What is the best approach to treating a patient with comorbid depression and epilepsy?

Treatment of Depression Comorbid with Epilepsy

For patients with comorbid depression and epilepsy, optimize seizure control first with appropriate antiepileptic drugs, then treat moderate-to-severe depression with SSRIs (sertraline, citalopram, or escitalopram) or SNRIs, while avoiding bupropion, clomipramine, maprotiline, and amoxapine. 1, 2, 3

Initial Management Priorities

Step 1: Optimize Seizure Control

• Achieve optimal seizure control as the foundational step before addressing depression, as some antiepileptic drugs (AEDs) have mood-stabilizing properties that may improve depressive symptoms 4, 5
• Consider AEDs with demonstrated mood improvement: valproate, carbamazepine, lamotrigine, gabapentin, or pregabalin 4, 3
• Minimize AED-related side effects, as these can worsen mood and quality of life 5
• Use antiepileptic drug monotherapy at the minimum effective dose when possible 1

Step 2: Screen and Diagnose Depression

• Use validated screening tools like the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to identify depression regardless of social or personal circumstances 6, 5
• Look for cardinal depressive symptoms: persistent depressed mood for at least 2 weeks, plus at least 4 of the following: appetite changes, sleep disturbances, psychomotor changes, loss of interest, fatigue, guilt/worthlessness, impaired concentration, or suicidal ideation 1
• Screen for suicidal ideation, as depression in epilepsy carries significant suicide risk 1

Pharmacological Treatment Algorithm

For Mild Depression

• Do not initiate antidepressants for mild depressive episodes 1
• Consider psychological interventions first (see below) 1
• If an AED change is needed, preferentially select one with mood-stabilizing properties (valproate, lamotrigine, carbamazepine) 4, 3

For Moderate-to-Severe Depression

First-line antidepressants (in order of evidence strength):

• Sertraline: Best evidence for efficacy and safety in epilepsy 2, 3
• Citalopram: Strong safety profile with low seizure risk 2, 3
• Escitalopram: Recommended as first-line SSRI 3
• Mirtazapine: Alternative with good safety data 2, 3
• Other acceptable options: Paroxetine, fluoxetine, fluvoxamine, venlafaxine, duloxetine, reboxetine 3

Antidepressants to AVOID in epilepsy:

• Bupropion: Significantly lowers seizure threshold 2, 3
• Clomipramine: High seizure risk 3
• Maprotiline: High seizure risk 3
• Amoxapine: Not recommended 3

Dosing Principles

• Start low, go slow, and use the lowest effective dose 2
• Monitor closely for suicidal thoughts/behaviors, especially in the first few months or when changing doses 7
• Continue antidepressant treatment for 9-12 months after recovery 1

Key Drug Interaction Considerations

• SSRIs and SNRIs have minimal problematic interactions with modern AEDs 5
• Concerns about antidepressants lowering seizure threshold are often overestimated and rarely outweigh the risk of untreated depression 2, 5
• The majority of antidepressant-related seizures occur with ultra-high doses or overdosing 3
• Monitor for serotonin syndrome if combining multiple serotonergic agents 7

Psychological and Behavioral Interventions

First-line Psychological Treatments

• Cognitive Behavioral Therapy (CBT): Proven effective in well-controlled trials for depression in epilepsy 1, 6, 5
• Interpersonal therapy: Recommended for depressive episodes in non-specialized settings 1
• Problem-solving treatment: Consider as adjunct in moderate-to-severe depression 1
• Online self-treatment programs: Underutilized but effective option 5

Adjunctive Interventions

• Relaxation training and physical activity: May be considered as adjunct treatment in moderate-to-severe depression 1
• Psychoeducational programs and family counseling: Recommended as adjunctive treatment for epilepsy 1
• Patient support groups: Valuable therapeutic option 6

Alternative and Adjunctive Therapies

Vagus Nerve Stimulation (VNS)

• Consider VNS for patients with refractory partial epilepsy and refractory depression, as it may benefit both conditions 4, 6
• Note: Efficacy for mood improvement in epilepsy patients remains unclear 2

Electroconvulsive Therapy (ECT)

• Not contraindicated for treatment-resistant or psychotic depression in epilepsy 4
• May have protective effect on suicide risk, particularly in severe depression with psychotic features 1

Referral Criteria

Refer to mental health specialists when:

• Depression is severe or difficult-to-treat 5
• Patient is acutely suicidal 5
• Treatment-resistant depression develops (multiple failed antidepressant trials) 1
• Complex psychiatric comorbidities exist (anxiety, substance use) 1

Critical Monitoring Parameters

Safety Monitoring

• Suicidal ideation: Especially during first few months of antidepressant treatment or dose changes 7
• New or worsening symptoms: Agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania 7
• Seizure frequency: Monitor for any changes after initiating antidepressants 2
• Serotonin syndrome symptoms: Agitation, hallucinations, tachycardia, hyperthermia, hyperreflexia, incoordination 7
• Bleeding risk: If patient takes anticoagulants, NSAIDs, or aspirin 7

Common Pitfalls to Avoid

• Do not withhold antidepressants due to unfounded fears about seizure threshold - the risk of untreated depression far exceeds the minimal seizure risk with modern antidepressants 2, 5
• Do not use benzodiazepines for initial treatment of depressive symptoms 1
• Do not stop antidepressants abruptly - taper gradually to avoid withdrawal symptoms 7
• Do not overlook depression screening - depression is commonly unrecognized in epilepsy patients 4, 2