What medications, including antidepressants (e.g. bupropion) and antipsychotics (e.g. clozapine), lower the seizure threshold in patients with or without a history of seizure disorders?

Medications That Lower Seizure Threshold

Multiple medication classes lower the seizure threshold, with antipsychotics (especially clozapine), bupropion, and certain other antidepressants posing the highest risk, requiring careful consideration before prescribing to any patient.

Antipsychotics

Highest Risk Agents

• Clozapine carries the most significant seizure risk among all antipsychotics, with approximately 3-5% of patients experiencing seizures at therapeutic doses, increasing to 5% at high doses 1, 2.
• The seizure risk with clozapine is dose-dependent and increases particularly when dosage changes are made rapidly 1.
• Chlorpromazine has the greatest seizure risk among first-generation antipsychotics and should be avoided when seizure risk is a concern 2, 3.

Lower Risk Antipsychotics

• Haloperidol, fluphenazine, pimozide, trifluoperazine, and molindone are associated with lower seizure risk 3.
• Risperidone confers relatively low seizure risk when used at appropriate doses (≤6 mg/24h) 2, 3.
• Aripiprazole demonstrates minimal seizure risk 2.
• All antipsychotic medications can lower seizure threshold in a dose-dependent manner, though seizures are rare (usually <1%) at therapeutic doses except for clozapine 1.

Antidepressants

Bupropion

• Bupropion has an estimated seizure risk of 0.4% at recommended doses (up to 300 mg/day), increasing to 1/1000 at 300 mg/day 4, 5, 6.
• The FDA label explicitly warns to use extreme caution when coadministering bupropion with other drugs that lower seizure threshold 4.
• Seizures can occur even in patients without personal or family history of seizure disorders 5, 6.
• The combination of bupropion with clozapine is particularly concerning, as both agents lower seizure threshold and may have additive or synergistic effects 7.

Other Antidepressants

• Tricyclic antidepressants (TCAs) carry relatively high seizure risk (0.4% to 1-2%) at effective therapeutic doses 8.
• Selective serotonin reuptake inhibitors (SSRIs) have low seizure risk (0.0%-0.4%), similar to the general population incidence 8.
• Venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline are metabolized by CYP2D6 and may have altered exposures when combined with bupropion 4.

Other Medication Classes

Commonly Prescribed Agents

• Theophylline is known to prolong seizure duration at both therapeutic and toxic levels 1.
• Systemic corticosteroids lower seizure threshold 4.
• Tramadol can lower seizure threshold 1.
• Trazodone has been associated with prolonged seizures during electroconvulsive therapy 1.

Substances of Abuse

• Cocaine lowers seizure threshold 1.
• Alcohol withdrawal can precipitate seizures in susceptible individuals 1.

Critical Clinical Considerations

Risk Factors That Compound Medication Effects

• History of seizure disorders or epilepsy 1.
• Concurrent use of multiple medications that lower seizure threshold 3.
• Rapid dose titration 1, 3.
• Metabolic factors including hypocalcemia, hypomagnesemia, and fever 1.
• Drug-drug interactions affecting metabolism 3.
• Recent discontinuation of benzodiazepines (which may have been providing seizure protection) 5.

Management Strategies

• When clozapine is necessary, use a "start low, go slow" approach and consider prophylactic anticonvulsant medication 1.
• Use low initial doses and increase gradually when prescribing medications that lower seizure threshold 4.
• Avoid combining multiple seizure threshold-lowering agents whenever possible 7.
• Do not exceed maximum recommended doses: bupropion should not exceed 300 mg daily to minimize seizure risk 9, 4.
• Monitor patients closely, particularly during dose initiation and titration 1.

Specific Drug Interactions

• Carbamazepine, phenobarbital, and phenytoin may decrease bupropion exposure through CYP450 induction, potentially requiring dose adjustment 4.
• Amoxicillin should be used cautiously with bupropion and other agents lowering seizure threshold 1.
• Benzodiazepines may increase seizure threshold and can complicate electroconvulsive therapy 1.

Common Pitfalls to Avoid

• Do not assume patients without seizure history are immune to medication-induced seizures—new-onset seizures can occur in previously unaffected individuals 5, 6.
• Avoid prescribing bupropion to patients already on clozapine; safer alternatives that do not lower seizure threshold should be utilized 7.
• Do not overlook metabolic causes (hypocalcemia, hypomagnesemia) that may synergistically increase seizure risk with medications 1.
• Recognize that seizure risk is often dose-dependent—exceeding recommended doses significantly increases risk 1, 4.