Bupropion

The defining safety concern. Risk increases above 450mg/day and is highest with IR, intermediate with SR, and lowest with XL formulations. At recommended doses of SR and XL, seizure incidence is low (often cited around 0.1%), but rises meaningfully with higher doses and patient risk factors. Contraindicated in seizure disorders and eating disorders (bulimia, anorexia nervosa). Also avoid during active alcohol or benzodiazepine withdrawal. Assess all seizure risk factors before prescribing.

Related to norepinephrine and dopamine enhancement. Morning dosing (or morning + early afternoon for SR) can help. This activation is therapeutic for some patients (fatigue-predominant depression) and intolerable for others (anxious depression). Screen for anxiety before prescribing.

Bupropion lacks the serotonergic effects that help with anxiety. In patients with comorbid anxiety, bupropion monotherapy can worsen anxiety symptoms. This is why SSRI + bupropion is often better than bupropion alone for depressed patients with significant anxiety.

Any antidepressant can precipitate hypomania or mania in vulnerable patients. Bupropion is often considered lower risk for mood switching than some serotonergic antidepressants, but the risk is not zero. Screen for bipolar spectrum before prescribing and consider mood stabilizer coverage when indicated.

Common. Usually manageable. Rarely a reason to discontinue.

Often self-limiting within the first 1-2 weeks. If persistent, usually responds to dose adjustment.

Driven by dopaminergic effects on appetite. Weight loss is often modest, typically a few pounds. This is why bupropion is incorporated into Contrave for weight management. Clinically meaningful weight loss is not guaranteed but is more likely with bupropion than any other antidepressant.

The most significant differentiator from SSRIs and SNRIs. Bupropion causes significantly less sexual dysfunction than SSRIs and SNRIs, with rates often near placebo levels. This makes it the first-line augmentation choice when SSRI-induced sexual dysfunction is the problem.

Bupropion has minimal serotonergic activity and does not meaningfully increase serotonin syndrome risk by itself. In combinations, the risk comes from the serotonergic agents (SSRIs, SNRIs, MAOIs, tramadol, etc.). Bupropion can still matter indirectly, its strong CYP2D6 inhibition may raise levels of co-prescribed serotonergic medications, which could increase their serotonergic effects. The interaction is pharmacokinetic, not pharmacodynamic.