Bipolar I disorder: current and future management options

Transcription

1 Bipolar I disorder: current and future management options Eduard Maron PhD, MD, Research fellow, Centre for Pharmacology and Therapeutics, Imperial College London; Allan H Young, Professor and Chair of Psychiatry PhD, MD, FRCPsych, FRCPC, Centre for Mental Health, Imperial College London Bipolar I disorder affects around one in every 100 adults and is a major public health issue. It is usually characterised by a combination of manic and depressive symptoms, with severe episodes of mood disturbance that can last for weeks or even months. Both men and women are affected, and the condition is a debilitating one that can adversely influence all areas of a person s life and his/her normal functioning. In this article, the authors look at the disease and its causes, and discuss both current and promising future treatment options. Although bipolar disorder has no single cause, growing evidence suggests that neurotransmitters are likely to be involved in the onset and development of this debilitating illness People with bipolar I disorder, still thought of as classical manic depression, usually experience a mixture of manic and depressive episodes (although a small number will experience mania only). It is distinct from bipolar II disorder, which is characterised by intermittent depressive episodes, and in which the related pathological upswings in mood are only mild and of short duration hypomania. In bipolar I disorder, patients will have experienced at least one manic episode usually lasting longer thana week, with symptoms including: persistently elevated expansive or irritable mood accompanied by features such as grandiosity; a decreased need for sleep; pressure of speech; flight of ideas; distractibility; increased activity; and excessive involvement in pleasur - able activities. Patients will usually also experience at least one major depressive episode during the course of the illness. WHAT CAUSES BIPOLAR DISORDER? Biological factors There is still not a single hypothesis that explains the onset and development of bipolar disorder due to the marked heterogeneity of data from studies exploring neurobiological abnormalities associated with bipolar features. 1 Historically, the monoaminergic neurotransmitter systems, including serotonin, norepinephrine and dopamine, were the main focus of theories and research about the aetiology of mood disorders, but despite growing evidence suggesting that many of these neurotransmitters are likely to be involved in bipolar disorder, no characteristic dysfunction of any single neurotransmitter system has yet been verified. 2 However, both hypothalamic pituitary adrenal (HPA) axis dysfunction and glucocorticoid resistance, which are well recognised in unipolar depression, may reflect a trait-related abnormality in bipolar disorder, given their presence across different phases of the illness, including euthymia and remission F U T U R E P R E S C R I B E R V O L 1 2 ( 3 ) w w w. f u t u r e p r e s c r i b e r. c o. u k

2 More recently, an abundance of research, incorporating diverse levels of scale and investigative techniques from chemical or molecular processes through to neuro imaging of neural networks, have implicated specific neuro - endocrine, neurotransmitter and intracellular signal transduction pathways in the pathophysiology of bipolar illness. In brief, the detected abnormalities in bipolar disorder include elevated protein kinase A activity, altered intracellular calcium signalling, enhanced proinflammatory cytokine pro duction, glucocorticoid receptor dysfunction, reduced prefrontal N-acetylaspartate, white matter abnormalities and impaired functioning of anter - ior limbic and prefrontal neural networks. 1 Genetic factors Combined evidence from family, twin and adoption studies suggests that bipolar disorder has a significant genetic component. Twin studies, for example, show a highly elevated concordance rate in monozygotic twins when compared with dizygotic twins, and bipolar illness is more likely to occur in biological parents of adopted children than in the adoptive parents. 2 Genetic association studies have identified numerous genes that confer vulnerability to bipolar disorder, many of which are known to function in the signalling pathways previously identified as relevant to the aetiology of this illness. 3 PREVALENCE Bipolar illness is a relatively common medical problem. Recent cross-sectional sur veys of community adults in 11 countries in the Americas, Europe and Asia showed that the overall lifetime prevalence was 0.6% for bipolar I, 0.4% for bipolar II and 1.4% for subthreshold bipolar disorder, thus yielding a total bipolar spectrum disorder prevalence estimate of 2.4% worldwide. 4 Also, it should be noted that bipolar disorder is often underdetected, mainly because milder forms of the illness are often missed or misdiagnosed. In contrast to major depressive disorder, bipolar I disorder has an equal prevalence among men and women and an earlier age of onset mean age of around 20 years. 4 Notably, manic episodes are somewhat more common in men and depressive episodes in women; but when manic episodes occur in women, they are more likely than men to present a mixed picture comprising both manic and depressive symptoms. As compared to men, women also have a higher risk of being rapid cyclers, meaning they will have four or more distinct episodes of bipolar disorder in a one-year period. Despite these differences, little research exists regarding gender-specific aetio - pathogenic or treatment considerations. It has also been found that bipolar I disorder is more common in divorced and single persons than among married people, and a higher than average incidence of bipolar illness is found among upper socioeconomic groups. 5 COSTS ASSOCIATED WITH BIPOLAR DISORDER A burden on the NHS Bipolar disorder represents a major public health issue due to its attendant high morbidity and mortality rates, and has been shown to impair both patients Early age of onset (before 25 years) Bipolar family history Agitated or cyclical depression Refractory depression Depression in person with extroverted traits Emotionally unstable personality disorder Faster onset of depressive episodes Hyperthymic temperament Periodic irritability or impulsivity Gambling Sexual misconduct Wanderlust Suicidal crises Table 1. Clinical features predictive of bipolar disorder quality of life and occupational functioning. It is associated with greater healthcare service utilisation and direct medical costs than unipolar depression, being the sixth leading cause of medical disability worldwide among people aged years. 6 9 A recent, retrospective cohort study estimated the direct annual cost of bipolar disorder to the NHS to be 342 million (at 2009/2010 prices). Hospitalisation accounted for 60%, outpatient and community mental health 26.7%, and medication in primary care 7.4% of the overall direct costs of care. 10 Importantly, this figure is larger than the 200 million estimated by the earlier analysis by Das Gupta and Guest, and yet may be an underestimate as it is based on a very conservative measure of prevalence. These data do indicate that, contrary to the anticipated positive impact of introducing the National Institute for Health and Clinical Excellence (NICE; 2006) bipolar guidelines and the Quality and Outcomes Framework (2004), the cost to the NHS of managing this illness has likely increased. w w w. f u t u r e p r e s c r i b e r. c o. u k F U T U R E P R E S C R I B E R V O L 1 2 ( 3 ) 1 5

3 Personal costs People with bipolar I disorder are at an increased risk of having one or more additional co-morbid mental health disorders. Male patients more frequently present with substance misuse, while females more frequently present with co-morbid anxiety and/or eating disorders. In general, the recent Epidemiological Catch ment Area study 11 showed that lifetime history of substance use, panic and obsesive-compulsive disorders was approximately twice as high among patients with bipolar I illness (61%, 21% and 21%, respectively) than in those with unipolar major depression (27%, 10% and 12%, respectively). Acute mania Stop antidepressant treatment Consider antipsychotics or mood stabilisers Combine antipsychotic and valproate or lithium if response is inadequate Monitor compliance, dose and plasma level (lithium, valproate) Consider adding short-term benzodiazepine Consider electroconvulsive therapy if refractory state Depressive episode Consider quetiapine monotherapy Consider lithium and lamotrigine combination Consider olanzapine and fluoxetine combination Consider adding antidepressants Consider electroconvulsive therapy if refractory state Prophylaxis Consider lithium, valproate, quetiapine or olanzapine as first-line prophylactic agents Continue treatment for at least two years Consider SSRI or cognitive behavioural therapy with a mood stabiliser or quetiapine for chronic or recurrent depression Combine lithium and valproate for the prophylaxis of rapid cycling illness See also: Taylor D, Paton C, Kapur S, eds. Prescribing Guidelines, 10th edn. The South London and Maudsley NHS Foundation Trust and Oxleas NHS Foundation Trust. Table 2. Treatment strategies for bipolar I disorder The mortality rate of the disease is two to three times higher than that of the general population, and the depressive phase of bipolar disorder represents one of the highest risk periods for suicide of all psychiatric illnesses. In particular, the risk that individuals with bipolar disorder will take their own life is 20 times greater than that of the general population, and nearly one-third of patients admit to at least one suicide attempt. 12 A CHALLENGING CONDITION TO TREAT Unfortunately, bipolar disorder is often undiagnosed or misdiagnosed in the clinical and community populations. This has led to a variety of negative consequences, perhaps the most obvious being a delay in effective therapy and, consequently, greater disability. 13 Earlier recognition of bipolar illness has emerged as a major challenge in everyday clinical practice. Patients may, for instance, not seek treatment when they are hypomanic, considering their symptoms to be a facet of everyday life, or may present to the physician while in a depressed phase. Additionally, numerous studies have shown that bipolar disorder is not only confused with personality, substance use and schizophrenic disorders, but also with depressive and anxiety disorders. Therefore, an accurate diagnosis should involve the careful clinical evaluation of patient and family histories, within the context of the number, severity and duration of mood symptoms, as well as the use of screening questionnaires. 13,14 Although there are predictive indicators of bipolarity (see Table 1), none of these confirms a bipolar diagnosis by itself, but should always be considered and raise the clinical index of suspicion. It should also be remembered that <10% of patients with bipolar I disorder experience only manic episodes throughout the course of the disease, and that the majority of patients most often start with depressive manifestations. 5 Impor tantly, bipolar I disorder misdiagnosed as unipolar depression has substantial clinical implications, including an increased risk of rapid cycling and likely increased costs of care, due to delayed use or under-prescription of mood-stabilising medications. Mood-stabilising therapy may be less effective when initiated after unsuccessful therapy for depressive episodes; moreover, antidepressants have been shown to be less effective than mood stabilisers in preventing depressive relapse in bipolar patients and are associated with increased rates of switching to a manic state. 13 MANAGEMENT OF BIPOLAR I DISORDER A number of pharmacotherapies are available for the treatment of bipolar I disorder, and the final therapeutic choice depends on the episode symptoms and severity, patient preference, drug safety and likely side-effects. Particularly, approved and off-label pharmacotherapeutic treatments for bipolar I disorder in the acute manic or depressive phase as well as the maintenance phase include agents such as mood stabilisers, atypical antipsychotics, anticonvulsants and antidepressants (see Table 2). The usefulness of antidepressants in bipolar mood treatment is a subject of continued debate. 15 The successful management of bipolar I disorder requires careful clinical and risk assessment for current and past phases to identify individually more suitable medica- 1 6 F U T U R E P R E S C R I B E R V O L 1 2 ( 3 ) w w w. f u t u r e p r e s c r i b e r. c o. u k

4 tion in order to resolve acute symptoms and prevent further disease development. In many cases, it is likely that combination therapy will be necessary to achieve these objectives. 14 In general, about 50% of individuals with mania respond to monotherapy with an antimanic agent, and 75% may respond to a combination of an atypical anti psychotic and either lithium or valproate. Once a successful acute treatment medication has been found and the mood episode is in remission, treatment must then be geared towards relapse prevention. Lithium still remains the gold standard for the treatment and maintenance of bipolar I disorder, and particularly for protection against suicide in bipolar patients. Data suggest, however, that it is more effective at preventing manic than depressive relapse. 12 A weakness of treatment with conventional mood stabilisers is the delayed onset of action; for example, in randomised controlled trials, separation from placebo may not be observed with lithium until the third week, and sodium valproate is often similarly slow to work. And, in order to avoid toxic effects of lithium, careful monitoring of plasma levels is needed. There is some evidence showing that valproate may be effective in patients who have failed to respond to lithium. 16 Valproate is also recommended 17 as a first-line option for the treatment of acute episodes of mania, in combination with an antidepressant for the treatment of acute episodes of depression, and for prophylaxis, but it should not be routinely used to treat bipolar illness in women of childbearing age due to its teratogenic effect. Atypical antipsychotics are another popular group of medications that may be used to treat all aspects of bipolar disorder. Olanzapine, risperidone, quetiapine and aripiprazole have been most robustly evaluated, and are licensed in the UK for the treatment of mania. Although olanzapine is probably most widely used, associated weight gain, which is linked to an increase in diabetes and metabolic syndromes, can be an issue that compromises treatment in some patients. 6 Despite the current availability of numerous treatment agents for bipolar I disorder, these may not provide sustained symptomatic remission in most, and the long-term outcome of treatment remains poor. A study investigating the outcome of treatment for bipolar disorder showed high rates of morbidity even during mainten ance therapy. 14 On longterm follow-up, 15% of all patients with bipolar I disorder are well, 45% are well but have multiple relapses, 30% are in partial remission and 10% are chronically ill. 5 Treatment is also complicated by problems with patient noncompliance with medication regimens, which may rise to 64% among patients, leading to high relapse and mortality risks. 18,19 Inter est ingly, recent evidence has shown that pharmacologically treated patients with bipolar disorder may also derive significant benefit from group psychoeducation, which may reduce length of hospitalisations and prevent both relapse risk and the number of recurrences. 20 FUTURE TREATMENTS There are a number of new agents, including N-acetylcysteine, omega 3 fatty acids, tamoxifen, asenapine, antiglucocorticoids, celecoxib, mod afinil and pramipexole, which have provided some interesting prelimin - ar y results in bipolar disorder, although further large, placebocontrolled studies are still needed before drawing definitive conclusions on their potential. 21 Despite extensive efforts to identify novel treatment targets for bipolar I disorder, few have demonstrated clearly significant therapeutic efficacy to date. Asenapine Asenapine is a novel atypical antipsychotic with a unique human receptor binding profile. Its mechanism of action involves antagonism at serotonin, dop - amine, noradrenaline and histamine receptors. It has shown promise in initial clinical trials in adults for acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. Recent studies in bipolar I disorder established the efficacy of asenapine in acute mania when compared with placebo, with superiority of asenapine beginning at day 2, and these studies also supported its good tolerability and therapeutic efficacy in long-term maintenance in bipolar patients. 22,23 This clinical evidence shows that asenapine is an efficacious and well-tolerated treatment option for patients with bipolar I disorder. CONCLUSIONS Bipolar I disorder is a recurring illness, with full-blown manic and depressive episodes frequently interspersed with periods of time with subsyndromal symptoms. It is a relatively common, chronic and disabling psychiatric illness that is w w w. f u t u r e p r e s c r i b e r. c o. u k F U T U R E P R E S C R I B E R V O L 1 2 ( 3 ) 1 7

5 associated with high levels of functional impairment, morbidity, mortality and an increased risk of suicide. It frequently goes unrecognised and undiagnosed, and thus can remain untreated or inappropriately treated. Despite available medications, new agents and/or combination therapies are needed to achieve the goal of achieving and sustaining euthymia in bipolar patients, and there are some interesting new data emerging. The successful future management of patients with bipolar I disorder requires multidisciplinary, systematic and comprehensive assessment of all facets of bipolar illness and a personalised healthcare approach. To enhance the therapeutic outcome in patients with bipolar I disorder, the recommended treatment programme should include the selection of medication on the basis of risk-benefit evaluation, a combination of primary prevention strategies, such as psychoeducation, increased physical activity, diet improvement, and secondar y inter ventions with targeted treatments. Particularly, treatment targets should move beyond acute symptoms and prevention of mood episodes to address cognitive deficits, emotional dysregulation, sleep and circadian problems, improvement of quality of life and general functionality, and the reduction of clinical complications. 24 Such a comprehensive treatment strategy may both improve outcomes and reduce the costs of bipolar disorder. 10 DECLARATION OF INTERESTS Dr Maron has received grants from, and has been a consultant or speaker for, Lundbeck and GlaxoSmithKline. Professor Young has received grants from, and has been a consultant or speaker for, pharmaceutical companies with products licensed for bipolar disorder. REFERENCES 1. Langan C, McDonald C. Mol Psychiatry 2009;14: Martinowich K, et al. J Clin Invest 2009; 119: Kato T. Trends Neurosci 2008;31: Merikangas KR, et al. Arch Gen Psychiatry 2011;68: Sadock BJ, Kaplan HI, Sadock VA, eds. Kaplan and Sadock s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th edn. Phila delphia, PA: Lippincott Williams & Wilkins, Frye MA. N Engl J Med 2011;364: Matza LS, et al. J Clin Psychiatry 2005; 66: Reed C, et al. Eur Psychiatry 2010;25: Sajatovic M. Am J Manag Care 2005;11(3 Suppl):S Young AH, Rigney U, Shaw S, et al. Annual cost of managing bipolar disorder to the UK healthcare system. J Affect Disord 2011;133: Das AK, et al. JAMA 2005;293: Baldessarini RJ, et al. Harv Rev Psychiatry 2010;18: Zimmerman M. Expert Rev Neurother 2010;10: Kasper S. Eur Neuropsychopharmacol 2003; 13(Suppl 2):S Nierenberg AA. J Clin Psychiatry 2008;69 (Suppl 5):S Pope HG Jr, et al. Arch Gen Psychiatry 1991;48: Grunze H, et al; WFSBP Task Force On Treatment Guidelines For Bipolar Disorders. World J Biol Psychiatry 2010;11: Colom F, et al. J Clin Psychiatry 2000;61: Schou M. Acta Psychiatr Scand 1997;95: Colom F, et al. Arch Gen Psychiatry 2003; 60: Gao K, Calabrese JR. Bipolar Disord 2005; 7(Suppl 5): McIntyre RS, et al. Bipolar Disord 2009; 11: McIntyre RS, et al. J Affect Disord 2010; 122: Leboyer M, Kupfer DJ. J Clin Psychiatry 2010;71: