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 [
[1]
]. 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) [
[2]
] 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) [3
, 4
]. 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) [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).
[5]
]. 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” [[6]
]). Since the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-IV) [[7]
]) the diagnostic distinction between “psychoreactive” (neurotic) and “endogenous” (psychotic) depression has been omitted [[8]
].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 [
9
, http://www.who.int/mediacentre/factsheets/fs369/en/ (due 20 August 2016).
10
]. 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% [[11]
]. 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 [[12]
]. Of note, unemployment may be both the cause and the effect of depression [[13]
]. Around one half of patients experience at least one relapse of a depressive episode [[4]
]. More than half of depressive patients suffer from at least one other comorbid mental disorder [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).
[11]
]; 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) [[14]
]. Neuropsychological deficits of executive functions and memory performance link depression to a dysfunction of frontotemporal networks [[15]
]. Consistently, neuroimaging has shown that patients with depressive sypmtoms exert greater effort to maintain normal cognitive performance, compared to controls [[16]
].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 [
[17]
]. Better data are reported from Canada (14% prevalence of diagnosed patients, with 85% treated) [[18]
]. In patients with depression, the suicide risk is increased by a factor of 30 [[19]
]. 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% [
20
, http://www.who.int/mediacentre/factsheets/fs999/en/ (due 23 August 2016).
21
]. Epilepsy makes the greatest neurological contribution to disability-adjusted life years [[22]
]. 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 [[23]
]. These patients carry a chronic burden [22
, 24
], 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 [25
, 26
]). 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 [27
, 28
, 29
]. Life expectancy is reduced and psychiatric disorders strongly contribute to premature mortality [[30]
]. 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) [31
, 32
]. The prevalence of current suicidal ideation in epilepsy patients is thought to be as high as 10% [[33]
]. 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 [- Bosak M.
- Turaj W.
- Dudek D.
- Siwek M.
- Szczudlik A.
Suicidality and its determinants among Polish patients with epilepsy.
Neurol Neurochir Polska. 2016; ([Epub ahead of print])https://doi.org/10.1016/j.pjnns.2016.07.009
[34]
].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 [
35
, 36
, 37
, 38
, 39
, 40
, 41
]. 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”) [42
, 43
]?- Akdemir V.
- Sut N.
- Guldiken B.
Factors affecting the quality of life in drug-resistant epilepsy patients.
Acta Neurol Belg. 2016; ([Epub ahead of print])https://doi.org/10.1007/s13760-016-0622-5
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 [
[44]
]. However, the diagnosis of abnormal mood states, irrespective of life conditions, is the appropriate method to identify individuals who may require professional medical support [40
, 41
].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 [
[45]
]) 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 [
41
, 46
, 47
]. 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 [48
, 49
]. 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 [[48]
]. Furthermore, adverse effects of antiepileptic medication were not found to influence NDDI-E scores, unlike the Beck Depression Inventory [[50]
] or the Centre for Epidemiological Studies depression [[51]
] 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 [
27
, 47
]. 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 [47
, 52
, 53
, 54
]. Some studies report that criteria for current severe depressive episodes are fulfilled in 15–20% of epilepsy patients [27
, 55
]. As compared to patients with idiopathic depression, the dysphoric mood appears to be generally pronounced in depressed epilepsy patients [56
, 57
, 58
], however adverse effects from anticonvulsants (e.g., levetiracetam) may contribute [[59]
]. Furthermore, increased anxiety is a frequent comorbidity of epilepsy [60
, 61
].Socioeconomic and psychosocial factors typically explain most of the variance in measures of mood [
62
, 63
, 64
], 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 [[65]
]. Even the expected correlation between mood disorders (or other psychiatric comorbidity) and temporal/mesiotemporal lobe epilepsy has not been consistently evidenced [66
, 67
]. 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 [[68]
] and frontal brain networks [[69]
], respectively.3. Treating depression in epilepsy
National psychiatric guidelines suggest a stepped-care model for the management of diagnosed depression (e.g., [
4
, 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).
45
]). 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 [70
, 71
]. 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 [4
, 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).
27
]. 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 [
72
, - Yrondi A.
- Arbus C.
- Valton L.
- Schmitt L.
Mood disorders and epilepsy surgery: a review.
Encephale. 2016; ([article in French] [Epub ahead of print])https://doi.org/10.1016/j.encep.2016.02.015
73
, 74
, 75
]. While epilepsy surgery is certainly still underutilized, the relationship between depression and epilepsy surgery is complex [[76]
]. Filho et al. reported that 54% of patients experienced an improvement in depression following amygdalo-hippocampectomy [[75]
]; however, sustained improvements in mood largely depended on a good postsurgical seizure outcome (>5 years) [[77]
]. 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) [[78]
]. 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 [- 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.
Epilepsia. 2016; ([Epub ahead of print])https://doi.org/10.1111/epi.13497
79
, 80
] and mood outcomes [[75]
]. A recent systematic review reported a prevalence of 30% for depression three months of surgery, with most cases experiencing a relapse of presurgical depression [[72]
]. However, whilst previous reviews found no psychiatric deterioration after epilepsy surgery [- Yrondi A.
- Arbus C.
- Valton L.
- Schmitt L.
Mood disorders and epilepsy surgery: a review.
Encephale. 2016; ([article in French] [Epub ahead of print])https://doi.org/10.1016/j.encep.2016.02.015
[81]
], more recent studies have reported cases of de novo depression postsurgery in seizure-free as well as non seizure-free patients [82
, 83
]. Individuals may find experiences in life after complete release from seizures demanding, especially in cases of personality disorders and family problems (“burden of normality”) [84
, 85
]. Surgical failure is reportedly associated with increased risk of suicide [[86]
]. 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 [
[87]
] and primidone [[88]
]. Conversely, mood stabilizing and psychotropic effects have been shown for lamotrigine [[89]
] and oxcarbazepine [[90]
]. Furthermore pregabalin has been associated with a substantial risk of recreational misuse [[91]
]. Mixed effects were reported for levetiracetam [[92]
] and topiramate [[93]
]. 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 [[94]
]. 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 [95
, 96
]. 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 [
62
, 63
, 64
, 65
, 97
, 98
]; however correlations between seizure frequency and risk of experiencing a major depressive episode have been demonstrated [[99]
]. 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 [[100]
]. Reducing the total drug load (if responsible) could potentially improve memory, however, the effects on QoL are uncertain [94
, 101
]. 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 [[102]
].3.2 Psychotherapy
Traditionally, the management of depression in neurological disorders and epilepsy has involved drug treatments (e.g., [
103
, 104
]) in line with previous healthcare advise [[105]
]. However, efficacy studies have recently provided evidence that psychotherapy should be considered the first-line therapy for eligible patients [106
, 107
, 108
]. 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 [109
, 110
, 111
, 112
, 113
, 114
, 115
, 116
, 117
, 118
]; whereas three randomized controlled trials found no evidence for (sustained) effects [119
, 120
, 121
] (Table 1). Evidence suggests that CBT-based interventions can aid the prevention of major depressive episodes and suicidality in patients with epilepsy [122
, 123
]. Single studies reported improved seizure control [[124]
]. Neurophysiological and neuroimaging data have provided insights into the mechanisms how psychotherapy may be effective for depression in epilepsy [[125]
]. 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 [[126]
]. 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 [[127]
]. 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 [[128]
].Table 1Randomized or matched clinical trials on psychotherapy for comorbid depression in epilepsy (modified and completed from [Mehndiratta & Sajatovic]).
| Authors | Intervention | Inclusion criteria | Samples | Psychometric measures | Outcome |
|---|---|---|---|---|---|
| Au et al. [109] | CBT vs. controls (matched assignment) | Exclusion: active serious medical disorder, psychotic features, severe mental deficiency, history of neurosurgery | Total N = 17 | QOLIE-31, ESES | CBT: improvement of QoL and self-efficacy 3 months after last therapy session |
| |||||
| Ciechanowski et al. [110] , long-term evaluation: Chaytor et al. [111] | PEARLS vs. usual care (waitlist) | Age >18, English speaking, ICD-9 diagnosis of epilepsy, attended epilepsy clinic within past 2 yrs., PHQ9 >10 | Total N = 80 | CSI, HSCL-20, QOLIE-31 | PEARLS yielded more improvement of depression over 12 months [110] and 18 months [111] |
| |||||
| Davis et al. [112] | CBT vs. waitlist | Adult patients with epilepsy and signs of depression self-reffering to a educational class for improved coping with depression | Total N = 13 | DACL, GCS, BDI, CAQ | Mood 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 |
| |||||
| Gillham [113] | 2 types of psychological intervention (cross-over control group design) vs. control group | Poorly controlled epilepsy, psychological disorder (rating scales)—control group: no psychological disorder | Total N = 40 | Self-rating measures of anxiety and depression | Both groups with baseline disorders had improved anxiety and depression after 42 weeks |
| |||||
| Lundgren et al. [114] | ACT vs. ST (control) | Pats. with very low incomes (government disability grant), minum of 4 seizures (past 3 months), EEG-verified epilepsy, no progressive disease | Total N = 27 | SWLS, WHOQOL-BREF, seizure index | ACT-specific improvements I all dependent measures after treatment, at 6- and 12-months follow-up; dramatic improvement of seizure index |
| |||||
| Lundgren et al. [115] | ACT vs. Yoga | Minimum of 3 seizures (past 3 months), EEG-verified epilepsy, no progressive disease | Total N = 18 | SWLS, WHOQOL-BREF, seizure index | Both groups showed improved QoL but ACT > yoga, ACT: improved seizure index |
| |||||
| Schröder et al. [116] | Deprexis a vs. waitlist controlDistance 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. | 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 completion | Total N = 78 | BDI, QOLIE-31, PESOS, WHOQOL-BREF | Deprexis improved mood (BDI) and energy/fatigue (from QOLIE-31) after program completion (9 weeks) but not overall QoL |
| |||||
| Tang et al. [117] | MBT + SS vs. SS only | Adult age, therapy-refractory epilepsy | Total N = 60 | QOLIE-31-P, BDI-II, BAI, neuropsychological assessment | Improved mood, anxiety, QoL, memory, seizure frequency/severity with better effects in MBT + SS vs. SS only 6 weeks after the last session |
| |||||
| Thompson et al. [118] (CDC) | UPLIFT a vs. usual care (waitlist)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. | Age >21, English speaking, MMSE >20, CES-D >13 and <38, diagnosis of epilepsy for 1 year | Total N = 53. | BDI, BRFSS, DSCES, PHQ-9, SCS, SWLS | UPLIFT improved mood, knowledge and skills post-treatment and 8 weeks beyond |
| |||||
| Fraser et al. [119] | PACES vs. no treatment (control) | Adult, established epilepsy (at least for 6 months), cognitively intact (MoCA >21); exclusion: severe mental illness/psychosis, IQ < 70 | Total N = 83 | PHQ-9, GAD-7, ESMS, ESES, QOLIE-31 | Treatment-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) |
| |||||
| McLaughlin et al. [120] | CBT vs. usual care (waitlist) | Age >60 years, MMSE > 24, English speaking | Total N = 37 | GDS, CIDI, WPSI | Mood improvement in both groups with no superiority for treatment (CBT) at 3-months follow-up, but better seizure improvement in CBT |
| |||||
| Tan and Bruni [121] | CBT vs. supportive counseling vs. waitlist | Adult patients with epilepsy | Total N = 27 | MMPI, WPSI, BDI, ratings (patient, neurologist, therapist) of global psychological adjustment, target complaints seizure control | no/little evidence for effects of psychological treatments, except of better outcome in therapist's global ratings of psychological adjustment for both treatment groups |
| |||||
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 [
116
, 118
]. Furthermore, evidence suggests that physical exercise for depression holds similar efficacy as psychotherapy, particularly as a complementary therapy to more traditional treatment [129
, 130
].3.3 Antidepressant drugs
3.3.1 Efficacy
Three randomized controlled trials on antidepressant drugs for depression in epilepsy have been published to date [
[131]
]. The first trial (N = 42 patients), performed in 1985 [[132]
], 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]) [[133]
], and venlafaxine (a selective serotonine noradrenaline reuptake inhibitor [SNRI]) versus placebo [[134]
]. 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” ([[131]
).More generally, recent psychiatric research found no to small effects of antidepressants in mild to moderate idiopathic depression [
135
, 136
], especially in children and youths [[137]
]. However, moderate therapeutic effects in severe depression were demonstrated, suggesting a need to reconsider the former distinction between minor (psychoreactive) and major (endogenous) depression [- 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.
Lancet. 2016; ([Epub ahead of print])https://doi.org/10.1016/s0140-6736(16)30385-3
[138]
]. 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 [4
, 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).
139
]. While several national psychiatric guidelines have adopted such findings and now emphasize the balance of psychotherapy and drug treatment for mild to moderate depression [[4]
], expert recommendations for the treatment of depression in epilepsy have not been revised accordingly as yet [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).
70
, 71
].3.3.2 Tolerability
Unwanted side effects (including suicidality) of modern antidepressants are typically underestimated, potentially as a consequence of biased scientific reporting [
140
, 141
, 142
]. 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 [[143]
]. 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 [[144]
]. 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 [38
, 145
, 146
, 147
]. Rather, antidepressant drugs appear to exert an anticonvulsant effect when used at therapeutic dosages in patients with depression (possibly via serotoninergic pathways) [[148]
].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) [
143
, 149
]. In idiopathic depression, topiramate and pregabalin showed a potential to augment the therapeutic efficacy of antidepressant drugs (e.g., SSRI/topiramate [[150]
]).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 [
143
, 151
, 152
]. In contrast, tricyclic or tetracyclic antidepressants and norepinephrine-dopamine reuptake inhibitors (NDRI) should be avoided in the first instance [[151]
]. Noradrenergic and specific serotonergic antidepressants (NaSSAs) are associated with the class of tetracyclic antidepressants, yet appear safe in epilepsy as well [[152]
].Of note, psychiatric guidelines stipulate close monitoring of patients receiving antidepressant drug therapy, particularly during titration or withdrawal [
[4]
]. Furthermore, the FDA has issued a warning for an increased risk of suicidality due to antidepressant use [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).
[141]
]. 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 [
153
, 154
]. Actually, infection (by parasites, bacteria or viruses) or neuroinflammation may be mediators of mood disorders [[155]
]. Epileptogenesis has also increasingly been linked to neuroinflammation [156
, 157
, 158
]. 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 [159
, 160
]. Shared etiological pathways of neuroinflammation, seizures and mood disorders [161
, 162
, 163
] could also explain their bidirectional relationships [34
, 164
, 165
, 166
].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) [
155
, 161
, 167
] 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) [168
, 169
]. Respective antibodies have been found in the serum or the cerebrospinal fluid in an increasing number of patients with limbic encephalitis [- Prüss H.
- Lennox B.R.
Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies.
J Neurol Neurosurg Psychiatry. 2016; ([Epub ahead of print])https://doi.org/10.1136/jnnp-2015-313000
170
, 171
]. As indicated by animal and clinical research, excessive stress and traumatic life experience can trigger neuroinflammation [172
, 173
, 174
, 175
] and the development of hippocampal dysfunctions and psychiatric comorbidities [176
, 177
, 178
]. Thus, neuroinflammation could represent the “missing link” of the bio-psycho-social model of mental disorders [[179]
]. Of note, physical exercise has proven anti-inflammatory [[180]
] and antidepressant effects [129
, 130
].4.2 Depressive mood states induced by seizures
Periictal (i.e., preictal, ictal, and postictal) states provide an intriguingly rich psychological and psychopathological phenomenology [
[181]
]. Also acute depressive episodes unrelated to the patients’ overall psychosocial situation may precede or follow seizures [182
, 183
, 184
]. Even transient states of acute suicidality were reported as a postictal symptom [- Dimitriadis K.
- Pfefferkorn T.
- Noachtar S.
Severe depression as the sole symptom of affective focal status epilepticus.
BMJ Case Rep. 2014; https://doi.org/10.1136/bcr-2013-201149
183
, 185
]. 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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