Epilepsy & Psychiatric Comorbidities

Psychiatric comorbidities are among the most prevalent and impactful conditions in people with epilepsy, affecting quality of life, treatment adherence, seizure control, and mortality. Depression and anxiety each occur in 25–40% of people with epilepsy — rates 2–5 times higher than in the general population. The relationship between epilepsy and psychiatric disorders is bidirectional: not only does epilepsy increase the risk of developing psychiatric conditions, but premorbid depression and anxiety increase the risk of subsequently developing epilepsy. This bidirectional model, supported by both epidemiologic data and animal models, suggests shared underlying neurobiological mechanisms involving serotonergic, noradrenergic, and GABAergic systems. Clinicians must systematically screen for psychiatric comorbidities, understand the psychotropic profiles of antiseizure medications (ASMs), and approach treatment without fear of lowering the seizure threshold.

Bottom Line

  • Depression: Prevalence 25–50% in epilepsy; NDDI-E (score >13) is the most validated screening tool; SSRIs (citalopram, escitalopram, sertraline) are first-line treatment with minimal interaction risk
  • Anxiety: Prevalence ~40%; brEASI and GAD-7 validated in epilepsy; SSRIs are first-line; benzodiazepines are appropriate short-term but carry dependency risk
  • Bidirectional relationship: Premorbid depression and stress increase epilepsy risk through serotonergic/noradrenergic depletion and enhanced kindling susceptibility
  • ASM psychotropic effects: Levetiracetam (irritability, depression), perampanel (aggression), topiramate (depression, cognitive impairment) can worsen psychiatric symptoms; lamotrigine and valproate have mood-stabilizing properties
  • Antidepressant safety: SSRIs and SNRIs at therapeutic doses do not meaningfully lower the seizure threshold; bupropion carries dose-dependent risk (especially >450 mg/day); clomipramine and clozapine have clinically relevant seizure risk
  • Psychosis of epilepsy: Postictal psychosis is most common (60%); forced normalization (alternative psychosis) occurs with seizure freedom; avoid clozapine
  • Suicidality: People with epilepsy have 3–5× increased suicide risk; the 2008 FDA warning on ASMs and suicidality has been questioned by subsequent meta-analyses showing no individual ASM consistently increases risk

Bidirectional Relationship Between Epilepsy & Psychiatric Disorders

The traditional view of psychiatric comorbidities as secondary consequences of epilepsy has been replaced by a bidirectional model. Population-based studies demonstrate that a history of depression increases the risk of developing epilepsy by 2–7-fold, and vice versa. In animal models, early postnatal stress enhances susceptibility to limbic epileptogenesis, and experimentally induced serotonin and norepinephrine depletion lowers the seizure threshold and facilitates kindling. These shared neurobiologic substrates suggest that epilepsy and depression/anxiety may be different manifestations of a common underlying brain dysfunction rather than a simple cause-and-effect relationship.

Five mechanisms of association between epilepsy and comorbidities have been proposed: (1) artifactual/chance association, (2) epilepsy causing the comorbidity (resultant), (3) the comorbidity causing epilepsy (causative), (4) shared risk factors, and (5) true bidirectional association. For cerebrovascular disease and epilepsy, bidirectionality is well-supported by clinical data. For depression and anxiety, the evidence from animal models is compelling, though human clinical evidence is still accumulating.

Depression in Epilepsy

Epidemiology & Impact

Depression is the most common psychiatric comorbidity in epilepsy, with prevalence estimates ranging from 25% to 50% depending on the population studied. The rate is highest in patients with drug-resistant temporal lobe epilepsy (approaching 50–60%) and in epilepsy monitoring unit populations. Depression in epilepsy is associated with decreased quality of life (accounting for more variance than seizure frequency), increased health care utilization, poorer medication adherence, increased risk of ASM intolerance and treatment failure, greater risk of SUDEP, and increased mortality. The presence of comorbid depression may be the single most important determinant of quality of life in people with epilepsy.

Screening Tools

Instrument Target Condition Format Positive Screen Epilepsy-Specific?
NDDI-E Major depressive disorder; suicidality 6-item, 4-level Likert scale Score >13 (meta-analytic optimum; original cutoff >15) Yes — designed to distinguish depression from ASM side effects and epilepsy-related cognitive effects
PHQ-9 Major depressive disorder 9-item, 4-level Likert scale Score ≥10 No — validated in epilepsy population
BDI-II Major depressive disorder 21 descriptive statements, 4-level Likert Score >11 No — validated in epilepsy population
HADS Depression and anxiety 14-item self-report Score >7 (per subscale) No — validated in epilepsy population
brEASI Anxiety disorders 8-item, 4-level Likert scale Score ≥7 Yes — derived from 18-item EASI
GAD-7 Generalized anxiety disorder 7-item, 4-level Likert scale Score >6 No — validated in epilepsy population

Practical Screening Approach

  • The ILAE recommends asking at least one mental health question at every visit
  • The NDDI-E is the most efficient and practical tool for a busy epilepsy clinic — validated in 13 languages, takes <3 minutes, and screens for both depression and suicidality
  • A positive screen is not diagnostic — it identifies patients who need referral for comprehensive psychiatric evaluation
  • The National Academy of Medicine recommends routine use of validated screening instruments for mental health in people with epilepsy
  • Screen at diagnosis, medication changes, seizure recurrence, and at least annually

Treatment of Depression in Epilepsy

The ILAE published clinical practice recommendations for the treatment of depression in adults with epilepsy in 2022. Key recommendations include:

  • Mild depression: Psychological treatments (CBT, mindfulness-based approaches) are first-line (Level B — probably effective)
  • Moderate to severe depression: SSRIs are first-line pharmacotherapy (Level B recommendation)
  • SSRI preference: Citalopram, escitalopram, and sertraline are preferred due to minimal CYP450 interactions with ASMs
  • Second-line: Venlafaxine (SNRI) is an appropriate second-line option (Level C — possibly effective)
  • Combination therapy: Pharmacotherapy plus psychotherapy may be more effective than either alone

Anxiety Disorders in Epilepsy

Approximately 40% of people with epilepsy report anxiety symptoms, with generalized anxiety disorder, panic disorder, and social phobia being the most common. Anticipatory anxiety — the persistent fear of having a seizure in public, at work, or while driving — is highly prevalent and contributes significantly to social avoidance, agoraphobia, and functional impairment. This seizure-specific anxiety may not meet criteria for any standard DSM-5 anxiety disorder but causes substantial disability.

Temporal Relationship of Anxiety to Seizures

Anxiety in epilepsy has a complex temporal relationship to seizures that has important diagnostic and therapeutic implications:

Temporal Pattern Timing Clinical Features Management
Ictal anxiety During seizure (aura) Sudden, intense fear or panic lasting seconds to minutes; often stereotyped; common in mesial temporal lobe epilepsy; associated with amygdala activation Optimize ASM for seizure control; may be misdiagnosed as panic disorder
Postictal anxiety Minutes to hours after seizure Generalized anxiety, agitation, or panic following a seizure; may last hours to days; often accompanies postictal depression Self-limited; short-acting benzodiazepine if severe; reassurance
Interictal anxiety Chronic, between seizures GAD, social phobia, panic disorder; anticipatory anxiety about seizures; may fluctuate with seizure frequency SSRI first-line; CBT; short-term benzodiazepine for acute episodes
Preictal anxiety Hours before seizure Prodromal anxiety or irritability preceding a seizure by hours; some patients can predict seizures based on this prodrome Optimize ASM; rescue benzodiazepine; self-management strategies

No specific evidence-based guidelines exist for treating anxiety in epilepsy; SSRIs remain reasonable first-line agents, and short-term benzodiazepine use is appropriate for acute anxiety but carries risks of dependence, cognitive impairment, and potential seizure exacerbation upon withdrawal. Gabapentin and pregabalin have anxiolytic properties and may serve a dual role as both ASM and anxiolytic in selected patients, though their efficacy as anxiolytics in epilepsy populations has not been specifically studied.

Psychosis of Epilepsy

Up to 6% of people with epilepsy have a history of psychosis. Psychotic episodes in epilepsy are categorized temporally in relation to seizures:

Type Proportion Clinical Features Pathophysiology Treatment
Postictal psychosis ~60% Occurs after cluster of bilateral convulsive seizures; lucid interval of 1–3 days; affect-laden with paranoid/persecutory delusions; short duration (days to weeks); negative symptoms uncommon Post-seizure rebound excitability; dopaminergic dysregulation; bilateral seizure spread Low-dose atypical antipsychotic (olanzapine, risperidone) for short course; benzodiazepines; self-limited
Interictal psychosis ~30% Clinically can be indistinguishable from schizophrenia; may develop after years of poorly controlled epilepsy; chronic course possible Chronic epileptic network disruption; hippocampal damage; limbic dysfunction Olanzapine or risperidone first-line; quetiapine (interacts with enzyme-inducing ASMs); avoid clozapine
Forced normalization / Alternative psychosis ~5–10% Paradoxical development of psychotic symptoms when seizures are controlled and EEG normalizes; may occur after epilepsy surgery or ASM optimization Proposed: seizure suppression unmasks latent psychotic vulnerability; neurochemical rebalancing May require reducing ASM to allow some seizure recurrence; low-dose antipsychotic; psychiatric consultation
Ictal psychosis Rare Part of seizure semiology (usually complex partial status); hallucinations, paranoia during seizure; resolves with seizure termination Direct effect of epileptic discharge, usually temporal lobe origin Treat the seizure (benzodiazepine, ASM optimization)

Antipsychotic Use in Epilepsy

  • Clozapine: Generally avoided when feasible — dose-dependent seizure risk (~1–4% overall, rising at doses ≥600 mg/day); potent reduction of seizure threshold; if used, consider valproate coverage and slow titration
  • Chlorpromazine: Significant seizure risk, especially at high doses; avoid
  • Olanzapine and risperidone: Preferred first-line antipsychotics in epilepsy; minimal seizure threshold effects
  • Quetiapine: Acceptable alternative but interacts with enzyme-inducing ASMs (CYP3A4 substrate)
  • Aripiprazole: Low seizure risk; reasonable alternative
  • All antipsychotics carry theoretical seizure risk at supratherapeutic doses or with rapid titration

ADHD & Epilepsy

ADHD occurs in 20–40% of children with epilepsy and persists into adulthood in a substantial proportion. The relationship is likely bidirectional, with shared risk factors including genetic variants affecting neurodevelopment and neurotransmitter function. ASMs can exacerbate ADHD symptoms: phenobarbital and benzodiazepines cause inattention, while levetiracetam may cause irritability mimicking ADHD-related behavioral problems. Conversely, stimulant medications (methylphenidate, amphetamines) at therapeutic doses do not significantly increase seizure risk and are considered safe in patients with well-controlled epilepsy. Atomoxetine is an alternative nonstimulant option with no meaningful seizure threshold effects. The concern that stimulants lower the seizure threshold has not been borne out by clinical studies.

ASMs & Psychiatric Effects

ASM Beneficial Psychotropic Effects Harmful Psychotropic Effects Clinical Considerations
Lamotrigine Reduced depression, mood stabilization, decreased mania Insomnia; irritability (usually children with intellectual disability) FDA-approved for bipolar maintenance; preferred ASM in patients with comorbid depression
Valproate Decreased agitation, aggression, irritability, mania; mood stabilization Depression (less common) FDA-approved for bipolar mania; avoid in women of childbearing potential due to teratogenicity
Carbamazepine Decreased aggression, mania; mood stabilization Irritability, impaired attention Historically used for mood disorders; extensive drug interactions limit utility
Levetiracetam None established Anxiety, depression, irritability; more common in children and patients with preexisting psychiatric history Behavioral effects reported in 5–15% of patients; may require dose reduction or switch; pyridoxine (vitamin B6) may help irritability
Brivaracetam None established Similar to LEV but possibly lower rates of behavioral effects May be better tolerated than levetiracetam in patients with psychiatric vulnerability
Perampanel None established Irritability, aggression (dose-dependent), depression, hostility Psychiatric effects reported in 8–20% of patients; more common at doses ≥8 mg/day
Topiramate Reduced binge eating, mania; mood stabilization Depression, impaired cognition (word-finding, memory), attention difficulties, irritability Cognitive and mood effects are dose-dependent; significant impact on quality of life
Phenobarbital Anxiolytic, sedative Aggression, impaired cognition and attention, depression, irritability, decreased libido Most significant psychiatric adverse effect profile among older ASMs
Gabapentin/Pregabalin Anxiolytic, sedative, mood stabilizing Irritability, agitation (usually children with intellectual disability) Gabapentin is FDA-approved for generalized anxiety (in some countries); useful for comorbid neuropathic pain
Zonisamide Decreased mania Aggression, emotional lability, irritability, depression Psychiatric effects less common than topiramate but still notable

Antidepressant Safety in Epilepsy

A longstanding and largely unjustified concern among neurologists has been that antidepressants lower the seizure threshold. This fear has contributed to significant undertreatment of depression in epilepsy. Current evidence strongly supports that SSRIs, SNRIs, and most antidepressants at therapeutic doses do not meaningfully increase seizure risk. In fact, some evidence suggests that SSRIs may have anticonvulsant properties through serotonergic mechanisms.

Antidepressant Class Seizure Risk Specific Agents Notes
SSRIs Very low (may be anticonvulsant) Citalopram, escitalopram, sertraline (preferred in epilepsy); fluoxetine, paroxetine First-line for depression and anxiety in epilepsy; citalopram, escitalopram, sertraline minimize CYP450 interactions
SNRIs Very low Venlafaxine (ILAE second-line), duloxetine Appropriate alternative; venlafaxine has best evidence after SSRIs
Bupropion Dose-dependent; elevated at >450 mg/day Bupropion IR, SR, XL Immediate-release formulation has highest seizure risk; extended-release at ≤300 mg/day may be acceptable; use with caution
Tricyclic antidepressants Low at therapeutic doses; high in overdose Amitriptyline, nortriptyline, desipramine Seizure risk primarily in overdose; anticholinergic effects problematic
Clomipramine Elevated (∼1–2% at therapeutic doses) Clomipramine Highest seizure risk among tricyclics; avoid in epilepsy
Mirtazapine Low Mirtazapine Sedating; may benefit insomnia; weight gain

Suicidality & the FDA Warning

In 2008, the FDA issued a class-wide warning that all ASMs may increase the risk of suicidal ideation, suicide attempts, and completed suicide. This warning was based on a meta-analysis of 199 randomized controlled trials involving 11 ASMs, which found an odds ratio of 1.8 for suicidal ideation/behavior with ASMs compared to placebo. However, this warning has been extensively criticized and substantially undermined by subsequent evidence:

  • The original meta-analysis was driven primarily by topiramate trials in non-epilepsy indications (migraine, weight loss) and may not be generalizable to epilepsy populations
  • A 2021 meta-analysis by Klein et al. in JAMA Neurology examining 10 newer ASMs found no evidence of increased suicidality for any individual drug studied
  • Longitudinal studies demonstrate that peak suicidality occurs in the period shortly before ASM prescription (ie, when seizures are uncontrolled) rather than after starting treatment
  • The elevated baseline suicide risk in epilepsy (3–5-fold higher than the general population) is driven primarily by the disease itself, psychiatric comorbidities, and psychosocial burden — not by ASM treatment
  • Uncontrolled seizures and failure to treat psychiatric comorbidities pose greater risk than ASM-associated suicidality

Managing Suicidality Risk in Epilepsy

  • Screen for suicidality at every visit using the NDDI-E (validated for suicidality in epilepsy; item 4 specifically addresses thoughts of death)
  • Directly ask about suicidal ideation — this does not increase risk and is considered standard of care
  • Optimize seizure control — uncontrolled seizures are the greatest driver of psychiatric morbidity
  • Treat comorbid depression and anxiety aggressively with SSRIs and/or psychotherapy
  • Monitor patients initiating ASMs known to cause psychiatric effects (levetiracetam, perampanel, topiramate, phenobarbital) within the first 2–4 weeks
  • Refer to psychiatry for patients with active suicidal ideation, prior suicide attempts, or treatment-resistant depression
  • Do not withhold effective ASM therapy based solely on the 2008 FDA warning — the risk of uncontrolled seizures outweighs the theoretical ASM-related suicidality risk

Psychogenic Nonepileptic Events (PNES)

Psychogenic nonepileptic events (PNES, formerly “pseudoseizures”) are a critical differential diagnostic consideration in any epilepsy clinic. PNES are paroxysmal episodes of altered movement, sensation, or experience that resemble epileptic seizures but are not associated with epileptiform EEG correlates. They are classified as a functional neurological disorder (conversion disorder) and represent the second most common diagnosis made in epilepsy monitoring units, accounting for 20–40% of admissions.

Feature Epileptic Seizures PNES
Duration Usually <2 minutes (GTC); variable for focal Often prolonged (>2 minutes, may last 10–60 minutes)
Motor pattern Stereotyped; tonic phase → clonic phase with declining frequency Waxing/waning intensity; asynchronous movements; pelvic thrusting; side-to-side head movements
Eye closure Eyes usually open during GTC seizure Eyes frequently closed and may resist opening
Postictal confusion Typical after GTC; gradual recovery Variable; may have rapid return to baseline; crying common
Tongue biting Lateral tongue biting (specific for epilepsy) Tip of tongue biting (less specific)
Urinary incontinence Common in GTC Can occur (less specific than previously thought)
Prolactin elevation Elevated 15–20 minutes after GTC (sensitivity ~60%) Normal
EEG correlate Epileptiform activity during event No epileptiform activity; normal background or muscle artifact
Psychiatric history Variable PTSD, trauma history, dissociative symptoms common (60–80%)

Key Principles in PNES Management

  • Diagnosis: Video-EEG monitoring with capture of a typical event is the gold standard; semiologic features alone are insufficient for definitive diagnosis
  • Coexistence: 10–30% of patients with PNES also have epilepsy — both diagnoses should be considered; do not assume all events are PNES simply because one captured event was nonepileptic
  • Communication: Delivery of the diagnosis is therapeutic — frame as a recognized neurological condition, not “faking”; avoid the term “pseudoseizures”; use “functional seizures” or “nonepileptic events”
  • Treatment: CBT is the evidence-based treatment (NES Treatment Trial showed significant reduction in seizure frequency); SSRIs for comorbid depression/anxiety; gradual ASM withdrawal when epilepsy has been excluded
  • Emergency department: Avoid IV benzodiazepines for recognized PNES; unnecessary intubation has been reported; educate ED staff
  • Prognosis: With appropriate diagnosis and treatment, approximately 50% of patients achieve significant reduction in episodes within 1 year; poor prognostic factors include longer duration of misdiagnosis, comorbid personality disorder, and ongoing litigation

Impact of Psychiatric Comorbidities on Epilepsy Treatment Outcomes

Psychiatric comorbidities are not merely bystander conditions in epilepsy — they directly affect epilepsy treatment outcomes in multiple ways. Depression is associated with a 2–3-fold increased risk of ASM intolerance and treatment failure. Patients with comorbid depression or anxiety are significantly less likely to adhere to their ASM regimen. Psychiatric comorbidities predict poorer surgical outcomes: patients with preoperative depression or psychosis have lower rates of seizure freedom after epilepsy surgery. Depression is also an independent risk factor for SUDEP, potentially through mechanisms involving autonomic dysregulation and nocturnal seizure vulnerability.

The economic burden of psychiatric comorbidities in epilepsy is substantial. Patients with comorbid depression and epilepsy have significantly higher health care utilization (more hospitalizations, ED visits, and specialist consultations) and higher total health care costs compared with epilepsy patients without psychiatric comorbidity. These findings underscore that treating psychiatric comorbidities is not ancillary to epilepsy care but rather a core component of comprehensive epilepsy management that improves both seizure-related and non-seizure-related outcomes.

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