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Diagnosing and treating depression in epilepsy

Open ArchivePublished:October 31, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.018

      Highlights

      • Literature on depression in epilepsy is selectively reviewed.
      • Diagnosing depression entitles patients for professional support.
      • Psychotherapy has proven its efficacy in ten adequate clinical trials.
      • Due to lack of adequate studies, efficacy of antidepressants remains unclear.

      Abstract

      At least one third of patients with active epilepsy suffer from significant impairment of their emotional well-being. A targeted examination for possible depression (irrespective of any social, financial or personal burdens) can identify patients who may benefit from medical attention and therapeutic support. Reliable screening instruments such as the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) are suitable for the timely identification of patients needing help. Neurologists should be capable of managing mild to moderate comorbid depression but referral to mental health specialists is mandatory in severe and difficult-to-treat depression, or if the patient is acutely suicidal. In terms of the therapeutic approach, it is essential first to optimize seizure control and minimize unwanted antiepileptic drug-related side effects. Psychotherapy for depression in epilepsy (including online self-treatment programs) is underutilized although it has proven effective in ten well-controlled trials. In contrast, the effectiveness of antidepressant drugs for depression in epilepsy is unknown. However, if modern antidepressants are used (e.g. SSRI, SNRI, NaSSA), concerns about an aggravation of seizures and or problematic interactions with antiepileptic drugs seem unwarranted. Epilepsy-related stress (“burden of epilepsy”) explains depression in many patients but acute and temporary seizure-related states of depression or suicidality have also been reported. Limbic encephalitits may cause isolated mood alteration without any recognizable psychoetiological background indicating a possible role of neuroinflammation. This review will argue that, overall, a bio-psycho-social model best captures the currently available evidence relating to the etiology and treatment of depression as a comorbidity of epilepsy.

      Keywords

      1. Defining depression

      Mood is determined by the predominance for specific emotions, however, it is also related to cognitive mind-sets, behavioral predispositions and states of autonomic nervous control [
      • Amado-Boccara I.
      • Donnet D.
      • Olié J.P.
      The concept of mood in psychology.
      ]. Mood exerts a strong impact on a person’s ability to cope with different environmental conditions. Mood is strikingly stable in most people and occasional phases of variation typically recede within a small number of hours.
      In the International Classification of Diseases (ICD-10) [
      • World Health Organization
      The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines.
      ] unipolar depression is defined by the key symptoms of low and depressed mood, loss of interest and pleasure (anhedonia), and reduced energy and fatigue that persist for at least two weeks (occuring most days for most of the time) [
      • Barry J.J.
      Idiopathic depressive disorders: basic principles.
      ,

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ]. In addition, individuals with depression may also suffer from disturbed sleep, poor concentration or indecisiveness, low self-confidence, poor or increased appetite, suicidal ideation, agitation or slowing of movements, and feelings of guilt or self-blame. According to the ICD-10 classification, a depressive episode is classified as mild (F32.0) if at least four symptoms (including at least two key symptoms) are present; mild depression typically allows for the continuation of the patient’s normal work and life. A total of five or six depressive symptoms (including at least two key symptoms) define a moderate depressive episode (F32.1); in which the patient would experience some impairment in their work and life. In a severe major depressive episode, all three key symptoms should be present with a total of seven or more symptoms. Severe depression has a devastating effect on functioning in daily life and can be life-threatening. If the duration of depressive mood extends over more than two years (more days with, than without, depressive mood) the disorder is classified as dysthymia (F34.1) [
      • Griffiths J.
      • Ravindran A.V.
      • Merali Z.
      • Anisman H.
      Dysthymia: a review of pharmacological and behavioral factors.
      ]. In dysthymia, symptoms are usually mild and may even fail the criteria for a minor depressive episode but the risk for major depressive episodes is increased (“double depression” [
      • Keller M.B.
      • Hirschfeld R.M.
      • Hanks D.
      Double depression: a distinctive subtype of unipolar depression.
      ]). Since the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-IV) [
      • American Psychiatric Association
      Diagnostic and statistical manual of mental disorders.
      ]) the diagnostic distinction between “psychoreactive” (neurotic) and “endogenous” (psychotic) depression has been omitted [
      • Rogler L.H.
      Making sense of historical changes in the diagnostic and statistical manual of mental disorders: five propositions.
      ].
      With around 350 million people affected worldwide, depression is a leading cause of disability and a major cause of the overall global burden of disease [,
      • Murray C.J.
      • Lopez A.D.
      The global burden of disease. A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020.
      ]. In Germany, the 12-months incidence rate of unipolar depressive disorders is estimated at 1–2 persons per 100 adults (aged 18–79 years); the prevalence is rated at 8%, i.e., 6.2 million adults are believed to suffer from depression each year; and the lifetime prevalence is estimated at 16–20% [
      • Jacobi F.
      • Höfler M.
      • Strehle J.
      • Mack S.
      • Gerschler A.
      • Scholl L.
      • et al.
      Psychische Störungen in der Allgemeinbevölkerung. Studie zur Gesundheit Erwachsener in Deutschland und ihr Zusatzmodul Psychische Gesundheit (DEGS1-MH).
      ]. The risk of developing depression is increased twofold in women compared to men, as well as in single persons compared to indivduals living with significant others, and in persons from lower versus upper classes [
      • Jacobi F.
      • Höfler M.
      • Siegert J.
      • Mack S.
      • Gerschler A.
      • Scholl L.
      • et al.
      Twelve-month prevalence, comorbidity and correlates of mental disorders in Germany: the mental health module of the German health interview and examination survey for adults (DEGS1-MH).
      ]. Of note, unemployment may be both the cause and the effect of depression [
      • Andreeva E.
      • Magnusson Hanson L.L.
      • Westerlund H.
      • Theorell T.
      • Brenner M.H.
      Depressive symptoms as a cause and effect of job loss in men and women: evidence in the context of organisational downsizing from the Swedish longitudinal occupational survey of health.
      ]. Around one half of patients experience at least one relapse of a depressive episode [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ]. More than half of depressive patients suffer from at least one other comorbid mental disorder [
      • Jacobi F.
      • Höfler M.
      • Strehle J.
      • Mack S.
      • Gerschler A.
      • Scholl L.
      • et al.
      Psychische Störungen in der Allgemeinbevölkerung. Studie zur Gesundheit Erwachsener in Deutschland und ihr Zusatzmodul Psychische Gesundheit (DEGS1-MH).
      ]; furthermore, the risk for developing a somatic disease (e.g., cardiovascular, tumor, diabetes) in the year after the onset of depression is increased nearly twofold (1.8) [
      • Ormel J.
      • Vonkorff M.
      • Oldehinkel A.J.
      • Simon G.
      • Tiemens B.G.
      • Ustün T.B.
      Onset of disability in depressed and non-depressed primary care patients.
      ]. Neuropsychological deficits of executive functions and memory performance link depression to a dysfunction of frontotemporal networks [
      • Srivastava K.
      • Ryali V.
      • Prakash J.
      • Bhat P.S.
      • Shashikumar R.
      • Khan S.
      Neuropsychophysiological correlates of depression.
      ]. Consistently, neuroimaging has shown that patients with depressive sypmtoms exert greater effort to maintain normal cognitive performance, compared to controls [
      • Harvey P.O.
      • Fossati P.
      • Pochon J.B.
      • Levy R.
      • Lebastard G.
      • Lehéricy S.
      • et al.
      Cognitive control and brain resources in major depression: an fMRI study using the n-back task.
      ].
      Depression is underdiagnosed and undertreated in many countries. According to recent data form Germany, depression is only diagnosed in one third of individuals fulfilling the diagnostic criteria; less than one third (6–9%) of diagnosed patients receive appropriate treatments; and less than half of the treated patients (2.5–4%) are still compliant with medication three months after the beginning of treatment [
      • Wittchen U.
      • Jacobi F.
      • Klose M.
      • Ryl L.
      Depressive Erkrankungen (Heft 51) Gesundheitsberichterstattung des Bundes.
      ]. Better data are reported from Canada (14% prevalence of diagnosed patients, with 85% treated) [
      • Wong S.T.
      • Manca D.
      • Barber D.
      • Morkem R.
      • Khan S.
      • Kotecha J.
      The diagnosis of depression and its treatment in Canadian primary care practices: an epidemiological study.
      ]. In patients with depression, the suicide risk is increased by a factor of 30 [
      • Harris E.C.
      • Barraclough B.
      Suicide as an outcome for mental disorders. A meta-analysis.
      ]. Therefore, timely diagnosis and state-of-the-art management provisions can save patients’ lives.

      2. Diagnosing depression in epilepsy

      2.1 The burden of epilepsy

      Epilepsy is a chronic neurological disorder affecting around 50 million individuals worldwide, with a self-reported active prevalence of 70% [,
      • Kroner B.L.
      • Fahimi M.
      • Gaillard W.D.
      • Kenyon A.
      • Thurman D.J.
      Epilepsy or seizure disorder? The effect of cultural and socioeconomic factors on self-reported prevalence.
      ]. Epilepsy makes the greatest neurological contribution to disability-adjusted life years [
      • Beghi E.
      Addressing the burden of epilepsy: many unmet needs.
      ]. Whilst in the majority of patients, seizures can be successfully controlled by anticonvulsants or epilepsy surgery, seizures are therapy-resistant in at least 25% of patients [
      • Brodie M.J.
      • Barry S.J.
      • Bamagous G.A.
      • Norrie J.D.
      • Kwan P.
      Patterns of treatment response in newly diagnosed epilepsy.
      ]. These patients carry a chronic burden [
      • Beghi E.
      Addressing the burden of epilepsy: many unmet needs.
      ,
      • Hermann B.
      • Jacoby A.
      The psychosocial impact of epilepsy in adults.
      ], facing the risk of unpredictable, potentially life-threatening and often socially embarrassing seizures; in fact, the permanent threat of seizures strongly reminds of those experimental conditions by which animal models of depression are made (e.g., Porsolt's forced-swimming test [
      • Porsolt R.D.
      • Le Pichon M.
      • Jalfre M.
      Depression: a new animal model sensitive to antidepressant treatments.
      ,
      • Seligman M.E.P.
      • Maier S.F.
      Failure to escape traumatic shock.
      ]). Epilepsy is associated with restricted employment opportunities and mobility, lower income, lower odds of finding a life companion, social marginalization and stigmatization. Epilepsy is strongly associated with a range of mental and somatic comorbidities [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ,
      • Keezer M.R.
      • Sisodiya S.M.
      • Sander J.W.
      Comorbidities of epilepsy: current concepts and future perspectives.
      ,
      • Centers for Disease Control and Prevention (CDC)
      Comorbidity in adults with epilepsy—United States, 2010.
      ]. Life expectancy is reduced and psychiatric disorders strongly contribute to premature mortality [
      • Fazel S.
      • Wolf A.
      • Långström N.
      • Newton C.R.
      • Lichtenstein P.
      Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study.
      ]. Many patients also suffer from neurocognitive impairments (e.g., episodic memory disorder), or cognitive side effects of antiepileptic drugs (AEDs), resulting in further worsening of quality of life (QoL) [
      • Pohlmann-Eden B.
      • Aldenkamp A.
      • Baker G.A.
      • Brandt C.
      • Cendes F.
      • Coras R.
      • et al.
      The relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy—current knowledge and understanding.
      ,
      • Witt J.A.
      • Elger C.E.
      • Helmstaedter C.
      Adverse cognitive effects of antiepileptic pharmacotherapy: each additional drug matters.
      ]. The prevalence of current suicidal ideation in epilepsy patients is thought to be as high as 10% [
      • Bosak M.
      • Turaj W.
      • Dudek D.
      • Siwek M.
      • Szczudlik A.
      Suicidality and its determinants among Polish patients with epilepsy.
      ]. A bidirectional relationship between suicidality and epilepsy was recently suggested, with an almost 3-fold increase of the risk of suicide attempts before the diagnosis of epilepsy was made, and a further almost 2-fold increased risk for recurrent suicide attempts after that diagnosis [
      • Hesdorffer D.C.
      • Ishihara L.
      • Webb D.J.
      • Mynepalli L.
      • Galwey N.W.
      • Hauser W.A.
      Occurrence and recurrence of attempted suicide among people with epilepsy.
      ].

      2.2 Depression comorbidity or suffering?

      Experts continue to complain that depression is an underdiagnosed and undertreated comorbidity in pediatric and adult patients with epilepsy [
      • Rodin E.A.
      • Shapiro M.A.
      • Lennox K.
      Epilepsy and life performance.
      ,
      • Fiest K.M.
      • Patten S.B.
      • Jetté N.
      Screening for depression and anxiety in epilepsy.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Nolan E.E.
      • Gadow K.D.
      • Vitale S.A.
      • Andriola M.R.
      • et al.
      Symptoms of depression and anxiety in pediatric epilepsy patients.
      ,
      • Kondziella D.
      • Asztely F.
      Don't be afraid to treat depression in patients with epilepsy.
      ,
      • Wiegartz P.
      • Seidenberg M.
      • Woodard A.
      • Gidal B.
      • Hermann B.
      Co-morbid psychiatric disorder in chronic epilepsy: recognition and etiology of depression.
      ,
      • Kanner A.M.
      Depression in neurological disorders: why should neurologists care?.
      ,
      • Fiest K.M.
      • Patten S.B.
      • Altura K.C.
      • Bulloch A.G.
      • Maxwell C.J.
      • Wiebe S.
      • et al.
      Patterns and frequency of the treatment of depression in persons with epilepsy.
      ]. But do neurologists really ignore the sustained impairment of emotional well-being in their patients? Does depression in epilepsy really represent a comorbidity (i.e., a mental disorder in addition to epilepsy) or should it rather be considered a natural and adequate reaction to living with epilepsy (i.e., not a comorbid “mental disorder”) [
      • Elger C.E.
      • Hoppe C.
      What is depression in epilepsy?.
      ,
      • Akdemir V.
      • Sut N.
      • Guldiken B.
      Factors affecting the quality of life in drug-resistant epilepsy patients.
      ]?
      Psychopathological manuals such as the ICD-10 describe abnormal psychological states irrespective of whether these psychological states appear reasonable or expected given the affected individual’s current life circumstances. For example, an acute stress reaction (F43.0) occurs in reaction to exceptional physical and/or mental stress, and would potentially entitle a patient to medical treatment. However, acute stress reactions represent the expected “normal” reaction in individuals experiencing acute trauma and, in this sense, the affected persons are not thought to suffer from a mental disorder. A similar logic could be applied in the case of depression. A depressive episode is certainly an abnormal psychological state potentially requiring medical intervention. However, according to current criteria, a patient’s circumstances have do not contribute to the diagnostic process. Nevertheless it is possible, that one reason why neurologists fail to diagnose depression in patients with epilepsy is that they believe that the depressive symptoms are an adequate response to the burden of living with epilepsy [
      • Gabb M.G.
      • Barry J.J.
      The link between mood disorders and epilepsy: why it is important to diagnose and treat.
      ]. However, the diagnosis of abnormal mood states, irrespective of life conditions, is the appropriate method to identify individuals who may require professional medical support [
      • Kanner A.M.
      Depression in neurological disorders: why should neurologists care?.
      ,
      • Fiest K.M.
      • Patten S.B.
      • Altura K.C.
      • Bulloch A.G.
      • Maxwell C.J.
      • Wiebe S.
      • et al.
      Patterns and frequency of the treatment of depression in persons with epilepsy.
      ].

      2.3 Case identification

      The National Institute for Health and Care Excellence (NICE) guidelines for depression in adults with a chronic health problem (CG91, 2009 [
      ]) provide a practical algorithm for case identification which can be applied in the context of epilepsy. All patients, who confirm that they have been feeling down, depressed or hopeless, or that they have little interest or pleasure in doing things for the last month, need to be assessed by a physician competent in mental health assessments. The more detailed assessment should include enquiries about feelings of worthlessness, poor concentration, thoughts of death, and psychosocial functioning. The detailed assessment must consider the influence of the underlying chronic condition and its treatment.
      Whilst the Structured Clinical Interview for DSM-IV Axis I Disorders is considered the psychiatric “gold standard” for diagnosis, several psychometric surveys and easy-to-use screening instruments with established high sensitivity and specificity are available for the reliable identification of patients at high risk of depression in epilepsy [
      • Fiest K.M.
      • Patten S.B.
      • Altura K.C.
      • Bulloch A.G.
      • Maxwell C.J.
      • Wiebe S.
      • et al.
      Patterns and frequency of the treatment of depression in persons with epilepsy.
      ,
      • Kanner A.M.
      • Strobel Parsons A.
      Screening instruments for depression in neurological disorders: their application in the clinic and in research.
      ,
      • Hoppe C.
      • Elger C.E.
      Depression in epilepsy: a critical review from a clinical perspective.
      ]. The latest development is the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), a 6-item patient self-report questionnaire for the reliable detection of major depression [
      • Gilliam F.G.
      • Barry J.J.
      • Hermann B.P.
      • Meador K.J.
      • Vahle V.
      • Kanner A.M.
      Rapid detection of major depression in epilepsy: a multicentre study.
      ,
      • Micoulaud-Franchi J.A.
      • Barkate G.
      • Trébuchon-Da Fonseca A.
      • Vaugier L.
      • Gavaret M.
      • Bartolomei F.
      • et al.
      One step closer to a global tool for rapid screening of major depression in epilepsy: validation of the French NDDI-E.
      ]. This questionnaire combines items from generic depression scales that should not be affected by common adverse effects of antiepileptic drugs or cognitive problems often seen in epilepsy. Researchers identified 46 items fitting such criteria, and discriminant analysis decreased the items to 6. Researchers found the NDDI-E to have good internal consistency reliability (0.85) and test–rest relability (0.78), and the questionnaire has been extensively validated [
      • Gilliam F.G.
      • Barry J.J.
      • Hermann B.P.
      • Meador K.J.
      • Vahle V.
      • Kanner A.M.
      Rapid detection of major depression in epilepsy: a multicentre study.
      ]. Furthermore, adverse effects of antiepileptic medication were not found to influence NDDI-E scores, unlike the Beck Depression Inventory [
      • Beck A.T.
      • Ward C.H.
      • Mendelson M.
      • Mock J.
      • Erbaugh J.
      An inventory for measuring depression.
      ] or the Centre for Epidemiological Studies depression [
      • Radloff L.S.
      The CES-D scale: a self report depression scale for research in the general population.
      ] questionnaires.
      The regular use of validated screening instruments is highly recommended for licensed neurologists and general practitioners, as well as neurological units and epilepsy centers. In fact, in view of the high prevalence of depression in epilepsy and its relevance to patients, there are no excuses not to screen for signs of sustained impairment of emotional well-being requiring professional support.

      2.4 Epidemiology and characteristics of depression in epilepsy

      The active prevalence of depressive disorders in epilepsy patients is thought to be 15–50%, depending on the methodological factors, such as study setting, socioeconomic conditions, selected measures, and definitions used; with a lifetime history of depressive disorders found in at least 30% of all patients [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ,
      • Hoppe C.
      • Elger C.E.
      Depression in epilepsy: a critical review from a clinical perspective.
      ]. Therefore the risk of depressive disorders (including dysthymia) is increased around twofold in epilepsy compared to the general population. However, similar prevalence rates are found for other neurological and somatic chronic diseases [
      • Hoppe C.
      • Elger C.E.
      Depression in epilepsy: a critical review from a clinical perspective.
      ,
      • Fu C.W.
      • Tan A.W.
      • Sheng F.
      • Luan R.S.
      • Zhan S.Y.
      • Chen W.Q.
      • et al.
      The prevalence of anxiety symptoms and depressive symptoms in patients with somatic disorders in urban China: a multicenter cross-sectional study.
      ,
      • Reijnders J.S.
      • Ehrt U.
      • Weber W.E.
      • Aarsland D.
      • Leentjens A.F.
      A systematic review of prevalence studies of depression in Parkinson’s disease.
      ,
      • McLaughlin D.P.
      • Pachana N.A.
      • McFarland K.
      Depression in a community-dwelling sample of older adults with late-onset or lifetime epilepsy.
      ]. Some studies report that criteria for current severe depressive episodes are fulfilled in 15–20% of epilepsy patients [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ,
      • Wiglusz M.S.
      • Landowski J.
      • Michalak L.
      • Cubała W.J.
      Reevaluating the prevalence and diagnostic subtypes of depressive disorders in epilepsy.
      ]. As compared to patients with idiopathic depression, the dysphoric mood appears to be generally pronounced in depressed epilepsy patients [
      • Mula M.
      The interictal dysphoric disorder of epilepsy: legend or reality.
      ,
      • Mori Y.
      • Kanemoto K.
      • Onuma T.
      • Tanaka M.
      • Oshima T.
      • Kato H.
      • et al.
      Anger is a distinctive feature of epilepsy patients with depression.
      ,
      • Amiri M.
      • Hansen C.P.
      The interictal dysphoric disorder in patients with epilepsy: a doubtful disorder lacking diagnostic tools.
      ], however adverse effects from anticonvulsants (e.g., levetiracetam) may contribute [
      • Mula M.
      • Agrawal N.
      • Mustafa Z.
      • Mohanalingham K.
      • Cock H.R.
      • Lozsadi D.A.
      • et al.
      Self-reported aggressiveness during treatment with levetiracetam correlates with depression.
      ]. Furthermore, increased anxiety is a frequent comorbidity of epilepsy [
      • Kwon O.Y.
      • Park S.P.
      Depression and anxiety in people with epilepsy.
      ,
      • Munger Clary H.M.
      Anxiety and epilepsy: what neurologists and epileptologists should know.
      ].
      Socioeconomic and psychosocial factors typically explain most of the variance in measures of mood [
      • Lacey C.J.
      • Salzberg M.R.
      • D'Souza W.J.
      Risk factors for depression in community-treated epilepsy: systematic review.
      ,
      • Lacey C.J.
      • Salzberg M.R.
      • D'Souza W.J.
      What factors contribute to the risk of depression in epilepsy? Tasmanian epilepsy register mood study (TERMS).
      ,
      • Kui C.
      • Yingfu P.
      • Chenling X.
      • Wenqing W.
      • Xiuhua L.
      • Di S.
      What are the predictors of major depression in adult patients with epilepsy.
      ], and evidence suggests that the full bio-psycho-social model of mood (disorder) in epilepsy explains significantly more variance than a more limited biological-biomedical model [
      • Elliott J.O.
      • Richardson V.E.
      The biopsychosocial model and quality of life in persons with active epilepsy.
      ]. Even the expected correlation between mood disorders (or other psychiatric comorbidity) and temporal/mesiotemporal lobe epilepsy has not been consistently evidenced [
      • Swinkels W.A.
      • van Emde Boas W.
      • Kuyk J.
      • van Dyck R.
      • Spinhoven P.
      Interictal depression, anxiety, personality traits, and psychological dissociation in patients with temporal lobe epilepsy (TLE) and extra-TLE.
      ,
      • Kondziella D.
      • Alvestad S.
      • Vaaler A.
      • Sonnewald U.
      Which clinical and experimental data link temporal lobe epilepsy with depression?.
      ]. However, complex and bidirectional interactions between depressive mood and neurocognitive impairment of executive functions and episodic memory have been demonstrated, indicating a mediating role of the mesiotemporal [
      • Helmstaedter C.
      • Sonntag-Dillender M.
      • Hoppe C.
      • Elger C.E.
      Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization.
      ] and frontal brain networks [
      • Dulay M.F.
      • Busch R.M.
      • Chapin J.S.
      • Jehi L.
      • Najm I.
      Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy.
      ], respectively.

      3. Treating depression in epilepsy

      National psychiatric guidelines suggest a stepped-care model for the management of diagnosed depression (e.g., [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ,
      ]). In epilepsy, the complex interaction between mood, seizures, drug treatment and the psychosocial burden related to epilepsy suggests that neurologists play a key role in the treatment of this disorder. Compliance with psychiatric treatment guidelines and epilepsy-specific treatment recommendations is advised [
      • Barry J.J.
      • Ettinger A.B.
      • Friel P.
      • Gilliam F.G.
      • Harden C.L.
      • Hermann B.
      • et al.
      Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders.
      ,
      • Kerr M.P.
      • Mensah S.
      • Besag F.
      • de Toffol B.
      • Ettinger A.
      • Kanemoto K.
      • et al.
      International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy.
      ]. Referral to a psychiatrist becomes mandatory in cases of severe (major) depression with psychotic symptoms, active suicidal intent and after the failure of two first-line treatments [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ,
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. Psychopharmacological drug polytherapy and off-label medications should only be prescribed by a psychiatrist.

      3.1 Optimizing epilepsy treatment

      3.1.1 Improving seizure control

      Arguably, the ideal treatment outcome for patients with epilepsy is to achieve complete and sustained seizure freedom through drug treatment or epilepsy surgery [
      • Yrondi A.
      • Arbus C.
      • Valton L.
      • Schmitt L.
      Mood disorders and epilepsy surgery: a review.
      ,
      • Karakis I.
      • Montouris G.D.
      • Piperidou C.
      • Luciano M.S.
      • Meador K.J.
      • Cole A.J.
      The effect of epilepsy surgery on caregiver quality of life.
      ,
      • Jette N.
      • Wiebe S.
      Update on the surgical treatment of epilepsy.
      ,
      • Filho G.M.
      • Mazetto L.
      • Gomes F.L.
      • Marinho M.M.
      • Tavares I.M.
      • Caboclo L.O.
      • et al.
      Pre-surgical predictors for psychiatric disorders following epilepsy surgery in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis.
      ]. While epilepsy surgery is certainly still underutilized, the relationship between depression and epilepsy surgery is complex [
      • Krahn L.E.
      • Rummans T.A.
      • Peterson G.C.
      Psychiatric implications of surgical treatment of epilepsy.
      ]. Filho et al. reported that 54% of patients experienced an improvement in depression following amygdalo-hippocampectomy [
      • Filho G.M.
      • Mazetto L.
      • Gomes F.L.
      • Marinho M.M.
      • Tavares I.M.
      • Caboclo L.O.
      • et al.
      Pre-surgical predictors for psychiatric disorders following epilepsy surgery in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis.
      ]; however, sustained improvements in mood largely depended on a good postsurgical seizure outcome (>5 years) [
      • Hamid H.
      • Liu H.
      • Cong X.
      • Devinsky O.
      • Berg A.T.
      • Vickrey B.G.
      • et al.
      Long-term association between seizure outcome and depression after resective epilepsy surgery.
      ]. Ramos-Perdigués et al. found epilepsy surgery patients experienced a significant decrease in psychiatric symptoms (n = 85) compared to control patients undergoing pharmacological treatment (n = 68) [
      • Ramos-Perdigués S.
      • Baillés E.
      • Mané A.
      • Carreño M.
      • Donaire A.
      • Rumia J.
      • et al.
      A prospective study contrasting the psychiatric outcome in drug-resistant epilepsy between patients who underwent surgery and a control group.
      ]. Acute major depression and a lifetime history of severe depression (and other mental disorders) appear to be presurgical predictors for surgical failure in terms of both seizure [
      • Metternich B.
      • Wagner K.
      • Brandt A.
      • Kraemer R.
      • Buschmann F.
      • Zentner J.
      • et al.
      Preoperative depressive symptoms predict postoperative seizure outcome in temporal and frontal lobe epilepsy.
      ,
      • de Araújo Filho G.M.
      • Gomes F.L.
      • Mazetto L.
      • Marinho M.M.
      • Tavares I.M.
      • Caboclo L.O.
      • et al.
      Major depressive disorder as a predictor of a worse seizure outcome one year after surgery in patients with temporal lobe epilepsy and mesial temporal sclerosis.
      ] and mood outcomes [
      • Filho G.M.
      • Mazetto L.
      • Gomes F.L.
      • Marinho M.M.
      • Tavares I.M.
      • Caboclo L.O.
      • et al.
      Pre-surgical predictors for psychiatric disorders following epilepsy surgery in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis.
      ]. A recent systematic review reported a prevalence of 30% for depression three months of surgery, with most cases experiencing a relapse of presurgical depression [
      • Yrondi A.
      • Arbus C.
      • Valton L.
      • Schmitt L.
      Mood disorders and epilepsy surgery: a review.
      ]. However, whilst previous reviews found no psychiatric deterioration after epilepsy surgery [
      • Macrodimitris S.
      • Sherman E.M.
      • Forde S.
      • Tellez-Zenteno J.F.
      • Metcalfe A.
      • Hernandez-Ronquillo L.
      • et al.
      Psychiatric outcomes of epilepsy surgery: a systematic review.
      ], more recent studies have reported cases of de novo depression postsurgery in seizure-free as well as non seizure-free patients [
      • Barbieri V.
      • Cardinale F.
      • Luoni A.
      • Russo G.L.
      • Francione S.
      • Tassi L.
      • et al.
      Risk factors for postoperative depression in 150 subjects treated for drug-resistant focal epilepsy.
      ,
      • Desai S.
      • Shukla G.
      • Goyal V.
      • Srivastava A.
      • Srivastava M.V.
      • Tripathi M.
      Changes in psychiatric comorbidity during early postsurgical period in patients operated for medically refractory epilepsy—a MINI-based follow-up study.
      ]. Individuals may find experiences in life after complete release from seizures demanding, especially in cases of personality disorders and family problems (“burden of normality”) [
      • Kemp S.
      • Garlovsky J.
      • Reynders H.
      • Caswell H.
      • Baker G.
      • Shah E.
      • et al.
      Predicting the psychosocial outcome of epilepsy surgery: a longitudinal perspective on the ‘burden of normality'.
      ,
      • Wilson S.J.
      • Wrench J.M.
      • McIntosh A.M.
      • Bladin P.F.
      • Berkovic S.F.
      Profiles of psychosocial outcome after epilepsy surgery: the role of personality.
      ]. Surgical failure is reportedly associated with increased risk of suicide [
      • Bell G.S.
      • Gaitatzis A.
      • Bell C.L.
      • Johnson A.L.
      • Sander J.W.
      Suicide in people with epilepsy: how great is the risk.
      ]. Therefore identifying risk factors for possible postsurgical maladjustment is a mandatory requirement of presurgical work-up.

      3.1.2 Improving tolerability of antiepileptic drug treatments

      Depression as an adverse drug effect (i.e., iatrogenic depression) has been consistently reported for phenobarbital [
      • Brent D.A.
      • Crumrine P.K.
      • Varma R.R.
      • Allan M.
      • Allman C.
      Phenobarbital treatment and major depressive disorder in children with epilepsy.
      ] and primidone [
      • Lopez-Gomez M.
      • Ramirez-Bermudez J.
      • Campillo C.
      • Sosa A.L.
      • Espinola M.
      • Ruiz I.
      Primidone is associated with interictal depression in patients with epilepsy.
      ]. Conversely, mood stabilizing and psychotropic effects have been shown for lamotrigine [
      • Ettinger A.B.
      • Kustra R.P.
      • Hammer A.E.
      Effect of lamotrigine on depressive symptoms in adult patients with epilepsy.
      ] and oxcarbazepine [
      • Mazza M.
      • Della Marca G.
      • Di Nicola M.
      • Martinotti G.
      • Pozzi G.
      • Janiri L.
      • et al.
      Oxcarbazepine improves mood in patients with epilepsy.
      ]. Furthermore pregabalin has been associated with a substantial risk of recreational misuse [
      • Schjerning O.
      • Rosenzweig M.
      • Pottegård A.
      • Damkier P.
      • Nielsen J.
      Abuse potential of pregabalin: a systematic review.
      ]. Mixed effects were reported for levetiracetam [
      • Helmstaedter C.
      • Fritz N.E.
      • Kockelmann E.
      • Kosanetzky N.
      • Elger C.E.
      Positive and negative psychotropic effects of levetiracetam.
      ] and topiramate [
      • Fritz N.
      • Glogau S.
      • Hoffmann J.
      • Rademacher M.
      • Elger C.E.
      • Helmstaedter C.
      Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy.
      ]. Potential affective side effects should be considered if anticonvulsant drug regimens are revised; additionally the potential effects of anticonvulsants on thyroid hormones should be accounted for [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus study).
      ]. It should be noted that anticonvulsants have a Food and Drug Administration (FDA) black box warning for an increased risk of suicidality; however there is much debate of this risk [
      • Mula M.
      • Sander J.W.
      Suicide risk in people with epilepsy taking antiepileptic drugs.
      ,
      • Fountoulakis K.N.
      • Gonda X.
      • Baghai T.C.
      • Baldwin D.S.
      • Bauer M.
      • Blier P.
      • et al.
      Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy.
      ]. Generally, careful monitoring of side effects, especially of mood during uptitration of a new drug, appears crucial for prevention of depression and suicidality. Reducing the dosage or even withdrawal of the drug may become necessary.

      3.1.3 Balancing improved seizure control and drug tolerability

      In patients with active epilepsy, seizure frequency only tends to have a weak association with measures of mood and QoL [
      • Lacey C.J.
      • Salzberg M.R.
      • D'Souza W.J.
      Risk factors for depression in community-treated epilepsy: systematic review.
      ,
      • Lacey C.J.
      • Salzberg M.R.
      • D'Souza W.J.
      What factors contribute to the risk of depression in epilepsy? Tasmanian epilepsy register mood study (TERMS).
      ,
      • Kui C.
      • Yingfu P.
      • Chenling X.
      • Wenqing W.
      • Xiuhua L.
      • Di S.
      What are the predictors of major depression in adult patients with epilepsy.
      ,
      • Elliott J.O.
      • Richardson V.E.
      The biopsychosocial model and quality of life in persons with active epilepsy.
      ,
      • Boylan L.S.
      • Flint L.A.
      • Labovitz D.L.
      • Jackson S.C.
      • Starner K.
      • Devinsky O.
      Depression but not seizure frequency predicts quality of life in treament-resistant epilepsy.
      ,
      • Thapar A.
      • Roland M.
      • Harold G.
      Do depression symptoms predict seizure frequency—or vice versa?.
      ]; however correlations between seizure frequency and risk of experiencing a major depressive episode have been demonstrated [
      • Zis P.
      • Yfanti P.
      • Siatouni A.
      • Tavernarakis A.
      • Gatzonis S.
      Determinants of depression among patients with epilepsy in Athens, Greece.
      ]. Therefore the reduction of seizure frequency through intensified anticonvulsant polytherapy does not necessarily improve well-being (but may yield other benefits, such as a reduced risk of ictal injury). Nonetheless, determined drug treatment may increase subjectively experienced adverse events, with a demonstrable negative impact on cognitive performance, mood and overall QoL [
      • Gilliam F.
      Optimizing health outcomes in active epilepsy.
      ]. Reducing the total drug load (if responsible) could potentially improve memory, however, the effects on QoL are uncertain [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus study).
      ,
      • Gilliam F.G.
      • Fessler A.J.
      • Baker G.
      • Vahle V.
      • Carter J.
      • Attarian H.
      Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial.
      ]. As regards QoL, the Standard and New Antiepileptic Drugs (SANAD) trial found no superiority for newer anticonvulsants (lamotrigine, gabapentin, oxcarbazepine and topiramate) as compared to classic drugs (carbamazepine, valproate) at 2-years follow-up [
      • Jacoby A.
      • Sudell M.
      • Tudur Smith C.
      • Crossley J.
      • Marson A.G.
      • Baker G.A.
      • et al.
      Quality-of-life outcomes of initiating treatment with standard and newer antiepileptic drugs in adults with new-onset epilepsy: findings from the SANAD trial.
      ].

      3.2 Psychotherapy

      Traditionally, the management of depression in neurological disorders and epilepsy has involved drug treatments (e.g., [
      • Mula M.
      Basic principles in the management of depression in neurologic disorders.
      ,
      • Garcia C.S.
      Depression in temporal lobe epilepsy: a review of prevalence, clinical features, and management considerations.
      ]) in line with previous healthcare advise [
      • Ramaratnam S.
      • Baker G.A.
      • Goldstein L.H.
      Psychological treatments for epilepsy.
      ]. However, efficacy studies have recently provided evidence that psychotherapy should be considered the first-line therapy for eligible patients [
      • Mehndiratta P.
      • Sajatovic M.
      Treatments for patients with comorbid epilepsy and depression: a systematic literature review.
      ,
      • Kanner A.M.
      The treatment of depressive disorders in epilepsy: what all neurologists should know.
      ,
      • Fernie B.A.
      • Kollmann J.
      • Brown R.G.
      Cognitive behavioural interventions for depression in chronic neurological conditions: a systematic review.
      ]. Ten controlled studies (some randomized) have indicated that psychotherapy – particularly Cognitive-Behavioral Therapy (CBT) and mindfulness-based CBT such as Acceptance and Commitment Therapy (ACT) – are associated with significant improvements on outcome measures of depression and significant increases in QoL [
      • Au A.
      • Chan F.
      • Li K.
      • Leung P.
      • Li P.
      • Chan J.
      Cognitive-behavioral group treatment program for adults with epilepsy in Hong Kong.
      ,
      • Ciechanowski P.
      • Chaytor N.
      • Miller J.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      PEARLS depression treatment for individuals with epilepsy: a randomized controlled trial.
      ,
      • Chaytor N.
      • Ciechanowski P.
      • Miller J.W.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      Long-term outcomes from the PEARLS randomized trial for the treatment of depression in patients with epilepsy.
      ,
      • Davis G.R.
      • Armstrong Jr., H.E.
      • Donovan D.M.
      • Temkin N.R.
      Cognitive-behavioral treatment of depressed affect among epileptics: preliminary findings.
      ,
      • Gillham R.A.
      Refractory epilepsy: an evaluation of psychological methods in outpatient management.
      ,
      • Lundgren T.
      • Dahl J.
      • Melin L.
      • Kies B.
      Evaluation of acceptance and commitment therapy for drug refractory epilepsy: a randomized controlled trial in South Africa—a pilot study.
      ,
      • Lundgren T.
      • Dahl J.
      • Yardi N.
      • Melin L.
      Acceptance and commitment therapy and yoga for drug-refractory epilepsy: a randomized controlled trial.
      ,
      • Schröder J.
      • Brückner K.
      • Fischer A.
      • Lindenau M.
      • Köther U.
      • Vettorazzi E.
      • et al.
      Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial.
      ,
      • Tang V.
      • Poon W.S.
      • Kwan P.
      Mindfulness-based therapy for drug-resistant epilepsy: an assessor-blinded randomized trial.
      ,
      • Thompson N.J.
      • Walker E.R.
      • Obolensky N.
      • Winning A.
      • Barmon C.
      • DiIorio C.
      • et al.
      Distance delivery of mindfulness-based cognitive therapy for depression: project UPLIFT.
      ]; whereas three randomized controlled trials found no evidence for (sustained) effects [
      • Fraser R.T.
      • Johnson E.K.
      • Lashley S.
      • Barber J.
      • Chaytor N.
      • Miller J.W.
      • et al.
      PACES in epilepsy: results of a self-management randomized controlled trial.
      ,
      • McLaughlin D.P.
      • McFarland K.
      A randomized trial of a group based cognitive behavior therapy program for older adults with epilepsy: the impact on seizure frequency, depression and psychosocial well-being.
      ,
      • Tan S.Y.
      • Bruni J.
      Cognitive-behavior therapy with adult patients with epilepsy: a controlled outcome study.
      ] (Table 1). Evidence suggests that CBT-based interventions can aid the prevention of major depressive episodes and suicidality in patients with epilepsy [
      • Thompson N.J.
      • Patel A.H.
      • Selwa L.M.
      • Stoll S.C.
      • Begley C.E.
      • Johnson E.K.
      • et al.
      Expanding the efficacy of project UPLIFT: distance delivery of mindfulness-based depression prevention to people with epilepsy.
      ,
      • Martinović Z.
      • Simonović P.
      • Djokić R.
      Preventing depression in adolescents with epilepsy.
      ]. Single studies reported improved seizure control [
      • Tang V.
      • Michaelis R.
      • Kwan P.
      Psychobehavioral therapy for epilepsy.
      ]. Neurophysiological and neuroimaging data have provided insights into the mechanisms how psychotherapy may be effective for depression in epilepsy [
      • Charyton C.
      • Elliott J.O.
      • Moore J.L.
      • Klatte E.T.
      Is it time to consider cognitive behavioral therapy for persons with epilepsy? Clues from pathophysiology, treatment and functional neuroimaging.
      ]. A recent uncontrolled prospective study indicated the cost-effectiveness and efficacy of an ACT program for depression, anxiety, QoL, self-esteem, and work and social adjustment; these associations had medium to large positive effects which were sustained at the 6 month follow-up [
      • Dewhurst E.
      • Novakova B.
      • Reuber M.
      A prospective service evaluation of acceptance and commitment therapy for patients with refractory epilepsy.
      ]. However, the evidence in favor of psychotherapy still remains limited by methodological factors such as small sample-sizes, short follow-up intervals, and lack of blinding, among others; publication bias toward positive studies similarly seems probable [
      • Flint J.
      • Cuijpers P.
      • Horder J.
      • Koole S.L.
      • Munafò M.R.
      Is there an excess of significant findings in published studies of psychotherapy for depression.
      ]. Therefore, whilst current evidence suggests that psychotherapy should be considered in patients with drug-resistant epilepsy, further high-quality research is needed before findings can be generalized [
      • Gandy M.
      • Sharpe L.
      • Perry K.N.
      Cognitive behavior therapy for depression in people with epilepsy: a systematic review.
      ].
      Table 1Randomized or matched clinical trials on psychotherapy for comorbid depression in epilepsy (modified and completed from [Mehndiratta & Sajatovic]).
      AuthorsInterventionInclusion criteriaSamplesPsychometric measuresOutcome
      Au et al.
      • Au A.
      • Chan F.
      • Li K.
      • Leung P.
      • Li P.
      • Chan J.
      Cognitive-behavioral group treatment program for adults with epilepsy in Hong Kong.
      CBT vs. controls (matched assignment)Exclusion: active serious medical disorder, psychotic features, severe mental deficiency, history of neurosurgeryTotal N = 17QOLIE-31, ESESCBT: improvement of QoL and self-efficacy 3 months after last therapy session
      • CBT (n = 8) mean age 38.3 ± 7.0 yrs.
      • Controls (n = 9) mean age 41.4 ± 7.7 yrs.
      Ciechanowski et al.
      • Ciechanowski P.
      • Chaytor N.
      • Miller J.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      PEARLS depression treatment for individuals with epilepsy: a randomized controlled trial.
      , long-term evaluation: Chaytor et al.
      • Chaytor N.
      • Ciechanowski P.
      • Miller J.W.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      Long-term outcomes from the PEARLS randomized trial for the treatment of depression in patients with epilepsy.
      PEARLS vs. usual care (waitlist)Age >18, English speaking, ICD-9 diagnosis of epilepsy, attended epilepsy clinic within past 2 yrs., PHQ9 >10Total N = 80CSI, HSCL-20, QOLIE-31PEARLS yielded more improvement of depression over 12 months
      • Ciechanowski P.
      • Chaytor N.
      • Miller J.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      PEARLS depression treatment for individuals with epilepsy: a randomized controlled trial.
      and 18 months
      • Chaytor N.
      • Ciechanowski P.
      • Miller J.W.
      • Fraser R.
      • Russo J.
      • Unutzer J.
      • et al.
      Long-term outcomes from the PEARLS randomized trial for the treatment of depression in patients with epilepsy.
      • PEARLS arm (n = 40), mean age 44.4 ± 11.1 yrs.
      • Usual care arm (n = 40), mean age 43.4 ± 11.0 yrs.
      Davis et al.
      • Davis G.R.
      • Armstrong Jr., H.E.
      • Donovan D.M.
      • Temkin N.R.
      Cognitive-behavioral treatment of depressed affect among epileptics: preliminary findings.
      CBT vs. waitlistAdult patients with epilepsy and signs of depression self-reffering to a educational class for improved coping with depressionTotal N = 13DACL, GCS, BDI, CAQMood improvement only in CBT (sign. group effects only for DACL, GCS) and drop of rate of depressed pts. only in CBT (from 75%/88% to 50% for BDI and GCI, resp.) 6 weeks after treatment
      • CBT (n = 8) mean age 33.5 yrs.
      • Waitlist (n = 5) mean age 32.4 yrs.
      Gillham
      • Gillham R.A.
      Refractory epilepsy: an evaluation of psychological methods in outpatient management.
      2 types of psychological intervention (cross-over control group design) vs. control groupPoorly controlled epilepsy, psychological disorder (rating scales)—control group: no psychological disorderTotal N = 40Self-rating measures of anxiety and depressionBoth groups with baseline disorders had improved anxiety and depression after 42 weeks
      • Type 1 (n = 19)
      • Type 2 (n = 21)
      Lundgren et al.
      • Lundgren T.
      • Dahl J.
      • Melin L.
      • Kies B.
      Evaluation of acceptance and commitment therapy for drug refractory epilepsy: a randomized controlled trial in South Africa—a pilot study.
      ACT vs. ST (control)Pats. with very low incomes (government disability grant), minum of 4 seizures (past 3 months), EEG-verified epilepsy, no progressive diseaseTotal N = 27SWLS, WHOQOL-BREF, seizure indexACT-specific improvements I all dependent measures after treatment, at 6- and 12-months follow-up; dramatic improvement of seizure index
      • ACT (n = 14) mean age 38.9 yrs.
      • ST (n = 13) mean age 42.5 yrs.
      Lundgren et al.
      • Lundgren T.
      • Dahl J.
      • Yardi N.
      • Melin L.
      Acceptance and commitment therapy and yoga for drug-refractory epilepsy: a randomized controlled trial.
      ACT vs. YogaMinimum of 3 seizures (past 3 months), EEG-verified epilepsy, no progressive diseaseTotal N = 18SWLS, WHOQOL-BREF, seizure indexBoth groups showed improved QoL but ACT > yoga, ACT: improved seizure index
      • ACT (n = 10) mean age 21.9 yrs.
      • Yoga (n = 8) mean age 25.8 yrs.
      Schröder et al.
      • Schröder J.
      • Brückner K.
      • Fischer A.
      • Lindenau M.
      • Köther U.
      • Vettorazzi E.
      • et al.
      Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial.
      Deprexis
      Distance delivery via internet/phone—Abbreviations: BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory (version 2); BRFSS, Behavioral Risk Factor Surveillance System; CAQ, Community Adjustment Questionnaire; CBT, Cognitive behavioral therapy; CDC, Centers for Disease Control and Prevention; CES-D, Center for Epidemiological Studies Depression Scale; CIDI, Composite International Diagnostic Interview; CSI, Cornell Services Index; Deprexis, psychological online intervention for depression; DACL, Depression Adjective Checklist, Form E; DSCES, Depression Coping Self-Efficacy Scale.; ESES, Epilepsy Self Efficacy Scale; ESMS, Epilepsy Self-Management Scale; GAD-7, Generalized Anxiety Disorder 7-item scale; GCS, Hudson Generalized Contentment Scale; GDS, Geriatric Depression Scale; HSCL-20, Hopkins SymptomChecklist-20; MBCT, Mindfulness-based cognitive therapy; MBT, mindfulness-based therapy; MMPI, Minnesota Multiphasic Personality Inventory; MMSE, MiniMental Status examination; MoCA, Montreal Cognitive Assessment; PACES, Program for Active Consumer Engagement in Self-Management; PEARLS, Program to Encourage Active, Rewarding Lives for Seniors (age >60 yrs.); PESOS, Performance, Sociodemographic aspects, Subjective estimation (questionnaire for people with epilepsy); PHQ-9, PatientHealth Questionnaire-9; QOLIE-31, Quality of Life in Epilepsy Inventory (31 items version); QOLIE-31, patient-weighted Quality of Life in Epilepsy Inventory (31 items version); RCT, randomized controlled trial; SCS, Self-Compassion Scale; seizure index, defined by (seizure frequency x duration); SS, social support condition; ST, supportive therapy; SWLS, Satisfaction with Life Scale; UPLIFT, Using Practice (mindfulness) and Learning to Increase Favorable Thoughts (CBT) (i.e., internet/phone based minfulness based CBT); WHOQOL-BREF, World Health Organization Quality of Life instrument, short version; WPSI, Washington Psychosocial Seizure Inventory.
      vs. waitlist control
      Low-threshold inclusion; exclusion if: no self-reported epilepsy, no self-reported depressive symptoms, self-reported psychosis, bipolar disorder, suicidality (emergeny phone number displayed), lack of time for program completionTotal N = 78BDI, QOLIE-31, PESOS, WHOQOL-BREFDeprexis improved mood (BDI) and energy/fatigue (from QOLIE-31) after program completion (9 weeks) but not overall QoL
      • Depresis (n = 38) mean age 40.0 ± 11.9 yrs.
      • Waitlist control (n = 40) mean age 35.0 ± 10.0 yrs.
      Tang et al.
      • Tang V.
      • Poon W.S.
      • Kwan P.
      Mindfulness-based therapy for drug-resistant epilepsy: an assessor-blinded randomized trial.
      MBT + SS vs. SS onlyAdult age, therapy-refractory epilepsyTotal N = 60QOLIE-31-P, BDI-II, BAI, neuropsychological assessmentImproved mood, anxiety, QoL, memory, seizure frequency/severity with better effects in MBT + SS vs. SS only 6 weeks after the last session
      • MBT + SS (n = 30) mean age 34.8 ± 10.3 yrs.
      • SS only (n = 30) mean age 35.5 ± 11.2 yrs.
      Thompson et al.
      • Thompson N.J.
      • Walker E.R.
      • Obolensky N.
      • Winning A.
      • Barmon C.
      • DiIorio C.
      • et al.
      Distance delivery of mindfulness-based cognitive therapy for depression: project UPLIFT.
      (CDC)
      UPLIFT
      Distance delivery via internet/phone—Abbreviations: BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory (version 2); BRFSS, Behavioral Risk Factor Surveillance System; CAQ, Community Adjustment Questionnaire; CBT, Cognitive behavioral therapy; CDC, Centers for Disease Control and Prevention; CES-D, Center for Epidemiological Studies Depression Scale; CIDI, Composite International Diagnostic Interview; CSI, Cornell Services Index; Deprexis, psychological online intervention for depression; DACL, Depression Adjective Checklist, Form E; DSCES, Depression Coping Self-Efficacy Scale.; ESES, Epilepsy Self Efficacy Scale; ESMS, Epilepsy Self-Management Scale; GAD-7, Generalized Anxiety Disorder 7-item scale; GCS, Hudson Generalized Contentment Scale; GDS, Geriatric Depression Scale; HSCL-20, Hopkins SymptomChecklist-20; MBCT, Mindfulness-based cognitive therapy; MBT, mindfulness-based therapy; MMPI, Minnesota Multiphasic Personality Inventory; MMSE, MiniMental Status examination; MoCA, Montreal Cognitive Assessment; PACES, Program for Active Consumer Engagement in Self-Management; PEARLS, Program to Encourage Active, Rewarding Lives for Seniors (age >60 yrs.); PESOS, Performance, Sociodemographic aspects, Subjective estimation (questionnaire for people with epilepsy); PHQ-9, PatientHealth Questionnaire-9; QOLIE-31, Quality of Life in Epilepsy Inventory (31 items version); QOLIE-31, patient-weighted Quality of Life in Epilepsy Inventory (31 items version); RCT, randomized controlled trial; SCS, Self-Compassion Scale; seizure index, defined by (seizure frequency x duration); SS, social support condition; ST, supportive therapy; SWLS, Satisfaction with Life Scale; UPLIFT, Using Practice (mindfulness) and Learning to Increase Favorable Thoughts (CBT) (i.e., internet/phone based minfulness based CBT); WHOQOL-BREF, World Health Organization Quality of Life instrument, short version; WPSI, Washington Psychosocial Seizure Inventory.
      vs. usual care (waitlist)
      Age >21, English speaking, MMSE >20, CES-D >13 and <38, diagnosis of epilepsy for 1 yearTotal N = 53.BDI, BRFSS, DSCES, PHQ-9, SCS, SWLSUPLIFT improved mood, knowledge and skills post-treatment and 8 weeks beyond
      • MCBT arm (n = 26) median age 34.0 yrs.
      • Usual care arm (n = 27), median age 31.0 yrs.
      Fraser et al.
      • Fraser R.T.
      • Johnson E.K.
      • Lashley S.
      • Barber J.
      • Chaytor N.
      • Miller J.W.
      • et al.
      PACES in epilepsy: results of a self-management randomized controlled trial.
      PACES vs. no treatment (control)Adult, established epilepsy (at least for 6 months), cognitively intact (MoCA >21); exclusion: severe mental illness/psychosis, IQ < 70Total N = 83PHQ-9, GAD-7, ESMS, ESES, QOLIE-31Treatment-specific positive effects on nearly all measures after treatment (8 weeks), but mostly not sustained at the 6-months follow-up (except of improved self-management)
      • PACES (n = 41) mean age 44.9 ± 12.5
      • Control (n = 42) mean age 45.4 ± 12.6
      McLaughlin et al.
      • McLaughlin D.P.
      • McFarland K.
      A randomized trial of a group based cognitive behavior therapy program for older adults with epilepsy: the impact on seizure frequency, depression and psychosocial well-being.
      CBT vs. usual care (waitlist)Age >60 years, MMSE > 24, English speakingTotal N = 37GDS, CIDI, WPSIMood improvement in both groups with no superiority for treatment (CBT) at 3-months follow-up, but better seizure improvement in CBT
      • CBT arm (n = 18), age mean age 67.6 ± 7.27 yrs.
      • Usual care arm (n = 19), mean age 67.37 ± 7.46 yrs.
      Tan and Bruni
      • Tan S.Y.
      • Bruni J.
      Cognitive-behavior therapy with adult patients with epilepsy: a controlled outcome study.
      CBT vs. supportive counseling vs. waitlistAdult patients with epilepsyTotal N = 27MMPI, WPSI, BDI, ratings (patient, neurologist, therapist) of global psychological adjustment, target complaints seizure controlno/little evidence for effects of psychological treatments, except of better outcome in therapist's global ratings of psychological adjustment for both treatment groups
      • CBT (n = 9)
      • Supportive counseling (n = 9)
      • Waitlist (n = 9)
      a Distance delivery via internet/phone—Abbreviations: BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory (version 2); BRFSS, Behavioral Risk Factor Surveillance System; CAQ, Community Adjustment Questionnaire; CBT, Cognitive behavioral therapy; CDC, Centers for Disease Control and Prevention; CES-D, Center for Epidemiological Studies Depression Scale; CIDI, Composite International Diagnostic Interview; CSI, Cornell Services Index; Deprexis, psychological online intervention for depression; DACL, Depression Adjective Checklist, Form E; DSCES, Depression Coping Self-Efficacy Scale.; ESES, Epilepsy Self Efficacy Scale; ESMS, Epilepsy Self-Management Scale; GAD-7, Generalized Anxiety Disorder 7-item scale; GCS, Hudson Generalized Contentment Scale; GDS, Geriatric Depression Scale; HSCL-20, Hopkins SymptomChecklist-20; MBCT, Mindfulness-based cognitive therapy; MBT, mindfulness-based therapy; MMPI, Minnesota Multiphasic Personality Inventory; MMSE, MiniMental Status examination; MoCA, Montreal Cognitive Assessment; PACES, Program for Active Consumer Engagement in Self-Management; PEARLS, Program to Encourage Active, Rewarding Lives for Seniors (age >60 yrs.); PESOS, Performance, Sociodemographic aspects, Subjective estimation (questionnaire for people with epilepsy); PHQ-9, PatientHealth Questionnaire-9; QOLIE-31, Quality of Life in Epilepsy Inventory (31 items version); QOLIE-31, patient-weighted Quality of Life in Epilepsy Inventory (31 items version); RCT, randomized controlled trial; SCS, Self-Compassion Scale; seizure index, defined by (seizure frequency x duration); SS, social support condition; ST, supportive therapy; SWLS, Satisfaction with Life Scale; UPLIFT, Using Practice (mindfulness) and Learning to Increase Favorable Thoughts (CBT) (i.e., internet/phone based minfulness based CBT); WHOQOL-BREF, World Health Organization Quality of Life instrument, short version; WPSI, Washington Psychosocial Seizure Inventory.
      Realistically, the availability of psychotherapy is limited by its nature, and the requirement of patients’ dedication to a therapy which can be quite demanding (e.g., weekly visits). In the future, evidence-based programs for distance delivery of psychotherapy via the internet, known as Teletherapy, improve accessibility [
      • Schröder J.
      • Brückner K.
      • Fischer A.
      • Lindenau M.
      • Köther U.
      • Vettorazzi E.
      • et al.
      Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial.
      ,
      • Thompson N.J.
      • Walker E.R.
      • Obolensky N.
      • Winning A.
      • Barmon C.
      • DiIorio C.
      • et al.
      Distance delivery of mindfulness-based cognitive therapy for depression: project UPLIFT.
      ]. Furthermore, evidence suggests that physical exercise for depression holds similar efficacy as psychotherapy, particularly as a complementary therapy to more traditional treatment [
      • Cooney G.M.
      • Dwan K.
      • Greig C.A.
      • Lawlor D.A.
      • Rimer J.
      • Waugh F.R.
      • et al.
      Exercise for depression.
      ,
      • Arida R.M.
      • de Almeida A.C.
      • Cavalheiro E.A.
      • Scorza F.A.
      Experimental and clinical findings from physical exercise as complementary therapy for epilepsy.
      ].

      3.3 Antidepressant drugs

      3.3.1 Efficacy

      Three randomized controlled trials on antidepressant drugs for depression in epilepsy have been published to date [
      • Maguire M.J.
      • Weston J.
      • Singh J.
      • Marson A.G.
      Antidepressants for people with epilepsy and depression.
      ]. The first trial (N = 42 patients), performed in 1985 [
      • Robertson M.M.
      • Trimble M.R.
      The treatment of depression in patients with epilepsy. A double-blind trial.
      ], compared amitriptyline (a tricyclic antidepressant) versus nomifensine (a dopamine reuptake inhibitor) versus placebo, and found similar efficacy of both antidepressants at the 6-week follow-up; however Hamilton Depression Rating Scale scores improved more with nomifensine at the 12-months follow-up. Two further randomized controlled trials compared paroxetine (a selective serotonine reuptake inhibitor [SSRI]) versus doxepin (a tricyclic antidepressant [TCA]) [
      • Li W.
      • Ma D.
      A randomized controlled trial to evaluate the efficacy of paroxetine and doxepin in treating epileptic patients with depression.
      ], and venlafaxine (a selective serotonine noradrenaline reuptake inhibitor [SNRI]) versus placebo [
      • Zhu S.
      • Luo L.
      • Gui Y.
      • et al.
      Short-term efficacy of venlafaxine treating the depression in epilepsy patients.
      ]. The first study in 2005 (N = 67 patients) found no significant difference between the two drugs under examination, whilst the latter study in 2004 (N = 64 patients) reported a more than 3-fold increase of the likelihood for response (>50% reduction of depressive symptoms) for venlafaxine as compared to placebo. Referring to these studies, a recent Cochrane review concluded “… that there is very limited evidence demonstrating a significant effect of antidepressants on depressive symptoms in epilepsy” ([
      • Maguire M.J.
      • Weston J.
      • Singh J.
      • Marson A.G.
      Antidepressants for people with epilepsy and depression.
      ).
      More generally, recent psychiatric research found no to small effects of antidepressants in mild to moderate idiopathic depression [
      • Turner E.H.
      • Matthews A.M.
      • Linardatos E.
      • Tell R.A.
      • Rosenthal R.
      Selective publication of antidepressant trials and its influence on apparent efficacy.
      ,
      • Kirsch I.
      • Deacon B.J.
      • Huedo-Medina T.B.
      • Scoboria A.
      • Moore T.J.
      • Johnson B.T.
      Initial severity and antidepressant benefits: a meta-analysis of data submitted to the food and drug administration.
      ], especially in children and youths [
      • Cipriani A.
      • Zhou X.
      • Del Giovane C.
      • Hetrick S.E.
      • Qin B.
      • Whittington C.
      • et al.
      Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.
      ]. However, moderate therapeutic effects in severe depression were demonstrated, suggesting a need to reconsider the former distinction between minor (psychoreactive) and major (endogenous) depression [
      • Malki K.
      • Keers R.
      • Tosto M.G.
      • Lourdusamy A.
      • Carboni L.
      • Domenici E.
      • et al.
      The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.
      ]. Of note, CBT as compared to antidepressive drug therapy alone has shown superiority with regard to prevention of relapse/recurrence of depressive episodes in idiopathic depression [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ,
      • Clarke K.
      • Mayo-Wilson E.
      • Kenny J.
      • Pilling S.
      Can non-pharmacological interventions prevent relapse in adults who have recovered from depression? A systematic review and meta-analysis of randomised controlled trials.
      ]. While several national psychiatric guidelines have adopted such findings and now emphasize the balance of psychotherapy and drug treatment for mild to moderate depression [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ], expert recommendations for the treatment of depression in epilepsy have not been revised accordingly as yet [
      • Barry J.J.
      • Ettinger A.B.
      • Friel P.
      • Gilliam F.G.
      • Harden C.L.
      • Hermann B.
      • et al.
      Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders.
      ,
      • Kerr M.P.
      • Mensah S.
      • Besag F.
      • de Toffol B.
      • Ettinger A.
      • Kanemoto K.
      • et al.
      International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy.
      ].

      3.3.2 Tolerability

      Unwanted side effects (including suicidality) of modern antidepressants are typically underestimated, potentially as a consequence of biased scientific reporting [
      • Coupland C.A.
      • Dhiman P.
      • Barton G.
      • Morriss R.
      • Arthur A.
      • Sach T.
      • Hippisley-Cox J.
      A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database.
      ,
      • Hetrick S.E.
      • McKenzie J.E.
      • Cox G.R.
      • Simmons M.B.
      • Merry S.N.
      Newer generation antidepressants for depressive disorders in children and adolescents.
      ,
      • Sharma T.
      • Guski L.S.
      • Freund N.
      • Gøtzsche P.C.
      Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports.
      ]. In epilepsy, possible seizure inducing effects of antidepressants are the most critical. For example, TCAs have been associated with an increased risk of seizure occurrences in psychiatric populations [
      • Mula M.
      The pharmacological management of psychiatric comorbidities in patients with epilepsy.
      ]. A large register-based longitudinal cohort study (N = 238,963 patients) found increased hazard ratios for new-onset epilepsy during a 5-year period in treated versus non-treated psychiatric patients with idiopathic depression for all antidepressant drug classes [
      • Hill T.
      • Coupland C.
      • Morriss R.
      • Arthur A.
      • Moore M.
      • Hippisley-Cox J.
      Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: cohort study using a primary care database.
      ]. However, if epilepsy is already present, fear of seizure aggravation as a side effect of modern antidepressive drug therapy (i.e., SSRI, SNRI) seems unwarranted [
      • Kondziella D.
      • Asztely F.
      Don't be afraid to treat depression in patients with epilepsy.
      ,
      • Kanner A.M.
      Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: a review of the evidence.
      ,
      • Habibi M.
      • Hart F.
      • Bainbridge J.
      The impact of psychoactive drugs on seizures and antiepileptic drugs.
      ,
      • Johannessen Landmark C.
      • Henning O.
      • Johannessen S.I.
      Proconvulsant effects of antidepressants—what is the current evidence.
      ]. Rather, antidepressant drugs appear to exert an anticonvulsant effect when used at therapeutic dosages in patients with depression (possibly via serotoninergic pathways) [
      • Hamid H.
      • Kanner A.M.
      Should antidepressant drugs of the selective serotonin reuptake inhibitor family be tested as antiepileptic drugs?.
      ].

      3.3.3 Interactions of antidepressant and antiepileptic drugs

      Critical pharmacokinetic interactions, usually in terms of plasma level reductions, have been reported in both directions for enzyme-inducing anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital) and antidepressants including modern SSRIs (e.g., bupropion/carbamazepine, fluoxetine/phenytoin, sertraline/lamotrigine) [
      • Mula M.
      The pharmacological management of psychiatric comorbidities in patients with epilepsy.
      ,
      • Spina E.
      • Perucca E.
      Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs.
      ]. In idiopathic depression, topiramate and pregabalin showed a potential to augment the therapeutic efficacy of antidepressant drugs (e.g., SSRI/topiramate [
      • Mowla A.
      • Kardeh E.
      Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial.
      ]).

      3.3.4 Clinical recommendations

      Consistent with general recommendations, and if no other contraindication exists (e.g., pharmacokinetic interaction, effects on reproductive or bone health), SSRIs (e.g., citalopram, sertraline, fluoxetine) and SNRIs (e.g., venlafaxin, duloxetin) represent the first-line agents for pharmacological treatment [
      • Mula M.
      The pharmacological management of psychiatric comorbidities in patients with epilepsy.
      ,
      • Noe K.H.
      • Locke D.E.
      • Sirven J.I.
      Treatment of depression in patients with epilepsy.
      ,
      • Borgmann M.
      • Holtkamp M.
      • Adli M.
      • Behr J.
      Depression und Epilepsie. Zwei Krankheitsbilder mit gemeinsamen Ursachen? [Depression and epilepsy. Two clinical pictures with common causes?].
      ]. In contrast, tricyclic or tetracyclic antidepressants and norepinephrine-dopamine reuptake inhibitors (NDRI) should be avoided in the first instance [
      • Noe K.H.
      • Locke D.E.
      • Sirven J.I.
      Treatment of depression in patients with epilepsy.
      ]. Noradrenergic and specific serotonergic antidepressants (NaSSAs) are associated with the class of tetracyclic antidepressants, yet appear safe in epilepsy as well [
      • Borgmann M.
      • Holtkamp M.
      • Adli M.
      • Behr J.
      Depression und Epilepsie. Zwei Krankheitsbilder mit gemeinsamen Ursachen? [Depression and epilepsy. Two clinical pictures with common causes?].
      ].
      Of note, psychiatric guidelines stipulate close monitoring of patients receiving antidepressant drug therapy, particularly during titration or withdrawal [

      Leitliniengruppe Unipolare Depression* (Eds.). S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression—Langfassung (2nd edition, version 3) [German Guidelines Unipolar Depression]; 2015. Websource: www.depression.versorgungsleitlinien.de; [cited 27 August 2016]; DOI: 10.6101/AZQ/000277 (*cooperating organizations: DGPPN, BÄK, KBV, AWMF, ACKPA, AkdÄ, BPtK, BApK, DAGSHG, DEGAM, DGPM, DGPs, DGRW, BDK, BDP, BPM, BVDN, BVDP, BVVP, CPKA, DÄVT, DFT, DGGPP, DGPT, DGVT, DPG, DPV, DPtV, DVT, GwG, Stiftung Deutsche Depressionshilfe).

      ]. Furthermore, the FDA has issued a warning for an increased risk of suicidality due to antidepressant use [
      • Hetrick S.E.
      • McKenzie J.E.
      • Cox G.R.
      • Simmons M.B.
      • Merry S.N.
      Newer generation antidepressants for depressive disorders in children and adolescents.
      ]. It is therefore advisable to monitor side effects and the potential impact on seizures and mood.

      4. Epilepsy-specific depressive disorders

      Epilepsy provides intriguing cases of affective dysregulation emerging acutely with no recognizable psychoetiological background, reminding of the concept of “endogenous depression”.

      4.1 Limbic encephalitis

      Sickness behavior during infectious diseases is strongly reminiscent of behavioral alterations in depression [
      • Dantzer R.
      Cytokine, sickness behavior, and depression.
      ,
      • Maes M.
      • Berk M.
      • Goehler L.
      • Song C.
      • Anderson G.
      • Gałecki P.
      • Leonard B.
      Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways.
      ]. Actually, infection (by parasites, bacteria or viruses) or neuroinflammation may be mediators of mood disorders [
      • Rosenblat J.D.
      • Cha D.S.
      • Mansur R.B.
      • McIntyre R.S.
      Inflamed moods: a review of the interactions between inflammation and mood disorders.
      ]. Epileptogenesis has also increasingly been linked to neuroinflammation [
      • Vezzani A.
      • French J.
      • Bartfai T.
      • Baram T.Z.
      The role of inflammation in epilepsy.
      ,
      • Bien C.G.
      • Schulze-Bonhage A.
      • Deckert M.
      • Urbach H.
      • Helmstaedter C.
      • Grunwald T.
      • et al.
      Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy.
      ,
      • Lin Q.
      • Wang X.
      Differences in epileptic symptoms depending on the type of autoimmune-mediated limbic encephalitis.
      ]. For example, limbic encephalitis is a syndrome of (i) new-onset temporal lobe seizures; (ii) severe anterograde dysmnesia and loss of isolated autobiographic episodic memories; and (iii) rapidly evolving psychiatric alterations such as psychotic elements and hallucinations, increased irritability, apathy or agitation, obsessive-compulsive disorders, personality changes, and depression [
      • Asztely F.
      • Kumlien E.
      The diagnosis and treatment of limbic encephalitis.
      ,
      • Machado S.
      • Pinto A.N.
      • Irani S.R.
      What should you know about limbic encephalitis.
      ]. Shared etiological pathways of neuroinflammation, seizures and mood disorders [
      • Kandratavicius L.
      • Peixoto-Santos J.E.
      • Monteiro M.R.
      • Scandiuzzi R.C.
      • Carlotti Jr., C.G.
      • Assirati Jr., J.A.
      • et al.
      Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay.
      ,
      • Kitten S.
      • Gupta N.
      • Bloch R.M.
      • Dunham C.K.
      Voltage-gated potassium channel antibody associated mood disorder without paraneoplastic disease.
      ,
      • Butler C.
      • Zeman A.Z.J.
      Neurobiological syndroms which can be mistaken for psychiatric conditions.
      ] could also explain their bidirectional relationships [
      • Hesdorffer D.C.
      • Ishihara L.
      • Webb D.J.
      • Mynepalli L.
      • Galwey N.W.
      • Hauser W.A.
      Occurrence and recurrence of attempted suicide among people with epilepsy.
      ,
      • Hesdorffer D.C.
      • Hauser W.A.
      • Annegers J.F.
      • Cascino G.
      Major depression is a risk factor for seizures in older adults.
      ,
      • Martin R.C.
      • Faught E.
      • Richman J.
      • Funkhouser E.
      • Kim Y.
      • Clements K.
      • et al.
      Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. medicare beneficiaries.
      ,
      • Valente K.D.
      • Busatto Filho G.
      Depression and temporal lobe epilepsy represent an epiphenomenon sharing similar neural networks: clinical and brain structural evidences.
      ].
      Neuroinflammatory mechanisms may involve abnormalities of the blood–brain-barrier, glutamate dysregulation, glial pathology (e.g., microglia activation) or altered activity of enzymes (e.g., up-regulation of kynurenine) [
      • Rosenblat J.D.
      • Cha D.S.
      • Mansur R.B.
      • McIntyre R.S.
      Inflamed moods: a review of the interactions between inflammation and mood disorders.
      ,
      • Kandratavicius L.
      • Peixoto-Santos J.E.
      • Monteiro M.R.
      • Scandiuzzi R.C.
      • Carlotti Jr., C.G.
      • Assirati Jr., J.A.
      • et al.
      Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay.
      ,
      • Kayser M.S.
      • Dalmau J.
      The emerging link between autoimmune disorders and neuropsychiatric disease.
      ] as well as pathological autoimmune responsivity to neuromolecular antigens (e.g., NMDA receptor/NMDA-R, voltage-gated potassium complex channel/VGKC, glutamic acid decarboxylase/GAD) [
      • Vincent A.
      • Bien C.G.
      • Irani S.R.
      • Waters P.
      Autoantibodies associated with diseases of the CNS: new developments and future challenges.
      ,
      • Prüss H.
      • Lennox B.R.
      Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies.
      ]. Respective antibodies have been found in the serum or the cerebrospinal fluid in an increasing number of patients with limbic encephalitis [
      • Bataller L.
      • Kleopa K.A.
      • Wu G.F.
      • Rossi J.E.
      • Rosenfeld M.R.
      • Dalmau J.
      Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes.
      ,
      • Gultekin S.H.
      • Rosenfeld M.R.
      • Voltz R.
      • Eichen J.
      • Posner J.B.
      • Dalmau J.
      Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients.
      ]. As indicated by animal and clinical research, excessive stress and traumatic life experience can trigger neuroinflammation [
      • Koe A.S.
      • Salzberg M.R.
      • Morris M.J.
      • O'Brien T.J.
      • Jones N.C.
      Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.
      ,
      • Dubé C.M.
      • Molet J.
      • Singh-Taylor A.
      • Ivy A.
      • Maras P.M.
      • Baram T.Z.
      Hyper-excitability and epilepsy generated by chronic early-life stress.
      ,
      • van Campen J.S.
      • Jansen F.E.
      • de Graan P.N.
      • Braun K.P.
      • Joels M.
      Early life stress in epilepsy: a seizure precipitant and risk factor for epileptogenesis.
      ,
      • Galtrey C.M.
      • Mula M.
      • Cock H.R.
      Stress and epilepsy: fact or fiction, and what can we do about it.
      ] and the development of hippocampal dysfunctions and psychiatric comorbidities [
      • Bernard C.
      The diathesis-epilepsy model: how past events impact the development of epilepsy and comorbidities.
      ,
      • Lopez-Castroman J.
      • Jaussent I.
      • Beziat S.
      • Genty C.
      • Olié E.
      • de Leon-Martinez V.
      • et al.
      Suicidal phenotypes associated with family history of suicidal behavior and early traumatic experiences.
      ,
      • Becker C.
      • Bouvier E.
      • Ghestem A.
      • Siyoucef S.
      • Claverie D.
      • Camus F.
      • et al.
      Predicting and treating stress-induced vulnerability to epilepsy and depression.
      ]. Thus, neuroinflammation could represent the “missing link” of the bio-psycho-social model of mental disorders [
      • Ingram R.E.
      • Luxton D.D.
      Vulnerability-stress models.
      ]. Of note, physical exercise has proven anti-inflammatory [
      • Mathur N.
      • Pedersen B.K.
      Exercise as a mean to control low-grade systemic inflammation.
      ] and antidepressant effects [
      • Cooney G.M.
      • Dwan K.
      • Greig C.A.
      • Lawlor D.A.
      • Rimer J.
      • Waugh F.R.
      • et al.
      Exercise for depression.
      ,
      • Arida R.M.
      • de Almeida A.C.
      • Cavalheiro E.A.
      • Scorza F.A.
      Experimental and clinical findings from physical exercise as complementary therapy for epilepsy.
      ].

      4.2 Depressive mood states induced by seizures

      Periictal (i.e., preictal, ictal, and postictal) states provide an intriguingly rich psychological and psychopathological phenomenology [
      • Hoppe C.
      Preictal, ictal and postictal cognition.
      ]. Also acute depressive episodes unrelated to the patients’ overall psychosocial situation may precede or follow seizures [
      • Blanchet P.
      • Frommer G.P.
      Mood change preceding epileptic seizures.
      ,
      • Kanner A.M.
      • Trimble M.
      • Schmitz B.
      Postictal affective episodes.
      ,
      • Dimitriadis K.
      • Pfefferkorn T.
      • Noachtar S.
      Severe depression as the sole symptom of affective focal status epilepticus.
      ]. Even transient states of acute suicidality were reported as a postictal symptom [
      • Kanner A.M.
      • Trimble M.
      • Schmitz B.
      Postictal affective episodes.
      ,
      • Fincham R.
      • Anderson S.
      Postictal depression following subtle seizures.
      ]. Evidently, AEDs are the first-line therapy for these conditions.

      5. Conclusion

      Patients with epilepsy experiencing sustained impairment of emotional well-being must be identified in a timely manner. Reliable screening instruments such as the NDDI-E are now available. Diagnosing depression irrespective of life conditions is the appropriate way to identify patients in possible need of medical support. Guideline-based management of depression comorbidity in epilepsy represents the best practice by neurologists. Referral to a psychiatrist is mandatory in cases of severe and difficult-to-treat depression, or if there is evidence of suicidal intent. Optimizing epilepsy treatment in terms of both seizure control and tolerability is essential. Psychotherapy has been shown to have therapeutic efficacy in a series of randomized controlled trials, yet psychotherapy still appears to be underutilized by neurologists. Modern antidepressants (SSRI, SNRI, NaSSA) are thought to be safe to use in epilepsy, however, due to the lack of appropriate studies the evidence is still inconclusive, particularly for mild depression. In general, a bio-psycho-social model most appropriately covers the available evidence in terms of the etiology and treatment of depression in epilepsy. The concept of comorbid depression in epilepsy rekindles arguments about the traditional psychoreactive-endogenous distinction in psychopathology.

      Conflict of interest statement

      With regard to the present study none of the authors has to disclose conflicts of interest.

      Funding

      No funding.

      Acknowledgement

      We wish to thank Ms. Charlotte Putzer, M.Sc. for valuable comments on a former version of this paper.

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