What are your thoughts on using bupropion (an antidepressant) to treat persistent anhedonia after discontinuing antipsychotics?

Bupropion for Post-Antipsychotic Anhedonia

Bupropion is a reasonable treatment option for persistent anhedonia after antipsychotic discontinuation, given its unique dopaminergic mechanism that directly targets reward circuitry dysfunction, though evidence specific to this indication remains limited.

Mechanistic Rationale

Bupropion's mechanism makes it theoretically well-suited for anhedonia:

• Bupropion acts as a norepinephrine and dopamine reuptake inhibitor, uniquely among antidepressants, which directly addresses the dopaminergic reward pathway dysfunction underlying anhedonia 1, 2
• The medication has no appreciable serotonergic activity, distinguishing it from SSRIs that are less effective for anhedonia 2, 3
• Recent evidence identifies bupropion as one of the most promising anti-anhedonic agents alongside vortioxetine, agomelatine, ketamine, and brexpiprazole, while traditional SSRIs and SNRIs show minimal benefit for this specific symptom 3

Clinical Evidence for Anhedonia

• A 2025 narrative review specifically examining anhedonia treatments lists bupropion among drugs showing promising anti-anhedonic effects, based on its dopaminergic mechanism 3
• A 2022 case series demonstrated that bupropion successfully treated negative symptoms including anhedonia in three patients with schizophrenia after antipsychotic treatment controlled positive symptoms 4
• The medication has demonstrated efficacy equivalent to SSRIs and SNRIs for major depression with superior tolerability, particularly regarding sexual function and sedation 5, 6

Practical Dosing Protocol

Start conservatively and titrate based on response:

• Begin with 150 mg once daily (sustained-release formulation) for 3 days, then increase to 150 mg twice daily (300 mg total daily dose) 1
• Maximum dose is 400 mg/day for sustained-release or 450 mg/day for extended-release formulations 1, 7, 2
• Expect initial response within 2 weeks, with full therapeutic effect at 4-6 weeks 2

Critical Safety Considerations

Absolute contraindications that must be ruled out:

• Seizure disorders or any history of seizures - this is an absolute contraindication as bupropion lowers seizure threshold with a 0.1% risk at therapeutic doses 8, 1, 7, 9
• Current or recent MAOI use (within 14 days) 7, 9
• Eating disorders (anorexia or bulimia) - these conditions increase seizure risk 1, 7
• Abrupt discontinuation of alcohol or sedatives - withdrawal states increase seizure risk 1

Important monitoring requirements:

• Monitor blood pressure and heart rate regularly, especially during the first 12 weeks, as bupropion can cause hypertension 7, 9
• Assess for neuropsychiatric symptoms within 1-2 weeks of initiation, including agitation, irritability, or unusual behavioral changes 8
• Evaluate therapeutic response at 6-8 weeks and modify treatment if inadequate response 8

Tolerability Advantages

Bupropion offers specific benefits relevant to post-antipsychotic patients:

• Lowest sexual dysfunction rate (~8%) among antidepressants, compared to much higher rates with SSRIs 8, 1, 5
• No weight gain or sedation, unlike many antipsychotics and other antidepressants 5, 6
• May provide dual benefit if smoking cessation is also needed, with proven efficacy (OR 2.07 vs placebo) 8, 1, 9

Common Side Effects

Expect these manageable effects:

• Disturbed sleep, dry mouth, headaches, and nausea are most common but generally well-tolerated and do not typically require discontinuation 8, 9
• Agitation, insomnia, and tremor may occur, particularly at higher doses 2
• These side effects are generally self-limited with resolution in 4-5 days for most patients 2

Clinical Caveats

Important limitations to acknowledge:

• Direct evidence for post-antipsychotic anhedonia specifically is limited - most data comes from depression trials and one small case series in schizophrenia 3, 4
• If no response by 6-8 weeks, consider alternative strategies such as combination therapy or switching to other anti-anhedonic agents like vortioxetine or agomelatine 8, 3
• Dose must be gradually titrated - never start at maximum dose due to dose-dependent seizure risk 2