Epilepsy & Behavior 13 (2008) S1 S29. Contents lists available at ScienceDirect. Epilepsy & Behavior. journal homepage:

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1 Epilepsy & Behavior 13 (2008) S1 S29 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: Consensus statement: The evaluation and treatment of people with epilepsy and affective disorders John J. Barry a, *,1, Alan B. Ettinger b,1, Peggy Friel c,1, Frank G. Gilliam d,1, Cynthia L. Harden e,1, Bruce Hermann f,1, Andres M. Kanner g,1, Rochelle Caplan h,2, Sigita Plioplys i,2, Jay Salpekar j,2, David Dunn k,l,2, Joan Austin k,l,2, Jana Jones m,2 a Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA, USA b Department of Neurology, Long Island Jewish Medical Center, New Hyde Park, NY, USA c Swedish Neuroscience Institute, Seattle WA, USA d Columbia University, New York, NY, USA e Weil Medical College of Cornell University, New York, NY, USA f University of Wisconsin School of Medicine and Public Health, Madison, WI, USA g Department of Neurological Sciences and Department of Psychiatry, Rush Medical College, Rush Epilepsy Center, Rush University Medical Center, Chicago, IL, USA h Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA i Department of Child and Adolescent Psychiatry, Children s Memorial Hospital, Chicago, IL, USA j Center for Neuroscience and Behavioral Medicine, Children s National Medical Center, George Washington University School of Medicine, Washington, DC, USA k Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA l Indiana University School of Nursing, Indianapolis, IN, USA m Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA article info abstract Article history: Received 7 April 2008 Accepted 9 April 2008 Available online 23 May 2008 Keywords: Depression Anxiety Bipolar disorder Postictal depression Ictal depression Interictal depression Suicidality Intractable epilepsy Temporal lobe epilepsy Antidepressants Affective disorders in people with epilepsy (PWE) have become increasingly recognized as a primary factor in the morbidity and mortality of epilepsy. To improve the recognition and treatment of affective disorders in PWE, an expert panel comprising members from the Epilepsy Foundation s Mood Disorders Initiative have composed a Consensus Statement. This document focuses on depressive disorders in particular and reviews the appearance and treatment of the disorder in children, adolescents, and adults. Idiosyncratic aspects of the appearance of depression in this population, along with physiological and cognitive issues and barriers to treatment, are reviewed. Finally, a suggested approach to the diagnosis of affective disorders in PWE is presented in detail. This includes the use of psychometric tools for diagnosis and a stepwise algorithmic approach to treatment. Recommendations are based on the general depression literature as well as epilepsy-specific studies. It is hoped that this document will improve the overall detection and subsequent treatment of affective illnesses in PWE. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction Depression has become increasingly recognized as a pivotal factor in determining the quality of life of people with medical diseases. Morbidity and mortality and overall prognosis of many medical illnesses are adversely affected by the presence of depression. This is true for cardiovascular disease, cancer, HIV/AIDS, and * Corresponding author. Fax: addresses: jbarry@leland.stanford.edu, lschreiber@efa.org (J.J. Barry). 1 For adults. Consultants on treatment issues: Charles DeBattista, M.D., Terrance Ketter, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA, USA. 2 For children and adolescents. neurological diseases like stroke, Parkinson s disease, multiple sclerosis, Alzheimer s disease, and epilepsy [1]. It has been estimated that by 2020, the second leading cause of disability, after cardiovascular disease, will be the presence of depression [2]. The presence of depression as a comorbidity in medical diseases increases the costs of the disorder by 50% [3]. Another fascinating observation is that depression and medical illnesses appear to have a bidirectional relationship. This has been noted for cardiovascular disease, cancer, HIV/AIDS, and the neurological illnesses stroke, dementia, Parkinson s disease, and epilepsy. Despite the growing recognition of the importance of depressive illness, many reports document that there is a lack of appropriate screening and treatment. There may be a myriad of /$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi: /j.yebeh

2 S2 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 reasons for physician neglect, but fear can be a significant factor. If you ask, you are responsible to treat. In PWE, there are a panoply of road blocks in the treatment of depressive disorders. The goal of this article is to resolve some of these obstacles by providing the physician with an understanding of the phenomenological spectrum of depressive disorders in PWE. In addition, this document attempts to provide a review of the barriers to treatment which range from iatrogenically induced depression, to drug interactions, to antidepressant-induced decrease in the seizure threshold. Finally, a stepwise recommendation of treatment options for children, adolescents, and adults with affective illness is presented. This guide is a resource tool for professionals who treat patients with epilepsy. It is designed to be a compendium of current knowledge about the definition, recognition, and treatment of childhood, adolescent, and adult affective disorders, but with a particular emphasis on depressive illness. 2. Composition of the expert panel The authors of this Consensus Statement represent members from a panel of neurologists, psychiatrists, psychologists, and social workers who have been part of the Mood Disorders Initiative sponsored by the Epilepsy Foundation. The group originally met in 2003 for the Epilepsy Foundation s Mood Disorders Expert Meeting in Alexandria, VA, USA. Prior to that meeting, the Foundation had sponsored a survey of concerns for PWE that highlighted the need for the development of a group to spearhead an initiative to improve the recognition and treatment of mood disorders in PWE. One of the target goals, the development of a screening tool to detect depression in PWE in the clinic, resulted in the Neurological Disorders Depression Inventory for Epilepsy, which is discussed in the Statement. Another important goal was the development of a Consensus Statement for practitioners. The panel represents a group of experts who have been working in the field of epileptology and have focused their interests in depression as a comorbidity of epilepsy. The group has authored extensively in the field. The Consensus Statement was designed to be a compendium of the published data in the field and to provide a concise stepwise method to treat PWE and depression in a clinical setting. It attempts to answer how to recognize the disorder, barriers to treatment and how to overcome them, treatment recommendations, and, for the neurologist, when to refer to psychiatry and what to expect from their psychiatry colleagues. 3. How to recognize depression in people with epilepsy 3.1. What is the problem? Depression is the most common comorbid psychiatric disorder in PWE [4]. For example, Tellez-Zenteno et al. used the Canadian Community Health Survey (CCHS 1.2) to investigate the prevalence of psychiatric comorbidity in PWE in the community compared with those without epilepsy [5]. The CCHS included the administration of the World Mental Health Composite International Diagnostic Interview to a sample of 36,984 subjects. A prevalence of epilepsy of 0.6% was identified in this cohort. A 17.4% lifetime prevalence of major depressive disorders was found in patients with epilepsy (95% CI: ) versus 10.7% (95% CI: ) in the general population. Furthermore, patients with epilepsy had a 24.4% (95% CI: ) lifetime prevalence for any type of mood disorder versus 13.2% (95% CI: ) among the general population. Its prevalence is significantly higher than in healthy controls, as well as in people with other chronic medical disorders [4 7]. Despite relatively higher prevalence rates, depression remains underrecognized and undertreated. For example, in a study of 97 consecutive patients with epilepsy and a depressive disorder severe enough to warrant pharmacotherapy, Kanner et al. found that referral for psychiatric treatment was suggested after more than 1 year from the onset of symptoms in 63% of patients with a spontaneous mood disorder and in 54% with an iatrogenic depressive episode [8]. Wiegartz et al found that 43% of PWE had a current major depressive disorder and 68% a minor depression; 38% of patients with lifetime histories of major depressive disorder had never been referred for treatment [9]. Furthermore, this problem is highly prevalent in other cultures and affects all age groups. For example, De-Marinis et al. identified a major depressive disorder with the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I) in 44 of 200 consecutive patients with epilepsy in Chile [presented as a poster at the 2006 Annual meeting of the American Epilepsy Society, San Diego, CA, USA]. In only 25% had this disorder been identified prior to their participation in the study. This problem is not restricted to adults with epilepsy. Ettinger et al. found symptoms of depression in 26% of 44 children, none of whom had been previously diagnosed or treated [10]. Prevalence rates of depression range from 20 to 55% in patients with refractory epilepsy, with the highest rates seen in epilepsyspecific clinics, and from 3 to 9% in patients with well-controlled epilepsy [11]. Although female gender predominance is seen for depression in the general population, this has been an inconsistent finding in surveillance of depression in patients with epilepsy. Two recent reports, however, have found that female gender is associated with depression in epilepsy [12,13]. In an evaluation of depressive symptoms in 201 patients with epilepsy, using the Beck Depression Index-21, high seizure frequency and symptomatic focal epilepsy were independent determinants of depression, and female gender showed a strong trend toward this association (P = 0.054) [12]. In a mailed survey for depression using the Center for Epidemiology Studies Depression Scale [CES-D]), comparing 775 persons with epilepsy, 395 with asthma, and 362 healthy subjects, depression was significantly associated with female gender, young age, lower income, worse quality-of-life scores, more disability, more social concerns, more adverse drug events, less past-month employment, and fewer working days [13]. Failure to identify comorbid mood disorders in epilepsy is not surprising given that physicians fail to inquire about this condition. For example, in a survey of neurologists, Gilliam found that 80% do not routinely screen patients with epilepsy for depression [14]. There are several reasons for this phenomenon: (1) There is the common misconception by patients, relatives, and (not infrequently) clinicians of depression being a normal reaction to facing a life with seizures and the expected obstacles in social, academic, professional, and economic domains. Accordingly, depressive episodes are not reported to the treating physician, even if symptoms persist for a protracted period, and physicians fail to inquire about them. (2) Frequently, depressive disorders have an atypical clinical expression in patients with epilepsy (see below). (3) Patients become accustomed to living in a chronic depressed state to the point where they end up forgetting what it was like to live in a euthymic mood. Thus, it is not rare for patients to deny feeling depressed, and it is only a spouse, parent, or close friend who reports mood changes in the patient. In fact, inquiring about specific symptoms (i.e., Are you unable to find pleasure in your daily activities? or Do you have to push yourself to go out? ) may allow the patient to recognize the existence of a pathologic mood state. (4) Patients and their relatives misperceive that the depressive symptomatology is part of the epilepsy and hence does not require special treatment. (5) The don t ask, don t tell phenomenon refers to a deliberate decision by nonpsychiatrists not to inquire about symptoms of depression because they do not know how to manage depression or where to refer. Indeed, this has become probably one of the more frequent obstacles in the

3 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 S3 diagnosis and treatment of comorbid psychiatric disorders in patients with medical and neurological disorders. This problem is addressed in great detail in the section on treatment of mood disorders [14]. It is typically assumed that mood disorders are a consequence of the seizure disorder. Yet, recent evidence suggests that a significant number of patients with new-onset epilepsy were already suffering from mood and anxiety disorders before they ever had a first seizure [15 18]. In fact, three population-based studies suggest that patients with depression have a four- to seven-fold higher risk of developing epilepsy than controls [16 18]. In a recently published study of children and adolescents with new-onset epilepsy, 19% were found to have a mood disorder and 24% an anxiety disorder at the time of diagnosis [15]; 45% had experienced the psychiatric disorders before the onset of the seizure disorder. Depression has a significant negative impact on the quality of life of PWE [19]. In addition, recent studies have demonstrated that the presence of untreated depression is associated with greater medical costs, independent of the cost of psychiatric treatment [20]. Depressed patients are also more likely to experience adverse events from their antiepileptic drugs (AEDs) [21,22]. Furthermore, a history of depression appears to be predictive of a worse response to pharmacological and surgical treatment of the seizure disorder. Indeed, in a study of 780 consecutive patients with new-onset epilepsy who were followed for a 20-year period, Hitiris et al. found that patients with comorbid psychiatric disease at the time of diagnosis of epilepsy were almost three times less likely to achieve seizure freedom with AEDs [23]. Most of the variance was accounted for by a history of depression. By the same token, in a study of 100 consecutive patients with temporal lobe epilepsy (TLE), Kanner et al. found that a lifetime history of depression is a predictor of failure to reach freedom from auras and disabling seizures following anterotemporal lobectomy (ATL) [24]. Clearly, mood disorders affect patients with epilepsy at multiple levels and their recognition and timely treatment are of the essence Mood disorders in epilepsy: Far from a homogeneous disorder The fourth edition (text revised) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) classifies mood disorders into Major Depressive Disorder (MDD), Dysthymic Disorder, Minor Depression, Bipolar Disorder, Cyclothymia, and Depressive Disorder Not Otherwise Specified [25,26]. This last category includes all forms of depression that do not meet full DSM-IV criteria for the suggested categories. The difference between Major Depressive Disorder and Dysthymic Disorder is based largely on severity, persistence, and chronicity. According to DSM-IV criteria, symptoms in both disorders may include combinations of depressed mood, anhedonia, worthlessness and guilt, decreased concentration ability, and recurrent thoughts of death and neurovegetative symptoms (i.e., weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue). A diagnosis of MDD is considered in patients with recurrent major depressive episodes, in which at least 2 weeks of either depressed mood or anhedonia must accompany four of the symptoms listed above. In contrast, dysthymic disorder is a more chronic but less intense process with symptoms persistent for more days than not for at least 2 years. Minor Depression is a category that is similar to a major depressive episode in duration but encompasses at least two but fewer than five of the depressive symptoms noted above. There are two types of Bipolar Disorder, depending on the occurrence of manic (type I) or hypomanic (type II) episodes in addition to major depressive episodes. The DSM-IV diagnosis for manic episodes includes the requirement of a distinct period of abnormally and persistently elevated mood lasting at least 1 week, of sufficient severity to cause marked impairment in social functioning. The diagnosis for a hypomanic episode includes the requirement of a distinct period of persistently elevated mood lasting throughout at least 4 days and observable as a disturbance by others. The diagnosis of Cyclothymia requires the presence of numerous hypomanic and minor depressive episodes for at least 2 years. Recent studies in patients with primary mood disorders indicate that the DSM classification may not be sufficient to include all forms of depression. Indeed, patients with a history of major depressive disorder may not achieve complete symptom remission and present with subsyndromic forms of depression. Recognition of these less severe presentations is of the essence, as these patients are at increased risk of experiencing a recurrence of major depressive episodes. In patients with epilepsy, the presence of subsyndromic forms of depression is associated with a worse quality of life. Indeed, in a study of 193 consecutive outpatients from five epilepsy centers, Kanner et al. identified psychiatric comorbidity with two structured interviews (SCID and Mini International Neuropsychiatric Interview [MINI]) [22]. Patients were also asked to complete self-rating screening instruments of symptoms of depression, such as the Beck Depression Inventory II (BDI-II) and the Center for Epidemiologic Studies Depression Scale (CES-D). A diagnosis of subsyndromic depression was made in patients who failed to meet any axis I diagnosis according to DSM-IV-TR criteria with the SCID and MINI, but whose scores on the BDI-II and/or CES- D were greater than 12 and 16, respectively. Among the 193 patients, 103 were totally asymptomatic, 22 met our diagnostic criterion of subsyndromic depressive episode, 10 met a DSM-IV criterion of major depressive disorder, 30 of an anxiety disorder, 24 of a mixed major depressive and anxiety disorder, and 4 of dysthymia. The Quality of Life in Epilepsy Inventory 89 (QOLIE-89) was used to assess patients perception of their quality of life. Patients with subsyndromic depressive episodes perceived their quality of life as being significantly worse (QOLIE-89 total score = 59 ± 11.5) than that of asymptomatic patients (80 ± 10, P < ). Furthermore, having only a major depressive disorder or a mixed major depressive and anxiety disorder had a differential impact on patients quality of life, as the latter perceived it to be worse than the former and than those with only anxiety. The comorbid occurrence of anxiety and mood disorders is relatively frequent and contributes to the heterogeneous characteristics of mood disorders. Indeed, in the study cited above, 24 of the 34 patients with major depressive disorders met DSM-IV-TR criteria for an anxiety disorder. Conversely, the 30 patients who met criteria for an anxiety disorder only on the MINI had a score on the BDI-II suggestive of symptoms of depression of mild severity (mean score = 13.3 ± 10.6) and significantly higher than that of asymptomatic patients (3.4 ± 3.3, P < ). Patients with epilepsy have a significantly higher suicidal risk than the general population [27 30]. For example, in the Canadian population-based study cited above, the lifetime prevalence of suicidal ideation was twice as high in patients with epilepsy (25%, 95% CI = ) as in the general population (13.3%, 95% CI = ) [4]. This figure was replicated in a population-based study specifically designed to compare suicidal risk among patients with epilepsy in Denmark [30]. Suicidal cases were identified in the Cause of Death Register from 1981 to Up to 20 controls, matched by sex, birth year, and calendar date, were assigned to each suicide case. The study included 21,169 suicidal cases and 423,128 controls. Patients with epilepsy were found to have a three times higher risk of committing suicide than controls, as 492 (2.32%) individuals who committed suicide had epilepsy compared with 3140 (0.74%) controls (risk ratio = 3.17, 95% CI = ) The risk ratio remained significantly higher after excluding individuals with a history of psychiatric disease and adjusting for socioeconomic factors (1.99, 95% CI = ). The highest risk of

4 S4 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 suicide was identified in patients with epilepsy and comorbid psychiatric disease, even after adjusting for socioeconomic factors (13.7, 95% CI = ). The finding that the highest risk of suicide among patients with epilepsy occurred during the first half year after diagnosis (5.35, 95% CI: ) was of great importance. This risk was particularly high in individuals with a history of comorbid psychiatric disease (29.2, 95% CI = ). Indeed, such risk is higher among depressed patients who also suffer from a comorbid anxiety disorder. Suicidal ideation can occur as part of an interictal mood/anxiety disorder or as postictal symptomatology (see below) [31]. For example, in a study of 100 consecutive patients with pharmacoresistant partial epilepsy, habitual postictal suicidal ideation was reported by 13 patients. The median duration of this symptom was 24 hours. In summary, it is critically important that the evaluation of mood disorders always encompasses an investigation of symptoms of anxiety disorders, during both the interictal and postictal periods. Furthermore, it is important to recognize the bidirectional relationship existing between suicidality and epilepsy. That is, not only do patients with epilepsy have a greater risk of experiencing suicidal ideation and behavior, but patients with a history of suicidality have a 5.1 greater risk of developing epilepsy [18] Unique clinical expressions of mood disorders in epilepsy Peri-ictal symptoms of depression Patients with epilepsy may experience symptoms of depression and anxiety temporally related to the occurrence of seizures, either before a seizure (preictally), as a clinical expression of the seizure (ictal), or following a seizure (postictally). It is not unusual for preictal symptoms to persist into the postictal period. Furthermore, we have found that interictal symptoms can worsen in severity during the postictal period (see below). These forms of depressive episodes are the least studied in a systematic manner and usually are not investigated by clinicians in routine evaluations of seizure disorders. Furthermore, their occurrence has never been factored in any study of the prevalence of depressive disorders in epilepsy and would not be detected with the standard diagnostic instruments used to generate DSM-based diagnoses Preictal depressive episodes There are very few studies in the literature of this form of depressive episodes, which typically present as a dysphoric mood preceding a seizure by several hours to days. Blanchet and Frommer investigated mood changes over the course of 56 days in 27 PWE who were asked to rate their mood on a daily basis. Mood ratings pointed to a dysphoric state 3 days prior to a seizure in 22 patients [32]. This change in mood was more accentuated during the 24 hours preceding the seizure. In our experience, preictal symptoms of depression manifest as irritability, poor frustration tolerance, motor hyperactivity, and aggressive behavior in children with epilepsy Ictal symptoms of depression Ictal symptoms of depression are the clinical expression of a simple partial seizure in which these symptoms constitute its predominant phenomenology. It has been estimated that psychiatric symptoms occur in 25% of auras ; 15% of these involve affect or mood changes [33]. For example, ictal symptoms of depression ranked second after symptoms of anxiety/fear which were the most common type of ictal affect in one study. At times, mood changes represent the only expression of simple partial seizures, and consequently, it may be difficult to recognize them as epileptic phenomena. They typically are brief, are stereotypical, occur out of context, and are associated with other ictal phenomena. The most frequent symptoms include feelings of anhedonia, guilt, and suicidal ideation. More typically, however, ictal symptoms of depression are followed by alteration of consciousness as the ictus evolves from a simple into a complex partial seizure Postictal symptoms of depression Postictal symptoms of depression (PSD) have been recognized for a very long time, but have been poorly studied in a systematic manner. Their prevalence in large populations of PWE has recently been investigated in a study that assessed the presence of PSD in 100 consecutive patients with poorly controlled partial seizure disorders [34]. Only symptoms that occurred following more than 50% of seizures for the previous 3-month period were included in the study. In this study, the postictal period was defined as the 72 hours that followed a seizure. The investigating also identified those symptoms that occurred during both interictal and postictal periods and compared their severity during these periods. Neurovegetative symptoms and fatigue, which are common postictal symptoms, as well as symptoms of depression, were analyzed separately, so as not to falsely inflate the prevalence of PSD. Among the 100 patients, 43 experienced a mean of 4.8 ± 2.4 PSD (range = 2 9, median = 5). The median duration of two-thirds of symptoms was 24 hours. Thirteen of these patients experienced a minimum of seven PSD lasting 24 hours or longer. As stated above, postictal suicidal ideation was identified in 13 patients. Eight patients experienced passive and active suicidal thoughts, whereas five reported only passive suicidal ideation. Ten of these 13 patients (77%) had a past history of either major depression or bipolar disorder, and this association was highly significant. Furthermore, the presence of postictal suicidal ideation was also significantly associated with a history of psychiatric hospitalization. Clearly, the presence of postictal suicidal ideation should alert the clinician to the existence of a current or past serious history of depression. Postictal symptoms of depression did not occur in an isolated manner, but more often than not were accompanied by postictal symptoms of anxiety and postictal neurovegetative symptoms. By the same token, 7 of the 100 patients reported habitual postictal psychotic symptoms. Every one of these patients also experienced symptoms of depression and anxiety. Thirty-seven patients had reported interictal symptoms of depression. These interictal symptoms worsened in severity during the postictal period in 30 patients (who, in addition, experienced de novo PSD). These data indicate that PSD are an integral part of the psychiatric symptoms frequently reported by patients with refractory partial seizure disorders. Yet, in none of the studies carried out to identify the prevalence of depression in epilepsy did the investigators discriminate between an interictal, preictal, or postictal occurrence. The impact that PSD may have in shaping the psychiatric clinical phenomena of depression in PWE is yet to be established. Yet, it is likely that preictal and postictal symptoms of depression may account for the frequent atypical characteristic of depressive disorders Atypical interictal expressions of depression in epilepsy It is not unusual for patients with epilepsy to experience depressive episodes that fail to meet any DSM criteria. Kraepelin [35] and then Bleuler [36] were the first authors to describe a pleomorphic pattern of symptoms that included affective symptoms consisting of prominent irritability intermixed with euphoric mood, fear, and symptoms of anxiety, as well as anergia, pain, and insomnia. Gastaut confirmed Kraepelin s and Bleuler s observations [37], and finally, Blumer coined the term interictal dysphoric disorder (IDD) to refer to this type of depression in epilepsy [38] and estimated that it occurred in two-thirds of depressed patients with epilepsy. Blumer described the chronic course of this disorder with recurrent symptom-free periods that

5 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 S5 responded well to low doses of antidepressant medication. In a more recent study, Kanner et al. confirmed Blumer s description of the pleomorphic characteristics of mood disorders [39]. Using DSM-III-R criteria, Mendez et al. had to classify almost 50% of depressive disorders as Atypical Depression [40]. Wiegartz et al. found that the depressive episodes of 25% of PWE were also classified as Atypical Depression Not Otherwise Specified [9]. Other investigators have been impressed as well by the atypical and pleomorphic presentation of depressive disorders in epilepsy. For example, among 97 consecutive patients with refractory epilepsy and depressive episodes severe enough to merit pharmacotherapy, Kanner et al. found that 28 (29%) met DSM-IV criteria for major depressive disorder [8]. The remaining 69 patients (71%) failed to meet criteria for any of the DSM-IV categories and presented with a clinical picture consisting of anhedonia (with or without hopelessness), fatigue, anxiety, irritability, poor frustration tolerance, and mood lability with bouts of crying. Some patients also reported changes in appetite and sleep patterns and problems with concentration. Most symptoms had a waxing and waning course, with repeated interspersed symptom-free periods of one to several days duration. The semiology most resembled a dysthymic disorder, but the recurrence of symptom-free periods intermittently precluded DSM criteria for this condition. Kanner referred to this form of depression as Dysthymic-Like Disorder of Epilepsy (DLDE) Why should nonpsychiatrists care? Clearly, no one expects neurologists or other nonpsychiatrists to remember the DSM-IV-TR classification and diagnostic criteria of mood disorders described above. Yet, it is important that they recognize the following expressions of these disorders: (1) major depressive episodes, as these represent their more common debilitating type; (2) postictal depressive symptoms or episodes, given their relatively high prevalence in patients with refractory epilepsy and the fact that they may persist even with the use of antidepressant medication given for interictal mood disorders; (3) suicidal ideation and behavior; (4) the comorbid occurrence of anxiety symptoms and disorders in depressed patients, as these are the ones at greater risk of suicidal ideation and attempts; (5) bipolar disorders or patients at risk for this form of mood disorder, as antidepressant medication must be used with great caution in these patients to avert a switch to manic or hypomanic episodes or, worse, a rapid cycling bipolar disorder, which is more refractory to treatment. In patients with a major depressive episode, the suspicion of bipolar disease must be considered in the following circumstances: (1) history of manic or hypomanic symptoms after exposure to an antidepressant drug; (2) family history of bipolar disease; and (3) a first major depressive episode before the age of 15, as these patients have a 40 to 60% probability of developing bipolar illness Recognition of iatrogenically caused depressive episodes Depressive episodes can be triggered by changes in AEDs in three ways: (1) after introduction of an AED with negative psychotropic properties; (2) after discontinuation of an AED with moodstabilizing properties in individuals with a mood disorder that had been in remission because of the therapeutic effect of the disease; and (3) after introduction of an AED with enzyme-inducing properties in patients taking psychotropic drugs (e.g., antidepressants) for the treatment of an underlying mood disorder. These AEDs cause a significant increase in the clearance of the psychotropic drugs, limiting their efficacy and often leading to recurrence of the depressive episode. It is important to keep in mind that AEDinduced depressive episodes are more likely to occur in patients with a prior history and/or a family history of mood or anxiety disorders or of alcoholism. Clearly, to avert the development of iatrogenically induced depressive episodes, clinicians must always inquire about such past personal or family psychiatric histories. Every AED, including those with positive psychotropic properties, can trigger psychiatric symptoms in epileptic patients, some with a greater severity than others [40,41]. Phenobarbital can result in depression that may occasionally be related to the presence of suicidal ideation and behavior. Other AEDs reported to often trigger symptoms of depression include primidone, tiagabine, vigabatrin, felbamate, topiramate, levetiracetam, and zonisamide [41 48]. Furthermore, identifying any current or prior depressive disorder may have an important effect on the threat of developing adverse cognitive events when exposed to topiramate. In fact, cognitive adverse events were reported by 41% of 592 patients in a study of topiramate polytherapy [48]; a history of a depressive disorder was a significant predictor of these cognitive adverse events Recognition of depressive disorders in the neurology clinic Ideally, every patient suspected of having a mood disorder should undergo a psychiatric evaluation to identify the type of mood disorder and comorbid psychiatric conditions. Unfortunately, this is very often an unlikely option, given the lack of availability of psychiatrists and lack of reimbursement of psychiatric services by third-party payers. Thus, it often falls on the neurologist to treat the comorbid mood disorder. How is a neurologist (or any clinician without special training in psychiatric aspects of epilepsy for this matter) expected to identify the existence of a depressive disorder in her or his patients with epilepsy in the midst of a busy clinic with already limited time allotted to address the epilepsy-related issues? An initial and very simple step is to inquire about the existence of the symptom of anhedonia, that is, the inability to find pleasure in most activities. In fact, identification of anhedonia is a very good predictor of the presence of depression and, often, unaffected by physical complaints secondary to drugs or underlying illness ; it is a barometer of the intensity of the depression in the medically ill. Second, having patients complete one of the self-rating screening instruments used to identify symptomatic patients can be very useful. In fact, a six-item screening instrument, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), was recently validated to identify major depressive episodes specifically in PWF [49]. This instrument has the advantage that it was constructed to minimize the potential for confounding by adverse events related to AEDs or cognitive problems associated with epilepsy that plague other instruments. Completion of this instrument takes less than 3 minutes. A score above 15 is suggestive of the possibility of a major depressive episode and serves as a red flag to carry out a more in-depth evaluation [50]. Other self-rating screening instruments developed to identify symptoms of depression in the general population, the BDI-II and the CES-D, have recently been found to be valid instruments to screen symptoms of depression in PWE [51]. Total scores >11 and 14, respectively, are suggestive of depressive disorders of at least mild to moderate severity. Also, the Mood Disorders Questionnaire (MDQ) has been used in PWE as a screen for the presence of symptoms consistent with a bipolar disorder [52]. Finally, the Hospital Anxiety and Depression Scale (HADS) is a useful screening instrument to identify symptoms of anxiety and depression, but it has yet to be validated in PWE. It should be emphasized that these instruments are not diagnostic by themselves of major depressive or other mood disorders, and when the score is suggestive of a mood disorder, patients should undergo a more in-depth evaluation. Once the diagnosis of a mood

6 S6 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 disorder has been established by psychiatric evaluation, these instruments can be given at every visit to measure changes in symptom severity or to document symptom remission. On the other hand, it is very useful to generate a list of symptoms for each patient that serves as target for pharmacological and /or psychotherapeutic interventions. Indeed, the aim of any of the selected therapies must be their total remission, lest an increased risk of recurrence of the depressive disorder exists. This is a proposed list of the most common symptoms of anxiety and depression that any nonpsychiatrist can use as a model [52]: Symptoms of Depression 1. Are you having difficulty finding pleasure in activities you used to enjoy? 2. Do you have to push yourself now to do things that you used to enjoy in the past? 3. Do people get on your nerves for things that never used to bother you before? 4. Do you have little tolerance for people? 5. Do you notice that your mood changes without any apparent reason? For example, one day you are happy, and without any reason you get moody, cranky, and cannot enjoy anything the next day? 6. Do you feel so bad that you feel completely hopeless? 7. Do you feel that there is nothing you can do to feel better about yourself? 8. Do you sometimes wish you were dead? 9. Do you think about ways of harming yourself? 10. Do you find yourself crying for things that never made you cry before? 11. Do you have difficulty falling asleep? 12. Do you wake up in the middle of the night and have difficulty falling asleep again? 13. Has your appetite changed? If so, how? 14. Have you lost or gained weight as a consequence of a change in your appetite? Symptoms of Anxiety 1. Do you worry about things you never worried about before? 2. Do you fear that something bad will happen to your loved ones, even though you know there is nothing to worry about? 3. Does your heart start beating fast, out of the blue, and you feel like you cannot catch your breath and that something terrible is going to happen to you, like having a heart attack, a stroke, etc.? 4. Do you get frightened of being left alone or leaving the house by yourself? 5. Do you find yourself pacing constantly and unable to relax? 3.7. The identification of mood disorders in research One of the most frequent methodological errors that occur repeatedly in research studies of depression in epilepsy is the sole reliance on screening instruments in the diagnosis of a depressive disorder. The argument to limit the psychiatric evaluation to the use of these instruments is that they have been validated to identify conditions such as major depressive episodes, some with acceptable levels of sensitivity and specificity, and the severity of the depressive episodes. Thus, the common argument suggests: If a patient has a score >30 on the BDI-II, what else can the patient have but a major depressive episode? Although this statement is probably correct, a major depressive episode can be the expression of more than one type of mood disorder, each with a different prognosis and treatment strategies. For example, a major depressive episode: (1) can be the first major depressive episode ever, which implies a 50% risk of experiencing additional episodes; (2) can be one of multiple episodes indicating a diagnosis of major depressive disorders with an almost 100% probability of recurrent episodes, lest the patient remains on prophylactic treatment; (3) can occur as part of bipolar disorder, which implies a worse prognosis for symptom remission and suicidal risk than major depressive disorders and calls for a different treatment strategy (i.e., very cautious use of antidepressant medication); (4) can occur as part of a double depression, which consists of recurrent major depressive episodes in the midst of a dysthymic disorder. Clearly, the use of screening instruments in psychiatric research in patients with epilepsy must be followed by structured psychiatric interviews designed to establish distinct Axis I diagnoses. With such diagnoses in hand, the use of screening instruments on a repeated basis can yield meaningful data with respect to change in severity of symptomatology after the start of treatment Comments Mood disorders are relatively frequent in patients with epilepsy and their early identification is essential to minimize suicidal risks, the negative impact on quality of life, and costs. Neurologists should be trained in the recognition of mood and anxiety disorders and the treatment of major depressive and dysthymic disorders. However, psychiatrists should be involved in the management of patients with bipolar disorders, suicidal ideation, or psychotic depressive episodes, or any patient whose depressive episodes have failed to respond to pharmacotherapy in the past. 4. Psychological and physiological factors associated with depression in epilepsy Similar to depression occurring in the absence of neurological disorders, depression in PWE is probably caused by multiple factors. Depression symptoms in different samples of patients with epilepsy have been associated with specific psychological profiles, structural brain abnormalities, and metabolic dysfunction. However, the causal relationships of these findings have not been determined, and no imaging test or psychological profile has been demonstrated to have diagnostic value. Very few studies have evaluated psychological correlates of persons with depression and epilepsy, especially regarding potential predictive or causal relationships [53]. Hermann et al. [54] used the BDI and the CES-D to examine the association of depression with a key component of the revised theory of learned helplessness (i.e., attributional style) defined by the Optimism/Pessimism Scale. The study sample consisted of 143 patients with unilateral TLE. The severity of depression symptoms was significantly associated with attributional style, even after controlling for potential confounding variables such as age, sex, age at onset of epilepsy, and laterality of epilepsy. The authors concluded that the results indicate that the concept of learned helplessness in general, and attributional style in particular, is related to the genesis of depression in epilepsy [54]. Several investigative groups have evaluated the association of structural MRI changes with depression in epilepsy. Quiske et al. [55] compared BDI scores in 60 patients with TLE. Mean depression scores were significantly higher in subjects with mesial temporal sclerosis (MTS), independent of lateralization of the MTS. The investigators concluded that depression is a good indicator of MTS, but not vice versa [55]. Mula et al. found that hippocampal volumes were associated with the occurrence of depression after initiation of topiramate [56], but not levetiracetam [57]. Briell-

7 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 S7 mann et al [58] did not find a difference in volumes or T2 relaxation times in hippocampi of patients with TLE with and without a history of depression, but rather demonstrated that depression was associated with more normal T2 relaxation times in the amygdala contralateral to the lobe of seizure onset. Richardson et al. [59] reported that both left and right amygdala volumes correlated with BDI scores in 18 subjects with TLE, but hippocampal volumes did not. Bromfield et al [60] were among the first to use [ 18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate metabolic correlates of depression in epilepsy. They studied metabolism in nine brain regions in 23 patients; 18 had TLE and 5 had poorly localized EEG abnormalities. Inferior frontal cortex was the only region that had an association, showing decreased metabolism in subjects with increased symptoms of depression. Salzberg and colleagues [61] reported similar findings after comparing resting FDG-PET scans of 9 patients who had a prior history of depression with those of 14 patients who did not have the prior history of depression. Using statistical parametric mapping to evaluate metabolic patterns, they found that subjects with prior depression had areas of hypometabolism in the ipsilateral inferior frontal lobe, compared with subjects with no prior history of depression. This finding suggests that dysfunction in extratemporal regions contributes to depression in patients with TLE. Some prior studies in subjects with nonepileptic depression also identified regions of hypometabolism, whereas others have found increased metabolism in specific mesial frontal areas. An earlier analysis limited to temporal lobe interictal FDG-PET hypometabolism found that patients with left temporal hypometabolism had higher rates of major depressive episodes compared with those with only right temporal abnormalities [62]. However, depression was also strongly associated with bilateral hypometabolism, and severity of depression was associated with increased severity of hypometabolism on the right. The association between the presence of temporal lobe hypometabolism and higher BDI scores was also reported in another study [63]. Although few studies have compared MR spectroscopy findings with measures of depression in epilepsy, a recent investigation found that the extent of voxels with abnormal N-acetyl aspartate/creatine ratios in hippocampi correlated with severity of depression symptoms in 31 subjects with TLE [64]. As the serotonin model of depression may also be relevant in epilepsy, several investigators have evaluated PET ligands that bind to 5HT1A receptors in TLE. Recent studies using trans-4-[ 18 F]fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide ( 18 F-FCWAY) have noted decreased binding with higher BDI scores [65,66] and the presence of major depression [67]. However, a study using carbonyl- 11 C WAY found an inverse correlation between decreased binding in the cingulate gyrus and increased Montgomery Åsberg Depression Rating Scale scores in subjects with TLE [68] Comments Specific psychological characteristics, as well as structural and functional brain abnormalities, have been demonstrated to be associated with increased symptoms of depression in relatively small samples of patients. A pessimistic attributional style appears to be a significant risk factor. The hippocampus and amygdala are the most frequently involved anatomical regions, but other limbic areas are also implicated by the results of some studies. TLE has been more frequently studied than other syndromes, so few conclusions can be drawn regarding idiopathic or extratemporal forms of epilepsy. 5. Depression and cognitive function An important aspect of the problem of depression in PWE is the degree to which depression may add to the cognitive burden of the disorder. The ways in which epilepsy and its treatment may affect neuropsychological status in epilepsy have been the subject of excellent reviews [69,70], but comparatively less is known about the added neuropsychological morbidity attributable to depression in epilepsy. Several investigations [71 74,55], but not all [75], have reported that comorbid depression is associated with additional cognitive pathology in persons with epilepsy. This is not surprising given the literature characterizing the cognitive status of patients without epilepsy with unipolar depression or bipolar disorder in whom impairments in memory and executive function have been reported [76 78]. Given the magnitude of the problem of psychiatric comorbidity in epilepsy in general, and depression in particular, the degree to which these psychiatric complications are associated with additional cognitive burden is important to determine, as is the degree of relief provided by effective depression treatment. There are several important issues to address in this literature and a few areas requiring investigation in the future are listed below Definition of depression Much of the previous research has examined the association of cognitive impairment with scores derived from self-report depression symptom inventories (e.g., BDI, CES-D). Many times, arbitrary cut scores (e.g., >10) are used to derive depressed and nondepressed groups. Although not uncommon in this literature, such procedures are of little diagnostic significance and are certainly not equivalent to formal psychiatric diagnoses. Epilepsy research is increasingly moving to DSM-IV- and ICD-10-defined diagnoses, and cognitive studies of depression in epilepsy should reflect this move as well Progression of depression It has now been established that in some epilepsies (e.g., chronic TLE), there may be progression of DSM-IV Axis I disorders, including mood and anxiety disorders [79]. The degree to which progressive cognitive changes may be associated with the progression of depression versus progression of the underlying neurobiology of the disorder needs to be determined The contribution of anxiety Anxiety is often comorbid with depression in epilepsy [79,80] and has been shown to be associated with its own neuropsychological morbidity in the general population. The degree to which depression only versus mixed mood disorders affect cognitive status in chronic epilepsy remains to be determined Relationship to epilepsy variables There is longstanding interest and debate regarding the relationship between depression and features of the epilepsies including seizure type, laterality of seizure onset, underlying neuropathology (e.g., hippocampal sclerosis), and other factors [81]. Some [71 73] but not all [75] groups have shown that depression in left TLE is associated with significant cognitive morbidity, thus representing an interaction between mood disorder and specific seizure features on cognition. Complex relationships between

8 S8 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 clinical seizure features and depression and their effects on mood remain to be fully characterized Cognitive domains Memory, attention, higher executive functions, and cognitive and psychomotor processing speed have been shown to be affected by depression in the general population [76 78]. The relative degree to which these abilities are affected in depressed persons with epilepsy remains to be determined. Further, some consensus on the best tests with which to assess these cognitive domains would prove helpful so various investigative groups around the world might share some common instrumentation Subjective memory complaints It is now well appreciated that subjective memory complaints are strongly associated with the degree of self-reported depressive symptoms on inventories such as the BDI and CES-D [82 85]. This represents another avenue through which to explore the effects of depression on real and perceived cognitive status Postictal depression and its interictal cognitive signature Postictal depression is a unique and serious psychiatric complication oftentimes independent of interictal depression [32]. The degree to which postictal psychiatric complications, including postictal depression in particular, may exhibit interictal cognitive markers would be of interest and importance. 6. Barriers to the detection and treatment of depression 6.1. Barriers to depression treatment in the general population: Patient factors Despite the high prevalence and significant personal and societal burden of mood disorders and the availability of effective treatments, the vast majority of people with mood disorders do not receive care. An even smaller subset receive evidence-based treatment [86]. Although the literature on the epilepsy population is limited, extrapolation from research on general barriers to mental health treatment can be helpful. The first steps in the help-seeking process for persons with mood disorders are awareness of symptoms and perception of the need for care. The most important predictors of the perception of need for care are severity of the psychopathology and life limitations imposed by the condition. With psychopathology controlled for, the following variables are associated with perceived need for care: marital loss, female gender, physical conditions, younger age (15 24 years), maternal psychopathology, insurance, and positive inclination toward mental health treatment [87]. In persons who perceive a need for care, it is somewhat counterintuitive that the severity of psychopathology does not affect the decision to seek help. At this stage, the main determinants are attitudinal and sociodemographic. Being older (45 54 years), having a physical condition, and having a positive attitude toward mental health seeking were associated with seeking professional help [87]. Misperceptions about antidepressant medication also contribute to an unwillingness to undergo further psychiatric evaluation. Many people believe that antidepressants are addictive, and prefer psychological treatment approaches or no treatment at all [88]. In one study in which 211 depressed patients were surveyed for treatment preference prior to initiating treatment, 53% were receptive to antidepressant medication, and 69% were receptive to counseling. Concern about the stigma of depression is also a factor for predicting adherence to antidepressant medication [89] Barriers to depression treatment in people with epilepsy: Patient factors A recent study evaluated the reasons why adult patients with epilepsy who endorsed significant depressive symptoms refused further evaluation and treatment for a possible mood disorder [90]. In this study, 113 consecutive adult patients were evaluated for depressive symptoms using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) [91]. The results of the scale were immediately discussed with the patient by a clinical social worker, and the decision to refer for further psychiatric intervention was based on the scale score and follow-up interview. Of 113 patients, 67 patients (59%) did not need referrals as indicated by the above assessment. Of the 46 who were determined to need referral (including all patients with at least moderate depression), 17 (15%) were already under the care of a mental health professional. Twenty-nine patients (26%) were referred for further treatment for possible depression. Of these, 17 (56% of 29) refused to accept information about mental health referral. The most frequently stated reasons for declining referral were: 1. Patients felt that they did not need treatment for depression and seemed not to recognize that they may be depressed. 2. Patients thought that their current mood problems were related to an acute, temporary situation. 3. Patients stated they did want to consider taking another medicine. 4. Patients who scored in the severe and very severe ranges who refused therapy stated that it had not been helpful in the past. These specific reasons (that clearly were barriers to treatment) are very similar to those revealed in the general population, starting with the challenge of the self-awareness of symptoms and the perception of the need for mental health care. However, the findings also suggest that patients with epilepsy seem reluctant to acknowledge the possibility of being depressed. The reasons for this are unclear, but are likely complex and may include the stigma of depression, and reluctance to accept the burden of additional diagnoses and the possibility of further medication treatment. Patients also frequently stated that any current mood problems were due to an acute situation that may resolve in the foreseeable future, such as undergoing treatment for a brain tumor, recent pregnancy, and family and employment stressors. Because of the increased risk of depression and suicide in patients with epilepsy, these findings indicate that the epilepsy population would benefit from ongoing surveillance and discussion of mood problems and monitoring of depressive symptoms Barriers to depression treatment in people with epilepsy: Physician factors Access to care There are many economic factors that represent barriers to the access to mental health services for patients with epilepsy and depression. These factors include potential lack of health insurance, possible lack of acceptance of insurance by mental health care practitioners (many of whom understandably are unable to practice with potentially onerous restrictions imposed by managed care plans), and a paucity of psychiatrists in various regions of the country. Some psychiatrists are uncomfortable caring for patients with concomitant serious neurological disorders like epilepsy; specific, sometimes unfounded fears of managing epilepsy are described below.

9 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 S Fear of lowering the seizure threshold A common assumption is that all antidepressants (ADs) lower the seizure threshold. Yet many lines of evidence belie this commonly held dogma. Assessment of the epileptogenic risk of ADs is confounded by the paucity of controlled AD trials in epilepsy and the possibility (reminiscent of observations with AEDs) that lower doses may have more anticonvulsant effects while higher doses may be proconvulsant (perhaps via antimuscarinic or antihistaminic effects) [92,93]. Furthermore, a seizure that occurs during AD administration, and therefore is presumed to be caused by the AD, needs to be interpreted with a caveat of recalling spontaneous seizure point incidence rates (often cited as slightly less than 0.1%) [94]. These spontaneous rates are often no different than the rates associated with some specific ADs. On the other hand, lack of differences in the mean rates of two populations may belie individual cases of seizures that appear to be associated with an AD. Another confounder is the insufficient quantity of reliable AD exposure data from either premarketing trials or postmarketing experience to generate accurate statistics on seizure rates (particularly for such a low-frequency event). Premarketing trials with their notorious rigid inclusion and exclusion criteria may not be representative of a more general population. In postmarketing data, there is immense variability in the nature of the patients, associated independent comorbid conditions that could give rise to seizures, lengths of observation, and drug combinations. Many fears about AD-induced seizures are based on seizures associated with AD overdoses, which may have little predictive value with respect to the risk of seizures with routine AD dosing [95 97]. Other factors to consider include the nature of possible prior seizures, effects of concomitant agents (both directly on seizure threshold and through pharmacokinetic effects on the AD), variability in rates of escalation or final dose, effects of concomitant conditions, and possible occult illicit substance abuse [93]. Effects on seizure threshold vary among the different ADs, yet some limited case series describe possible antiepileptic effects of some ADs such as fluoxetine [98] and citalopram [99], although these studies need to be further replicated. Monoamine oxidase inhibitors (MAOIs), which are uncommonly used because of the risk of other adverse effects, are also believed to have antiepileptic action [100]. The possibility of AD antiepileptic effects is also supported by commonalities in neurochemical effects between ADs and antiepileptic drugs (AEDs). For example, selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and MAOIs, as well as some antiepileptic treatments (e.g., lamotrigine and vagal nerve stimulation), may work in part by enhancing norepinephrine concentrations [101]. Similarly, serotonin levels may be increased by the SSRIs as well as by some AEDs including carbamazepine, lamotrigine, zonisamide, and valproic acid [ ]. In animal studies, these commonalities are demonstrated in the deficiency of norepinephrine in the highly seizure-prone GEPR-3 rat [105] and the knowledge that AD therapies are often believed to work through enhancement of noradrenergic transmission [ ]. Although a detailed review of the estimated seizure risk associated with each of the ADs is beyond the scope of this consensus statement, a number of general recommendations can be provided. ADs best avoided in epilepsy include amoxapine [109,110], clomipramine [ ], bupropion [ ], and maprotiline [ ]. Overall, the SSRIs and SNRIs are associated with low rates of seizures (usually approximating the rate of spontaneous seizures in the general population) and are considered to be more optimal than tricyclic antidepressants (TCAs). However, even before the advent of the newer ADs, TCAs were reasonably tolerated in PWE, particularly when administered in low doses and advanced very slowly (a principle that should also apply to use of any AD) Antidepressant antiepileptic drug interactions Many clinicians are understandably intimidated by the complex potential drug interactions between ADs and AEDs, possibly leading to a disinclination to treat depression. Although these interactions are complicated, several general principles can help the clinician manage the pharmacokinetic issues. One salient principle is the fact that many AEDs and ADs are metabolized in the liver. This means that either class of drugs is vulnerable to possible effects of the CYP-450 hepatic enzyme system. Agents in either class may be metabolized by specific isoenzymes, in which case a second agent that induces or inhibits that isoenzyme can result in reduced (and potential loss of efficacy) or increased (and possible toxicity) levels of the first agent. For example, older-generation enzyme-inducing AEDs (EIAEDs: phenytoin, phenobarbital, primidone, carbamazepine) can lead to reduced levels of some TCAs. Conversely, also, discontinuing an EIAED previously used in combination with a TCA can increase TCA levels and even induce toxicity. Alternatively, valproate, an enzyme inhibitor, may inhibit the metabolism of some psychotropic agents. The effects on specific isoenzymes are summarized in Table 1. Agents that do not induce or inhibit the CYP isoenzyme system include levetiracetam, lamotrigine, gabapentin, pregabalin, tiagabine, and zonisamide. AEDs may also be a substrate for induction or inhibition by psychotropic medications. For example, fluoxetine inhibits many isoenzymes and may result in increased phenytoin and carbamazepine levels. Fluvoxamine inhibits the CYP1A2, 3A4, 2C9, and 2C19 isoenzymes; it may raise phenytoin levels. For these reasons, as well as the aforementioned issues related to lowering seizure threshold, many clinicians favor the use of the specific SSRIs or SNRIs that have little effect on the CYP system, such as citalopram and escitalopram. Pharmacokinetics is also an important factor in the selection of antiepileptic agents in patients with comorbid depression. In general, many neurologists are moving toward the use of the newer-generation AEDs, many of which have a more favorable side effect profile and fewer tendencies toward drug interactions. Additionally, AED psychotropic properties (extensively discussed in a recent review [123]) should Table 1 Antiepileptic drug (AED) effects on antidepressants (ADs) Isoenzyme CYP1A2 CYP2C19 CYP3A4 CYP2D6 AD Amitriptyline Amitriptyline Amitriptyline Paroxetine Imipramine Imipramine Imipramine Fluoxetine Clomipramine Clomipramine Nortriptyline Venlafaxine Fluvoxamine Citalopram Desipramine Mianserin Moclobemide Clomipramine Nefazodone Sertraline Amitriptyline Clomipramine Nortriptyline Imipramine Desipramine Trazodone Maprotiline AED Inducer Phenytoin Phenytoin Phenytoin None Carbamazepine Carbamazepine Carbamazepine Phenobarbital Phenobarbital Phenobarbital Primidone Primidone Primidone Mildly with oxcarbazepine or topiramate AED inhibitor None Felbamate None None Topiramate Oxcarbazepine Source. Adapted from Table 4.2 in Kanner AM, Gidal BE. The use of psychotropic drugs in epilepsy: A review of pharmacokinetic, pharmacodynamic, and safety issues. In: Ettinger AB, Kanner AM, editors. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; p

10 S10 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 be strongly considered in selecting an agent given the high rates of comorbid depression, anxiety, and mood instability in epilepsy. For example, lamotrigine [124] and vagal nerve stimulation [125] not only are antiepileptic but may also have favorable effects on mood. Gabapentin [126] and pregabalin [127] may have anxiolytic effects. Conversely, agents like phenobarbital [128] and topiramate [129] may have adverse effects on mood. Levetiracetam [130], although usually very well tolerated, may exacerbate underlying depression and anxiety symptoms. Beyond pharmacokinetic effects, adverse synergistic pharmacodynamic effects (i.e., effects of these agents on the body) should also be noted. Examples include increased weight gain associated with the AEDs gabapentin, valproic acid, carbamazepine, and pregabalin and the ADs sertraline and paroxetine. Sexual dysfunction noted commonly in epilepsy may be exacerbated by EIAEDs (theoretically as a result of induction of metabolism of testosterone) and most ADs. Serotonin syndrome (described below) has been reported with the combination of carbamazepine and fluoxetine [131], whereas myoclonus has been noted with the mixture of lamotrigine and escitalopram [132] Antidepressant side effects Although the neurologist may be inclined to relegate prescribing of ADs to mental health care specialists, in fact, many nonpsychiatric clinicians such as primary care physicians and neurologists do prescribe antidepressants. Overall, newer ADs such as the SSRIs are felt to have a much more favorable safety profile compared with TCAs, especially with respect to cardiac complications. However, the clinician needs to be on guard for a number of notable side effects with the SSRIs [114, ]. These include the rare serotonin syndrome characterized by transient symptoms of hyperthermia, muscle rigidity, myoclonus, and altered mental status. Risks for this potentially fatal syndrome include the combination of SSRIs with a MAOI, making this combination contraindicated. This kind of interaction resulting from combination of an SSRI and a TCA is much less common. Concepts of drug interactions discussed earlier also apply here in which SSRIs (e.g., paroxetine, fluoxetine, and, to a lower extent, sertraline) may increase TCA levels (see Section 6). Other side effects include activation of manic symptoms; therefore, examination for evidence of bipolar symptoms is indicated before prescribing an AD. Questionnaires such as the Mood Disorder Questionnaire, which efficiently screens for bipolar symptoms, may be useful. Suicidal ideation has been described especially in youth receiving ADs such as SSRIs [137] (see Section 5). This implies that proper treatment must include a careful system of regular and frequent follow-up with the patient (see Section 6). Other symptoms described include gastrointestinal upset, insomnia, and akithesia. Sexual dysfunction in epilepsy, which runs the gamut of decreased libido, difficulty attaining orgasm, and disturbances in arousal and ejaculatory function, are well established. The EIAEDs may exacerbate these symptoms and SSRIs may increase these symptoms further [138]. Although physician and patient alike are often reluctant to raise the issue of sexual dysfunction, this is another important area that needs to be followed. Although the TCAs are less frequently used today in epilepsy, it is worthwhile reviewing side effects with this class of drugs as well [134, ]. Potential adverse effects include sedation or insomnia, nausea, sexual dysfunction, weight gain, anticholinergic symptoms (e.g., blurry vision, urinary hesitancy, constipation, and confusion), cardiac arrhythmias and orthostatic hypotension, tremor and agitation, and potential induction of mania as described earlier. Especially, in combination with MAOIs, TCAs may induce sympathomimetic effects Comments The seriousness of depression and suicide in persons with epilepsy merits ongoing surveillance for mood destabilization, especially in the months after the initial diagnosis and when seizures are pharmacoresistant. The physician treating the patient s epilepsy has a pivotal role in assessing mood disorders and helping the patient to accept the diagnosis and obtain treatment. Ideally a nurse or social worker can assist the patient in formulating a plan of action, solving problems, and accessing community resources. Addressing a treatment approach for depression in persons with epilepsy requires recognition of some important general concepts regarding the patients points of view. Attention to patients knowledge of mental health conditions and their attitudes toward treatment is essential in guiding an initial course of treatment. Many people with mood disorders, including people with epilepsy, may not be aware that their feelings constitute depression. They do not attribute their symptoms to a mental health problem, want to deal with the problems by themselves, or think that the symptoms will go away. Further, they may not believe that treatment will help. Younger people with mood disorders express concerns about embarrassment from using mental health services and fear of involuntary hospitalization [142]. Patients are more likely to become engaged in their treatment if they are assisted in formulating a plan of action with specific steps of where to go and how to access treatment. This assistance should include such nuts and bolts problem solving to overcome objective barriers as transportation, obtaining funding for treatment, and finding time for treatment [143]. The risks of using ADs in persons with epilepsy should be demystified. As discussed, the risk of inducing seizures appears to be low with the use of the newer-generation ADs. AD and AED pharmacokinetic interactions are confined primarily to mild to moderate interactions between the first-generation SSRIs, TCAs, and the standard older AEDs. These interactions are less problematic with most of the newer AEDs and more recently marketed ADs (see Table 1) [144]. Depression in PWE causes significant misery and risk of suicide. On the other hand, the treatment of such is relatively low risk and often effective. Because of the frequent presence of this serious and eminently treatable condition, neurologists treating persons with epilepsy should develop a comfort level for assessing the presence of depression and for initiating AD treatment in depressed patients with epilepsy, with a plan for follow-up and referral when appropriate. 7. Mood and anxiety disorder in pediatric epilepsy: Diagnosis and treatment This section provides a consensus with guidelines for clinicians on how to diagnose and treat mood and anxiety disorders in children and adolescents with epilepsy. Described here are the problems involved in making these diagnoses in children, clinical approaches to address these diagnostic difficulties, criteria for psychiatric and psychological referrals of these children, commonly used diagnostic and screening instruments, and the findings obtained with these instruments in pediatric epilepsy. After brief review of the multimodal treatments for these disorders in youth with epilepsy, the psychopharmacological treatment of depression, anxiety disorders, and bipolar disorder in children with epilepsy is described. The group consensus underscores that the treatment of these disorders in children requires the expertise of mental health professionals, a child psychiatrist for psychopharmacological intervention, and a child psychiatrist, psychologist, or social worker for the nonpharmacological treatments.

11 J.J. Barry et al. / Epilepsy & Behavior 13 (2008) S1 S29 S11 As described in adults with epilepsy, this section of the Consensus Statement focuses on pediatric epilepsy. It provides a consensus on the diagnosis and treatment of mood and anxiety disorders in children and adolescents with epilepsy. However, unlike adults with epilepsy, only few studies have been conducted on mood and anxiety disorders in children with epilepsy [ ,10, ]. Some of these studies have focused on establishing a DSM-IV diagnosis [145,147,149], whereas others have identified mood and anxiety symptoms in children with epilepsy [146,148,10,150,151]. Similarly, there have been no double-blind studies on the psychopharmacological treatment of mood and anxiety disorders in youth with epilepsy. In terms of other treatment modalities, to date only one open treatment study examined use of cognitivebehavioral therapy (CBT) to prevent development of depression in adolescents with epilepsy [152]. Therefore, the consensus presented in this section integrates the findings of diagnostic and treatment studies of mood and anxiety disorders in children and adolescents without epilepsy, studies of youth with epilepsy, and the clinical experience of the authors of this section. In the first subsection, diagnostic issues, particularly problems involved in making a diagnosis of mood and anxiety disorders in children with epilepsy, how clinicians should approach diagnosis of these disorders in children, and available diagnostic and screening instruments, are discussed. The subsection concludes with a schematic presentation (Fig. 1) of guidelines for clinicians on clinically relevant information from parents and children that help rule in or rule out the diagnoses of mood and anxiety disorder. In the second subsection, treatment modalities (e.g., psychoeducation, cognitive-behavioral therapy, supportive therapy, family therapy, psychopharmacological treatment) used to treat mood and anxiety disorders in children without epilepsy and their application to comorbid affective and anxiety disorders in pediatric epilepsy are discussed. Although clinicians are provided with a decision tree and guidelines for the psychopharmacological treatment of these disorders in children with epilepsy, the group consensus stipulates that treatment of these disorders requires the expertise of a child psychiatrist. However, input from epileptologists or pediatric neurologists on possible epilepsy-related effects on the treatment response is essential for optimal care of youth with these disorders Diagnosis Diagnostic difficulties Depression and anxiety are common comorbid conditions identified in 12 26% of children with epilepsy [147,10,151,153]. More worrisome are the high suicide [145] and suicidal ideation [147,10] rates associated with epilepsy and mood disorders in children and adolescents. Unfortunately, mood and anxiety disorders, like other forms of psychiatric illness, remain underdiagnosed and undertreated in pediatric epilepsy [154]. Furthermore, the DSM-IV-TR criteria for mood and anxiety disorders are often inadequate to effectively diagnose children with these disorders [155]. For example, the distinction between episodic depression and a chronic course of dysthymia is less relevant in the pediatric population. Children also more commonly have a chronic course of illness, whereas adults may have a more episodic course. Additionally, although children infrequently experience true dysphoria, a key component of major depressive disorder, they suffer from irritability significantly more often than adults. Recent efforts to describe behaviors, such as explosive mood and outerdirected irritability have led to wider consideration that aggressive and disruptive behavior may represent underlying depression or bipolar disorder in a pediatric population [ ], as well as anxiety disorders [159]. The appreciation of irritability as sufficient mood disruption for meeting requirements for categorization with major depressive disorder or even bipolar spectrum disorder has improved our understanding of mood disorder phenomenology in children [160]. Children with undiagnosed anxiety also can present with irritability and aggressive behavior [159]. Fig. 1. History and examination to rule in/out diagnosis of mood and anxiety disorders in pediatric epsilepsy.