Amitriptyline × Bupropion

The combination works along two lines. Kinetics: bupropion and its metabolite hydroxybupropion inhibit CYP2D6 (bupropion SmPC), an enzyme that clears amitriptyline. The amitriptyline SmPC names bupropion as a potent CYP2D6 inhibitor that can markedly raise tricyclic levels. With another tricyclic, desipramine, bupropion increased peak concentration and AUC 2- to 5-fold, and the enzyme stayed inhibited for at least 7 days after the last bupropion dose (bupropion SmPC). Seizures: bupropion seizure risk is dose-related and rises with drugs that lower the seizure threshold, antidepressants included (bupropion labels).

Seizures: their risk rises when bupropion is combined with antidepressants (bupropion labels). Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat and dizziness on standing. High amitriptyline levels can cause arrhythmias, QT prolongation and marked hypotension (amitriptyline SmPC). Bupropion itself can cause insomnia and dry mouth (bupropion SmPC).

Use the combination only when it is clinically justified. The bupropion SmPC for smoking cessation says bupropion should not be used in patients taking antidepressants unless there is a justified clinical reason, and then a maximum of 150 mg a day should be considered for the rest of the course. The FDA bupropion label asks for extreme caution, a low starting dose of bupropion and gradual increases, up to 300 mg a day. Assess seizure risk factors in every patient before starting. Bupropion is contraindicated with a current or past seizure disorder, a central nervous system tumour, bulimia or anorexia nervosa. If a seizure occurs, stop bupropion and do not restart it (bupropion labels). When bupropion is added to amitriptyline, consider a lower amitriptyline dose based on response and monitoring of its plasma level (amitriptyline SmPC). Bupropion keeps inhibiting the enzyme for at least 7 days after it is stopped, which matters when doses are changed (bupropion SmPC).