What is the recommended tapering schedule for fluoxetine and how should I transition to bupropion (Wellbutrin)?

Transitioning from Fluoxetine to Bupropion

Due to fluoxetine's exceptionally long half-life (4–6 days for the parent drug and 4–16 days for its active metabolite norfluoxetine), you can stop fluoxetine abruptly without tapering and start bupropion immediately—no washout period is required for safety, though monitoring for overlapping side effects is prudent. 1, 2

Why Fluoxetine Does Not Require Tapering

• Fluoxetine's pharmacokinetic profile essentially eliminates withdrawal risk because the drug and its active metabolite decline gradually over weeks, creating a "self-tapering" effect that prevents the abrupt receptor changes seen with shorter-acting antidepressants 1, 3.
• Studies demonstrate that fluoxetine can be dosed as infrequently as once weekly or even once every third day due to this prolonged elimination, confirming that abrupt cessation does not trigger discontinuation symptoms 2, 4, 5.
• In contrast, antidepressants with shorter half-lives (paroxetine, venlafaxine, duloxetine) require gradual dose reductions of 10–25% every 1–2 weeks to avoid withdrawal symptoms such as dizziness, nausea, anxiety, and sensory disturbances 3, 6.

Recommended Transition Protocol

Step 1: Stop Fluoxetine Immediately

• Discontinue fluoxetine on day 1 without dose reduction—the long half-life provides built-in protection against withdrawal 1, 3.
• Inform the patient that fluoxetine will remain in their system for 4–6 weeks after the last dose, so any residual effects (therapeutic or adverse) will fade gradually 1, 2.

Step 2: Start Bupropion on the Same Day

• Initiate bupropion 37.5 mg every morning on day 1, then increase by 37.5 mg every 3 days as tolerated 7.
• Target dose is typically 150 mg twice daily (maximum for depression/anxiety management in older guidelines), though current practice often uses 300–450 mg/day divided into two doses 7.
• Give the second daily dose before 3 p.m. to minimize insomnia risk, as bupropion is activating 7.

Step 3: Monitor for Overlapping Effects During Weeks 1–6

• Fluoxetine's serotonergic effects will persist for several weeks while bupropion's noradrenergic/dopaminergic effects build, creating a brief period of dual-mechanism exposure 1, 2.
• Watch for activation symptoms (anxiety, agitation, insomnia) during the first 2–3 weeks, as both drugs can be stimulating—if these emerge, slow bupropion titration or hold at the current dose 7.
• Avoid adding benzodiazepines for transient anxiety, as this introduces new withdrawal risks; instead, use sleep hygiene education, trazodone 25–50 mg at bedtime for insomnia, or brief cognitive-behavioral interventions 6, 7.

Critical Safety Considerations

Seizure Risk with Bupropion

• Do not use bupropion in patients with seizure disorders, eating disorders (anorexia/bulimia), or abrupt alcohol/benzodiazepine discontinuation, as these conditions lower the seizure threshold 7.
• The seizure risk is dose-dependent: keep total daily dose ≤450 mg and individual doses ≤150 mg (immediate-release) or ≤200 mg (sustained-release) 7.

Drug Interactions

• Fluoxetine is a potent CYP2D6 inhibitor, which can elevate levels of drugs metabolized by this enzyme (e.g., tricyclic antidepressants, certain beta-blockers, antipsychotics) 1.
• Review the patient's medication list and anticipate that CYP2D6 substrates may require dose adjustments over the next 4–6 weeks as fluoxetine clears 1.

When to Avoid This Direct Switch

• If the patient has been on fluoxetine for severe depression with psychotic features, coordinate the switch with a psychiatrist, as bupropion lacks efficacy for psychotic depression and the patient may need concomitant antipsychotic coverage 7.
• If the patient is taking multiple CNS-active medications (e.g., opioids, benzodiazepines), prioritize tapering those agents first due to higher withdrawal and overdose risks before addressing the antidepressant switch 8.

Expected Timeline and Outcomes

• Week 1–2: Fluoxetine's therapeutic effects remain present; bupropion begins to exert mild activating effects. Patients may notice improved energy before mood fully lifts 7, 1.
• Week 3–4: Fluoxetine levels decline to ~50% of steady-state; bupropion reaches therapeutic levels. This is the highest-risk window for activation symptoms 1, 7.
• Week 6–8: Fluoxetine is essentially cleared; bupropion monotherapy is established. Full antidepressant response to bupropion typically requires 4–8 weeks at target dose 7.

Common Pitfalls to Avoid

• Do not taper fluoxetine unnecessarily—this prolongs the transition without clinical benefit and may confuse the patient about which drug is causing which effect 1, 3.
• Do not rush bupropion titration to compensate for stopping fluoxetine; the gradual 3-day increment schedule minimizes seizure risk and allows tolerance assessment 7.
• Do not abandon the patient if activation symptoms emerge—slow the titration, optimize sleep hygiene, and provide reassurance that these effects typically resolve within 2–3 weeks 7, 6.

Monitoring Requirements

• Follow up within 1–2 weeks after initiating bupropion to assess tolerability, sleep, anxiety, and energy levels 6.
• Monthly visits are appropriate once the target bupropion dose is reached, with screening for mood changes, suicidal ideation, and substance use 6.
• Document the transition plan in the medical record, including the rationale for no fluoxetine taper and the bupropion titration schedule, to ensure continuity if the patient sees another provider 6.