What medication is recommended for anxiety and insomnia in a patient with a history of seizures on Keppra (levetiracetam)?

Medication for Anxiety and Insomnia in a Patient with Seizures on Keppra

For a patient with seizures on levetiracetam (Keppra), use ramelteon 8 mg for sleep onset insomnia or low-dose doxepin 3-6 mg for sleep maintenance insomnia, combined with Cognitive Behavioral Therapy for Insomnia (CBT-I), while avoiding benzodiazepines due to their seizure threshold-lowering effects and potential for withdrawal seizures. 1

First-Line Treatment Approach

Initiate CBT-I immediately as the foundation of treatment, as it provides superior long-term outcomes for insomnia without medication risks and can be delivered through individual therapy, group sessions, telephone-based programs, or web-based modules. 1 CBT-I includes stimulus control therapy (using bed only for sleep, leaving bed if unable to sleep within 20 minutes), sleep restriction therapy, relaxation techniques, and cognitive restructuring of negative thoughts about sleep. 2, 1

Optimal Pharmacotherapy Selection

For Sleep Onset Insomnia

Ramelteon 8 mg taken 30 minutes before bedtime is the safest first-line choice because it:

• Has no effect on seizure threshold and does not interact with levetiracetam 1
• Shows no evidence of rebound insomnia or withdrawal effects even after six months of nightly use 3
• Has no DEA scheduling, making it appropriate for patients with substance use concerns 2
• Demonstrates no next-day impairment or cognitive effects 3

For Sleep Maintenance Insomnia

Low-dose doxepin 3-6 mg at bedtime is the preferred option because it:

• Reduces wake after sleep onset by 22-23 minutes with moderate-quality evidence 1
• Has minimal anticholinergic effects at these low doses (unlike higher antidepressant doses) 1
• Does not lower seizure threshold at these doses 1
• Shows no significant adverse events compared to placebo at 6 mg 3

For Combined Sleep Onset and Maintenance Issues

Consider combining ramelteon 8 mg with doxepin 3-6 mg, as this combination is explicitly recommended by the American Academy of Sleep Medicine for patients when initial treatments are unsuccessful. 3 This targets both sleep initiation (ramelteon) and maintenance (doxepin) through complementary mechanisms without significant drug interactions. 3

Critical Medications to AVOID

Benzodiazepines (Lorazepam, Clonazepam, Diazepam)

Do not use benzodiazepines in this patient because:

• They lower seizure threshold and can precipitate breakthrough seizures 2
• Withdrawal from benzodiazepines causes seizures, creating a dangerous cycle in epilepsy patients 4
• They cause significant cognitive impairment, falls, respiratory depression, and dependence 2, 1
• The American Academy of Sleep Medicine explicitly recommends against benzodiazepines as first-line treatment for insomnia 1

Z-Drugs (Zolpidem, Eszopiclone, Zaleplon)

While these are first-line for primary insomnia 2, 1, exercise caution in seizure patients as they carry risks of:

• Complex sleep behaviors (sleep-driving, sleep-walking) 1
• Potential seizure threshold effects (though less than benzodiazepines) 1
• Cognitive and psychomotor impairment 1

If Z-drugs are necessary, use the lowest doses: zolpidem 5 mg (not 10 mg), zaleplon 5 mg, or eszopiclone 1-2 mg. 1

Over-the-Counter Antihistamines

Never recommend diphenhydramine or other antihistamines because:

• They lack efficacy data for insomnia 2, 1
• They cause significant daytime sedation and delirium risk, especially in elderly patients 1
• They have problematic anticholinergic effects 1

Anxiety Management Considerations

For comorbid anxiety, consider adding or switching to a sedating antidepressant such as:

• Mirtazapine 7.5-15 mg at bedtime (lower doses are more sedating) for combined anxiety, depression, and insomnia 1
• Sertraline or escitalopram during the day for anxiety, combined with ramelteon or low-dose doxepin at night 1

Important: Levetiracetam itself can cause behavioral adverse effects including anxiety and mood changes in some patients (10-15% incidence). 5, 6 If anxiety worsened after starting Keppra, discuss with the prescribing neurologist whether this is medication-related.

Levetiracetam-Specific Considerations

Levetiracetam has several unique properties relevant to this case:

• Does not interact with GABA systems (unlike benzodiazepines), making it mechanistically distinct 7, 5
• No cytochrome P450 interactions, so it does not interact with most psychiatric medications 5
• May have anxiolytic properties in some contexts, though data are preliminary 6, 4
• Generally has no effect on sleep architecture when used for seizures 8
• Can cause behavioral side effects including anxiety, irritability, and mood changes in 10-15% of patients 5, 6

Implementation Algorithm

1. Start CBT-I immediately with all patients, regardless of medication decisions 1
2. Assess primary sleep complaint:
   • Sleep onset difficulty → Ramelteon 8 mg 1
   • Sleep maintenance difficulty → Doxepin 3-6 mg 1
   • Both → Consider combination therapy 3
3. Reassess after 1-2 weeks for efficacy on sleep latency, maintenance, and daytime functioning 1
4. Monitor for adverse effects: morning sedation, cognitive impairment, or complex sleep behaviors 1
5. Use lowest effective dose for shortest duration, with goal of tapering once CBT-I effects are established 1

Common Pitfalls to Avoid

• Never prescribe benzodiazepines to patients with seizure disorders due to withdrawal seizure risk and seizure threshold lowering 2, 4
• Do not use trazodone, as it is explicitly not recommended by the American Academy of Sleep Medicine for insomnia (harms outweigh benefits) 1
• Avoid combining multiple sedating medications without careful monitoring, as this significantly increases fall risk and cognitive impairment 1
• Do not prescribe sleep medications without implementing CBT-I, as behavioral interventions provide more sustained effects 1
• Never use barbiturates (phenobarbital) for insomnia in this context, despite their antiepileptic properties, due to severe respiratory depression and hypotension risks 2

Monitoring and Follow-Up

• Assess treatment response at 1-2 weeks focusing on sleep onset latency, wake after sleep onset, total sleep time, and daytime functioning 1
• Monitor for medication side effects including daytime sedation, dizziness, cognitive changes, and complex sleep behaviors 1, 3
• Coordinate with neurology to ensure seizure control remains stable and that psychiatric medications do not interfere with antiepileptic therapy 5
• Reassess need for continued pharmacotherapy every 3-6 months, with goal of tapering medication as CBT-I effects consolidate 1