Bupropion

Bupropion is a noradrenaline and dopamine reuptake inhibitor, an aminoketone antidepressant, used for major depression, seasonal affective disorder prevention and smoking cessation. It has no serotonergic effect, so it rarely causes sexual dysfunction or weight gain, but it lowers the seizure threshold in a dose-related way and strongly inhibits CYP2D6.

Classification. Aminoketone antidepressant, noradrenaline and dopamine reuptake inhibitor.

Mechanism. Weak inhibition of dopamine and noradrenaline reuptake, plus noncompetitive antagonism of nicotinic acetylcholine receptors, which helps smoking cessation.

Pharmacokinetics. Rapidly absorbed. Metabolised by CYP2B6 to hydroxybupropion (active, the main circulating compound), with other active metabolites that are cleared renally. Half-life about 21 hours (hydroxybupropion about 20 hours). Metabolites accumulate in kidney impairment.

All regimens are oral with no loading dose.

Major depression, adults (sustained-release).

• Start 150 mg each morning for 3 days, then 150 mg twice daily with at least 8 hours between doses.
• Maximum 400 mg daily, with no single dose over 200 mg.
• Duration: at least 6 months after remission.

Major depression, adults (extended-release).

• Start 150 mg each morning; increase to 300 mg after at least 4 days.
• Maximum 450 mg daily as a single morning dose.

Seasonal affective disorder prevention. Extended-release 150 mg each morning, started before symptoms begin in autumn, increased to 300 mg after 1 week if tolerated, then reduced to 150 mg for 2 weeks before stopping in early spring.

Smoking cessation. Sustained-release 150 mg each morning for 3 days, then 150 mg twice daily. Start 1 to 2 weeks before the quit date. Treat for 7 to 12 weeks; stop if no abstinence by week 7. Maximum 300 mg daily.

Dose limits. Severe liver impairment: maximum 150 mg every other day. Mild to moderate liver impairment and creatinine clearance under 90 mL/min: reduce the dose or frequency.

Contraindications. Seizure disorder, current or past bulimia or anorexia nervosa, abrupt withdrawal from alcohol, benzodiazepines, barbiturates or antiepileptic drugs, CNS tumour, recent severe head injury, MAOI use now or within 14 days of stopping it, hypersensitivity, use with other bupropion products.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Seizures (about 0.1% at up to 300 mg daily and about 0.4% at 450 mg daily), hypertension, psychosis and agitation, mania, angle-closure glaucoma, serum sickness-like reactions, severe hypersensitivity.

Common adverse effects. Insomnia, dry mouth, headache, nausea, anxiety, tremor, constipation, raised blood pressure, weight loss.

Interactions. Strong CYP2D6 inhibition raises tricyclic antidepressants, metoprolol, risperidone, haloperidol and flecainide, and reduces the activation of tamoxifen and codeine. Clopidogrel and ticlopidine inhibit CYP2B6 and raise bupropion. Ritonavir, efavirenz, carbamazepine and rifampicin lower levels. Tramadol, antipsychotics, theophylline, systemic corticosteroids and quinolones add seizure risk. Alcohol lowers the seizure threshold. Khat adds sympathomimetic load.

Common prescribing errors. Dosing over 450 mg daily; giving single sustained-release doses over 200 mg; evening dosing causing insomnia; prescribing in eating disorders or alcohol dependence withdrawal.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk.
• Breastfeeding: transfers into milk and rare infant seizures are reported; use with caution.
• Children: not advised in under 18 years.
• Older adults: start 150 mg; check blood pressure.
• Kidney impairment: reduce dose or frequency when creatinine clearance is under 90 mL/min.
• Liver impairment: reduce the dose or frequency in mild to moderate impairment; maximum 150 mg every other day in severe impairment.

Formulations. Sustained-release tablets 100 mg and 150 mg; extended-release tablets 150 mg and 300 mg. Swallow whole; do not crush, chew or split. Give the last daily dose before mid-afternoon to limit insomnia.

Baseline. Seizure history and risk factors, alcohol and sedative use, eating disorder history, blood pressure, mood history including past mania, suicide risk, pregnancy status, medicines list.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality, agitation and seizure risk. Check blood pressure at each review, particularly if combined with nicotine replacement. For smoking cessation, review at 1 to 2 weeks and at the quit date.

Stopping. Taper is not required for the depression indication, but reduce gradually if the dose is over 300 mg daily.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. A seizure needs emergency care and permanent withdrawal of the drug.