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 Table of Contents  
Year : 2019  |  Volume : 7  |  Issue : 1  |  Page : 104-111

Epilepsy and depression: An update

Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

Date of Web Publication12-Jun-2019

Correspondence Address:
Dr. Marco Mula
Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, Blackshaw Road, London SW17 0QT
United Kingdom
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_54_19

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Depression is one of the most frequent comorbidities in patients with epilepsy affecting 1 in 4 patients, and this is due to psychological and neurobiological reasons. This is a narrative review of the epidemiological, neurobiological, and clinical aspects of depression in epilepsy. References have been identified through Medline/PubMed searches till February 2019 using the terms “epilepsy” AND “depression”. Additional articles were identified from the author's own files and from chosen bibliographies. Epilepsy and depression have a complex bidirectional relationship suggesting shared neurobiological mechanisms and the possibility that depression is a premorbid symptom of some epilepsy syndromes. The phenomenology of depression can be different from that seen outside epilepsy, but epilepsy-specific screening instruments, such as the Neurological Disorders Depression Inventory for Epilepsy, are now available to be used in routine clinical practice. Sertraline and citalopram can be considered first-line treatment in moderate to severe depression while psychological treatments should always be offered to mild to moderate cases.

Keywords: Antidepressant drugs, antiepileptic drugs, depression, epilepsy

How to cite this article:
Mula M. Epilepsy and depression: An update. Arch Med Health Sci 2019;7:104-11

How to cite this URL:
Mula M. Epilepsy and depression: An update. Arch Med Health Sci [serial online] 2019 [cited 2023 Feb 5];7:104-11. Available from: https://www.amhsjournal.org/text.asp?2019/7/1/104/260018

  Introduction Top

Psychiatric disorders are frequently encountered in people with epilepsy, with a lifetime history of 1 every 3 individuals.[1],[2] Depression is probably the most frequent psychiatric comorbidity in epilepsy, and the close relationship between these two conditions has been very well for more than 2000 years. In fact, the Greek physician Hippocrates reported that “melancholics ordinarily become epileptics, and epileptics, melancholics: what determines the preference is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy.[3]

The close connection between epilepsy and depression can be explained by a number of factors. Epilepsy is still today a highly stigmatized condition, leading to discrimination and marginalization; it has significant social limitations (e.g., driving license loss); the unpredictable nature of epileptic seizures and the social embarrassment potentially associated with them can lead to poor self-esteem, social withdrawal, and demoralization.[4] Nevertheless, the relationship between epilepsy and depression has also clear neurobiological underpinnings, and these will be discussed in the subsequent section.

Although depression is a frequently encountered problem, it is still underdiagnosed and undertreated unless it is severe enough to cause major problems or disability. This is due to multiple factors, including the patients' reluctance to volunteer spontaneously mental health issues, a paucity (or total lack) of a specific training of neurologists to recognize and manage psychiatric problems, and a lack of time in very busy outpatient clinics.

This is a narrative review about the epidemiology, neurobiology, and clinical aspects of depression in epilepsy, focusing mainly on research published during the last 10 years. References have been identified through Medline/PubMed searches till February 2019 using the terms “epilepsy” AND “depression.” Additional articles were identified from the author's own files and from chosen bibliographies.

  Neurobiology of Depression in Epilepsy Top

Neurobiology of depression has been investigated for decades with a large amount of literature regarding molecular mechanisms and brain networks involved. Patients with major depression without epilepsy show a 10%–20% bilateral decrement in the hippocampal volumes,[5] decreased cortical thickness in the frontal lobe, and decreased glial/neuronal cell density in the cingulate gyrus, rostral and caudal orbitofrontal cortex, and dorsal prefrontal cortex.[6],[7] Many of these changes have been also reported in patients with chronic temporal lobe epilepsy and may explain the increased prevalence of depression in these patients.[8],[9],[10],[11] However, studies published during the last 15 years have shown that the relationship between epilepsy and depression is not just unidirectional as people with depression have a 2 times increased risk of developing epilepsy.[12] These findings suggest that the same neurobiological changes underlying depression can also lead to the occurrence of spontaneous seizures.

Further insights into this subject come from animal models of epilepsy or depression. Serotonin dysfunction is well-known in depression, but low serotonin levels have been also reported in animal models of epilepsy such as genetically epilepsy-prone rats,[13] pilocarpine status epilepticus model in Wistar rats,[14] and Rhesus monkeys.[15] A deletion of the 5-HTC2 receptor subunit lowers the seizure threshold for audiogenic seizures in mouse models of epilepsy[16] and reduced postsynaptic and increased presynaptic density of 5-HT1 receptors are described in both animal models of epilepsy and depression.[17] It is, therefore, tempting to speculate that a progressive dysfunction in serotonin neurotransmission can be responsible for the occurrence of both conditions. This would also suggest that depression can represent a premorbid symptom in some epileptic syndromes.

Another classic neurobiological mechanism of depression, namely the hyperactivation of the hypothalamic-pituitary-adrenal axis, is implicated also in epilepsy. In fact, pretreatment with corticosterone accelerates the kindling process in animal models of epilepsy,[18] and high cortisol levels promote cortical hyperexcitability through a downregulation of gamma-aminobutyric acid receptors and a progressive reduction in the total number of CA3 neuronal cells.[19]

All these findings are obviously fascinating but do not explain why not all patients with depression develop epilepsy and vice versa. One possibility is that the complex reorganization of brain circuits leading to the two conditions occurs in predisposed individuals and such a predisposition is due to a combination of genetic background and environmental factors.[8] The diathesis–stress model is exemplary psychological theory that is used to explain the interaction between genetic and environmental factors. According to this model, if the combination of the background predisposition and stress exceeds a threshold, the individual develops specific disorders.[20] The diathesis–stress model has been historically used to explain schizophrenia or mood disorders,[21] but it can be easily applied to this context as well, explaining why some patients develop only epilepsy or only depression or both depending on the individual combinations of predisposing factors and environmental contributors/stressors.

  Epidemiology and Clinical Implications Top

In the general population, depression is a common condition, affecting between 5% and 10% in Western countries but epidemiological studies around the world suggest a consistent prevalence rates in different cultural and social backgrounds.[22] There are now good epidemiological data about the size of the problem in epilepsy. A systematic review and meta-analysis of 14 population-based studies has shown an overall prevalence of active (current or last 12 months) depression in adults with epilepsy of 23.1% with increased overall risk of 2.7 (95% confidence interval 2.09–3.6) compared with the general population.[23] However, in selected samples, such as patients with drug-resistant epilepsy, prevalence rates are much higher than that and up to 55%.[24]

Data about children with epilepsy are less abundant than adults but still confirm an increased prevalence of depression as compared to children without epilepsy. A long-term prospective study in children with epilepsy followed for up to 9 years reported a 13% prevalence of depression.[25] A large US nationwide survey showed depression in 8% of children with a current diagnosis of epilepsy, in 7% of children with a previous history of seizures and in 2% of controls.[26] Similar figures are reported by a UK community-based study of children with active epilepsy age between 5 and 15 years.[27]

As shown in adults, the prevalence of depression in children seems to reflect the severity of the underlying seizure disorder as depression is more common in those with drug-resistant epilepsy, low IQ, language delays, or lower scores on neuropsychological assessment.[28],[29],[30] Conversely, neurotypical (normal neurologic, cognitive, and imaging examinations) young adults with childhood-onset epilepsies do not present increased prevalence rates of psychiatric disorders.[31] Nevertheless, a number of psychological factors should be taken into account when discussing the relationship between epilepsy and depression in children. A US study pointed out that the attitude of adolescents with epilepsy toward their condition, namely an external locus of control, correlates strongly with depression.[32] Psychosocial difficulties in the family such as limited emotional support, poor communication, inadequate support of child autonomy, and maternal depression are also relevant contributors to depression in children with epilepsy.[32],[33],[34] As discussed in the diathesis-stress model, it is evident that apart from the neurobiological variables, social variables, stigma, and parental attitudes play an important role. For all these reasons cited, a continuous screening, tailored multidisciplinary approaches including psychotherapy, occupational, and vocational therapy are needed.

As already alluded in the previous section, it is now established that the relationship between epilepsy and depression is clearly bidirectional. Data from the UK General Practice Research Database showed that the incidence-rate ratio of depression is significantly higher in the 3 years preceding the onset of epilepsy.[12] A population-based study in Sweden showed that the age-adjusted odds ratio for the development of epilepsy is 2.5 for patients with depression.[35] Other three population-based studies confirmed that patients with depression have a three to seven times increased risk to develop epilepsy.[36],[37],[38] All these data taken together clearly suggest either that depression may represent a premorbid phase of some epileptic syndromes which may have distinctive features as compared to other syndromes. In this regard, coming data on the role of depression as a prognostic marker are quite interesting. In fact, depression seems to be associated not only with poor quality of life[39] but also with antiepileptic drug (AED) resistance,[40],[41] increased seizure severity,[42] increased side effects of AEDs,[43] increased risk of accident and injuries,[44] poor outcome after epilepsy surgery,[45] and increased mortality due to both suicide and SUDEP.[46] These findings have implications for the development of future treatments and disease-modifying agents and suggest the importance of incorporating psychiatric comorbidities as part of any epileptological assessment.

  Clinical Phenomenology of Depression in Epilepsy Top

Depression in epilepsy can occur in a number of different clinical contexts and not just as a comorbid disorder. In fact, people with epilepsy can develop depressive symptoms around the ictus as peri-ictal symptoms or as a side effect of the antiseizure treatment (i.e., drugs or surgery). The first step in the management of depression in epilepsy is to dissect out the various potential contributors. In fact, different contributing factors may need different approaches in parallel including psychotherapy, counseling, antidepressant drugs, and changes in the AED regime.

Peri-ictal depressive symptoms

Psychiatric symptoms in epilepsy can be classified according to their temporal relation to seizure occurrence (peri-ictal/paraictal symptoms vs. interictal symptoms),[2] and this approach has several advantages because it allows tailored management plans [Table 1].
Table 1: Depressive symptoms in epilepsy and their relationship with seizures

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Mood changes, including irritability and dysphoria, can sometimes precede a seizure by hours to days.[47] The neurobiology of this phenomenon has never been investigated. A cross-sectional study showed that up to 30% of patients report preictal mood changes,[48] but the exact prevalence is still unknown.

Depressed mood as a focal seizure has been occasionally reported and according to some authors can be observed in 1% of patients with temporal lobe epilepsy.[49] It is usually described as an intense, out of the context, feeling of anhedonia and guilt with or without suicidal ideation, lasting from a few seconds to minutes with preserved awareness. Ictal fear or ictal panic is definitely more frequent than ictal depression, and it has a strong localizing and lateralizing value for the nondominant temporal structures, mainly the amygdala.[50],[51]

Postictal depression and postictal worsening of depressive symptoms are better documented than other peri-ictal depressive symptoms. A cross-sectional study from a monitoring unit showed that up to 18% of patients can report depressive symptoms lasting more than 24 h,[52] and similar figures have been shown by another cross-sectional study using a structured questionnaire.[53] Contropolar mood changes such as manic/hypomanic symptoms are also described as postictal symptoms by a similar proportion of patients (i.e., 22%) but are often associated with psychotic symptoms.[52] Postictal mania has a stronger localizing value than postictal depression, and it has been associated with frontal epileptic discharges in the nondominant hemisphere.[54]

Interictal depression

Patients with epilepsy can develop depressive syndromes entirely identical to those described by international classificatory systems such as the Diagnostic and Statistical Manual of Mental Disorder (DSM) or the International Classification of Diseases (ICD). However, many authors have reported a number of atypical features which are not present in these classificatory systems.[55],[56],[57] Historically, Bleuler reported that patients with epilepsy can develop a unique mood disorder characterized by a pleomorphic pattern of depressive symptoms intermixed with euphoric moods, irritability, fear, and anxiety as well as anergia, pain, and insomnia.[58] In modern times, this formulation has been rejuvenated by Blumer who coined the term interictal dysphoric disorder (IDD) to refer to a somatoform-depressive disorder claimed to be typical of patients with epilepsy.[59] Subsequent studies pointed out that IDD can be diagnosed in up to 12% of patients, but it is not specific of epilepsy, and it can be diagnosed also in other neurological disorders, such as migraine.[53] These studies have pointed out that interictal depression in epilepsy is not simply characterized by chronic dysthymic-like features, but many patients present also with mood instability and dysphoric symptoms. Still, depression in epilepsy seems to be more frequently comorbid with anxiety disorders as compared to depressive syndromes outside epilepsy,[53],[60] and this point, along with peri-ictal symptoms, the effect of AEDs on mood, and the mood instability, largely account for the atypical features of depression in epilepsy.[61]

Given the complexity of the phenomenology of inter-ictal depression, it is easy to understand that structured clinical interviews shaped on DSM or ICD criteria may not be always valid. For this reason, some authors tried to develop clinical instruments tailored on these atypical manifestations. An adapted version of the Structured Clinical Interview for DSM Axis I (SCID-I), named SCID-E, has been suggested,[62] and a specific epilepsy questionnaire to be used with the Mini International Neuropsychiatric Interview, named the Epilepsy Addendum for Psychiatric Assessment, has also been reported.[63] Although occasionally used for research purposes, the relative benefits of these various instruments in clinical practice is still matter of debate.

A couple of questionnaires for the assessment of IDD are also available, mainly for research purposes. The seizure questionnaire[64] investigates the eight key symptoms of the IDD as theorized by Blumer. Patient and next of kin answer the questionnaire jointly, and the examiner reviews the answers. Another questionnaire, again developed research purposes, named the IDD Inventory, is available.[53] The reliability and utility of these questionnaires have been debated. The pleomorphic nature of the IDD itself along with the issue of peri-ictal symptoms makes the development of an epilepsy-specific clinical instrument quite challenging.

However, for routine clinical practice, there are now excellent clinical instruments validated in the epilepsy population for the routine screening of depression. The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E)[65] was specifically developed for this purpose and showed a sensitivity of 81% and a specificity of 90%. Other well-known clinical instruments such as the Beck Depression Inventory, the Hospital Anxiety Depression Scale, and the Hamilton Rating Scale for Depression have been validated in the epilepsy population, but the NDDI-E, validated in 13 languages, was considered the most efficient and practical screening tool for screening for major depression in a variety of settings.[66]

Treatment-related depression

It is now established that depression may well be a treatment emergent adverse event of AED, and this is seen more frequently in people with epilepsy than in other conditions where these drugs are widely used such as pain, migraine, movement disorders, or primary psychiatric disorders.[67] AED-related depression was initially associated with long-term exposure to barbiturates but became evident, over time, that many different compounds can be associated with depression as a treatment-emergent adverse event, especially topiramate, vigabatrin, perampanel, and levetiracetam.[68] This has obviously revived the concept of forced normalization, the phenomenon which describes the sudden switching off of seizures in people with intractable epilepsy who then develop an alternative psychiatric syndrome, very often a psychotic disorder, but depressive symptoms are also described.[69] It has been reported that up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events regardless of the mechanism of action of the individual AED, and this is mainly driven by the underlying psychiatric comorbidity, representing the fertile ground on which these paradoxical reactions develop.[70]

Apart from an individual predisposition of the patient, it is also established that the rapidity of the titration rate of the AED is another relevant variable. In fact, even if it is true that some compounds seem to be more frequently associated with depression or psychiatric problems than others,[68],[71],[72] it is also established that a rapid titration of the drug can increase the risk exponentially.[73],[74] A retrospective study in a large cohort of consecutive patients treated with topiramate showed that while a previous history of depression is associated with a 3.5-times increased risk of developing depression as a treatment-emergent adverse event, the use of a rapid titration schedule in someone with a previous history of depression is associated with a 23-times increased risk.[75] For this reason, all patients should be counseled for treatment-emergent psychiatric adverse events of AEDs, and slow titration rates should be routinely adopted in people at risk.

Depression is also a well-known complication of epilepsy surgery, and all patients are usually counseled that up to 30% of them can develop transitory depressive symptoms within the first 3 months after epilepsy surgery.[76],[77] Some authors pointed out that the phenomenology of postsurgical depression can be different from that of interictal depression with the former being more severe, and more frequently associated with clear anhedonic features than inter-ictal depression, which, on the contrary, tends to have dysthymic/dysphoric features.[77] However, it has been also reported that some patients, after surgery, may present with a physical and mental asthenia which goes along with avoidance of or withdrawal from social interactions.[78] This should be distinguished from depression as it does not usually respond to antidepressant drug treatment.

  Treatment of Depression in Epilepsy Top

In general terms, data on treatment of depression in epilepsy are still limited and rely on individual clinical experience.[79] Two documents, an International Consensus Statement and a US consensus paper, have issued a number of recommendations.[80],[81] Given the paucity of data in epilepsy, it seems reasonable to apply international guidelines of treatment outside epilepsy adapting them to the specific needs of people with epilepsy, namely interactions and seizure risk.

Psychological treatments

According to the National Institute for Clinical Excellence (NICE) guidelines for depression, psychological therapies represent first-line treatment for mild to moderate depression in both the general population[82] and in individuals with a chronic health problem.[83] Data in people with epilepsy are still limited, but systematic reviews and meta-analysis have shown that psychological therapies are associated with a significant improvement in quality of life.[84],[85] A document from the Psychology Task Force of the International League Against Epilepsy recommends psychological treatments in people with epilepsy and mild to moderate depression, but the level of evidence is still moderate and further studies are needed.[86]


A Cochrane review showed that data on the pharmacological treatment of depression are limited and the level of evidence is still low due to the poor quality of available studies.[87] In fact, there are only two randomized controlled trials for depression in epilepsy, the first, published more than 30 years ago, comparing nomifensine, amitriptyline, and placebo[88] and the second investigating the antidepressant effect of a traditional Chinese medicine remedy, Xylaria Nigripes, as compared to placebo.[89] In addition, both studies are significantly underpowered as they involve a limited number of individuals, and nomifensine is no longer available in many countries as it was withdrawn from the US, Canadian, and UK markets quite a few years ago. Apart from these two controlled trials, there are many open studies mostly of selective serotonin reuptake inhibitors (SSRIs) in relatively small unselected samples of people with different epileptic syndromes: sertraline,[55],[90] citalopram,[91],[92],[93] fluoxetine,[90] reboxetine,[93] and mirtazapine.[93] One of them focused on children and adolescents with epilepsy and depression.[90] Even if these studies provide a low level of evidence, they clearly show that SSRIs are safe and effective with response rates ranging from 24%[92] to 97%.[90] The variability in response rates can be due to many reasons such as the heterogeneity of participants (from newly diagnosed patients to drug-resistant cases) and pharmacokinetic interactions with AEDs.[79] However, these response rates are quite high and even higher than those reported in patients with depression without epilepsy. For this reason, it is entirely reasonable to apply guidelines of treatment outside epilepsy, and according to NICE, sertraline and citalopram should be considered first-line option in people with depression in the context of a chronic medical condition.[83]

Interactions between antidepressant and antiepileptic drugs

AEDs have a different potential for pharmacokinetic interactions. Among first-generation drugs, carbamazepine, phenytoin, and barbiturates are inducers of several drug-metabolizing enzymes including the CYP and the UGT systems, while valproate is an inhibitor.[79],[94] Among second-generation AEDs, oxcarbazepine is a weak inducer, while topiramate has some inducing properties at doses higher than 200 mg per day.[94] Third-generation AEDs have a better pharmacokinetic profile with a low propensity for pharmacokinetic interactions. Conversely, the majority of antidepressants have a complex metabolism, and some of them may inhibit some metabolic pathways.[94]

The clearance of almost all antidepressants is increased by inducers with a reduction in blood levels of about 25% for all SSRIs, mirtazapine and venlafaxine.[79],[94] However, there is no clear evidence that these interactions are clinically relevant with the exception of bupropion whose clearance can be increased by up to 90% when carbamazepine is introduced.[79] For this reason, dose adjustments in routine clinical practice are note needed. SSRIs, especially fluoxetine and fluvoxamine, are inhibitors of the CYP2C9 and may potentially interact with phenytoin and to a lesser extent with valproate[79] while other more recent antidepressants seem to have a low potential for pharmacokinetic interactions.

Seizure worsening

Historically, antidepressants have been linked to epileptic seizures as a treatment emergent adverse event, and epileptic seizures are still listed in the information leaflet of all antidepressants. However, this was based on an a priori assumption rather than on any clinical evidence.[79] In fact, a meta-analysis of food and drug administration data clearly showed that the occurrence of seizures during treatment with antidepressants is not different, if not lower than that with placebo.[95] High doses of clomipramine (>150 mg), maprotiline and bupropion immediate release formulation are the only drugs that correlates with a significant risk of seizures as a treatment emergent adverse event.[79],[96] Obviously, these data come from patients with a primary psychiatric disorder, and it is still unknown whether these findings can be transferred to people with epilepsy, but available data from the open studies suggest no deterioration in seizure frequency.

Financial support and sponsorship


Conflicts of interest

The author declares that there is no conflict of interest with the present paper. Outside the submitted work, Dr Mula has received consultancy fees from UCB Pharma, Eisai Europe Limited, Bial and Elsevier. Dr Mula also has intellectual property rights with Elsevier and Springer.

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