How does Wellbutrin (bupropion) affect the seizure threshold?

Wellbutrin (Bupropion) and Seizure Threshold

Bupropion is absolutely contraindicated in patients with seizure disorders because it lowers the seizure threshold through its effects on dopaminergic, adrenergic, and nicotinic acetylcholinergic receptor systems, and must be discontinued immediately if a patient experiences a seizure. 1, 2, 3

Mechanism of Seizure Risk

Bupropion reduces the seizure threshold through multiple mechanisms: effects on dopaminergic and adrenergic systems, plus inhibition of nicotinic acetylcholinergic receptors. 1 This pharmacologic action creates dose-dependent seizure risk that increases substantially at higher doses. 3

Absolute Contraindications

Bupropion is contraindicated in all patients with:

• Any history of seizure disorder 2, 3
• Conditions that predispose to seizures, including: 1, 3
  • Arteriovenous malformation 1, 3
  • CNS tumor or CNS infection 3
  • Severe head injury 3
  • Severe stroke 3
  • Anorexia nervosa or bulimia (which have documented higher seizure incidence) 1, 3
  • Brain metastases 1

This contraindication applies regardless of formulation—whether prescribed as Wellbutrin for depression, Zyban for smoking cessation, or naltrexone-bupropion ER (Contrave) for obesity. 2

Dose-Dependent Seizure Risk

The seizure incidence varies dramatically by dose: 3, 4

• At ≤300 mg/day: approximately 0.1% (1/1,000 patients) 3
• At 300-450 mg/day: approximately 0.4% (4/1,000 patients) 3, 4
• At 450-600 mg/day: risk increases nearly tenfold 3

The maximum dose must never exceed 450 mg once daily for extended-release formulations. 3

High-Risk Clinical Situations

Use extreme caution or avoid bupropion entirely in patients with: 5, 1, 3

Metabolic Disorders

• Hypoglycemia 1, 3
• Hyponatremia 1, 3
• Severe hepatic impairment 1, 3
• Hypoxia 1, 3

Diabetes Management

• Diabetes mellitus treated with oral hypoglycemics or insulin 1, 3

Substance Use/Withdrawal

• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 3
• Use of illicit drugs (e.g., cocaine) 3
• Abuse or misuse of CNS stimulants 3
• Excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates 3

Concomitant Medications That Lower Seizure Threshold

• Other bupropion products 3
• Antipsychotics 3, 6
• Tricyclic antidepressants 3
• Theophylline 3
• Systemic corticosteroids 3
• Clozapine (particularly high risk—clozapine alone has 10% cumulative seizure risk at 3.8 years; combination with bupropion may have additive or synergistic effects) 6

Other Risk Factors

• Use of anorectic drugs 1, 3
• Untreated hyperthyroidism (when combined with phentermine formulations) 5

Guideline Recommendations Across Specialties

Multiple specialty societies uniformly recommend avoiding bupropion in seizure-prone patients: 5, 1, 2

• American Gastroenterological Association: "should be avoided in patients with seizure disorders and used with caution in patients at risk of seizures" 5
• American Diabetes Association: "contraindicated in patients with uncontrolled hypertension and/or seizure disorders" 5
• National Comprehensive Cancer Network: explicitly recommends avoiding bupropion in patients with seizure history or elevated seizure risk 1
• American College of Gastroenterology: bupropion "should not be used in patients with a history of seizures" 2

Clinical Cases and Real-World Evidence

Seizures can occur even in patients without traditional risk factors: 7, 8

• A 66-year-old woman with no personal or family seizure history developed new-onset seizures 4 days after starting bupropion for smoking cessation 7
• A 25-year-old woman with no premorbid epilepsy history had a witnessed generalized convulsion at a modest blood level (83 ng/ml) and dose (600 mg/day) 8
• Three patients developed generalized tonic-clonic seizures within days of starting bupropion 300 mg/day, with two having no seizure history 9

Management Algorithm If Seizure Occurs

If a patient on bupropion experiences a seizure: 2, 3

1. Discontinue bupropion immediately and do not restart 3
2. Consider alternative treatments based on indication: 2
   • For depression: SSRIs, mirtazapine, or nortriptyline 2
   • For smoking cessation: nicotine replacement therapy or varenicline 2
   • For obesity: GLP-1 agonists 2

Risk Mitigation Strategies

If bupropion must be used despite risk factors (though generally not recommended): 3

• Use low initial doses 3
• Increase dose gradually 3
• Never exceed 450 mg once daily 3
• Monitor closely for neuropsychiatric symptoms 3

Critical Pitfall to Avoid

Do not assume safety based on absence of personal seizure history. Case reports demonstrate that new-onset seizures can occur in patients with no personal or family history of seizures, no predisposing neurological conditions, and at therapeutic doses and blood levels. 7, 8, 9 The drug's pharmacologic mechanism of lowering seizure threshold operates independently of pre-existing vulnerability in some patients.