johnson syndrome was 0.1% for adult patients. Compared with the other antiepileptic agents, lamotrigine has a favourable cognitive profile. One study showed improvement of cognitive activation after introducing treatment (Aldenkamp et al, 2003) OXCARBAZEPINE Oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate (May et al, 2003). In 1 study, the 4 most common adverse events experienced by elderly patients taking oxcarbazepine were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). In addition, it was noted that elderly patients taking concomitant natriuretic drugs were more likely to develop serum sodium levels <135 meq/l (Kutluay et al, 2003) VALPROATE Valproic acid has been shown to be effective in the acute treatment of bipolar disorder in several studies. Young and cols (2004) reviewed 5 studies, 4 of which were retrospective and involved elderly manic patients taking valproate. A total of 137 patients were observed. The dosages ranged from 250 to 2250 mg/d. Valproate concentrations ranged from 25 to 120 ηg/ml. Overall, 59% of patients met criteria for improvement. In a case series of 6 patients, 5 improved with valproate alone or in combination with other agents) (Mordecai et al, 1999) Another retrospective study, involving 59 patients, found similar response rates between valproate (75%) and lithium (82%) in the treatment of mania in older adult and elderly patients when therapeutic levels were achieved (Chen et al, 1999). Although controlled studies have not been completed, valproate in combination with lithium may be helpful for geriatric patients with rapid cycling BD (Schneider and Wilcox, 1998). The combination may also be beneficial for elderly patients who arc only partially responsive to lithium monotherapy (Schneider and Wilcox, 1998; Goldberg et al, 2000). In terms of pharmacokinetics, age-associated changes involve decreased protein binding and decreased albumin levels. Valproic acid is mostly bound to albumin, resulting in an increase in the free (unbound) fraction of the drug. Because the unbound fraction of the drug is pharmacologically active, elderly patients may require lower dosages (Calabrese et al, 2003a). The elimination half-life may be prolonged as well, due to the greater volume of distribution in the aged (Bryson et al, 1983). Chen and cols (1999) have therefore suggested a lower therapeutic range for elderly patients comprised between 65 and 90 ηg/ml. Valproic acid is extensively metabolized in the liver. It is a weak inhibitor of drug oxidation. Serum concentrations of drugs that undergo oxidative metabolism (cg, phenobarbital, phenytoin, tricyclic antidepressants) may be increased (Eastham et al, 1998). The total valproate concentration-dose ratio is decreased by phenytoin and carbamazepine (Young et al, 2004). Valproate also inhibits

137 the metabolism of lamotrigine (Young et al, 2004). The most common adverse effects associated with valproate are gastrointestinal symptoms, somnolence, and weight gain. Other adverse effects include hair thinning, thrombocytopenia, and elevated liver enzyme levels (Sajatovic et al, 2005). The same authors report that patients with urea cycle disorders may develop hyperammonemic encephalopathy. Pancreatitis occurs in <1% of patients and is usually seen in younger patients, early in treatment. The risk of hepatic failure also appears to be lessened with increased age (Bowden, 2003). Valproate has been associated with Parkinsonism in elderly patients. In 1 case report, a 66-year-old woman with a bipolar disorder developed Parkinsonism after taking valproate for 3 years (Guzelcan et al, 2004). Approximately 5 weeks after she stopped taking the drug, the parkinsonism improved. It appears that Parkinsonism as an adverse effect of valproate occurs mainly in patients aged >50 years who have been on valproate for a long period of time. Once the medication is discontinued, Parkinson symptoms decrease within a few months. The authors of the case report maintain that Parkinsonism as an adverse effect of valproate is very likely to occur in patients with BD. The mechanism whereby this occurs, however, is unclear (Guzelcan et al, 2004) ANTIPSYCHOTICS Traditional antipsychotic agents have held extra-pyramidal symptoms (EPS) and tardive dyskinesia increases with age. Atypical antipsychotics appear to have much lower rates of EPS and tardive dyskinesia, and may therefore be a better choice for geriatric patients (Van Gerpen et al, 1999). Additionally, antipsychotics, especially low-potency agents, have anticholinergic effects. These can contribute to tachycardia, constipation, urinary hesitancy/obstruction, and cognitive impairment, α1-receptor antagonism by antipsychotic drugs may cause orthostatic hypotension, which in turn can contribute to falls. Unfortunately, published controlled studies of atypical antipsychotic agents in the elderly are lacking, and information regarding these agents has been extrapolated from mixed-age populations (U.S. FDA, 2006). Several concerns have been raised regarding the use of atypical antipsychotic agents in the elderly. Any potential benefit from these agents must now be balanced against the risks associated with their use. The Food and Drug Administration (FDA), the U.S. equivalent of European Agency of the Drugs (EMEA), has placed a black box warning on all atypical agents cautioning of increased mortality in elderly patients with dementia-related psychosis. There appears, in trials, to be a risk of death in drug-treated patients of between 1.6 to 1.7 times that seen in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was -4.5%, compared with a rate of-2.6% in the placebo group. Most of the deaths appeared to be either cardiovascular (cg, heart failure, sudden death) or infectious in nature (FDA, 2006) A meta-analysis reported results consistent with the FDA's report (Schneider et al, 2005). No drug appeared to be individually responsible for the effect but rather each contributed to the overall effect. Although these trials did not involve elderly patients with bipolar disorder, it appears likely that the risks reported by the FDA can be extrapolated to occur with the use of these medications in the elderly for any condition. Results from a study on 367 psychiatric inpatients with mixed diagnosis (schizophrenia and BD) treated with second-generation antipsychotic agents (82) indicate that older age is significantly associated with the metabolic syndrome and that there is a 2-fold increase in the predicted 10-year CHD risk in patients with the metabolic syndrome treated with second-generation antipsychotic agents.

138 CLOZAPINE Shulman and cols (1997) assessed the efficacy of clozapine in 3 elderly men with BD type I (most recent episode manic with psychotic features). The patients were refractory or intolerant to treatment with lithium, valproate, benzodiazepines, and traditional neuroleptics both alone and in combination. Scores on the Clinical Global Impressions scale improved with clozapine. There were no significant drops in granulocyte counts, and patients had sustained improvement, on average, over 11 months. The risk of agranulocytosis is between 0.3% and 1.0% in the younger population. This risk appears to be increased for older adults (Barak et al, 1999). Other adverse effects that are of concern in the elderly include sedation, postural hypotension, anticholinergic effects, and increased risk for seizures RISPERIDONE Risperidone was found to be effective in elderly bipolar patients in 1 case series (Yerrabolu et al, 2000). Adverse effects of concern in the aged include postural hypotension, dose-dependent EPS, and hyperprolactinaemia (Bai et al, 2002). There is no effect on QT dispersion, although it does prolong the QT interval (Yerrabolu et al, 2000). The use of both risperidone and olanzapine may be associated with increased rates of cerebrovascular adverse events, including stroke and transient ischemic attacks. In 4 placebo-controlled trials, which lasted 1 to 3 months and involved >1200 patients with Alzheimer's disease or vascular dementia, cerebrovascular adverse events were twice as common in the risperidone treated group (4%) as in the placebo group (2%) (Wooltorton, 2002). However, there has been some controversy regarding this apparent increased risk for stroke. A recent retrospective study found that older adults with dementia who were taking atypical antipsychotic agents had a risk of ischemic stroke similar to those taking typical antipsychotics (Gill et al, 2005) OTHER ANTIPSYCHOTICS Basingd on our literature review there appear to be few reports of use of these agents specific to elderly bipolar disorder patients. Olanzapine, like risperidone, may be associated with an increased risk of cerebrovascular events (Woolterton, 2004). One case report found it to be effective in the treatment of stuporous catatonia in an 85-yearold bipolar patient (Nicolato et al, 2006). In 1 open-label study, quetiapine, when given within the recommended dosage range, had a benign EPS profile, with potentially greater tolerability and comparable efficacy to risperidone in older outpatients (aged years) with psychotic disorders (Mintzer et al, 2004). Aripiprazole has demonstrated reduction of both positive and negative symptoms of schizophrenia (Madhusoodanan et al, 2004). It lacks any significant EPS, tardive dyskinesia, sedation, weight gain, anticholinergic effects, or corrected QT prolongation in elderly patients with schizophrenia or schizoaffective disorder. It appears to be a safe and effective medication for elderly patients (Mahusoodanan et al, 2004). However, trials in geriatric elderly patients with bipolar disorder have yet to be completed ANTIDEPRESSANT Gijsman and cols (2004) reviewed randomized controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression. The trials

139 involved patients aged up to 70 years; 75% of the patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. The rate of switching to mania or hypomania for tricyclic antidepressants was 10%; for all other antidepressants it was 3.2%; and for placebo it was 4.7%. The conclusion was that antidepressants are effective in the short-term treatment of bipolar depression. The trial data did not suggest that switching is a common early complication of treatment with antidepressants (Guijman et al, 1998). Others have noted antidepressantassociated mania in late life occurs most often with tricyclic antidepressants (Young et al, 2003). Thus, it may be prudent to use a Selective Serotonin Re-Uptake Inhibitor (SSRI) rather than a tricyclic antidepressant as first-line treatment when choosing an antidepressant (Gijman et al, 1998). Schaffer and cols (2006) conducted a population-based retrospective cohort study of 1072 elderly (aged >66 years) outpatients with BD who had been dispensed an antidepressant prescription. The control group consisted of 3000 elderly bipolar patients who were not taking any antidepressants. SSRIs accounted for 68% of the antidepressant prescriptions, while tricyclics, serotonin and norepinephrine reuptake inhibitors, and other antidepressants comprised the remainder. The principal finding was that elderly bipolar patients who were prescribed an antidepressant were significantly less likely to be admitted for mania than elderly bipolar patients who were not taking an antidepressant. Antidepressant use was not associated with a significant decreased rate of hospitalization for depression (Schaffer et al, 2006) BENZODIAZEPINES Potential benefits must be weighed against risks in the elderly. Significant adverse effects that may be associated with benzodiazepine use in the elderly include falls, cognitive impairment, sedation, and impairment of driving skills. Long-term use of benzodiazepines should be discouraged because of the risk of dependence, which can be a serious problem in the elderly. Unrecognized and untreated benzodiazepine dependence can lead to serious medical complications (Madhusoodanan and Bogunovic, 2004) PSYCHOTHERAPY Bipolar disorder is often only partially treated by medications. This has led to recent developments in the adjunctive psychological treatment of this disorder. A recently published review examined outcome studies of psychological interventions reported since 1990 (Jones, 2004). The interventions included psychoeducation, CBT, interpersonal and social rhythm therapy, and psychoanalytic therapy. The research indicated that a range of psychological approaches appeared to benefit people with bipolar disorder. The clearest evidence was for individual CBT, which had an impact on symptoms, social functioning, and risk of relapse. Unfortunately, many of the studies were uncontrolled and of poor quality. They were also restricted to younger adults, and so it remains unclear how elderly patients would respond to psychotherapeutic interventions (Jones, 2004) ELECTROCONVULSIVE THERAPY ECT has been frequently demonstrated to be a safe and effective treatment for BD in the elderly (Greenberg and Fink, 1992) The decision to use ECT in an elderly patient is

140 complex and should be based on the patient's illness, risks of treatment compared with alternative or no treatment, and both the patient's and family's wishes (Greenberg and Fink, 1992) Approximately 80% of patients with mania who receive ECT show remission or marked clinical improvement (Mukherjee et al, 1994). In the treatment of elderly patients with depression, there appears to be no significant difference between unilateral and bilateral ECT, either in improvement or in the number of treatments needed. Post-ictal recovery times and memory impairment are greater, however, with bilateral ECT as compared with unilateral ECT (Fraser and Glass, 1980; Little et al, 2004). ECT is generally well tolerated by geriatric patients. It is the treatment of choice for elderly patients with mania who are intolerant of, or refractory to, pharmacologic management or who have a severe behavioural disturbance that necessitates a rapid response (Eastham et al, 1998). The mortality rate associated with ECT has been reported to be 0.01%. (Alexoupoulos et al, 1984; Burke et al, 1987; Greenberg and Fink, 1992). Geriatric patients develop more medical problems in the course of ECT that require medical treatment or temporary discontinuation of treatment than do younger controls, (Alexoupoulos et al, 1984). In 1 study, complications occurred in 35% of the elderly patients as opposed to 18% of a younger age group (Burke et al, 1987). The most important of these were cardiovascular in nature. The risk for complications was found to be increased in the very old, those in poor general health, and those taking multiple medications, especially cardiovascular agents. There was no relationship between either complications or outcome or between complications and the number or laterality of treatments (Burke et al, 1987). Despite the increased frequency of adverse events in the aged, the majority of medical problems that occur are reversible (Alexoupoulos et al, 1984).

141 011 COST-EFECTIVENESS ANALYSIS INTRODUCTION BURDEN OF BIPOLAR DISORDER SOMATIC COMORBIDITIES COSTS DERIVED FROM DELAY IN DIAGNOSIS COST/EFECTIVITY OF TREATMENTS DRUGS PRESCRIPTIONS PSYCHOSOCIAL INTERVENTIONS PHYSICAL TREATMENTS INTRODUCTION Bipolar illness is associated with high costs to society in healthcare resources and lost productivity. Its prevalence, the significant impairment and the high rates of comorbidity associated contribute to these costs. Apart from these intrinsic aspects, related to the high morbidity of the illness, other factors may determine the overall cost of BD in a Health Service. The delay in the diagnosis of BD may cause an increase in the costs by increasing the use of useless therapies, the days spent ill and the hospitalizations. The pattern of drug prescription, as well as other available therapies, may greatly influence the costs of every patient with variable, not always optimized results in the outcome of his/her disorder. Measures of population health commonly used in cost-effectiveness analyses are: the Disability-adjusted life year (DALY), a time-based measure that combines in a single indicator years of life lost from premature death and years of life lived with a disability; the Quality-adjusted life-year (QALY), an index of health gain where survival duration is weighted or adjusted by the patient s quality of life during the survival period, which is also used as a measure of disease burden, including both the quality and the quantity of life lived, as well as a tool to assess the value for money of a medical intervention. The QALY is based on the number of years of life that would be added by the intervention: each year in perfect health is assigned the value of 1.0 down to a value of 0.0 for death; the Incremental cost-effectiveness ratio (ICER) of an intervention, which is defined as the ratio of the change in costs of a therapeutic intervention (compared to the alternative, such as doing nothing or using the best available alternative treatment) to the change in effects of the intervention.

142 11.2. BURDEN OF BIPOLAR DISORDER BD presents with a broad burden of illness (MacQueen et al, 2001, Calabrese et al, 2003) and substantial adverse effects on role functioning (Bauer et al, 2002; Hirschfeld et al, 2000; Simon, 2003). Mood disorders also impose significant burdens on families, caregivers, and employers (Wells and Sherbourne, 1999; Hirschfeld et al, 2003). The World Health Organization ranks bipolar disorder as one of the top 10 causes of disability in the world (WHO, 2002). More than 90% of bipolar patients present recurrences; residual symptoms and recurrent episodes over time may lead to progressive deterioration in functioning (Tohen et al 2003b; Perlis et al, 2006). Functional recovery tends to lag behind symptom improvement so that patients suffer from varying levels of disability and impairment even when symptoms have improved (Dion et al, 1988; Keck et al, 1998; Tohen et al, 2003b). Although there have been recent advances in pharmacotherapy and outpatient therapy, hospitalisation still accounts for a substantial portion of the direct costs. A variety of outpatient services are increasingly important for the care of patients with bipolar disorder and costs in this area continue to grow. Indirect costs due to morbidity and premature mortality comprise a large portion of the cost of illness. Lost workdays or inability to work due to the disease cause high morbidity costs. Intangible costs such as family burden and impaired health-related quality of life are common, although it has proved difficult to attach monetary values to these costs (Kleinman et al, 2003). Mood disorders are common in working populations (Kessler et al, 1994, 2003) and have significant effects on work performance. Studies have found that mood disorders are associated with significantly increased direct and indirect costs, including expenditures for healthcare treatment as well as the costs of diminished or lost productivity (Jarvinen et al, 1998; Greenberg et al, 1993). Studies have also found that bipolar disorder can have severe and often enduring negative effects on occupational functioning (Michalak et al, 2007), resulting in significant indirect costs through lost productivity. Wyatt and Henter (1995) estimated that the economic costs of bipolar disorder from a societal perspective were $45 billion a year in the United States, with the economic losses due to work impairment accounting for the largest proportion (nearly $18 billion annually) of this total. This estimate translates into annual workplace costs of over $125,000 for a company with 1,000 employees. In the UK, the economic value of work days lost due to BD has been estimated to be several times larger than the direct medical cost (Das Gupta and Guest, 2002), and this cost to employers and sufferers is not reflected in reported National Health Service costs. Basing on a review of 1996 insurance claims from approximately 1.66 million individuals, (Peele et al, 2003) reported that BD was the most expensive behavioural healthcare diagnosis both for patients themselves and for their insurance plans in the US. For every behavioural health care dollar spent on outpatient care for bipolar disorder, $1.80 was spent on inpatient care, suggesting that strategies to prevent acute episodes could decrease the financial burden of the illness SOMATIC COMORBIDITIES However, the burden of bipolar disorder is not limited to the psychiatric symptoms and dysfunction related to the illness (Kupfer 2005); somatic comorbidities are frequently

143 found in patients with BD (Carney and Jones, 2006; Soreca et al, 2009). They present higher risk than the general population for numerous serious metabolic comorbidities, including overweight and obesity (Keck and McElroy, 2003), diabetes (Cassidy et al, 1999), hypertension (Johannessen et al, 2006), dyslipidemia (Kilbourne, 2005) and metabolic syndrome (Basu et al 2004; Fagiolini et al, 2005). Several factors contributing to these findings, such as problems attending to a healthy lifestyle (poor diet, habitual inactivity, and excessive nicotine use) (Judd et al, 2002; Katon, 2003; Grant et al, 2004; Vornik and Browen, 2006), higher rates of substance use/psychiatric comorbidities (Kessler et al, 2005), and medications for the treatment of BD, contribute to the worsening of physical health (McElroy et al, 2002; Keck and McElroy, 2003; Katon, 2003; Centorrino et al, 2006). These risks factors may lead to the early onset of medical comorbidities with poor long-term outcomes and likely contribute significantly to the overall health care costs (Bryant-Comstock et al, 2002; Taylor and MacQueen, 2006) in BD. Moreover, mood disorders are increasingly being appreciated as multisystem conditions with consequences on circadian rhythms, immunologic, endocrine, vascular, and neural functions (Soreca et al, 2009). A retrospective analysis of medical service and prescription claims compared 28,531 BD patients to 85,593 controls for 1 year. BD patients were found out to have a significantly higher prevalence of metabolic comorbidities than the general population; annual medical service treatment costs for metabolic conditions were twice that of the control cohort ($531 versus $233). The bipolar cohort had significantly higher overall medical service and prescription drug costs than those of the control cohort ($12,764 versus $3,140). Prescription medication costs for metabolic conditions were higher as well, with bipolar cohort per-patient costs of $571 versus $301 for the control cohort (Centorrino et al, 2009) COSTS DERIVED FROM DELAY IN DIAGNOSIS The delay in the diagnosis of BD can lead to high healthcare costs (Hirschfeld et al, 2003, 2005). Birnbaum et al. (2003) compared treatment patterns and costs for patients with recognized and unrecognized bipolar disorder with those of depressed patients without bipolar disorder, using claims data from seven large national employers for 585,584 individuals younger than 65 years of age. They found that, of 9,009 patients treated for depression with antidepressants, 93.1% did not have bipolar disorder, 3.3% had recognized bipolar disorder, and 3.7% had unrecognized bipolar disorder. The patients with unrecognized bipolar disorder incurred significantly greater mean monthly medical ($1179) and indirect ($570) costs in the 12 months after initiation of antidepressant treatment compared with those with recognized bipolar disorder ($801 and $514). These investigators concluded that accurate recognition of bipolar disease was associated with lower medical costs as well as lower indirect costs due to work loss. Shi et al. (2004) compared hospital use, suicide risk, and healthcare costs of patients with recognized and unrecognized bipolar disorder with those of patients with nonbipolar mood disorders, using data from 25,460 adults in the California Medicaid program with a new episode of antidepressant therapy. They found that patients with unrecognized bipolar disorder were more likely to attempt suicide and be hospitalized than those with recognized bipolar disorder and non-bipolar mood disorders. Patients with bipolar disorder also had significantly higher total costs (almost $1,000 per person per year more in direct healthcare costs) than those with non-bipolar illness in the first year post-treatment; likewise, healthcare costs for patients with recognized bipolar

144 disorder were also nearly $700 less per person per year than for those with unrecognized bipolar disorder, primarily due to lower costs for ambulatory care and hospital services. McCombs and cols (2007) examined California Medicaid data from patients who had started new courses of antidepressant therapy for whom at least 6 years of posttreatment data were available. They found that growth in costs for patients with unrecognized bipolar disorder over 6 years was 171%, greatly exceeding the increase in costs associated with recognized BD (82%) and depression (95%). They also found that costs increased by $91/month for each month the diagnosis of bipolar disorder was delayed, while the average increase of $10/month prior to diagnosis of bipolar disorder was reversed to a savings of $1/month after diagnosis. These researchers concluded that early diagnosis of bipolar disorder may significantly reduce healthcare costs. A recent decision-analysis model was proposed and used (Menzin et al, 2009) to evaluate the outcomes and cost over 5 years of 1-time screening versus not screening for bipolar disorder with the use of MDQ (Hirschfeld, 2000b). Screening would lead to 5- year per-patient discounted-cost savings of $1.937 ($ with screening vs $ without screening), which is substantially higher than the screening-associated costs, resulting in a total budgetary savings of approximately $1.94 million. Using low sensitivity and high specificity values for MDQ, we found that screening results in savings of $1.173, while high sensitivity and low specificity values yield savings of $ COST/EFECTIVITY OF TREATMENTS DRUGS PRESCRIPTIONS The World Health Organization (WHO), through its CHOICE work programme (CHOosing Interventions that are Cost-Effective), proposed a form of cost-effectiveness analysis that provided policy makers with a set of results that were generalisable across settings (Tan Torres et al, 2003). It did this by evaluating the costs and effectiveness of new and existing interventions compared to a starting point, namely the absence of any intervention. Basing on this model, due to its established impact on reducing suicide, the older mood stabilising drug lithium was expected to generate more health gain in the population than newer mood stabilising drugs such as valproate (Chisholm et al, 2005). At a target coverage rate of 50% (5 cases out of 10 successfully treated) health gains for the treatment of bipolar disorder were in the range DALYs averted annually per one million population (Chisholm, 2005). The CHOICE work programme concluded that valproic acid was modelled to have a marginally greater prophylactic treatment effect and better adherence than lithium, but a lower acute treatment effect for depressive episodes and no effect on case fatality. It is the expected health gain associated with a demonstrated impact on suicide rates (Tondo et al, 2001b; Goodwin et al, 2003) that suggests lithium is a more beneficial and no more costly population-level treatment compared with valproic acid. Adjuvant psychosocial treatment alongside use of mood-stabilising drugs is expected to improve the cost-effectiveness of treatment for bipolar disorder, as a result of improved adherence (which in effect reduces the proportion of time spent in a manic or depressed state), and because the additional costs of psychosocial treatment are largely offset by a reduced probability of admission to hospital. Finally, and again because of expected reductions in the use of expensive hospital in-patient facilities, treatments provided within a community-based service model offer a more efficient (and because of improved accessibility, more equitable) use of resources than hospital-based services. Differences in cost-effectiveness ratio between interventions considered by the

145 CHOICE program are modest, but the single most cost-effective strategy for the basecase analysis is lithium with psychosocial care, delivered within a community-based service framework, each averted DALY costing $ in developed sub-regions such as Catalunya. This is equivalent to averting DALYs per $1 million expenditure (Chisholm et al, 2005). U.S. National Institute of Mental Health (NIMH) registered a substantial rise in the number of medications being prescribed for patients from 1974 to 1996, but without a greater benefit in outcome (Frye et al, 2000). This has been related to the fact that clinicians often add an increasing number of psychiatric medications as more options become available, even if a benefit is not documented (Goldberg et al, 2009). Randomized controlled studies on combinations of mood stabilizers are few in number and limited to relatively small sample sizes (Denicoff et al, 1997a, 1997b; Solomon et al, 1997), or active comparator combinations, as 2 mood stabilizers versus mood stabilizer plus antipsychotic (Small et al, 1995), that may have been underpowered to detect efficacy and/or tolerability differences between simpler versus more complex therapies. As for acute mania management, most studies focused on monotherapy versus combination of 2 antimanic drugs, but in routinely practice a good part of patients with BD receive 3 or more medications (Levine et al, 2000). Available data suggest that the outcomes associated with concomitant (two or more) antipsychotic therapy generally do not differ from antipsychotic monotherapy, and the former may be associated with severe side effects, such as extrapyramidal side effects and metabolic syndrome (Freudenreich and Goff, 2002) Also, concomitant therapy is highly expensive, with the greatest expenditure occurring when multiple atypical agents are used concurrently (Stahl and Grady, 2006). Prevalence studies conducted in the United States show that concomitant antipsychotic prescribing varies across patient populations, with estimates ranging from % in inpatient settings and % in outpatient settings (Weissman, 2002; Botts et al, 2003; Tapp et al, 2003; Biancosino et al, 2005; Kogut et al, 2005). The pattern of antipsychotic prescription in the US has been recently evaluated in a survey (Aparasu et al, 2009): overall, concomitant antipsychotic therapy was prescribed in 9% of the visits involving antipsychotic agents. Monotherapy was used in 91% of the visits. Recently, combination therapy of a traditional mood stabilizer and an antidepressant for acute bipolar depression showed no advantage over mood stabilizer monotherapy (Nemeroff et al, 2001; Sachs et al, 2007). Combination treatments with improved efficacy in acute depression are lithium-lamotrigine (van der Loos et al, 2009) and olanzapine-fluoxetine (Tohen et al, 2003). A recent, naturalistic study by Goldberg and cols (2009) on the STEP-BD sample (n=4035) found out that a substantial proportion of individuals with BD are on treatment with complex polypharmacy regimens (4 or more drugs), especially when in a depressive phase. The prescription of an atypical antipsychotic, the history of multiple depressive episodes, the use of antidepressant and at least 1 suicidal attempt were found to be related to complex polypharmacy regimens. Complex polypharmacy in any phase of BD was less prevalent in patients treated with lithium, valproate or carbamazepine rather than other agents with less definitive data. Patients with BD type II were as likely as those with BD type I to receive complex polytherapy, consistently with a history of frequent and difficult-to-treat depression and suicidal risk. A model analysis on the cost-effectiveness comparison of quetiapine combined with mood stabilizers versus mood stabilizers alone, from the perspective of UK National Health Service, has been conducted (Fajutrao et al, 2009). Primary outcomes included

146 the number of acute mood events, acute hospitalizations and their costs, while secondary outcomes were quality-adjusted life years (QALYs). Adjunctive quetiapine treatment was estimated to reduce the number of acute mood events by 54% (54% reduction in manic events and 55% reduction in number of acute depressive events). The total direct costs per patient over 2 years for these patients were 5% lower than for the mood stabilizer-only treated ones ( versus ). Adjunctive quetiapine therapy was associated with a 25% reduction in costs for acute maniaassociated hospitalizations and a 38% reduction in costs for acute depression associated hospitalizations. Overall, adjunctive quetiapine therapy was associated with a 29% reduction in total hospitalization costs due to acute mood events, showing lower costs and higher QALYs. A 24% difference in the costs of acute mood events may represent potential costs avoided for hospitalization in the quetiapine/mood stabilizers-treated patients. To date, few other studies have reported on the economic outcomes associated with pharmacologic interventions for the maintenance treatment of BD type I. An economic model of cost-effectiveness over 18 months from a direct-payer perspective, examined the long-term treatment with lamotrigine, lithium, or olanzapine (Calvert et al, 2006). Over the 18-month period analyzed, and for the 1,000 patient cohort, the model indicated that treatment with lithium monotherapy was the leastcostly treatment option in terms of total direct costs. The no-maintenance treatment option was the highest direct-cost option, due to more hospitalizations. For patients with recent manic episodes, the model indicated that lamotrigine may save hospital resources compared with lithium, through reduced admissions for depressive episodes. Lamotrigine monotherapy resulted in the fewest depressive episodes, achieved the most euthymic days, and gained the most QALYs of all 4 treatment options. Olanzapine avoided the most acute manic episodes in the model. All of the active treatment regimes dominated the no-maintenance treatment option for all measures of effectiveness. That is, maintenance treatments were less costly and more effective. Lamotrigine also dominated olanzapine for all measures of effectiveness used in the model. The incremental cost-effectiveness of lamotrigine compared with lithium was $2,400 per episode avoided, $30 per euthymic day gained, and $26,000 per QALY. Compared with lithium, we estimated olanzapine incremental cost-effectiveness ratios (ICERs) of $200 per euthymic day gained, $7,000 per acute episode avoided, and $374,500 per QALY. Overall, lamotrigine was associated with the most depression episodes avoided, the most days of euthyrnia, and the greatest QALY gains. The reduction in acute mood events associated with olanzapine was 0.23 compared with lithium, and 0.07 compared with lamotrigine (Calvert et al, 2006). Another UK-perspective study compared the cost-effectiveness of olanzapine and lithium maintenance therapy in bipolar I disorder over a 1-year period (McKendrick et al, 2007). The model estimated that patients treated with olanzapine would experience an average of 0.28 manic episodes and 0.30 depressive episodes. Correspondingly patients treated with lithium would experience an average of 0.52 manic episodes and 0.28 depressive episodes. Compared with lithium, olanzapine was estimated to significantly reduce the number of acute mood episodes per patient from 0.81 to The model also estimated 8 fewer inpatient days per year for patients receiving olanzapine treatment (12 days) compared with lithium treatment (20 days). From a patient perspective, maintenance treatment with olanzapine was estimated to result in 2.6 fewer days with acute symptoms over the 1-year period than treatment with lithium.

147 The annual cost for olanzapine maintenance treatment was 3619 and for lithium was Olanzapine reduced per patient average annual cost by 799 compared with lithium in the maintenance treatment of BD, however the cost difference was not statistically significant. The ICER was negative as olanzapine was estimated to reduce the number of mood episodes and lowered costs. Further analyses showed that 46% of the olanzapine total costs ( 1669/ 3619) were related to the treatment of mania compared with 72% of the lithium treatment costs ( 3174/ 4419). Only patients who successfully responded to olanzapine and lithium combination therapy for mania were included in the study. An additional bias in the clinical trial on which the model is based is that patients who were known to be resistant to lithium treatment were excluded, so that these findings obviously cannot be generalized to the whole population with BD type I (McKendrick et al, 2007). Both of these studies were based on results from pivotal clinical trials and did not consider costs attributable to adverse events, productivity losses, other indirect costs, or costs associated with suicide. A recent, sponsored study was aimed to determine the relative costs and costeffectiveness associated with atypical antipsychotics in BD. The studies included do not provide sufficient data to determine a ranking in resource consumption or costeffectiveness for the interventions considered (olanzapine, quetiapine and risperidone) (Fleurence et al, 2007). The same sponsor granted funds for an anterior study which compared charges for other mental health services associated with the treatment with olanzapine, quetiapine and risperidone treatment. Total charges for mental health services other than the study drug were not different for risperidone, olanzapine, and quetiapine in patients treated for bipolar disorder. However, based on prescription charges, olanzapine appears to be considerably more costly at an equivalent daily dose than either risperidone or quetiapine (Gianfrancesco et al, 2005). A base-case analysis (Bridle et al, 2004) based on 2 studies were made by using a probabilistic model developed to estimate costs from the perspective of the National Health Service. The results from the base-case analysis demonstrate that the choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. If the decision-maker is prepared to pay < 7179 per additional responder, then haloperidol is the optimal decision. If the decision-maker is prepared to pay > 7179 per additional responder, then olanzapine is the optimal decision. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental costeffectiveness ratio of olanzapine is reduced to 1236 (Bridle et al, 2004). According to an Eli-Lilly-sponsored study (Zhu et al, 2007), patterns of antipsychotic medication use significantly differ among atypical antipsychotics in the usual treatment of BD. Olanzapine was more likely to be used as monotherapy compared to quetiapine, risperidone and ziprasidone. The annual healthcare costs of olanzapine and risperidone associated with the treatment of BD were similar, and costs of both these medications were considerably lower than quetiapine or ziprasidone therapy (Zhu et al, 2007) In 2006, an economic model based on the NICE guideline estimated the costs and benefits associated with lithium, valproate, olanzapine, and no treatment/placebo over 5 years (NCCMH, 2006). Valproate was the dominant strategy compared with lithium, with an ICER of 260 and 341 per additional acute mood episode prevented for men and for women without child-bearing potential, respectively. In these subgroups, the ICERs for olanzapine compared with lithium were 11,810 per QALY gained for men

148 and 11,419 per QALY gained for women. For women with child-bearing potential, valproate use is not recommended, making olanzapine the most cost-effective treatment strategy, with ICERs of 3916 per additional acute mood episode prevented and 11,419 per QALY gained compared with lithium. However, potential limitations observed in that study prompted NICE to update the previous model to include a wider range of pharmacologic treatments using a lifetime horizon and to allow changes in active medications in case of failure with a previous therapy (Soares-Weiser et al, 2006) The results of the lifetime analysis of 7 treatments (lithium, valproate, carbamazepine, lamotrigine, olanzapine, imipramine, and the combination of lithium and imipramine) were given considering the polarity of the last episode in recent history, so that two subgroups were obtained. The results from the base-case analysis for patients with a recent history of depression suggest that valproate, lithium and the combination of lithium and imipramine are potentially cost-effective, depending on the amount that a decision-maker is willing to pay for additional health gain (in the study assessed through QALYs). If conventional amounts that the NHS is prepared to pay for health gain ( 20,000 40,000 per QALY) are used, then the lithium-based strategies appear to be potentially cost-effective for this group. For patients with a recent history of mania, then the choice of pharmacological intervention appears to be between olanzapine and lithium monotherapy. Again, using the conventional threshold as a reference point, the results suggest that lithium is the most cost-effective therapy. For the recently depressed subgroup of patients, the incremental cost of lithium compared with valproate was 10,409 per QALY gained and 21,370 per QALY gained from the combination of lithium and imipramine versus lithium monotherapy, For patients with a recent manic mood event, olanzapine dominated the other treatment strategies with the exception of lithium monotherapy. The ICER of lithium compared with olanzapine was per additional QALY gained (Soares-Weiser et al, 2007). Differences in costs of therapy, model considerations, time horizon, and frequency of health care contacts obiously complicate direct comparisons across studies. There is also substantial variability in the reported incremental cost per acute mood event avoided by various therapies. In the Fajutrao and cols study (2009) the I-year economic model comparing olanzapine with lithium yielded an incremental cost of 367 per mood event avoided, whereas the NICE 5-year model reported incremental costs ranging from to per acute mood event avoided by olanzapine versus lithium and to per acute mood event avoided by valproate versus lithium. (NCCMH, 2006; McKendrick et al, 2007). The study from Fajutrao and cols (2009) estimated an ICER of 506 per acute mood event avoided after considering the recommended intensive health care contacts and laboratory tests during initiation of therapy and during follow-up, and after differentiating the nature of outpatient treatment for acute depressive episodes (which did not require hospitalization), which may help to explain some of the differences observed between this estimate and the I-year estimate PSYCHOSOCIAL INTERVENTIONS A recent study from Miklovwitz and Scott (2009) concludes that adjunctive psychotherapies can be effective in preventing BD relapse or recurrence, reducing symptom severity, and possibly, hastening time to recovery from acute bipolar depression over a minimum 1 2 year periods. Most of the psychotherapies specifically tailored for BD that had an impact on depression (the greatest symptom burden in BD)

149 (Judd et al, 2002) involved a duration of minimum 12 sessions, and the effects appeared to be largely maintained, although in some cases weakened, in the 1-2 year postintervention period. Therapies structured to have a higher cost in the initial stages of treatment (i.e.: that require greater therapist skill and that develop during more sessions) are most likely to be associated with health gains and/or reductions in resource utilization in the medium to longer term. As an example, the STEP-BD comparison of up to 30 sessions of intensive therapy (FFT, IPSRT, or CBT) with 3 sessions of collaborative care found that intensive therapy was associated with a shorter time to recovery from depression, a greater likelihood of ongoing stability, and enhanced psychosocial functioning. Thus, in the psychotherapy of BD, "you get what you pay for". Moreover, the total cost of treatment is not an adequate reflection of the clinical and social needs of individual patients as better outcomes are often associated with greater resource utilization (e.g., a patient with greater insight seeking extra therapy to enhance quality of life, not just prevent relapses). Hence, calculating incremental cost-effectiveness ratios will be more informative if the assessment of cost versus benefit extends beyond the intervention phase. If the analysis includes medium to longer term follow-up, the additional costs of the resources utilized during the initial phase are readily offset by a relatively small reduction (about 10%) in the number of occupied hospital bed-days. Given that the likelihood of hospital admission among individuals receiving usual treatment is significantly greater than among those receiving adjunctive disorder-specific psychosocial interventions and admissions are usually of longer duration, the economic argument begins to shift in favor of these specifically tailored psychotherapies (Miklowitz and Scott, 2009). Intuitively, group psychosocial interventions, as patients or family psychoeducation, present as more cost-effective interventions in comparison of individual interventions. The average patient in the STEP-BD randomized study attended about half the course of therapy (median = 13 sessions), with a range of 0-30 sessions, although they were expected to attend up to 30 sessions in nine months. Attending about of the scheduled therapy sessions is a remarkably consistent cross-study finding (Scott and Colom, 2008), although obviously in real clinical practice more flexibility is needed. The optimal length of treatment will vary with the time since the onset of the last episode, the complexity of the illness or co-morbid problems identified, the availability of social supports, and the response to (and adherence with) medications. A further naturalistic investigation using a STEP-BD naturalistic cohort (n = 148) found that patients who had more severe levels of depression responded better to more frequent (i.e., weekly) psychosocial sessions than less frequent (i.e., monthly) sessions, whereas the reverse was true for patients who began with milder levels of depression (Miklowitz et al, 2006). More diluted session may be sufficient for stable patients, mirroring the maintenance therapy models that are frequently instigated for those with highly recurrent depression. In contrast, in some instances, therapy pauses may help some patients with complex problems to pace themselves, master new skills, and then return to therapy to move into a new phase of learning (Scott and Colom, 2005). A clearer assessment of optimal length of psychosocial interventions is needed. An important issue is the need to identify treatment moderators, as to say the conditions and subpopulations for whom various forms of psychotherapy are most effective. This aspect may represent the most efficient way to cut the costs of psychosocial treatments. Moderation is usually demonstrated by observing an interaction between treatment conditions (i.e., active treatment versus usual treatment) and variables (patients or

150 families/caregivers variables) measured prior to treatment (Kraemer et al, 2005). Posthoc analyses usually find out these moderators as few studies are adequately statistically powered to identify moderators, so that independent, further replication of the data is needed. As an example, Scott and cols (2006) had a sufficient sample size to allow a 'dismantling' analysis that identified a sub-group of CBT responders who had <12 prior BD episodes. This analysis was then replicated with the group psychoeducation sample of Colom et al. (2003) who also found that patients who had 12 prior episodes showed no benefit from the active compared to the control intervention (Scott, 2009). These findings may indicate that intensive therapy should be considered at an early point in the 'illness career' of individuals with BD rather than after multiple episodes. A recent sub-analysis on families psychoeducation (Reinares et al, 2009) seems to indicate a similar effect when subdividing patients between Stage I patients (with well established periods of euthymia who return to their baseline level of functioning in the absence of overt psychiatric morbidity between episodes) and more severe patients, following a recently proposed classification (Kapczinski et al, 2009). One of the advantages of using psychological therapies as adjuncts to pharmacological treatment should be the cost-effectiveness shown in the long-term as reported by Scott et al. (2009). In fact, if viewed only in the short-term, adjunctive psychological interventions imply enhanced use of health care resources and increased costs. A reflection arising is whether long-term cost advantages are reduced by the weakening of the persistence of the effect of CBT after 1-2 years and the consequent need for booster sessions or even maintenance psychotherapy. These findings seem to highlight the importance of an information-based training (principal mechanism of psychoeducation) for the persistence of the efficacy of a certain psychological intervention over time. In fact, shorter psychoeducational approaches, which merely provide information, appear to be less effective compared to more structured, longer psychoeducational strategies (Colom et al, 2009). The cost-effectiveness analysis from Scott et al (2009) deserves further consideration as it has been conducted in a sample afferent to the Catalan Health Service. The total mean cost for all outpatient services was lower in the control as compared to the psychoeducation group ( versus ), but this data change considerably when the cost of hospitalization is included, with the control group mean cost exceeding that of the psychoeducation group by over ( versus ). Hospitalization accounted for about 40% of the health care cost in the control group but only about 15% in the psychoeducation group. When actual numbers of inpatient beddays and emergency visits were explored for each group, the mean cost for each additional inpatient bed-day avoided was 128, and the mean cost for each additional emergency visit avoided was about 253 (Scott et al, 2009) PHYSICAL TREATMENTS A vast review on the cost-effectiveness of ECT in mental health included BD (Greenhalgh et al, 2005): it considered depression (unipolar and bipolar), schizophrenia, manic episodes, catatonia and special populations, so that information concerning BD population is difficult to extrapolate, as it is considered in different groups (namely, depression, manic episodes, catatonia and special populations). The report failed to identify economic studies related to ECT which fulfilled the inclusion criteria. Moreover, an economic model for BD was impossible to construct due to the lack of disposable data.

151 A Canadian study relating to ECT for the management of acute bipolar, treatmentresistant adolescents and young adults (aged 16-22) was conducted (Kutcher and Robertson, 1995). It considered only hospitalization costs, which were inferior for the ECT-treated patients ($58,608 versus $143,264 per admission). The design of the study, which was subject to major selection bias, as well as the estimation of hospitalisation costs only and the omission of all other relevant costs from the analysis, limit considerably the scope of it. No robust conclusions on the cost-effectiveness of ECT can thus be drawn. Many economic studies on BD undertaken to date suffer from sub-optimal design, an unclear cost perspective, or inadequate power. There is a consequent requirement to derive more appropriately powered and generalized estimates of both the costs and relative cost-effectiveness of interventions in order to usefully inform mental health policy and planning, both at the national and international level.

152 012 LEVELS OF INTERVENTIONS, FLOWS AND SETTINGS This guideline has been developed to fit with the local organization of Mental Health care and according to the severity and phase of the disease. The following table provides the rationale for levels, flows, and settings according to the patient s situation. OBJECTIVE INTERVENTIONS ACTORS A.- Screeing and diagnosis of bipolar disorder B.- Suicide risk assessment Screening Diagnostic criteria assessment Referal to a mental health specialist Primary care (PC) Primary care (PC). Emergency room specialists (ER) C.- Management of non severe bipolar disorder:mild to moderate mania, hypomania, acute mild to moderate bipolar depression D.- Maintenance treatment and relapse prevention E.- Acute care (severe episodes or self-harm risk): Medication & psychoeducation Medication &i psychoeducation Physical health monitoring Specialists (S) CSMA CSMA & PC Acute mania; Severe Hospitalitzation, medication, Hospitalization (acute behavioral disturbance acute ECT units) Suicide attempt; No self-care F.- Management of highly cpomplex patients: Rapid cyclers, severe medical and psychiatric comorbidity, treatment-resistance. Highly complex medication combinations, Maintenance ECT Specialized Units

153 013 MANAGEMENT OF BIPOLAR DISORDER FROM PRIMARY CARE INTRODUCTION 13.2 DIAGNOSING BIPOLAR DISORDER IN PRIMARY CARE THE BURDEN OF MISDIAGNOSIS IN PRIMARY CARE DIAGNOSIS IN PRIMARY CARE SCREENING TOOLS IN PRIMARY CARE ASSESSING THE DIAGNOSIS EXISTING BIPOLAR DISORDER IN PRIMARY CARE PHYSICAL HEALTH IN BD DIAGNOSING COMORBID PHYSICAL ILLNESSES CARDIOVALSCULAR ILLNESSES ENDOCRINOMETABOLIC ILLNESSES INFECTIVE ILLNESSES OTHER MEDICAL CONDITIONS PREVENTION OF COMORBID PHYSICAL ILLNESSES CARDIOVALSCULAR ILLNESSES ENDOCRINOMETABOLIC ILLNESSES TREATMENT OF COMORBID PHYSICAL ILLNESSES CARDIOVALSCULAR ILLNESSES ENDOCRINOMETABOLIC ILLNESSES INFECTIVE ILLNESSES OTHER MEDICAL CONDITIONS ANNUAL REVIEW OF PHYSICAL HEALTH WEIGHT GAIN MANAGEMENT CRISIS AND RISK MANAGEMENT PLANS INTRODUCTION Bipolar disorder is no longer an illness limited to diagnosis and management by the psychiatric profession. Overall, data suggest that only a third of all patients with mental illness are treated in the mental health sector, while approximately half of all patients with mental illness are seen by primary care physicians (Regier et al, 1993). As are patients with major depression and other mood disorders, stabilized bipolar patients with bipolar disorder are sometimes likely receiving treatments in the primary care setting. Another issue of interest is the consequence of the introduction of atypical antipsychotic drugs in BD clinical management. These drugs, initially welcomed by clinicians because of their efficacy and paucity of extrapyramidal side effects, bring the

154 need of a careful metabolic watch for their risk of weight gain, cardiovascualar diseases, metabolic syndrome and type 2 diabetes mellitus, all conditions which may emerge when treating BD with this class of drugs. Primary care clinicians may thus play a role in careful monitoring these somatic aspects in the multi-professional management of this complex illness DIAGNOSING BIPOLAR DISORDER IN PRIMARY CARE THE BURDEN OF MISDIAGNOSIS IN PRIMARY CARE The problem of misdiagnosis and underdiagnosis of bipolar spectrum disorder has been previously discussed (see ch.5). The diagnosis and treatment of BD is not without challenges. Even psychiatric caregivers often misdiagnose BD, delaying considerably the correct management of this condition (Ghaemi et al, 2000). Patients with BD may have a wide variety of symptoms when they first seek medical care. These complaints may include depression, anxiety, mood swings, euphoria, pressured speech, impulse control problems, substance abuse, legal trouble, fatigue, grandiosity, or increased activity. Many conditions may overlap with BD and can confuse the proper diagnosis. Major depression is the most common misdiagnosis of BD, including treatment-resistant, agitated, and atypical depression, but BD may also be mistakenly diagnosed as other conditions, including schizoaffective disorder, cluster B personality disorders, especially borderline personality disorder (see ch. 5). Comorbidity as well may complicate a correct diagnosis: 59.0% of bipolar patients presents with at least one lifetime comorbid anxiety disorder, 31.9% with at least one lifetime comorbid ICD, and 24.0% with at least one lifetime comorbid substance use disorder (Kessler et al, 2007). BD is commonly mistaken for unipolar depression for several reasons. First, patients are more likely to seek clinical help during the depressive phase of their illness rather than during the manic phase. Further, more than 50% of all patients with bipolar disorder have a major depressive episode before they experience a manic episode (Ghaemi et al, 1999). Research suggests that 30% of patients who have depressive symptoms may have some form of BD (Akiskal et al, 1995; Manning et al, 1997). The rate of misdiagnosis in BD is very high. In 2000, a survey tried to assess the rate of misdiagnosis. In all, 7 of 10 respondents had their disorder initially misdiagnosed by a mental health specialist. Respondents had an average of 3.5 misdiagnoses and four consultations before receiving an accurate diagnosis. More than a third sought help repeatedly for 10 years or more before their illness was accurately diagnosed (Hirschfeld et al, 2000). A recent meta-analysis (Mitchell et al, 2009) estimates the overall prevalence of depression in primary care as about 19,5%, with some difference in different Countries. Across 41 studies, general practitioner correctly identified depression about 47,3% of true cases. Diagnostic sensitivity varied greatly between individual studies, ranging from 6 6% to 78 8%. A general practitioner would correctly identify five out of ten cases, missing five true positives. The burden of depression in primary care is thus important, and it has been previously outlined that a part of the cases diagnosed with unipolar depression could be actually misdiagnosed BDs DIAGNOSIS IN PRIMARY CARE Primary care clinicians should then pay great attention to symptoms of mania, which have to be carefully investigated: distractibility, indiscretion or

155 disinhibition, grandiosity, flight of ideas, activity increase, sleep deficit or decreased need for sleep, and talkativeness (APA, 1994). Hypomania symptoms may be subtle to detect retrospectively, but should always be searched in a patient with a history of depression (Angst, 2000). The wide range of symptoms seen in patients with bipolar spectrum disorder, including impulsive behaviour, alcohol and substance abuse, fluctuations in energy level, and legal problems, are often attributed to problems other than bipolar disorder. It has been estimated that as many as one to two thirds of individuals with bipolar disorder do not receive appropriate treatment due to misdiagnosis (Carta and Angst, 2005). Particularly hypomania is an element of BD type II which is very often not recognized by the subject as pathological, and it is thus difficult to rule ou retrospectively (Vieta et al, 2005): it is under-diagnosed in 25 to 50% of depressive patients (Angst et al, 2005). However, the retrospective detection of hypomania is crucial for a correct diagnosis of bipolar disorder, and particularly for BD type II, and for treatment accuracy. The APA guidelines on the management of BD state that BD type II is frequently misdiagnosed as unipolar major depressive disorder and as a result may receive inadequate or inappropriate treatment (APA, 2002). An expert group concluded that the current diagnostic criteria have high specificity but might have too low a sensitivity and that a greater focus on certain symptoms (such as activation levels) or less emphasis on symptom duration may improve recognition of those at risk of BP episodes (Angst et al, 2003). Several often-overlooked criteria which can further assist in the correct diagnosis of bipolar disorder have been outlined. For example, unlike depression and other unipolar disorders, bipolar disorder commonly runs in families (Bowden 2001). The strongest indicators are a history of relatives in three consecutive generations or three or more relatives in one generation with recurring mood disorders. The same author underlines the importance of an early age-at-onset, as in childhood or adolescence, in another important element which could address the practitioner towards a diagnosis of BD. Another important issue is a history of poor response to antidepressant therapy. The unsuccessful use of several antidepressants is highly suggestive of bipolar disorder. Antidepressant treatment may be characterized by increased agitation, restlessness, or insomnia. Treatment-emergent hypomania may develop, generally within the first 2 weeks of antidepressanttherapy, often beginning and ending abruptly and sometimes showing mixed features. Other patients may have worsening depression with antidepressant treatment. Thus, erratic or uneven response to antidepressants, multiple antidepressant failures, and the emergence of manic symptoms all suggest a bipolar illness (Bowden, 2001). Other characteristic features of BD include a high risk for postpartum depression in women. Indeed, BD should be considered as a possibility in every woman who has postpartum depression, particularly if it is her first episode of major depression (Sharma et al, 2009). Key factors which may help general practitioner are summarized in tab

156 Tab Factors to keep in mind in differential diagnosis between unipolar and bipolar depression 1 Age at onset BD often begins in childhood or adolescence 2 Family history BD is characterized by a pedigree: 3 or more firstdegree relatives with a mood disorder, or 3 consecutive generations with evidence of a mood disorder). 3 Manic symptoms in the depressive phase, patients with BD can be energized and highly active. 4 Response to AD Antidepressants do not work well in most people with BD, often inducing manic symptoms SCREENING TOOLS IN PRIMARY CARE An easily administered screening instrument for self-assessment may be useful in clinical practice, particularly in primary care settings or settings in which a great number of medical patients are referred for psychiatric screening before medical treatments, such as interferon, hormone therapies with a burden of risk for psychiatric disorders (Carta et al, 2005). In the last 10 years, two screening instruments have been developed for this purpose. The Mood Disorder Questionnaire is a self-report, single-page, paper-and-pencil inventory that can be quickly and easily scored by a physician, nurse, or any trained medical staff assistant. The Mood Disorder Questionnaire screens for a lifetime history of a manic or hypomanic syndrome by including 13 yes/no items derived from both the DSM-IV criteria and clinical experience. The Mood Disorder Questionnaire was tested first in a tertiary care clinical sample and showed a sensitivity of 73% and a specificity of 90% (two thirds of the sample had BP-I) with a cut-off score of 7 or more (Hirschfeld et al, 2000). In a population sample (Hirschfeld et al., 2003) the sensitivity was 28% and the specificity was 97% for BP. Moreover, it seems to be sensitive to identify BP-I disorder but probably less so for BP-II disorder (Benazzi and Akiskal, 2003; Zimmermann et al, 2004). A Spanish version of the Mood Disorder Questionnaire is available (Sanchez-Moreno et al, 2008). The Hypomania Checklist-32 is a self-applied questionnaire being internationally developed, which purpose is to identify hypomanic symptoms in patients with major depressive disorder, so that it may help to rule out a diagnosis of BD type II or other BDs in the bipolar spectrum (Angst et al, 2005). As this group of patients is frequently diagnosed and treated in Primary Care, the use of this questionnaire is of great use with depressed patients in this setting to improve diagnosis and treatment in bipolar patients and thus their outcome, functioning and quality of life. The Hypomania Checklist -32 comprises a checklist of possible symptoms of hypomania that are rated yes (present or typical of me) or no (not present or not typical) by the subject. A Spanish Version of the Hypomania Checklist -32 is available (Vieta et al, 2007): this version exhibits good psychometric properties in relation to sensitivity and specificity. The psychometric study of the development of the HCL-32 scale in Spain exhibits high internal consistency and similar stability over time, in comparison with other instruments such as the MDQ and suggests that this scale may be very useful for the detection of bipolar disorder and past hypomania. A cut-off point of 14 affirmative responses indicates good sensitivity (0.85) and specificity (0.79). Compared with the MDQ, the HCL-32 presents

157 greater sensitivity for the detection of bipolar disorder. Furthermore, a cut-off point of 15 affirmative responses increases the questionnaire's specificity (0.83 versus 0.79), with its sensitivity remaining unaltered (0.85). Moreover, the HCL-32 was useful to discriminate between BD type II and unipolar patients, and also between BD typeii and controls, and therefore may be used in clinical practice for this purpose (Vieta et al, 2007). Interestingly enough, though, 26% of unipolar patients had a HCL-32 score of 14 or above, indicating either some false positives or, alternatively, that soft hypomania may be present even in clinically undisputable unipolar patients (Akiskal et al. 2003). Given the difficulties involved in both the retrospective and cross-sectional diagnosis of hypomania, which represent key aspects of appropriate management of bipolar disorders, this questionnaire represents a potential improvement in clinicians ability to detect and correctly treat bipolar disorder ASSESSING THE DIAGNOSIS Primary care clinicians should normally refer patients with suspected bipolar disorder for a specialist mental health assessment and development of a care plan, if either of the following is they detect periods of overactive, disinhibited behaviour lasting at least 4 days with or without periods of depression, or three or more recurrent depressive episodes in the context of a history of overactive, disinhibited behaviour. Patients in state of clear mania or severe depression or in danger to themselves or other people should urgently be referred to specialist mental health services EXISTING BIPOLAR DISORDER IN PRIMARY CARE When a patient with existing bipolar disorder registers with a practice, the general practitioner should consider referring them for assessment by specialist mental health services and, if appropriate, the developments of a care plan. BS should not be solely managed from Primary Care clinicians. Urgent referral to secondary mental health services should be done if there is an acute exacerbation of symptoms, in particular the development of mania or severe depression, or if there is an increase in the degree of risk, or change in the nature of risk, to self or others. A review by secondary care services or increased contact in primary care should be also considered if: - the patient s functioning declines significantly or their condition responds poorly to treatment or if treatment adherence is a problem - comorbid alcohol and/or drug misuse is suspected - the patient is considering stopping prophylactic medication after a period of relatively stable mood PHYSICAL HEALTH IN BD Despite its scarce consistence in literature, BD seems to cause a higher prevalence of different medical conditions (cardiovascular, metabolic, infective, neurologic and respiratory). Reasons for these incremented prevalences may be different: a difficulty in accessing health services, lifestyle, and allostatic load (McEwen, 2003), treatment sideeffects which may enhance risk factors (Meyer et al, 2005). Medical illnesses in psychiatric patients, especially in bipolar patients, are generally infra-diagnosed and treated (Koranyi, 1979; D Ercole et al, 1991; Kupfer, 2005; McIntyre et al, 2007).

158 DIAGNOSING COMORBID PHYSICAL ILLNESSES A recent Spanish consensus has drawed recommendations on the physical health management of bipolar patients (Bobes et al, 2008). As soon as practicable after initial presentation of a patient with bipolar disorder, healthcare professionals should: - establish and manage the patient s smoking status and alcohol use - perform thyroid, liver and renal function tests, blood pressure, and measure full blood count, blood glucose, lipid profile - measure weight and height - consider EEG, CT scan or MRI scan if an organic aetiology or a relevant comorbidity is suspected - consider drug screening, chest X-ray and ECG if suggested by the history or clinical picture CARDIOVALSCULAR ILLNESSES Systolic and diastolic arterial blood pression should be taken at first and each subsequent visit. If arterial pressure is normal and patients is visited on a regular basis a further evaluation at month 3 and subsequently every 6 months. If measures are equal or superior to 140/90mmHg, it should be repeated up until 3 times in 3-minutes-intervals. Arterial hypertension diagnosis is possible with 3 measures made in 3 different days, unless a unique measure of more than 180/110mmHg is obtained ENDOCRINOMETABOLIC ILLNESSES Weight, height, body mass index should be determined at first visit, as well as abdominal circumference. Some metabolic parameters should be monitored: glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and TSH blood levels and prolactin blood level in case of menstrual disorders, sexual dysfunction or paediatric patients. Once a month, weight should be monitored. In case of children or adolescents, height should be monitored too. The other parameters, if normal, should be checked at least once a year. Blood measures should be repeated if glycemia levels are between 100 and 126mg/dl, TSH levels >6mU/l or prolactin levels >20ng/ml. TSH should be repeated 3-6 months after lithium treatment beginning. A weight gain of >7% or the presence of a metabolic syndrome (defined as 3 or more criteria of the following fulfilled: abdominal circumference >102cm in males, >88cm in females; HDL-cholesterol <40mg/dl in males, <50mg/dl in females; arterial blood pressure >130/85mmHg; triglycerides >150mg/dl; glycemia >100mg/dl, see tab.13.2) need a closer monitoring of the parameter, every 6 months. Criteria for the diagnosis of metabolic syndrome are resumend in table Tab Criteria for metabolic syndrome. Three or more of the following: 1 Abdominal circumference >102cm (males) >88cm (females) 2 HDL-cholesterol <40mg/dl (males) <50mg/dl (females) 3 Arterial blood pressure >130/85mmHg 4 Triglycerides >150mg/dl 5 Glycemia >100mg/dl

159 INFECTIVE ILLNESSES At first visit, and always if risk behaviour is suspected, following serological measures should be made: anti-hiv antibodies (ELISA), anti-hbv and anti-hcv antibodies, RPR/VDRL OTHER MEDICAL CONDITIONS Patient s personal history of posible pepticulcer, migraine, respiratory illnesses or allergy should be collected PREVENTION OF COMORBID PHYSICAL ILLNESSES CARDIOVALSCULAR ILLNESSES Every bipolar patient should follow a hyposodic regimen and practice adecuate physical exercise, adapted to his/her physical condition. It is fundamental a weight reduction if overwight or obese ENDOCRINOMETABOLIC ILLNESSES Healthy lifestyle, physical exercise and appropriate regimen are recommendable INFECTIVE ILLNESSES Hepatitis B vaccine is recommendable in those patients who do not show evidence of infection TREATMENT OF COMORBID PHYSICAL ILLNESSES CARDIOVALSCULAR ILLNESSES If arterial blood pressure is not under control ( 140/90mmHg or less if subject has comorbid diabetes or renal insufficiency) primary care physician should manage it as usual. Psychiatrist should inform the general practitioner if the patients is on therapy with an antipsychotic, and which one, so that an appropriate antihypertensive drug may be chosen. If the patient is on therapy with lithium, attention to the type of antihypertensive drug (diuretics or renin-angyotensin antihypertensive) ENDOCRINOMETABOLIC ILLNESSES If dyslipidemia (total cholesterol >250mg/dl, triglycerides >200mg/dl), metabolic syndrome or diabetes (glycemia >126mg/dl) excessive weight gain (>7% of weight) and an alternative psychopharmacologic treatment is not recommendable, general practitioner should deal it as usual. An increase in blood TSH should be evaluated by an endocrinologist. A hyperprolactinemia not related to drug treatment, of clinical importance or above 200ng/ml should also be dealt by an endocrinologist INFECTIVE ILLNESSES If positive to serological investigation the patient should be derived to a specialist OTHER MEDICAL CONDITIONS Keep in mind possible interactions of lithium with no-steroid anti-inflammatory drugs used for symptomatic treatment of migraine. The possible onset of renal insufficiency has to be watched, so that lithium doses may be adjusted. Steroid anti-inflammatory

160 drugs, used in chronic inflammatory conditions such as pulmonary illnesses, may precipitate affective episodes. Valproate and carbamazepine may have important interactions, as valproate is a strong inhibitor of hepatic metabolism and carmabazepine a strong inductor, so that plasmalevels of some drugs may be altered ANNUAL REVIEW OF PHYSICAL HEALTH People with bipolar disorder should have at least an annual physical health review. This may be easily managed in primary care, to ensure that the following are assessed each year: - lipid levels, including cholesterol in all patients over 40 even if there is no other indication of risk plasma glucose levels - weight - smoking status and alcohol use - blood pressure. The results of the annual review should be given to the person, and to healthcare professionals in primary and secondary care (including whether the person refused any tests). A clear agreement between primary and secondary care professionals should be made about responsibility for treating any problems WEIGHT GAIN MANAGEMENT A special issue with pharmacological treatment is weight gain. If a person gains weight during treatment their medication should be reviewed, and the following considered: - dietary advice and support from primary care and mental health services - advising regular aerobic exercise - referral to mental health services for specific programmes to manage weight gain - referral to a dietician if the person has complex comorbidities (for example, celiac disease). Drug treatments such as high-dose antidepressants, sibutramine, or topiramate are not recommended to promote weight loss CRISIS AND RISK MANAGEMENT PLANS A risk assessment should be undertaken when: - bipolar disorder is first diagnosed - a person with bipolar disorder undergoes significant change in mental state or personal circumstances - a person with bipolar disorder is discharged from or is on leave from inpatient care. NICE guidelines (2009) recommend that if a patient is at risk of suicide, exploitation or severe self-neglect, is a significant risk to others (including neglect of dependents), or has a history of recurrent admissions, particularly compulsory admissions, a crisis plan should be developed in collaboration with the patient, covering: - a list of identified or potential personal, social or environmental triggers, and early warning symptoms of relapse - a protocol for increasing the dose of medication or taking additional medication (which may be given to the patient in advance) for patients who are at risk of rapid

161 onset of mania and for whom clear early warning signs can be identified protocols should be monitored regularly, and are not a substitute for an urgent review - how primary and secondary healthcare services have agreed to respond to any identified increase in risk, for example by increased contact - how the patient (and where appropriate their carer) can access help, and the names of healthcare professionals in primary and secondary care who have responsibilities in the crisis plan. A limited quantity of psychotropic medication should be prescribed for patients during periods of high risk of suicide.

162 014 GUIDELINES IMPLEMENTATION I. Introduction and Methods 5 II. Definition and Diagnosis of Bipolar Disorder 7 Diagnosis of Bipolar Disorder.. Differential Diagnosis III. Recommendations by levels Level 1: General recommendations for the whole system.. Screening and evaluation Suicide risk evaluation Level 2: Diagnosis of Bipolar Disorder Level 3: Diagnostic confirmation, pharmacologic treatment of the illness and its comorbidities, suicide prevention, psychotherapeutic management. Level 4: Treatment of complex outpatients: rapid cyclers, comorbidities.. with severe medical illnesses, treatment resistency. Level 5: Treatment of patients at high life-risk (for suicide attempts or comorbidities), with severe behavioural alteration or unable to treat themselves (hospitalization). IV. Treatment V. Implementation of the GPC.. VI. Information for patients and caregivers. VII. Annexes.. Annex 1: MINI-Interview Annex 2: HCL-32

163 I. INTRODUCTION AND METHODS INTRODUCTION We present here the "Clinical Practice Guidelines on Management of Bipolar Disorder in Catalonia" (hereinafter GPC), developed by the Bipolar Disorder Unit of Hospital Clinic of Barcelona and the Agency for Technology Assessment and Research (Catalan Agency for Health Information, Assessment and Quality CAHIAQ-) within the Quality Plan of the National Health System and included in the project GuiaSalud. The draft of these guidelines was carried out during the year 2009 by a multidisciplinary team, of professional and scientific societies of the different disciplines involved in Catalonia, and with the external review of two foreign, well known researchers. These GPCs are intended to promote evidence-based medicine and reduce the variability of diagnostic and therapeutic procedures. This is a particularly important objective in the area of mental health, where a high variability in the management of the deseases and an incomplete diffusion of the concept of clinical practice based on scientific evidence may be common. This guide includes a series of recommendations for diagnosis and treatment of bipolar disorder based on a systematic review and exaustive available scientific evidence and other recently published guidelines on this topic (NICE, 2009; Yatham et al, 2009; Grunze et al, 2009 and 2010, Goodwin 2009; Kasper et al, 2008). Bipolar disorder (BD), formerly called manic-depressive psychosis, is a severe mental illness characterized by high recurrency and high prevalence. It is estimated that about 300,000 Catalans could suffer from this illness. Among them, about could suffer from the most severe form, BD type I. There is considerable evidence regarding the diagnosis and treatment of BD type I, which is characterized by manic episodes, usually combined with depressive episodes; but the scientific basis for the management of BD type II (major depression with hypomania) and BD not specified are much weaker. The disease is characterized by a chronic and recurrent course, with possible maniac, hypomanic (mild mania), depression or mixed episodes, depending on the subtype, and seasons of complete or partial remission of symptoms. The disease is in most cases highly disabling, but there are occasional cases of people with a psychosocial adaptation that is higher than average in the general population. To implement these CPG, we followed the model of stepped care (Stepped Care) proponed by NICE (2007) because they take into account the need to fit recommendations into the levels of care where these recommentadions have to be applied. This model of multi-level care for major depression can be adapted to our health system and facilitates the integrated implementation of the Program of Mental Health Services in Primary Care, a priority project of the Master Plan. The CPG were developed basing on specific levels of evidence and grades of recommendations arising from some level of scientific evidence. Use of this CPG can be optimized taking into account the recommendations and common aspects arising from the CPG for Major Depression in adults and the CPG on Early Psicosis.

164 Methods These CPG were written according to the following methods: a) a systematic review of scientific literature on the management of BD has been made; b) we developed our levels of evidence starting from SIGN system, adapted to the features of the disease, characterized by acute episodes but also by a longitudinal morbility which is not separable from manic, hypomanic, depressive or mixed episodes; c) levels of evidence have been adapted characteristics of the scientific knowledge on the epidemiology and diagnosis of the illness; d) we drew some recommendations basing on the levels of evidence; e) we analyzed the systematic review according to the levels of evidence and grades of recommendations set; f) we classified our recommendations according to the health care levels; g) we added in the appendices the recommended indicators and tools described in the CPG. Levels of evidences and grades of recommendations The levels of evidence used to draw the therapeutic recommendations of the present GPC are showed in tables 1 and 2. Tab 1. Levels of evidence used in these guidelines. Level 1 Solid evidence of high efficacy and safety in short- and long-term treatment Level 2 Reasonable evidence of efficacy and safety in short- and long term treatment Level 3 Reasonable evidence of efficacy and safety in short term Level 4 Some evidence of effectiveness with wide experience Level 5 Some evidence of effectiveness without experience Level 6 Without evidence, but with some experience Level 7 Expert consensus Tab 2. Levels of evidence used in these guidelines - description. Level 1 At least two positive short-term 1 and one positive long-term 1 randomized controlled trials with data on safety compared to placebo and no-inferiority compared to a known standard treatment, with appropriate effect size 2 and safety and tolerability no inferior to the standard treatment Level 2 At least one positive short-term and one positive long term (6 months or more) randomized controlled trial with superiority compared to placebo, a moderate effect size, safety and tolerability comparable with actual treatment Level 3 Like level II without long-term data compared to placebo (less than 6 months), or a small effect size, o a rate between efficacy and safety inferior to actual treatments Level 4 At least one randomized comparative trial with effectiveness, safety/tolerability comparable to actual treatments, experience based on observational trials, case series and frequent use in clinical practice Level 5 Preliminary data on efficacy in a randomized controlled trial versus placebo, with limited sample, or as an add-on treatment, with little or null previous clinical experience Level 6 Observational studies, case series, acceptable safety and tolerance from Level 7 experience in other illnesses Experts opinion, theoretical fundaments for clinical use, single cases

165 1 Short term randomized controlled trial: follow-up lasting less than 6 months. Long term randomized controlled trial: follow-up lasting more than 6 months. 2 Large effect size: more than 0.5 Moderate effect size: between 0.3 and 0.5 Small effect size: between 0.3 and 0.1 Trivial effect size: less than 0.1 Cohen J Statistical power análisis for the behavioral sciences. 2 nd ed. New Jersey: Lawrence Erlbaum Grades of recommendation are showed in table 3. Table 3. Grades of recommendation A Corresponds to levels of evidence 1 and 2 B Corresponds to levels of evidence 3 and 4 C Corresponds to level of evidence 5 D Corresponds to levels of evidence 6 and 7 The levels of evidence used for studies on epidemiology, diagnosis, not aimed to interventions, as well as the resulting grades of recommendation, are showed in tables 4 and 5. Table 4. Levels of evidence for epidemiologic and clinic studies not aimed to interventions LEVEL 1. LEVEL 2. LEVEL 3. Solid scientific evidence, based on epidemiologic/clinical studies characterized by highly rigorous methods, highly representative, with wide sample sizes and independently replied results. Preliminary data from epidemiologic/clinical studies characterized by highly rigorous methods, not replied with independent results or replied in samples with possible selection bias. Expert consensus.

166 Table 5. Degrees of recommendations for epidemiologic and clinical factors. A level of evidence 1 B level of evidence 2 C level of evidence 3 Experts and Scientific Societies review The resulting document was submitted to a critic review made by independent scientific evaluators (one Spanish and two foreign experts on clinical guidelines on BD), by the Catalan Agency for Health Information, Assessment and Quality CAHIAQ- and by the Scientific Societies involved, like the Catalan Society of Psychiatry and Mental Health, the Catalan Society of Clinical Psychology, the Catalan Society for Family and Community Medicine, the Spanish Society for Family and Community Medicine, the SEMERGEN and the Centre of Biomedic Research in the Mental Health Network (CIBERSAM). Levels of intervention The care model used distinguishes between the following level, devices, objectives and interventions (Table 6). Table 6. Stepped care model according to levels of care for bipolar disorder Levels Responsible Objective Intervention 1 General BD detection and evaluation for Screening and suicide recommendations the risk of suicide risk evaluation Diagnostic criteria 2 Primary Care Team BD diagnosis evaluation, referral to specialist, physical health control Diagnostic confirmation, 3 Mental Health Team pharmacologic treatment of the Treatment and illness and its comorbidities, psychoeducation suicide prevention, psychotherapeutic management 4 Inpatient Care Team 5 Specialized Team Care Life-risk management (suicide attempt or comorbidity). Severe behavioural alteration, patients unable to treat themselves Highly complex patients: rapid cyclers, severe medical comorbidities, treatmentresistant patients Treatment, combined treatment, acute TEC Complex and combined pharmacological treatments, maintenance TEC

167 II DEFINITION AND DIAGNOSIS OF BIPOLAR DISORDER EPIDEMIOLOGY Bipolar disorder is a serious and recurring mental illness that has a relatively homogeneous distribution in all populations and cultures, confirming the relevance of genetic factors in its pathogenesis. No epidemiological studies estabilished precise and specific prevalence in Catalonia, but the best and most recent epidemiological studies, realized in United States of America, indicate that its lifetime prevalence may be assessed at 4.4% in general population (1% BD type I, 1.1% BD type II and 2.4% BD NOS, including Cyclothymia). Basing on this estimate, more than Catalans would suffer from some form of BD. DESCRIPTION Bipolar disorder is characterized by a chronic instability of the mood, which manifest as recurrent affective episodes of different polarity, but always, by definition, include some form of emocional, cognitive and/or psychomotor exaltation. The presence of these symptoms may be intense (manic episodes), milder (hypomania) and also mixed with depressive symptoms (mixed episodes). Mania may be associated with psychotic symptoms in more than 50% of cases: when this occurs it is is often, cross-sectionally confused with schizophrenia, especially in a fist episode. The disease almost always presents with depressive episodes that usually last longer than manic and hipomanic ones, and it is often unresponsive to the therapeutic strategies used in unipolar depression, despite the symptom similarity. This leads to the fact that depressed bipolar patients, especially tose with a BD type II pattern, may be misdiagnosed as unipolar. This aspect is strenghtened by the fact that patients tend to go to the doctor only during depressive episodes. Some patients (up to 15%) may present with forms characterized by a greater affective instability, like tose with a rapad-cycling course or with cyclothymia. These patients are often misdiagnosed as suffering from a borderline personality disorder with chronic emocional instability and the subsequent impact on their behaviour and personality. DIAGNOSIS Manic and depressive symptoms are evaluated in operational diagnostic criteria. The most used in clinical practice and in scientific research follow ICD-10 (1992) and DSM- IV-TR (2000) classifications. Their importante lies in the use of uniform diagnostic criteria between different professionals, which considerable increases inter-rater diagnostic reliability. We will focus on the DSM-IV-TR criteria because most of the scientific literatura on which this guide is based was conducted on patients enrolled following this classification. The DSM-IV-TR provides criteria for the diagnosis of manic and depressive episodes. Hipomaniacs episodes are diagnosed when 3 mania criteria are satisfied for at least 4 days, with no major work or social impairment and with no need for hospitalization. Mixed episodes require the concomitant presence of manic and depressive symptoms. The psychotic symptoms are not part of the diagnostic criteria but associated with the severity of manic and depressive (never hipomanic) episodes. The DSM-IV-TR

168 distinguishes between BD type I (accompanied by at least one manic or mixed episode during the course of illness), BD type II (at least one hipomanic and one depressive episodes, without manic or mixed episodes) and cyclothymia (chronic instability of mood, with hypomania and relatively mild depresión, wit brief but highly recurrent episodes), plus a residual category for atypical or unspecified BD. The diagnostic criteria for each type of episode and disorder are shown in tables 5, 6, 7, 8, 9, 10, 11 and 12. Tab. 5. DSM-IV-TR Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. 1. depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g. appears tearful). Note: In children and adolescents, can be irritable mood. 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3. significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4. insomnia or hypersomnia nearly every day 5. psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. fatigue or loss of energy nearly every day 7. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

169 Tab. 6. DSM-IV-TR Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar I Disorder. Tab. 7. DSM-IV-TR Criteria for Mixed Episode A. The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. B.. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, or light therapy) should not count toward a diagnosis of bipolar disorder.

170 Tab. 8. DSM-IV-TR Criteria for Hypomanic Episode A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar II Disorder. Tab9. DSM-IV-TR Cyclothymic Disorder A. For at least 2 years, the presence of numerous periods with hypomanic symptoms and numerous periods with depressive symptoms that do not meet criteria for a Major Depressive Episode. Note: In children and adolescents, the duration must be at least 1 year. B. During the above 2-year period (1 year in children and adolescents), the person has not been without the symptoms in Criterion A for more than 2 months at a time. C. No Major Depressive Episode, Manic Episode, or Mixed Episode has been present during the first 2 years of the disturbance. Note: After the initial 2 years (1 year in children and adolescents) of Cyclothymic Disorder, there may be superimposed Manic or Mixed Episodes (in which case both Bipolar I Disorder and Cyclothymic Disorder may be diagnosed) or Major Depressive Episodes (in which case both Bipolar II Disorder and Cyclothymic Disorder may be diagnosed). D. The symptoms in Criterion A are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism). F. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

171 Table 10. DSM-IV-TR Bipolar I Disorder 296.0x Single Manic Episode A. Presence of only one Manic Episode and no past Major Depressive Episodes. Note: Recurrence is defined as either a change in polarity from depression or an interval of at least 2 months without manic symptoms. B. The Manic Episode is not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified Most Recent Episode Hypomanic A. Currently (or most recently) in a Hypomanic Episode. B. There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified x Most Recent Episode Manic A. Currently (or most recently) in a Manic Episode. B. There has previously been at least one Major Depressive Episode, Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified 296.5x Most Recent Episode Depressed A. Currently (or most recently) in a Major Depressive Episode. B. There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified x Most Recent Episode Mixed A. Currently (or most recently) in a Mixed Episode. B. There has previously been at least one Major Depressive Episode, Manic Episode or Mixed Episode. C. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified Most Recent Episode Unspecified A. Criteria, except for duration, are currently (or most recently) met for a Manic, a Hypomanic, a Mixed, or a Major Depressive Episode. B There has previously been at least one Manic Episode or Mixed Episode. C. The mood symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The mood symptoms in Criteria A and B are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).

172 Table 11. DSM-IV-TR Bipolar II Disorder A. Presence (or history) of one or more Major Depressive Episodes. B. Presence (or history) of at least one Hypomanic Episode. C. There has never been a Manic Episode or a Mixed Episode. D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Hypomanic. This specifier is used if the current (or most recent) episode is a Hypomanic Episode. Depressed. This specifier is used if the current (or most recent) episode is a Major Depressive Episode. Table 12. DSM-IV-TR Bipolar Disorder Not Otherwise Specified The bipolar disorder not otherwise specified category includes disorders with bipolar features that do not meet criteria for any specific bipolar disorder. Examples include the following: A. Rapid alternation (over days) between manic symptoms that meet symptom threshold criteria but not minimal duration criteria for manic, hypomanic, or major depressive episodes B. Recurrent hypomanic episodes without intercurrent depressive symptoms. C. A manic or mixed episode superimposed on delusional disorder, residual schizophrenia, or psychotic disorder not otherwise specified. D. Hypomanic episodes, along with chronic depressive symptoms, that are too infrequent to qualify for a diagnosis of cyclothymic disorder E. Situations in which the clinician has concluded that a bipolar disorder is present but is unable to determine whether it is primary, due to a general medical condition, or substance induced. Several reliable diagnostic tools exist, such as the Mini International Neuropsychiatric Interview (Appendix 1), that can help the Primary Care physician realizing a diagnosis of a Major Depression Episode, or of a Manic Episode (and thus a diagnosis of BD), following the international classification criteria (DSM-IV-TR and/or ICD-10). DIFFERENTIAL DIAGNOSIS OF BIPOLAR DISORDER It is fundamental, especially in the field of Primary Care, to differentiate BD from other disorders such as unipolar depresión, dysthymia, schizophrenia in patients who present with psychotic symptoms, personality disorders in patients with apparently milder and more frequent episodes substance use disorders (which are often comorbid), attention deficit disorder with hyperactivity in children, with normal mood variations in adolescents and young adults.

173

174 III RECOMMENDATIONS BY LEVELS Level 1. General recommendations: - Screening for Bipolar Disorder - Suicide risk evaluation Screening for Bipolar Disorder * The most frequent reason for consult for people with BD is depression, so the most effective form of screening is the identification of bipolarity in depressed patients, according to following risk factors: - Family history of BD - Severe depression in adolescent or young adult - Score of 14 or more in HCL-32 (Angst i cols., 2005; Vieta i cols., 2007) A * Patients with incipient psychosis or recurrent psychotic pictures may evolve into a bipolar disorder. Following DSM-IV-TR, affective manic or depressive symptoms have to be excluded before diagnosis schizophrenia * To make a good screening for BD a clinician should have, whenever possible, additional sources of information to the patient, and preferably from those who live with him. A Suicide risk evaluation * Clinicians should probe suicidal ideation and planification in every unipolar or bipolar major depressive episode. * When recollecting information from a patient, a clinician should always ask for previous suicide attempts.

175 We propose the evaluation of the suicide risk by the use of the MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW Spanish Version (agost 1998). Adapted to Catalan. Section C: Suicide risk Acc ordi During last month: ng to C1 C2 Have you ever thought that it would be better to die, or did you wish you were dead? Have you ever wanted to harm yourself? NO NO the YES seve rity crite YES ria C3 Have you ever thought about suicide? NO YES of C4 Have you ever planned to commit suicide? NO ICD YES -10, C5 Have you ever tried to commit suicide? NO YES all During your life: case s of C6 Have you ever tried to commit suicide? NO YES depr essiv e IF the patient scored 1 or more to the previous questions =YES, a suicide risk exists: epis ode whic h, among its symptoms, include recurrent thoughts of death, or suicide, or suicidal behavior should be considered at least moderate or severe depressive episodes and have a specialist intervention to implement the recommendations of Levels 3 to 5. All bipolar depression require at least Level 3 care and, in some cases, higher. * In patients at high risk of suicide it is often recommended additional support. The urgent referral to a specialist in mental health has to be evaluated. * Hospitalization should be considered in patients with high risk of suicide

176 Level 2. Primary Care Team: - BD Diagnosis - Referral to Level 3 - Monitoring and management of physical health BD Diagnosis The confirmation of the diagnosis of BD is done with a clinical interview which should explore the presence of the most important symptoms and signs, according to the criteria of the international diagnostic classifications (ICD-10, DSM-IV-TR). Annex 1 includes the complete module diagnostic interview MINI-interview, developed for use in Primary Care. The practice on its use can significantly improve the diagnostic reliability of BD. Both in patients diagnosed with BD and Major unipolar Depression the risk of suicide should be systematically evaluated. Referral to Level 3 * * Patients diagnosed with BD type I or type II should be referred for psychiatric evaluation by a specialist for diagnosis confirmation and the assessing of a therapeutic plan. It is recommended to schedule the appointment with a specialist within 30 days. Regardless of their referral to the Mental Health Center, patients with BD should be monitored in their physical health, in coordination with Specialized Care * Patients with BD who are currently not in a manic, hypomanic or mixed episode should undergo structured and supervised physical exercise programs of moderate intensity, in frequency of minutes-session per week during weeks.

177 Level 3. Mental Health Team: management of Bipolar Disorder The management of bipolar disorder mainly corresponds to level 3, ie, the mental health centers (CSM). The main reason is the complexity of treatment, both pharmacological and psychoeducational, and the potencial severity of the disease. The mental health Team will coordinate with the Primary Care and the Levels 4 and 5 if the patient is being assisted also in those levels. Treatment of mild-moderate mania and hypomania * Treatment of acute mania often requires hospitalization, since in many cases it is accompanied by significant behavioural alterations, little insight or even psychotic symptoms. Mild to moderate mania and hypomania, especially when they occur in patients who received psychoeducation, may be managed in the CSM. * Mild manic episodes may increase in severity if an effective treatment is not introduced quickly or if the patients does not assume the prescribed treatment, In cases where treatment adherence is questionable family members should be involved in monitoring the treatment, otherwise the patient should be hospitalized. * Hypomanic episodes may worsen or switch to a depressive episode. It is fundamental to treat hypomania, since its very start, to avoid the development of a full manic or depressive episode. * Assuming it is possible, a mild-moderate manic or hypomanic episode will be treated by a drug with a level of evidence of 1 or 2, in monotherapy or in combination to another according to the personal history of the patient. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * Even though mania or hypomania do not respond to psychosocial interventions, a good therapeutic alliance between the clinician and the patient is recommended that may be supported by psychoeducative elements since the very beginning of the treatment in the effort to improve a good adherence to treatment * The presence of depressive symptoms during mania contistutes a mixed episode and brings a higher risk for suicide and a need for hospitalization. The treatment of a mixed episode is similar to that for a manic one. A A A B

178 Follow-up * All patients presenting with mild manic, hipomaniac, or mixed episodes, for whom hospitalization is not indicated, will be evaluated again before 8 days after the introduction of treatment. * At least one family member or care-giver should be envolved in the monitoring of the patient, so that it is possibile to evaluate effectiveness and tolerability to drug treatment and the patient s adherence * Befote beginning with pharmacological treatment the Mental Health professional has to adequately inform the patient on the benefits, expected from the treatment, as well as frequent and infrequent short- and long-term side effects and the duration of the treatment. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels anda n adjustment in the doses used depending on the side effects and the efficacy of the treatment. * Follow up of the patients with pharmacologic treatment must be close, at least in the first 8 weeks. A Duration of the treatment * Pharmacologic treatment of a manic episode has to be continued until symptom remission, to pass then to maintenance treatment. * In patients presenting a switch to depression drug therapy should be adjusted according to the recommendations for the treatment of bipolar depression. A B

179 Treatment of Bipolar Depression Bipolar depression is characterized by being preceded, at some point in the life of the patient, by a manic, mixed or hypomanic episode. Depressed patients that cannot recall reliable information about such previous episodes maght have bipolar depression, especially if they refer a family history for BD, symptoms like emocional lability, psicomotor inhibition, hypersomnia, overeating psychotic symptoms in childhood or adolescent. * Depressive episodes in the context of a BD do not require, in most cases, to be treated in a psychiatric ward, and can be manager in the CSM, except for tose cases in which a risk for suicide, agitation or catatonia is assessed. * Depressive episodes may prolong in time i fan appropriate treatment is not introduced, or the patient fails to take prescribed drugs. In cases where treatment adherence is questionable the clinician should involve family members in the monitoring of treatment or, in serious cases, proceed the patient to a hospital. * Depressive episode may switch to mania or hypomania spontaneously or secundarily to an antidepressant treatment. Clinicians must set psychoeducational and pharmacological measures to minimize this risk. * If possible, clinicians have to treat a bipolar depressive episode with a drug of level of evidence 1 or 2, in monotherapy or combination with another one, depending on the patient s history. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * The efficacy of psychological interventions in bipolar depression if not accompanied by an appropriate drug treatment, has not been demonstrated. * Subclinical, persistent or residual symptoms of depression are associated with cognitive dysfunction, poor psychosocial functioning, and increased risk of relapse. Clinicians should treat bipolar depression with the objective to achieve a full remission, if possible. A A B B B

180 Follow-up * All patients with BD who present a depressive episode should be evaluated again within 15 days after the introduction of the treatment. * At least one family member or caregiver should be envolved in the monitoring of the patients, so that clinician can compare the effectiveness and tolerability of the treatment as well as patient s adherente. * Befote beginning with pharmacological treatment the Mental Health professional has to adequately inform the patient on the benefits, expected from the treatment, as well as frequent and infrequent short- and long-term side effects and the duration of the treatment. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels anda n adjustment in the doses used depending on the side effects and the efficacy of the treatment. * Follow up of the patients with pharmacologic treatment must be close, at least in the first 8 weeks. A Duration of the treatment * Pharmacologic treatment of a depressive episode has to be continued until symptom remission, to pass then to maintenance treatment. * In patients presenting a switch to manic, hipomanic, or mixed episode drug therapy should be adjusted according to the recommendations for the treatment of manic, hipomanic, or mixed episode. A B

181 Maintenance treatment The maintenance treatment of BD corresponds mainly to the CSM, except in cases of high complexity, which will be atended at level 4 until they can be derived to level 3. During maintenance treatment it is especially important to work with the patient and, if possible, with the family or caregivers, to ensure that they understand the need for longterm treatment to prevent future relapses. * Euthymia or remission from an acute episode may lead the patient to think that the disease has passed and there is no need for treatment, but as this is a highly recurrent disease it is essential to establish a therapeutic relationship which allows to establish a proper treatment indefinitely. * Psychoeducational interventions are essential complements to medical treatment as they improve adherente to therapy and a good psychosocial adaptation. When adherence is questionable family members and caregivers should be envolved in monitoring the treatment. * Relapses may arise spontaneously, as well as induced by treatment. Clinician should avoid "bargaining" the medication with the patient, as it may lead to a subtherapeutic use of the prophylactic treatment. * If possible, clinicians have to treat a bipolar depressive episode with a drug of level of evidence 1 or 2, in monotherapy or combination with another one, depending on the patient s history. * In some situations, due to specific tolerability issues, treatment resistance or comorbidity, the use of therapeutic options of an inferior level of evidence can be used. * The efficacy of psychological interventions, if not accompanied by an appropriate drug treatment, has not been demonstrated, but, as adjunctive treatment, group or individual psychoeducative interventions (on patients or caregivers) and cognitive behavioural therapy have demonstrated an efficacy in preventing manic, as well as depressive, recurrences. * It is not recommended the withdrawal of an effective prophylactic drug treatment if there are no tolerability problems or special situations (pregnancy, contraindications) to do so. * Treatment with mood stabilizers like lithium, valproic acid or carbamazepine require a monitoring of the plasmatic levels with a minimum annual frequency. A B A B A

182 Level 4. Inpatient Vare Team: Hospitalization and emergency care - Life attempt (for suicide attempt or comorbidity) - Severe Behavioural Alteration Pti t bl t t tth l The following cases correspond to this level: a large proportion of cases of acute mania and severe cases of bipolar depression, mixed episodes, resistance to acute treatment, or special situations involving a risk for the patient and/or those who are near. Patients who require urgent medical assessment, those who have medical or psychiatric comorbidity, severe behavior disorders (such as large economic costs, megalomaniac projects, etc.), psychotic symptoms, high risk of suicide, acute neuropsychiatric disorders, multiple medicalconditions associated to elderly age, or difficulty in self care, frequently require urgent interventions in acute care units of hospitals, where treatments can be implemented in safe conditions and with the support of other specialists. Objectives of the treatment in the Acute Unit The main goal of the treatment at level 4 is to bring the patient back to lower levels, so that he can gain autonomy and self-management skills to make unnecessary hospital treatment. Short-term objectives are included: to treat emergency and the most debilitating symptoms. Long term objectives are also given: they have to be fulfilled in other levels, but require some attention from the time of hospitalization: the decision to choose which treatment can have a major impact on intermediate targets syuch as achieving clinical and functional remission, ensure a good tolerability and a good adherence to treatment. Objectives * To treat the most severe symptoms Agitation Psychotic symptoms Behavioural alterations Catatonia * To obtain clinical remission Subclinical residual symptoms favour recurrences and a worse psychosocial adaptation * To prevent recurrences and switches * To prevent suicide attempts * To ensure a good adherence to treatment * To minimize treatment adverse effects

183 Level 5. Specialized Care Team (Tertiary Care): Care for patients of high complexity Bipolar disorder is a complex disease that in difficult cases may require a very high degree of specialization and use of resources, which are available only in tertiary centers. The percentage of highly complex cases may be around 15-20%, depending on the definition given to the term "complex". For example, an estimated 15% of manic patients accomplish criteria for "Chronic mania or resistant to treatment (van Riel et al, 2008); according to the latest definition of resistant bipolar depression (Pacchiarotti et al, 2009) up to 28% of the depressed patients does not respond to the two first-level therapeutic strategies. It has alse been described that 18% of bipolar patients have an illness course characterized by rapid cycles, which means a frequency of relapses of 4 or more per year and an increased risk of suicide (Garcia-Amador et al, 2009). Comorbidities can be high in BD, especially with substance abuse, anxiety and personality disorders worsening the outcome and increasing the suicide risk (Vieta et al, 2000 and 2001). Patients may require complex treatments combined with different drugs and/or biophysical interventions such as electroconvulsive therapy, vagus nerve stimulation -using a subcutaneous device- or deep brain stimulation. In order to reach level 5, an acute patient should have not responded to treatments at level 3 and 4. For complex, non-acute patients, the level 4 step is not essential. For those patients who meet criteria for high complexity CSM Team and Tertiary Care Team have to coordinate in order to confirm the complexity of the case, plan a suitable therapeutic approach until the patient is able to continue his treatment at the CSM. The patient care center or specialized program will not involve a temporary separation from your CSM, but a co-operation between the two centers to optimize the tractament.

184 Criteria for complexity * Acute manic or mixed episode unresponsive to 3 different grade A recommendation therapeutic strategies, in full dose. * Resistant bipolar depression according to modern criteria with lack of response to three therapeutic strategies. * Rapid cycling unresponsive to long-term treatment. * Severe somatic comorbidity which requires a Level 3 treatment for the medical condition (i.e. transplant) in a patient with instable BD. * Severe psychiatric comorbidity which brings problems in treatment adherence and therapeutic response and high suicide risk. * Patients who require maintenance electroconvulsive therapy electroconvulsiu or other biophysical therapies. * Patients who require highly complex or specialized (i.e. neurocognitive rehabilitation) psychotherapeutic interventions. * Patients who require exhaustive monitoring of psychotropic drugs

185 IV TREATMENTS Following, we present the drugs available in Catalonia for the treatment of bipolar disorder in its various phases, accompanied by the level of recommendation based on level of evidence described in these CPG. Pharmacologic Treatment The lists and tables presented below refer to monotherapy in most cases, but it is noteworthy for which the best evidence available is in combination therapy with lithium and fluoxetine (both in bipolar depression). In acute mania, combination therapies based on scientific evidence are provided for some antipsychotics (aripiprazol, olanzapine, quetiapine and risperidone), combined with lithium or valproate. In maintenance treatment, there is evidence for positive combinations of olanzapine, quetiapine, long-acting injectable risperidone, and ziprasidone combiend to lithium or valproat. Acute Mania Treatment Drugs with level of recommendation A (in alphabetical order): Aripiprazole Carbamazepine Lithium Olanzapine Quetiapine Risperidone Ziprasidone A A A A A A A Drugs with level of recommendation B (in alphabetical order): Amisulpride Clorpromazine Clozapine Haloperidol Paliperidone Valproate B B B B B B

186 Drugs with level of recommendation C (in alphabetical order): Asenapine Oxcarbazepine Tamoxifen C C C Negative evidence (evidence of lack of efficacy) in acute mania: Gabapentin, Lamotrigine, Licarbazepine, Topiramate. Acute Bipolar Depression Treatment Drugs with level of recommendation A (in alphabetical order): Quetiapine Lamotrigine A A Drugs with level of recommendation B (in alphabetical order): Fluoxetine Lithium Olanzapine B B B Drugs with level of recommendation C (in alphabetical order): Armodafinil Carbamazepine Modafinil Pramipexole C C C C Negative evidence (evidence of lack of efficacy) in Acute Bipolar Depression: Aripiprazole, paroxetine, risperidone, ziprasidone.

187 Maintenance Treatment Despite similar grades of recommendation, treatments may vary according to their preventive efficacy profile. Treatments with better anti-manic prophylactic efficacy are more appropriate for patients with predominantly manic polarity, those with better antidepressive prophylactic efficacy are more appropriate for patients with predominantly depressive polarity. Most antipsychotics are more effective in preventing manic than depression, with the exception of quetiapine, which is neutral. Lithium and valproate are rather neutral, but could prevent better mania. Only lamotrigine seems more effective in preventing manic depression. Drugs with level of recommendation A (in alphabetical order): Aripiprazole Lamotrigine Lithium Olanzapine Quetiapine Long-acting injectable risperidone Ziprasidone A A A A A A A Drugs with level of recommendation B (in alphabetical order): Carbamazepine Clozapine Valproate B B B Valproate, despite having a degree of recommendation B in monotherapy, has positive data on maintenance when associated with other drugs (lithium, quetiapine and ziprasidone) Drugs with level of recommendation C (in alphabetical order): Asenapine Oxcarbazepine C C Negative evidence (evidence of lack of efficacy) in Maintenance Treatment: imipramine.

188 Electroconvulsive therapy It has a grade B recommendation for mania, acute bipolar depression and maintenance treatment. Psychological and psychosocial interventions Acute Mania Treatment None. There is no evidence of efficacy of psychosocial treatment in the acute phase of mania Acute Bipolar Depression Treatment There is limited evidence for the effectiveness of certain treatments. None of them exceed level C (listed in alphabetical order). Familiar Intervention Cognitive behavioural therapy Interpersonal and Social Rhythm Therapy C C C Maintenance Treatment In this phase of the illness more evidence of efficacy of psychological interventions has been produced. Psychological treatments are always complementary medication and never replace pharmacological treatment. Familiar intervention Group psychoeducation Family psychoeducation Cognitive behavioural therapy Interpersonal and Social Rhythm Therapy B B B B C V IMPLEMENTATION OF THE GPC

189 1 - Indicator of prevalence / frequency: Total population with BD awaited in the CSM (F30, F31, F34.0) Adults: - Numerator: Total number of people 18 of age or more who attended the CSM during previous year, diagnosed with F32, F33, F34.1, F Denominator: Total number of people 18 of age or more who attended the CSM during previous year, The percentage should be > 15% 2 Indicador of incidence / frequency: Population served with CSM in nine bipolar disorder diagnosis (F30, F31, F34.0) Adults: - Numerator: Total number people of 18 years of age or more who attended the CSM during previous year with a new diagnosis of F30, F31, F Denominator: Total number of people of 18 years of age or more who attended the CSM during previous year. 3 - Quality indicador The percentage should be > 5% Population affected by BD attending the CSM and treated with drugs with a recommendation grade A or B of this Guide (on treatment with stabilizer). - Numerator: Number of people of 18 years of age or more who attended the CSM during previous year, diagnosed with BD (F30, F31, F34.0), who received treatment with mood stabilizers during last year. - Denominator: Total number of people 18 years of age or more who attended the CSM during previous year, diagnosed with BD (F30, F31, F34.0). The percentage should be > 70% 4 Process/Multidisciplinary Indicador Population with BD attending the CSM, receiving a grade A or B recommendation psychological treatment in psychological treatment following the present GPC - Numerator: Number of people of 18 years of age or more who attended the CSM during previous year, received a diagnosis of BD (F30, F31, F34.0), and received psychoeducational treatment.

190 - Denominator: Total number of people of 18 years of age or more who atended the CSM during previous year, who received a diagnosis of BD (F30, F31, F34.0). The percentage should be > 50% 5 - Efficiency Indicador Population attending the CSM, diagnosed with BD, treated with mood-stabilizers with good cost-effectiveness profile (lithium). 6.- Outcome Indicador - Numerator: Number of people of 18 years of age or more, who attended the CSM during previous year, diagnosed with BD (F30, F31, F34.0), who received treatment with lithium. - Denominator: Total number of people of 18 years of age or more, who attended the CSM during previous year, diagnosed with BD (F30, F31, F34.0), who received any other drug treatment. The percentage should be > 30% Patients diagnosed with BD treated in the CSM who have not required hospitalization last year. - Numerator: Number of patients of 18 years of age or more who attended the CSM over the last year who have received a diagnosis of BD (F30, F31, F34.0) and have required hospitalization in an Acute Care Unit. - Denominator: Total number of patients of 18 years of age or more who attended the CSM over the last year who have received a diagnosis of BD (F30, F31, F34.0). The percentage should be <25%

191 VI. INFORMATION FOR PATIENTS AND FAMILIES Bipolar disorder is a disease characterized by episodic changes in mood, activity, sleep and energy. It is cyclic, consisting of phases of hyperactivity, irritability and euphoria, alternating with phases of tiredness, sadness and lack of energy. Sometimes these symptoms may appear simultaneously (mixed episode). Between episodes the patients may or may not return to normal physical, psychological and social functioning. This disease is characterized by an alteration in the regulation of emotions and energy, in which brain areas that deal with such functions do not work properly. Nowadays several effective treaments are disposable to control acute symptoms and to prevent relapses, and the illness may be kept under control in most cases. Pharmacological treatment is essential and should complement with psychoeducation or other psychological treatment of proved efficacy. The family plays an important role in supporting patients and helping them to recognize relapses and to take the correct treatment, thus improving drug adherence. In case of a serious relapse, either manic or depressive, hospitalization may be needed. Some patients have difficulty in understanding and accepting the disease, and tend to blame others for their symptoms. Patients affected by this disorder often need some time to assimilate the disease and do what is necessary to avoid complications. The diagnosis is mainly clinical, and there are no complementary or confirmatory assessment (i.e. neuroimaging, laboratory tests) disposable at the moment. For more information on symptoms, diagnosis, prognosis and treatment, please consult the following books and websites: Books: The disease of emotions: Bipolar disorder. E. Vieta, F. Colom, and A. Martinez-Aran. Column editions, De la euforia a la tristeza. El trastorno bipolar: cómo conocerlo y tratarlo para mejorar la vida. Francesc Colom & Eduard Vieta La esfera de los libros Webs:

192 015 INFORMATION FOR PATIENTS AND CAREGIVERS GENERAL INFORMATION COURSE OF ILLNESS ACUTE EPISODES MANIC EPISODES DEPRESSIVE EPISODES EVOLUTION AND PROGNOSIS TREATMENT MOOD STABILIZERS ANTIPSYCHOTICS ANTIDEPRESSANTS NO-PHARMACOLOGICAL TREATMENTS PREGNANCY AND GENETIC COUNSELLING THE RISK OF INTERRUPTING THE TREATMENT SUBSTANCES ABUSE AND BIPOLAR DISORDER RESOURCES GENERAL INFORMATION Bipolar disorder (once called manic-depressive illness ) is a mood disorder, which means that symptoms are disturbances or abnormalities of mood. It results from a change in the mechanisms that regulate mood. It appears that limbic system is the area in the brain in charge of acting as an authentic mood-o-meter, similar to the thermostat you have in your house: it keeps the temperature steady and activates the structures needed to maintain equilibrium. In the case of the thermostat, when it detects a temperature higher than the one it has been set at, it activates the air-conditioning unit and, in turn, it activates the heater if the temperature is excessively low. A person s mood tends to be regular and dependent on their environment. When people are suffering from bipolar disorders, their mood-o-meter is not working properly, so that their mood becomes unstable, variable, and independent from their environment. Bipolar disorder is an illness with a genetic component, but this does not mean that there is a 100% probability that the child of a person who has bipolar disorder will also have it. In fact, the odds of the child not having the disorder are still higher than those of having it, although logically the probability of someone having the disorder is higher than that in the general population. On the other hand, the odds would also vary depending on the degree of family relationship, being the probability of being affected by the illness higher if close kindred are also affected. There are several physiological mechanisms involved in bipolar disorders, most of them at the neurotransmitter level. Neurotransmitters are the substances in charge of carrying information in the brain. There is empirical evidence that some neurotransmitters (dopamine, serotonin, noradrenalin, acetylcholine) work abnormally in bipolar disorders.

193 There are also abnormalities in hormonal functioning, most of all in the thyroid hormone. We can currently say without a doubt that bipolar disorder has a biological base and is genetically transmitted. Theories that said that different psychological or social factors (childhood trauma, poor family relationships, and personality factors) caused bipolar disorder are no longer valid. We now know that all these factors can bring on the disorder or make it worse, but never cause it. Bipolar disorder is chronic and recurrent: this means that it is with the patients for their entire life, although it is not as severe at all stages in their life, and that the episodes tend to repeat themselves. Nearly 4% of the population suffers from some kind of bipolar disorder. Although many people believe otherwise, the truth is that bipolar disorder is a disorder that has existed throughout history, meaning that it is as old as human kind itself. The prevalence rates of this disorder are very similar in all countries, a fact which demonstrates that it is a universal disorder, in no way related to cultural or social circumstances. Fortunately, today we have very effective treatments to keep bipolar disorder in check, so that many people who would have in the past spent a large part of their time on the fringes of society or institutionalized can now lead normal lives (in other words, they are not slaves to their disorder). Many patients affected by bipolar disorder lead entirely well-adjusted social, family and sentimental lives and hold jobs just as well as anyone who is not bipolar. In fact, the list of people affected by bipolar disorder who now hold prominent places in history is endless: political leaders like Churchill, painters like Van Gogh, Gauguin or Pollock, brilliant composers like Schumann or Tchaikovsky, jazz musicians as Charles Mingus, renowned writers like Virginia Wolf, Hemingway, Charles Baudelaire, Herman Hesse, Edgar Allan Poe, etc. However, because many artists, musicians and writers suffer from bipolar disorder, sometimes the effects of this disease have been trivialized and considered, in some way as beneficial for artistic creativity. Actually, for those affected by the disease, it is extremely distressing and disruptive. We must start thinking that having a bipolar disorder does not have to be any more or less serious than having other chronic diseases like asthma or diabetes, and that for the most part of the disorder can be kept in check through proper-medication and by strictly following behavioural guidelines COURSE OF ILLNESS We now know that genetics play a fundamental role in bipolar disorders. In fact, we can safely state that the cause of this disorder is genetic; that is to say, it is marked by genes. This notion may seem strange to us, because the disorder may not manifest itself until adulthood, or because it might occur when no similar case is known in the affected person s family. This apparent contradiction is explained by the fact that certain illnesses with a hereditary component manifest themselves if certain environmental factors occur; that is why the disorder does not manifest itself from birth. On the other hand, family background can also be very remote and, because of this, the affected person may not be aware of it. This is particularly common in psychiatric disorders because they have been so misunderstood for so many years and because of the social taboo they have born. Because of this, a lot of families try to hide or create excuses for ill family members instead of trying to get them to get treatment. Spontaneous changes in genes, called mutations, may also explain why hereditary illnesses can appear in individuals who have no family history of the disorder.

194 Generally speaking, although there are exceptions, the disorder begins to become just barely noticeable during adolescence (a stage that in and of itself causes emotional instability) and reaches its peak in adulthood, when it manifests itself as a depressive or manic phase. A person is at highest risk of having his or her first episode when he or she is under the age of 50. The first episode is often preceded by a stressful environmental situation. From that moment on, the disorder begins to separate itself from environmental and psychological circumstances, so that the biological mechanisms regulating mood appear to perpetually swing back and forth, and make the affected person lose the reference point for his or her normal mood. With every relapse, the person becomes more vulnerable to stress, and this makes some patients have rapid cycling, which is the almost uninterrupted succession of depression and euphoria (people who have four or more episodes a year). In summary, we have to keep in mind the genetic factors that are responsible for a person being vulnerable to suffer from a particular disorder, and, on the other hand, the factors imploied in stress response. In the case of bipolar disorder, we should underscore the importance of the genetic component and the fact that the fators implied in stress response are responsible for the appearance of the disorder and for accelerating relapse into following episodes. Some possible triggers are the death of a close relative or job changes, although it is also true that relapses can occur without anything unpleasant or traumatic occurs (job promotion, change of address, etc.). Bipolar disorder is slightly more common in women tha men, but rapid cycling is much more frequent in female patients. Approximately 4 out of every 100 people will suffer from a bipolar disorder in their lives. This risk is higher in people with relatives who have this disorder- In men, it is more likely to occur a mania as onset episode, while a major depressive onset episode is more likely to occur in women ACUTE EPISODES MANIC EPISODES Mania is an exaggerated, persistently high or irritable state of mood. It is characterized by the following symptoms: increased self-esteem, decreased need for sleep, verbosity, rapid thinking, being easily distracted, psychomotor agitation, underestimating the risk and implication of pleasant activities that can have potentially serious consequences. Not all of these symptoms have to be present, in that there can be depression without sadness, manias in which irritability and anger overshadow happiness. Nevertheless, we have to recognize that one of the most classic symptoms of manic episodes is increased self-esteem, which can run from self-confidence lacking selfcritique to an obvious grandiose notion that attains delirious proportions. For example, people who are affected by this disorder can offer tips about things they know nothing about, they could write novels, compose a symphony or look to publish an invention that has no practical use. Delirious grandiose notions are common (i.e. having a special relationship with god or with a political, religious or entertainment figure, having some kind of special power or virtue, etc.). There always tends to be a decreased need for sleep: the person who is affected usually wakes up several hours earlier than usual feeling full of energy. When the sleep disorder is serious, the patient can go several days without sleep and no sensation of tiredness. Language is typically verbose, fast and hard to interrupt, and the person usually talks loudly. What the person talks about is usually characterized by the addition of jokes,

195 puns and somewhat funny remarks. The person can be theatrical, with dramatic mannerisms and songs. If the mood is predominantly irritable, the discourse will be riddled with complaints or hostile comments. Another classic symptom is increased thinking speed, which some patients have defined as watching two or three TV programs at once. Thoughts tend to come about faster than they can be put into words or even understood, and thought might be completely disorganized. In some patients, increased sex desire is common. This characteristic, along with not assessing the negative consequences of their behaviour, leads many people to break their sentimental relationships during manic episodes and to have numerous sexual relationships, promiscuity and other sexual behaviour uncommon for them. Symptoms like expansivity, optimism without any reason and poor judgment often lead to careless engagement in pleasant activities like unlimited shopping, fearless behaviour and unreasonable economic investments (accumulating a lot if unnecessary things: expensive antiques, 20 pairs of shoes, etc.). Subjects suffering a manic episode do not recognize that they are ill and they might resist attempts at treatment. They frequently justify or rationalize their behaviour, they travel impulsively to other cities, change the way they dress, their makeup or their personal appearance to a flashier or sexually suggestive style that may be inappropriate. They also behave strangely, offering advice about things they do not know anything about or giving away money. All of this can be accompanied by pathological gambling, antisocial behaviour, and toxic substance abuse. Ethical considerations are often forgotten, and the people seem unaware of the feelings of others. Irritability or inability to accept opinions and stances contrary to their own are not uncommon, and this can lead to verbal or physical abuse against connotation that the press gives to the word manic, we should indicate that significant aggression is uncommon during the manic phase. Contrary to popular belief, mania is not usually dangerous or violent. During manic phases, psychotic symptoms tend to appear. There are two kinds: hallucinations (perceptions without an object to motivate it, that is hearing noises or voices, seeing things or peoples, etc.) and delusions (more or less absurd or unfounded beliefs that go against all reason, that is, believing that you are fluent in a language you have never studied, believing you are being pursued by the KGB, or that the FC Barcelona Soccer Team has offered you a multi-million dollar contract to be their next forward) DEPRESSIVE EPISODES The essential characteristic of a depressive episode is that it involves a period of at least 2 weeks during which there is a state of depressed mood or a loss of interest or pleasure for almost all activities. To consider that a person is suffering from depression and not simply that he is sad or worried about negative events there should also be present, in addition to sadness or irritability, another four symptoms from a list, which includes changes in appetite or weight, changes in sleep pattern (generally oversleeping, but also insomnia sometimes), slowing of movements, fatigue, loss of usual interests, lack of energy, feelings of inferiority or guilt, difficult thinking, concentrating or taking decisions, and thoughts of death or ideas of suicide. Frequently, depressed people describe their mood as sad, hopeless, having the blues, like being in a well. In spite of this, during bipolar depression it is usual for the sadness not to be the dominant emotion: a sensation of inhibition, emotional emptiness, indifference or passiveness may dominate the episode instead. Anxiety is also common.

196 Other depressed people place a special emphasis on their physical complaints (widespread discomfort or pain without any medical cause). Some show a heightened state of irritability (i.e. persistent anger, tendency to respond by discussing with others, or feelings of frustration about things that are not important). As we can see, bipolar depression can take on various forms and still be the same illness. We almost always find a noticeable lack of interest and ability to enjoy life. When a person is depressed, he or she tends to be less interested in activities that were usually gratifying (hobbies, going to the movies, theatre or going for a walk, getting together with family and friends, etc.). In most cases, there is also a significant decrease or complete disinterest in sexual desire, although this is reversible. In some cases, the patient loses his or her appetite and must take great pains to eat. In other instances, the person is hungrier and eats without any order, usually candy and chocolate. As a result, there is the possibility of weight loss as well as weight gain. Sleep alterations are very common: oversleeping or hypersomnia and drowsiness during the day. Sometimes the patients wakes up during the night and has a lot of trouble falling back to sleep (sleep maintenance insomnia) or sleeping (inability to sleep). Psychomotor changes include restlessness (inability to stay seated for long periods of time, general anxiety, nervous hand movements) but also slowing down (language, thinking and movements are slower and the tone of voice is softer). Lack of energy, feeling tired and fatigued are very common symptoms. People feel fatigued persistently without having done any kind of physical exercise, so that any easy task requires a lot of effort. The efficiency with which they carry out their daily tasks and routines is greatly reduced, for example taking care of themselves or their hygiene, which can become so exhausting to the patient that he or she stops doing it. Feelings of being useless or guilt involve a negative, unrealistic evaluation of oneself or feelings of guilt, and worry about mistakes, even if they were insignificant. This can lead patients to misinterpret trivial events, which they wind up considering as proof of the many personal flaws they think they have. Patients commonly feel exaggeratedly responsible for adversities. Thoughts about death or suicide are very common (one out of every three patients attempt suicide at least once in their life) and, although we will be discussing it in detail in another session, we can put forth that suicidal ideas are always a symptom of an illness. The perceived inability in solving problems and in facing adversities are among the reasons that may lead depressed patients to consider attempting suicide. Depressive episodes can be preceded by psycho-social stress factors like the death of a loved one or separation. These events can trigger the episode but not cause it. In most cases, however, these episodes occur spontaneously, without any stress factor being present. For women, having a baby can act as a trigger, just like it can lead to a manic episode, and menstruation can also become a factor to take into account. We understand mixed phases to be ones where depressive symptoms are mixed together (i.e. pessimism, ideas about death or incapacity) with manic symptoms (agitation restlessness, rapid thought), generally largely overshadowed by irritability, anxiety, lability and restlessness EVOLUTION AND PROGNOSIS Bipolar disorders set in earlier than unipolar disorders (depression without episodes of euphoria). They usually emerge for the first time before age 30 and it is very unusual for the first episode to take place after age 50. The first episode may be both manic and

197 depressive or mixed. The duration of the episodes may vary, even though it is rather constant for each patient. Without treatment the natural evolution of an episode prolongs from a few weeks to several months, but with treatment it is possible to shorten its duration so that an improvement is noticed 2-3 weeks after the beginning of the treatment in the case of a depressive episode and a few days later in the case of a manic one. The onset of a new episode is much lower if the person who suffers from the disorder takes the medication correctly. If it starts anyway, the episode will be much less severe, it will have fewer consequences and will last for a shorter period of time. Continuing the treatment means reducing the risk of suffering an immediate change toward an episode of the contrary sign, for example from mania to depression. After the first episode (mania, depressive or mixed) years may pass without any symptom being felt by the patient (euthymic state), but we must take into account that bipolar disorder is a recurrent disorder, which means that many of those who suffer from it will present with future episodes. Luckily, this is something that can be faced and managed, as nowadays the possibility of following a pharmacological treatment may greatly improve the prognosis of the illness. This objective cannot be achieved without the patient participation in this process of avoiding the relapses: consequently, it is fundamental to have information about the disorder, since it permits to have a better control over the illness. Certain effects or consequences of the disorder consist of the fact that various aspects of he person s life, such as marriage, children, friends, or work, may be affected. Even though most people who suffer from bipolar disorder return to total normality in the periods between episodes, some (20-30%) continue showing affective liability or instability and interpersonal or work difficulties. Once again, we will insist on the fact that both correct pharmacological treatment and psychotherapy are fundamental tools to minimize the sequelae. The manic episodes usually start suddenly, with symptoms rapidly increasing over a few days. Frequently, they appear after some type of psycho-social stress, lasting from a few weeks to several months and in general are shorter and end more abruptly than the depressive episodes. In many cases, a depressive episode immediately precedes or follows a manic episode, without an intermediate period of euthymia. But what most often happens is that, after a manic episode, the person enters a low period that may be confused with a depressive episode. This is characterized by apathy, lack of energy, reduced attention, concentration and/or memory, hypersomnia, increase in appetite, etc. The person is often dysphoric, and this condition must be fought by increasing the level of activity and not spending too much time in bed, otherwise this stage lasts much longer. It is better to introduce not immediately antidepressants, since there is a risk of decompensating the patient again towards a manic phase. In this stage of dysphoria, the patient has often a sensation of malaise and feelings of guilt for what he has done during the manic episode. The mixed episodes may emerge after a manic episode or a depressive episode, lasting from a few weeks to several months, and lead to a period with few or no symptoms, or may evolve toward a depressive episode. The evolution of a mixed episode toward a manic episode is much less frequent. Hypomanic episodes start suddenly, with a rapid increase in symptoms, in 1 or 2 days. They usually last between a few weeks and several months, but are shorter and have a more sudden end than the depressive episodes. It seems that 5-15% of the people with hypomania will end up having a manic episode.

198 There are indications that changes in sleep-wake rhythm, such as those during travel or sleep deprivation, may precipitate or exacerbate manic, mixed or hypomanic episodes. On the other hand, if psychotic symptoms appear during an episode, it is most probable that they will reappear in subsequent episodes. Depressive episodes tend to develop ever days or weeks, but usually an untreated episode lasts 6-10 months. Remission from symptoms is possible with an adequate treatment. After each new relapse, the person affected becomes more vulnerable or likely to suffer new decompensation, that is the more episodes he experienced the more probable it is that he will suffer subsequent relapses; in addition, the time interval between episodes tends to shorten, while the duration of the episodes tends to increase. Rapid cycling, which consists of presenting with more that 4 episodes a year, affects 10-15% of the patients in some stage of their lives. This is a stage in which the evolution of the disorder becomes worse, even if this worsening is reversible. We now know that the efficacy of lithium in these cases is not so high, but there are alternatives, such as carbamazepine, valproic acid, lamotrigine or oxcarbazepine, which are also mood stabilizers; otherwise, the use of an atypical antipsychotic like risperidone or olanzapine as a maintenance treatment is also possible. On the other hand, there are indications that hyperthyroidism (deficient functioning of the thyroid) may play a role in the predisposition to rapid cycling. This is the reason why preventive checkups are done. Antidepressants may also act as triggers of rapid cycling so that they must be avoided whenever there are no marked or severe depressive symptoms. In the case of a dysphoric state, an adequate assumption of mood stabilizer and behavioural measures (avoid social isolation, going out and meeting with friends, fulfil study and/or work obligations, sleep for a limited period of time but not during the day, etc.) are necessary steps. It is calculated that three-quarters of the patients hospitalized for mania will in the end be re-hospitalized for a new episode. The relapse prevention strategy, consisting of a good adherence to treatment and better knowing the disorder, will lead, in the event of relapse, to a lower intensity of symptoms and therefore to a reduction of the possibility of being re-hospitalized TREATMENT MOOD STABILIZERS We call mood stabilizers the drugs designed to maintain mood stability. Patients affected by bipolar disorder need to take this type of drugs during their entire lives, and their purpose is not only to avoid new episodes from taking place, but also to reduce the severity and duration of a hypothetical new relapse. Among mood stabilizers, the mostly indicated drug for the treatment of a pure bipolar disorder, without any type of complication, is certainly lithium. Lithium has a strong preventive action, especially towards manic relapses, and also helps reducing the mood instability that affects many patients between episodes. On the other hands, we must stress its usefulness in preventing suicide; however, the sudden withdrawal of this drug may precipitate a relapse, so discontinuation when decided by the psychiatrist should always be gradual. Abandoning the treatment suddenly and without following the indications of the psychiatrist may be the cause of a future resistance to the drug: in other words, it is likely not to work when the treatment is resumed. The most frequent side effects of lithium are tremor (especially in the first weeks), diarrhoea, increase in the need to urinate and drink, liquid retention. More infrequent side effects are acne and gastrointestinal upset.

199 The rest of the drugs used as mood stabilizers are generally anticonvulsants: that is, drugs indicated for the treatment of epilepsy. This does not mean that the bipolar disorder is a disorder which is close to epilepsy, even though they may share certain psychobiological mechanisms. Among anticonvulsant mood stabilizers the main ones are valproate, carbamazepine, oxcarbazepine, and lamotrigine. Valproate is an efficient drug to maintain euthymia, and it has a great antimanic action. It may also be efficient in the treatment of rapid cycling in mixed phases. Among its side effects, the main ones are weight increase and, more rarely, the change of hair texture or hair loss. Carbamazepine is another frequently used mood stabilizer. It has been shown to be efficient in preventing relapses in bipolar disorders, included in cases of rapid cycling. In general, carbamazepine is not associated with significant side effects, even though in certain cases it may cause vision problems (diplopia or double vision), fatigue and difficulty urinating. In exceptional cases it causes a drop in the blood sodium levels (hyponatremia). If this complication emerges, the psychiatrist must stop the drug. Without doubt, carbamazepine is very efficacious, but somewhat difficult to manage if the patient is taking other medications because of its many interactions, so that if a patient takes it he must always tell their psychiatrist when the physician prescribes him a new drug. An interaction that must be always taken into account is that produced in patients who take oral contraceptives (popularly known as the pill ), because carbamazepine reduces the efficacy of this drug and, therefore, its efficacy as a contraceptive is lost. Oxcarbazepine is an evolved for of carbamazepine which, is also associated with the risk of hyponatremia (drop in blood sodium levels), although it has less side effects. Lamotrigine is one of the most efficient drugs in preventing depressive episodes, but it has null efficacy in preventing manic or mixed episodes. Its most common side effect is the emergence of an allergic reaction on the skin (red spots that burn, known as exanthema or skin rash), which is not severe in most cases and which is avoided if the dose of the drug is increased slowly until reaching the desired dose. If the spots or pimples appear on mucosa (e.g. on the lips), we must immediately consult a psychiatrist because it may be a signal of a more serious complication. Another drug used as mood stabilizer, levothyroxine, is especially efficacious in the treatment of rapid cycling and in cases of hyperthyroidism. Atypical antipsychotics have proven to be efficacious, in different degrees, in the prevention of affective episodes. Fortunately, psychopharmacology is a field which experiences constant progress, so that it is likely that the list of mood stabilizers soon increases. Patients who are on therapy with lithium, valproate, carbamazepine, must periodically undergo controls of the drug blood levels, to make sure that: 1. The drug reaches a sufficiently high concentration to be therapeutic, which means useful. 2. The concentration of the drug is not excessive, since at high-enough levels it may be toxic 3. The patient is taking the medication correctly. The frequency of the tests will vary. In the beginning, we must do many, until we find the optimal serum level which corresponds to the maximum therapeutic effect of the medication and the lowest number of side effects. Once this level is established the psychiatrist will request a level determination in the following situations: 1. Routine control every 6 months.

200 2. Whenever the dose of mood stabilizer is modified or other drugs that may interact with them are modified. 3. When it is suspected that the patient is taking the drug incorrectly. 4. When intoxication or too high levels are suspected. In general, we will suspect lithium intoxication in the presence of symptoms such as intense tremor, vertigo, vomiting, convulsions, vision problems, intense diarrhoea, movement coordination problems, or confusional states. Carbamazepine and valproate have lower toxic potential than lithium, Lithium levels in the blood must range between 0.4 and 1.4mEq/l: below these levels it would have no therapeutic effect and above them the risk of intoxication would be very high. The levels of carbamazepine must be between 5 and 15 mg/ml and those of valproate 50 and 100 mg/ml. We must take into account that lithium is a salt and therefore its levels may oscillate depending on various factors, such as for example hyposodic diet (low-salt diet) or in periods of severe dehydratation (e.g. due to saunas or viral infections that cause fever or vomiting, intense physical exercise and subsequent profuse sweat). Consequently, patients who take lithium must avoid sudden changes in the salt content of their diet. This is also recommendable for patients treated with carbamazepine because of the risk of hyponatremia. The determination of serum levels must be done 10 days after changing the dos, because within a shorter period of time the dose change is not reflected in the test. It is necessary to avoid taking the mood stabilizer intake immediately prior the test, to avoid altering test results ANTIPSYCHOTICS The treatment for a manic or hypomanic phase greatly depends on the intensity of the symptoms. The early identification of this type of decompensation is essential to prevent its intensity from becoming too strong and, consequently, to avoid hospitalization and especially aggressive treatments, with all the side effects they imply in spite of the recent pharmacological progresses. In most cases, early identification will prevent a new episode. The manic episode may successfully be treated only with psychotropic drugs, while the psychological interventions would be more indicated to prevent and facilitate early identification. Consequently, it is senseless to try to treat mania with psychotherapy. Progress in the research of psychotropic drugs has allowed us to increase the efficacy of the new antimanic drugs and reduce their side effects. There are several types of antimanic drugs, and some of them are described below. Atypical antipsychotics. These are drugs marketed especially in the last decade in the effort of reaching the efficacy of the older antipsychotics without having to manage their side effects. The efficacy of most of these atypical antipsychotics has been demonstrated in maintenance treatment and, for this reason, they may be used at low doses as mood stabilizers (in general, they are used in combination with a classical mood stabilizer), to avoid manic relapses, the emergence of psychotic symptoms and, in some cases, depressive relapses. Aripiprazole. It is one of the newest introduced compounds. It has a very good antimanic action and prevents manic relapses. The occurrence of weight gain is very rare and of minimal entity. Olanzapine. Among these new compounds, olanzapine is maybe the one we have more information about, coming from rigorous and scientific studies carried out in thousands of patients worldwide. It is a highly efficacious drug in the treatment of mania, regardless of the subtype (euphoric or mixed), and quite adequate for maintenance

201 treatment; it can help also in the treatment of certain depressive phases. As side effects, it causes mainly metabolic effects (i.e. weight gain, hypertriglyceridemia, hypercholesterolemia, diabetes). Quetiapine. It has proven efficacy in the prevention of manic as well as depressive episodes. At low doses, it has an antidepressant effect. Among its side effects, there are weight gain (but less than olanzapine or risperidone) and practically no sexual dysfunction. In some cases it may reduce blood pressure so that it is not indicated in hypotensive patients. Another common side effect is sedation. Risperidone. This one of the most widely used drugs, very efficacious antimanic and a powerful antipsychotic. It is also used in maintenance treatment at low doses, in combination with a classical mood stabilizer. Its side effects are similar to those of haloperidol, even though milder. It produces less weight gain than olanzapine, but may change hormonal changes, such as an increase in prolactin and sexual dysfunction (e.g. erection problems or anorgasmia). Ziprasidone. Its efficacy in the treatment and prevention of manic episodes has been demonstrated. Weight gain is a rare occurrence, although it may have some cardiac side effects. Neuroleptics or classical antipsychotics. Classic neuroleptics have been for decades the absolutely necessary tool in the successful therapy of many manic picture, and in spite of their substitution with newer, better tolerated drugs, they are rapid and efficacious in the treatment of mania. As their name indicates, they are efficacious in treating the psychotic symptoms (i.e. delusions an hallucinations), which are not infrequent in mania, but they as well treat grandiose thinking, agitation and irritability, they normalize the course of thought (i.e. slow down the accelerated thinking that is typical in mania and some hypomanic states) and their content, which is often characterized by strange and inadequate ideas. Since they were replaced by atypical antipsychotics, most classical neuroleptics are no longer used today, although some continue being used broadly due to their quick action, which has not yet been reached by the newer drugs: this is the case of haloperidol. The simple administration of few drops of haloperidol for few days sometimes slows down a new episode, providing we detected it in time. Its most frequent side effects are muscle rigidity, tremor, the emergence of tics, a feeling of sadness, restlessness in the legs (akathisia), and various anticholinergic effects (dry mouth, etc.). The possibility of the emergence of these side effects, which are quite reversible a few days after stopping the drug, makes the psychiatrist opt for the lowest dose possible. Moreover, most of these side effects disappear or are alleviated with the administration of anti-parkinson drugs ANTIDEPRESSANTS Unlike the treatment of manic episodes, in which antipsychotics are practically the only possible treatment, we have several alternatives to treat depressive phases. Quetiapine. It is the only antipsychotic with a clear antidepressant action. Its potential to induce mania is null, so that it is a very safe treatment option. Lamotrigine. Its antidepressant action is usually slow, especially because the physician must increase the dose quite slowly to avoid the emergence of side effects, vut it is very safe because its potential to induce mania is practically zero. Antidepressants. This heterogeneous class of drugs has a controversial role in the treatment of bipolar depression. They are generally used in clinical practice, but only in association with mood stabilizers or antimanic agents, due to the possibility of inducing manic and mixed phases or rapid cycling.

202 - Tricyclic antidepressants. They have constituted a main weapon of pharmacotherapy against depression for almost 30 years, as they were among the first psychotropic drugs discovered. They are probably the most rapid and efficacious drugs in the treatment of bipolar depression, nut they also produce more side effects or discomfort, and are associated with a higher risk of causing a change of phase. They tend to produce sedation in most patients, even though some patients feel stimulated. They often cause hypotension, which tends to be postural. Sometimes there is weight gain during the treatment. The most broadly used are imipramine and clomipramine. - Selective serotonin reuptake inhibitors (SSRIs). These drugs are practically as efficacious as the tricyclics, but cause less side effects and have less potential to induce mania or hypomania so that currently they are a group of drugs used broadly to treat bipolar depression Their side effects are typically reduced to slight digestive discomfort at the beginning of the treatment and, occasionally, sexual dysfunction. Some of the most used SSRIs are fluoxetine and paroxetine, which are highly indicated in depressions with a large anxiety component, and finally Sertraline and citalopram. - Selective serotonin and noradrenalin reuptake inhibitors (SSNRIs). These are among the most recent antidepressants. Their effect may be more potent than SSRIs. They may be considered as efficacious as tricyclics and are also associated with less side effects, even though their potential to induce mania may be higher than the SSRIs. Among disposable SSNRIs venlafaxine is very often used. Another mixed action drug (noradrenergic and serotonergic) is mirtazapine, which seems to be less effective and induces serious weight gain and sedation. - Monoamine oxidase inhibitors (MAOIs). Their use is relatively limited, in spite of their great efficacy, because they interact with many commonly used drugs (e.g. those used to treat a cold). In addition, they force the patient to follow a special diet, since they also interact with fermented foods with high tyramine content and may cause a hypertensive crisis, cerebral haemorrhage or infarction if this rule is not closely followed. Consequently, the patient who takes MAOIs must not eat any of the following foods: sausage, fermented cheese, wine and beer, pickles, foods in vinegar or marinade, most canned foods, avocados figs, bananas, caviar, prawns, dried fish, smoked meat or fish and precooked dishes. Some of the most common MAOIs are tranuylcypromine and phenelzine. Moclobemide is a MAOIs that presents less risk of drug and food interactions NO-PHARMACOLOGICAL TREATMENTS Electroconvulsive therapy (ECT). It is highly efficacious in the case of inhibited depressions or depressions unresponsive to drug treatments. It is a very safe therapy. Psychological therapies. The only psychological therapies whose efficacy in the treatment of bipolar depression has been (limitedly) demonstrated are cognitive therapy and interpersonal therapy, which are combined with the administration of antidepressants and always with stabilizers. Is has not demonstrated that psychoanalysis has any usefulness in the treatment of bipolar disorders PREGNANCY AND GENETIC COUNSELLING One of the topic that most worries our patients is the genetic burden of the illness and the possibility of transmitting the illness to children. Many couples in which one of the

203 members has a chronic disease of genetic origin, such as bipolar disorder, discuss the possibility of having children and the risk of having children who may undergo the same illness. This probability will depend on many factors, including the number of family members with the same disease,, the number of children, the subtype of the disorder, whether the person affected is the future father or the future mother, and, of course, hazard. Other factors that have a very big weight are obviously the paternal or maternal vocation, the idea a person ha of his or her disorder, the family context and the severity of the disorder, since a decompensated bipolar disorder is probably incompatible with performing the obligations of a father or mother. In general we can affirm that the risk that the children of bipolar disorder patients will also have the disorder is higher than in the children of those who do not have it. In any case, the risk for the children of those affected is about 20%, which means that the child has more possibility not to have the disorder (80%) than to have it (20%). This risk is much higher if both the father and the mother have BD or another affective disorder. It must be stressed that we do not always speak of immediate inheritance, because sometimes the disorder skips one or two generations, and the disorder is not always inherited with the same intensity or the same form: a bipolar I father may have a child with type II bipolar disorder, for example. It is highly recommendable that, if a patient wants to have a child, she must duly plan the pregnancy, since there is a certain risk that some of the most broadly used medications to treat bipolar disorders would cause malformations in the foetus. We must consequently consider the possibility of stopping these medications without omitting to take into account the risk of relapse, since a relapse during pregnancy makes is difficult and is also undesirable. The person who wishes to become pregnant must tell her psychiatrist in advance so that the latter starts the progressive removal of the drugs he finds inappropriate, or even to indicate what is the best time according to the clinical evolution; ideally, a pregnancy should be better planned during a period of stability, both because it is a very important decision that must be made responsibly, and this rarely happens when the patient is in a manic or depressed phase, and because the reduction in the dose of medication implies a risk of relapse which we cannot add to the higher risk of relapse that the patient has if she suffered an episode recently. Lithium has been associated with an increase in the risk of emergence of certain congenital malformations, such as Ebstein s anomaly (a cardiac malformation), but it is a relatively low risk (2 out of 1000 babies). If the psychiatrist and the patient agree to remove lithium temporarily, such removal must be done progressively throughout the 6 months prior to the pregnancy. Lithium is usually reintroduced without too many risks starting in the second trimester of pregnancy, since the teratogenic risk is especially significant when foetus forms during the first trimester. On the other hand, the psychiatrist may choose drugs with lower teratogenic risk or, in the event of a relapse, opt for treatment with electroconvulsive therapy, which is safe both for the patient and for the foetus. Valproate is associated with a certain risk of spina bifida in the foetus, which is somewhat lower for carbamazepine. In both cases it is highly recommendable to also take folic acid before pregnancy. In case the removal of lithium may imply a high risk for immediate relapse, it may be maintained throughout the pregnancy, controlling the risk of malformations with periodic ultrasounds. If a malformation is detected, the woman may decide on voluntary interruption of the pregnancy, if she wishes so. In any case, postpartum is the phase which bears the highest risk for relapse. Concretely, 50% of untreated patients present with a manic or depressive episode after giving birth; this may be caused by the normal sudden drop in estrogens. For this reason,

204 if the treatment was interrupted, it is particularly important to re-introduce it immediately after the birth. Breastfeeding should be avoided; it is preferable to bottle-feed the baby and give up breastfeeding, since certain medications (e.g. lithium) may pass from the mother s blood to the milk and constitute a risk of intoxicating the baby. To conclude, we will remind the patients that certain medications interact with oral contraceptives (the pill), for example carbamazepine and, to a lesser degree, oxcarbazepine, and their efficacy is reduced, so that the patients who take carbamazepine must use another type of contraceptive measures (barrier contraceptives, such as the condom or the IUD). Hormonal contraceptives may cause emotional disturbances but not decompensation THE RISK OF INTERRUPTING THE TREATMENT Approximately half of people affected by bipolar disorder abandon their treatment during the first prescription year, and many others stop it in subsequent months. Practically, seven out of every ten patients stop the medication at some time in their life, and nine out of every ten patients think very seriously of abandoning it. Stopping the treatment, on the other hand, is the most common trigger of relapses. The reasons that are most frequently argued to stop the medication are: - Feeling bad because it is the medication and not the person himself who controls his own mood. - Believing that one is capable of controlling the bipolar disorder without need to take any drug. - Missing the hypomania state. - Denying the disorder. - Overestimating the side effects. - Being afraid of long-term consequences. - Having erroneous beliefs about the medication ( it creates dependence, it makes you stupid, etc.). - Being misinformed. - Lowering one s guard in periods of euthymia and not understanding the chronic character of the disorder. - The beginning of a hypomanic or manic phase. Lithium and, in general, mood stabilizers may avoid a relapse in most cases, but in order to fulfil this purpose it is necessary that the patient takes it correctly, without omitting any intake. Using the tactic of taking lithium when one starts feeling bad usually leads to a relapse, since it is a drug with very slow action. Taking mood stabilizers guarantees long periods of euthymia and subsequently a better quality of life. The attitude of the family is crucial in maintaining therapeutic adherence, so that a good information on the disorder to family and care-givers is needed. What are the risks of interrupting the treatment with lithium? Interrupting the treatment with lithium or any other mood stabilizer is associated with a sudden worsening of the natural evolution of the disorder and often to hospitalization; more than half of the patients suffer a relapse in the 6 months following the suspension of the mood stabilizer, and nine out of ten have a relapse during the following year. It has been observed that the risk of suicide increases dramatically among the patients who have stopped taking their mood stabilizer. In addition, in the case of lithium, there is the added risk that the drug becomes inefficient when the person starts taking it again after abrupt interruption.

205 Some patients argue that taking or not taking the medication makes no difference, because they have suffered relapses even while taking it. The possibility of suffering an episode never disappears, but the probability of a relapse is much lower in medicated patients. Additionally relapses during pharmacological treatment will be shorter, less severe and, of course, more infrequent SUBSTANCES ABUSE AND BIPOLAR DISORDER By drugs we mean all substances, whether legal (alcohol, tobacco, coffee) or illegal (marijuana, cocaine, hallucinogens) that can modify the state of consciousness, behaviour, thoughts, and emotions, and create dependency or abuse behaviours. Most studies available indicate that up to 60% of the patients abuse or depend on some drug, especially alcohol. This abuse obviously makes the course and prognosis of the disorder worse. Patients who consume toxic agents experience more episodes and admissions than those who refrain from consuming them. Many patients who have substance abuse or dependency problems enter into a selfmedicating relationship with drugs, that is, they seek relief for some of their symptoms, generally before being diagnosed with BD. Frequently, the alcohol abuse of many patients affected by bipolar disorder and alcoholism began when the substance was used as an anxiolytic, before proper treatment was received, or patients dependent on cocaine began their dependence with the drug hoping consciously or unconsciously that it would cheer them up when they were in the apathy or depressed phase. This type of behaviour perfectly fits the Spanish proverb bread today, hunger tomorrow, as, apart from generating dependency and an endless list of physical problems, consumption of toxic agents eventually worsens the psychiatric symptoms: Alcohol causes depression in the medium term, increases anxiety, de-structures sleep, reduces impulse control, causes cognitive deterioration, increases aggressiveness, and may cause the appearance of psychotic symptoms and mania. Marijuana creates an amotivational syndrome characterized by great apathy; it depresses, can trigger a mania, interfere with sleep, increase anxiety, and cause psychotic symptoms in the form of paranoid delusions. Cocaine can trigger any type of episode: rapid cycling, anxiety, aggressiveness, psychotic symptoms, interference with sleep, cognitive deterioration, and many other symptoms that generally end up with constant hospital admissions. Hallucinogens and design drugs also involve a great deal of risk, even if they are taken just once, and may make hospitalization necessary. They bring on psychotic symptoms such as visual and/or auditory hallucinations and delirium in any individual, even a person without a mental disorder, and these symptoms can persist for a long time with flashbacks (repetition of the symptoms weeks or months after the substance was taken). In a person with BD, taking hallucinogens or design drugs can cause mania, psychotic symptoms, anxiety, etc. The danger of coffee is mainly its ability to alter sleep structure. As we know, enjoying the right amount of high-quality sleep is essential for keeping BD compensated. We emphasize sleep quality. Many people say that even when they drink coffee after dinner they sleep eight hours; they may sleep eight hours, but their sleep is probably of poor quality. It is advisable not to drink coffee for eight hours before bedtime, as the half-life of coffee is just eight hours. On the other hand, there is absolutely no harm in having a couple of cups of coffee in the daytime (such as one in the morning and the other after lunch), although this depends on each individual because the effect of coffee is highly variable. During depressive phases, it is acceptable to drink a little more coffee,

206 always in the morning and provided there is no anxiety. Coffee is totally inadvisable in anxious patients and patients with a history of panic attacks. Also, no type of caffeine (coffee or cola drinks) should be drunk during hypomanic, manic, and mixed phases, or with a suspicion that one of them is starting. As far as smoking is concerned: from the psychiatric standpoint, smoking does not involve serious risks, although we know it is very harmful to the physical health. In any event, the only problem with patients smoking is when they quit smoking. We have six important tips: 1. Never try to quit smoking during a decompensation. 2. It is advisable to attempt to quit smoking in periods of greatest stability (six months euthymia or more). 3. Do not try to quit cold turkey (stop suddenly). 4. It is advisable to seek the help of psychological therapies to quit smoking in a rational, risk-free manner. 5. The use of substitutes is recommended (nicotine chewing gum or patch) to avoid the withdrawal syndrome, which may give rise to anxiety and irritability. 6. The use of quitting drugs such as bupropion is entirely contraindicated in patients affected by bipolar disorder, except during depressive phases, as bupropion is an antidepressant and can hence cause hypomanic or manic decompensation. Another aspect that calls for comment is the misuse or abuse by some patients of their medications, which become treated like street drugs. The only psychoactive drugs that can create dependency if not used properly and strictly according to the doctor s prescription are the anxiolytics (benzodiazepines such as alprazolam, diazepam, or lorazepam). Thus, although the doctor should avoid prescribing these drugs to patients at risk of addiction, we must always remember the importance of following the psychiatrist s prescription to the letter RESOURCES For more information on symptoms, diagnosis, prognosis and treatment, please consult the following books and websites: Books: The disease of emotions: Bipolar disorder. E. Vieta, F. Colom, and A. Martinez-Aran. Column editions, De la euforia a la tristeza. El trastorno bipolar: cómo conocerlo y tratarlo para mejorar la vida. Francesc Colom & Eduard Vieta La esfera de los libros Webs:

207 016 CURRENT AND FUTURE RESEARCH The progress of biomedical research in the area of bipolar disorder has been outstanding for the last 15 years. Clinical trials, neurobiological research, and large epidemiological studies have been performed and delivered in form of publications that have had an important impact on the field. Current trends in research involve genetics, geneenvironment interactions, biomarkers, neuroimaging, novel treatment targets, and clinical trials on new drugs, devices, and psychotherapy. The development of treatment guidelines is an ongoing process which requires constant updates and reviews. The progress of Medicine in general, and Psychiatry in particular, is making this process a high-speed one. Most guidelines are out-of-date at the very date of their publication. These guidelines have been made with this issue in mind and may not get out-of-date so quickly as others. The progress of the field, however, will likely impact their timeliness in the future, and this would be a signal of scientific and social progress. Among the most obvious unmet needs in bipolar disorder, which require further effort in research and funding, ther are: 1. Pragmatic and comparative clinical trials that inform clinical practice, rather than just registration of new drugs. 2. Studies and trials focused on subgroups, including: a. Bipolar II disorder b. Rapid cycling c. Bipolar depression d. Cyclothymia 3. Neurocognition and treatments for cognitive impairment 4. Early detection and intervention 5. The role of antideprssants in bipolar depression and maintenance 6. Development of devices for better follow-up, monitoring,a nd treatment 7. Role of epigenetic factors, neural pathways, and connectivity As regards as the specific situation in Catalunya, research in the area of bipolar disorder is well developed and high-quality, but there are also a number of deficiencies: 1. Lack of good, large epidemiological studies on the prevalence and incidence of bipolar disorder in th Catalan general population 2. Limited number of groups working on preclinical and traslational research These guidelines aim at being not only a document with recommendations on how to diagnose and treat bipolar disorder, but to foster insight on how to improve and give direction to clinical and translational research on bipolar disorder in Catalunya.

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282 ANNEXES

283 ANNEXE 1 A1. LITERATURE SYSTEMATIC REVIEW A1.1. EPIDEMIOLOGY AND DIAGNOSIS A1.2. TREATMENT A Pharmacological treatment A Psychosocial treatment A Other treatments A1.3. SPECIAL POPULATIONS A Women and bipolar disorder A Paediatric bipolar disorder A Bipolar disorder in the elderly A1.4. TREATMENTS COST-EFFECTIVENESS IN BIPOLAR DISORDER A1.5. RCTs TABLES A1. LITERATURE SYSTEMATIC REVIEW A1.1. EPIDEMIOLOGY AND DIAGNOSIS - Population samples: string Catalan sample or Spanish sample were combined to bipolar disorder and the following strings: Epidemiology: epidemiology, epidemiological study, general population study and survey Diagnosis: diagnosis, misdiagnosis, course of illness, number of episodes, course specifier, rapid cycling, seasonal, onset, predominant polarity A1.2. TREATMENT PUBMED was searched in order to locate papers with treatment guidelines and randomized controlled trials (RCTs) concerning the treatment interventions tested in the treatment of bipolar illness. The search was last performed on the 31 st of December The authors searched for papers concerning add-on therapy. The authors scanned relevant review articles and utilized their reference list (Fountoulakis and Vieta, 2008; Sachs, 2008; Jung and Newton, 2009; Lam et al, 2009; Miklowitz, 2009; Payne and Pudic, 2009; Vieta et al, 2009). A Pharmacologic treatment literature search 1. In order to locate RCTs, PUBMED was searched with the combination of the words bipolar and randomized with each one of the following words: amisulpride, aripiprazole, asenapine, carbamazepine citalopram, fluoxetine, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, risperidone, tamoxifen, topiramate, valproic/valproate/divalproex, and ziprasidone.

284 2. A second strategy was applied for lithium, valproate and carbamazepine because it appeared that older trials (conducted during the 1970s) were missing from the previous search. Thus the names of the substances plus the word placebo were used in the search. The authors searched for placebo-controlled as well as for clinical trials with an active comparator with the compounds used as monotherapy. Papers concerning add-on therapy were also included in order to complete the picture. Moreover, web pages containing lists of clinical trials were also scanned. These sites included and as well as the official sites of all the pharmaceutical companies with products used for the treatment of BD. Some of the older studies of the 1970s were difficult to trace on the basis of an electronic search alone. Therefore the authors scanned relevant review articles and utilized their reference list (Bech, 2002, 2006; Burgess et al, 2001; Cipriani et al, 2006a,b; Davis et al, 1999; Gao et al, 2005; Gijsman et al, 2004; Macritchie et al, 2001, 2003; Rendell et al, 2003, 2006; Smith et al, 2007). A Psychological treatment The following search strategies were followed: In order to locate RCTs, Medline was searched with the combination of the words bipolar and randomized with each one of the following words: psychotherapy, psychosocial intervention, cognitive behavioural therapy, interpersonal social rhythm therapy psychoeducation, family-focused psychoeducation, and systematic care. A Other treatments The following search strategies were followed: In order to locate studies, Medline was searched with the combination of the words bipolar and randomized with each one of the following words: electroconvulsive therapy, ECT, chronobiological intervention, magnetic transcranial stimulation, rtms, vagal stimulation, VNS and light therapy. A1.3. SPECIAL POPULATIONS A Women and bipolar disorder The following search strategies were followed: (1) In order to locate treatment guidelines, PUBMED was searched with the combination of each one of the key words mania, manic, bipolar, manicdepression, manic-depressive combined with keywords gender, gender differences, pregnancy, teratogenic risk, breastfeeding and subsequently combined with keywords treatment guidelines and treatment algorithms. (2) In order to locate studies, Medline was searched with the combination of the words mania, manic, bipolar, manicdepression, manic-depressive combined with the words gender, gender differences, pregnancy, teratogenic risk, breastfeeding. The authors scanned relevant review articles and utilized their reference list (Goodwin and Jamison, 2007; Ng et al, 2009).

285 Results were subsequently divided in two distinct sections: - one concerning pregnancy and teratogenic risks, - one concerning treatment during breastfeeding. A Paediatric bipolar disorder The following search strategies were followed: (1) In order to locate treatment guidelines, PUBMED was searched with the combination of each one of the key words paediatric, child and adolescent combined woth the key words mania, manic, bipolar, manicdepression, manicdepressive, subsequently combined with keywords treatment guidelines and treatment algorithms. (2) In order to locate RCTs, Medline was searched with the combination of the words bipolar and randomized with each one of the following words: amisulpride, aripiprazole, asenapine, carbamazepine citalopram, fluoxetine, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, risperidone, tamoxifen, topiramate, valproic/valproate/divalproex, and ziprasidone. The authors searched for placebo-controlled as well as for clinical trials with an active comparator with the compounds used as monotherapy. Papers concerning add-on therapy were also included in order to complete the picture. Moreover, web pages containing lists of clinical trials were also scanned. These sites included and as well as the official sites of all the pharmaceutical companies with products used for the treatment of BD. Authors also scanned relevant review articles and utilized their reference list (Chang, 2008; Leibenluft and Rich, 2008; Nandagopal et al, 2009; West and Pavuluri, 2009). A Bipolar disorder in the elderly Medline was searched in order to locate papers with treatment guidelines and randomized controlled trials (RCTs) concerning bipolar disorder in the elder population. The search was last performed on the 31 st of December The following search strategies were followed: (1) In order to locate treatment guidelines, Medline was searched with the combination of each one of the key words mania, manic, bipolar, manicdepression, manicdepressive combined with keywords elderly and late-life, and subsequently combined with keywords treatment guidelines and treatment algorithms. (2) In order to locate studies, Medline was searched with the combination of the words mania, manic, bipolar, manicdepression, manic-depressive combined with the words elderly and late-life. The authors scanned relevant review articles and utilized their reference list (Aziz et al, 2006; Goodwin and Jamison, 2007). A1.4. TREATMENTS COST-EFFECTIVENESS IN BIPOLAR DISORDER A systematic review of the published literature was conducted to identify studies that explored cost-effective treatments for bipolar disorder. The following databases were searched for relevant published literature: Cochrane Controlled Trials Register (CCTR), PUBMED. English-language articles were searched.

286 The literature search was not limited to any specific study design, hence the searches were conducted without methodological filters and consisted of the terms for the drug intervention: amisulpride, aripiprazole, asenapine, carbamazepine citalopram, fluoxetine, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, risperidone, tamoxifen, topiramate, valproic/valproate/divalproex, and ziprasidone, combined with the keywords costs, cost-effectiveness, healthcare costs, economy, mental health services and also with the keyword bipolar disorder. The authors scanned relevant review articles and utilized their reference list (Goodwin and Jamison, 2007; Miklowitz and Scott, 2009). In addition, the bibliographies of retrieved articles were searched for further relevant studies.

287 1.5. RCTs tables. ACUTE MANIA Author Year Drug Sample Active comparator Trial length Completed study Bowden et al Valproate 69 BD I Research Criteria Lithium 3 weeks 48% Lithium 47,8% Valproate Bowden et al Quetiapine 206 BD I - DSM IV TR 1 manic/mixed Lithium 3 weeks 53,1% Lithium 53% Quetiapine Bowden et al Valproate 300 BD I - DSM IV TR 1 manic/mixed Lithium 12 weeks 92,4 Lithium 92% Valproate Freeman et al Valproate 27 BD I - DSM IIIR Lithium 3 weeks 92,3% Lithium 64,3% Valproate Goldsmith et al Lamotrigine 91 BD I - DSM IV Lithium 3 weeks 41,7% Lithium 44,1% Lamotrigine Ichim et al Lamotrigine 30 BD I - DSM IV 1 manic/mixed Lithium 4 weeks 60% Lithium 53,3% Lamotrigine Keck et al Aripiprazole 325 BD I - DSM IV TR Rating Scales Inclusion Criteria Lithium 3 weeks 45,8% Lithium 46,8% Aripiprazole Kushner et al Topiramate 563 BD I - DSM IV TR 1 manic/mixed Lithium 3 weeks 46% Lithium 27% Topiramate Li et al Quetiapine 154 BD I - DSM IV TR Lithium 4 weeks 59,7% Lithium 77,9% Quetiapine McElroy et al Valproate 36 BD I - DSM IIIR Haloperidol 1 weeks 47,6% Valproate 33,3% Haloperidol McIntyre et al Quetiapine 201 BD I - DSM IV 1 manic/mixed Haloperidol 3 weeks 42,6% Quetiapine 56,1% Haloperidol McIntyre et al Asenapine 775 BD I - DSM IV Olanzapine 3 weeks 54,7% Olanzapine

288 Rating Scales Inclusion Criteria 42,6% Asenapine Niufan et al Olanzapine 140 BD I - DSM IV Lithium 4 weeks 73,2% Lithium 87% Olanzapine Perlis et al Olanzapine 339 BD I - DSM IV Risperidone 3 weeks 62,1% Olanzapine 59,5% Risperidone Segal et al Risperidone 45 BD I - DSM IV Lithium/Halope ridol 4 weeks 90,3% Lithium 80% Haloperidol 86,7% Risperidone Small et al Carbamazepine 52 BD I - DSM IIIR 1 manic/mixed Lithium 8 weeks 33,3% Lithium 33,3% Carbamazepine Smulevich et al Risperidone 198 BD I - DSM IV 1 manic/mixed Haloperidol 3 weeks 47,7% Risperidone 47,2% Haloperidol Tohen et al Olanzapine 231 BD I - DSM IV Valproate 3 weeks 42,3% Valproate 54,4% Olanzapine Tohen et al Olanzapine 453 BD I - DSM IV Haloperidol 6 weeks 62% Haloperidol 55% Olanzapine Tohen et al Olanzapine 416 BD I - DSM IV TR Valproate 3 weeks 40,8% Olanzapine 40,3% Valproate Vieta et al Aripiprazol 347 BD I - DSM IV 1 manic/mixed Haloperidol 3 weeks 50,9% Aripiprazole 42,6% Haloperidol Vieta et al Ziprasidone 350 BD I - DSM IV 1 manic/mixed Haloperidol 3 weeks 54,7% Haloperidol 36,9% Ziprasidone Vieta et al Paliperidone 388 BD I - DSM IV 1 manic/mixed Quetiapine 3 weeks 49% Quetiapine 44,2% Paliperidone Young et al Aripiprazole 333 BD I - DSM IV TR Rating Scales Inclusion Criteria Haloperidol 3 weeks 47% Aripiprazole 49,7% Haloperidol Zajecka et al Olanzapine 120 BD I - DSM IV Valproate 3 62% Valproate 68% Olanzapine

289 ACUTE BIPOLAR DEPRESSION Author Year Drug Sample Placebo Active comparator Trial length Completed study Calabrese et al Lamotrigine 195 BD I DSM IV YES NO 7 weeks 51% Lamotrigine 200mg 41% Lamotrigine 50mg 26% Placebo Calabrese et al Quetiapine 360 BD I 182 BD II DSM-IV depressive episode YES NO 8 weeks 58,2% Quetiapine 600mg 57,6% Quetiapine 300mg 36,1% Placebo Calabrese et al Lamotrigine 892 BD I and II HAM-D YES NO Variable 54% % Lamotrigine 29%% Placebo (only in study 1) Ghaemi et al Valproate 18 BD I DSM-IV YES NO 6 weeks 33,3% Valproate Lombardo et al Ziprasidone 928 BD I HAM-D YMRS 12 14,3% Placebo YES NO 6 weeks 53% Ziprasidone 50% Placebo Thase et al Quetiapine 472 YES NO 8 weeks 59% Quetiapine 45% Placebo Thase et al. (CN138096) 2008 Aripiprazole 341 YES NO 8 weeks 43% Aripiprazole 39% Placebo Thase et al. (CN138146) 2008 Aripiprazole 352 YES NO 8 weeks 45% Aripiprazole 44% Placebo Tohen et al Olanzapine/Fluoxetine 933 YES Olanzapine 8 weeks 56 % Olanzapine/Fluoxetine 39 % Olanzapine 30 % Placebo Zhang et al Carbamazepine Carbamazepine + Free and Easy Wanderer Plus 124 BD I DSM-IV depressed 111 BD I DSM-IV manic YES NO 12 weeks 63.8% Carbamazepine 34.8% Placebo 84,8% Carbamazepine + herbal

290 MAINTENANCE TREATMENT: MONOTHERAPY RCTs Author Year Drug Sample Placebo Bowden et al Valproate N=571 BD I manic/mixed Bowden et al Lamotrigine M N=349 BD I Manic/hypo-manic/mixed Calabrese et al Lamotrigine D N=966 BD I depressive Keck et al Aripiprazole N=567 BD I Manic/mixed Prien et al Lithium N=205 Manic/depressive, manic type Quiroz et al Risperidone LAI N=501 BD I manic/mixed/ stabilized on risperidone Active comparator Trial length NO Lithium 1 year 38% valproate 24% lithium 25% placebo Completed study YES Lithium 76 weeks 5% (n=3) lamotrigine 2% (n=1) lithium 0% placebo YES Lithium 76 weeks 17% (n=38) lamotrigine 17% (n=20) lithium 10% (n=12) placebo YES NO 26 weeks/ 100 weeks 50% (n=39/78) aripiprazole 34% (n=28/83) placebo 19% (n=5/27) placebo and 18% (n=7/39) aripiprazole completed 74 week extension phase YES NO ~2 years 57%lithium *19% PBO *did not relapse during the study YES NO ~2 years 21% (31/149) placebo vs. 47% (72/154 ) risperidone LAI Tohen et al N=731 BD I manic/mixed YES NO 48 weeks 21% (n=48) olanzapine 7% (n=9) placebo Weisler et al Quetianpine N=2438 BD I Manic/mixed/depressive YES Lithium Up to 104 weeks Study terminated after interim analysis (following 150 mania and 150 depression events) provided positive results

291 MAINTENANCE TREATMENT: COMBINATION THERAPY RCTs Author Year Drug Sample Placebo Active comparator Bowden 2009 Ziprasidone N=586 BD I manic, mixed Suppes 2009 Quetiapine N=1953 BD I Manic, mixed, depressive Tohen 2004 Olanzapine N=160 BD I Manic, mixed Vieta et al Quetiapine plus N=1461 BD I Lithium or Manic, mixed, Divalproex depressive Trial length (weeks) Completed study 6 months 66% (84/127) ziprasidone vs 48% (54/113) placebo 104 weeks 64% (n=110/310) quetiapine vs. 79% (n=66/313)placebo (176/623) 18 months 69% (n=16/51) olanzapine vs. 90% (n=5/48) placebo (n=21/99)) 104 weeks 37% (134/367) quetiapine vs. 63% (213/336) placebo (347/703)

292 ANNEXE 2 SCREENERS FOR BIPOLAR DISORDER A2.1. HCL-32 (1 of 3) (Angst et al, 2005)

293 ANNEXE 2 HCL-32 (2 of 3)

294 ANNEXE 2 HCL-32 (3 of 3)

295 2. MDQ (Hirschfeld et al, 2000)

296 ANNEXE 3 CGI-BP (Spearing et al, 1997)