How do I taper from sertraline (Zoloft) to bupropion (Wellbutrin)?

Tapering from Sertraline to Bupropion

Taper sertraline gradually over 10-14 days using 10% monthly reductions (or slower for long-term users), then initiate bupropion at 37.5 mg daily after sertraline is discontinued, increasing by 37.5 mg every 3 days to a target of 150 mg twice daily. 1

Sertraline Discontinuation Protocol

Tapering Schedule

• For patients on sertraline short-term (<1 year): Reduce dose by approximately 10% per month, with each new dose being 90% of the previous dose (not a straight-line reduction from starting dose) 2
• For patients on sertraline long-term (≥1 year): Use slower tapers of 5-10% reductions per month, as longer treatment duration increases likelihood and severity of discontinuation symptoms 2, 3
• Discontinue over 10-14 days minimum to limit withdrawal symptoms, though slower tapers are preferable for most patients 1

Pre-Taper Assessment

• Evaluate and treat depression, anxiety, and insomnia before initiating the taper, as these conditions should be addressed to improve outcomes 2
• Assess patient motivation and readiness, as patient agreement is key to successful tapering 2
• Document baseline symptoms to objectively assess any symptom return during the taper 4

Monitoring During Taper

• Follow up at least monthly (or more frequently) during the tapering process 2
• Watch for SSRI discontinuation symptoms including flu-like symptoms (fatigue, myalgias, headache), sensory disturbances (paresthesias, "electric shock" sensations), sleep disturbances (insomnia, vivid dreams), and psychiatric symptoms 3
• Monitor for return of original psychiatric symptoms, emergence of new psychiatric symptoms, and suicidal ideation 3
• If clinically significant withdrawal symptoms emerge, slow the taper rate further or pause the taper 2

Managing Withdrawal Symptoms

• Use over-the-counter analgesics for headache and myalgias, antiemetics for nausea 3
• Implement sleep hygiene measures for insomnia 3
• Consider adjuvant medications for specific withdrawal symptoms (anxiety, insomnia) as needed 2
• Maximize non-pharmacologic treatments including cognitive behavioral therapy 2

Bupropion Initiation

Timing and Starting Dose

• Begin bupropion only after sertraline is fully discontinued to minimize risk of serotonin syndrome, as bupropion inhibits cytochrome P450 2D6 and can increase SSRI blood levels 5
• Start at 37.5 mg every morning 1
• Increase by 37.5 mg every 3 days as tolerated 1
• Target dose is 150 mg twice daily (maximum 300 mg/day for sustained-release formulation) 1

Dosing Considerations

• Give second dose before 3 p.m. to minimize risk of insomnia 1
• Do not exceed 450 mg/day of immediate-release or 400 mg/day of sustained-release formulation due to seizure risk 6
• Onset of antidepressant action is 2 weeks with full efficacy at 4 weeks 6

Contraindications and Precautions

• Do not use in agitated patients or those with seizure disorders 1
• Bupropion is activating and may cause rapid improvement of energy level but can worsen agitation 1
• Common side effects include agitation, dry mouth, insomnia, headaches, nausea, and tremor 6

Critical Safety Considerations

Serotonin Syndrome Risk

• Although bupropion has minimal serotonergic activity, rare cases of serotonin syndrome have been reported when combined with SSRIs 5
• Complete sertraline discontinuation before starting bupropion is the safest approach to avoid this potentially fatal complication 5
• Early manifestations of serotonin syndrome (myoclonic jerks, confusion, agitation) can be misinterpreted as depression worsening 5

Alternative Strategy: Cross-Tapering

• While not explicitly recommended in guidelines, some clinicians use cross-tapering (gradually reducing sertraline while simultaneously introducing bupropion) 7
• This approach carries theoretical risk of serotonin syndrome and should only be considered in patients who cannot tolerate complete SSRI discontinuation 5, 7
• If cross-tapering is attempted, use very slow sertraline reductions and low initial bupropion doses with close monitoring 7

Common Pitfalls to Avoid

• Never abruptly discontinue sertraline except in emergencies, as this precipitates severe withdrawal symptoms 2, 3
• Do not use straight-line tapers that subject patients to increasingly large absolute dose reductions as they approach zero 2
• Do not start bupropion while patient is still on therapeutic doses of sertraline due to drug interaction and serotonin syndrome risk 5
• Do not mandate zero as the target for all patients—some may require a pause at low-dose sertraline before complete discontinuation 2
• Do not abandon patients during the taper—provide frequent support through telephone, telehealth, or face-to-face visits 2
• Do not misinterpret early withdrawal symptoms as depression relapse—this can lead to unnecessary medication changes 3, 5