How to taper off Wellbutrin (bupropion) 450mg to Zoloft (sertraline)?

Switching from Wellbutrin 450mg to Zoloft

When transitioning from bupropion (Wellbutrin) 450mg to sertraline (Zoloft), taper bupropion by reducing to 300mg daily for 1-2 weeks, then to 150mg daily for another 1-2 weeks before discontinuation, followed by a 3-5 day washout period before initiating sertraline at 25-50mg daily. 1, 2

Bupropion Tapering Protocol

The FDA label specifically recommends that when discontinuing bupropion extended-release 300mg daily, the dose should be decreased to 150mg once daily prior to discontinuation. 2 For your 450mg dose (which is the maximum approved dose), apply this principle stepwise:

Week 1-2:

• Reduce from 450mg to 300mg daily (33% reduction) 2
• Monitor for withdrawal symptoms including irritability, anxiety, insomnia, and mood changes 1, 3

Week 3-4:

• Reduce from 300mg to 150mg daily (50% of current dose) 2
• Continue monitoring for discontinuation symptoms

Week 5:

• Discontinue the 150mg dose 2
• Allow a 3-5 day washout period before starting sertraline 1

Why This Washout Period Matters

Bupropion has no appreciable serotonergic activity, making it unique among antidepressants. 4 This means there is minimal risk of serotonin syndrome when transitioning to an SSRI like sertraline. However, the brief washout allows bupropion and its active metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) to clear, reducing the risk of overlapping side effects. 4

Initiating Sertraline

After the washout period:

• Start sertraline at 25-50mg daily 1
• Increase to target therapeutic dose (typically 50-200mg daily) over 1-2 weeks based on tolerability
• Full antidepressant effect may take 4-6 weeks 4

Managing Withdrawal Symptoms

Bupropion discontinuation symptoms are generally milder than with SSRIs but can include: 3

• Somatic symptoms: Fatigue, headache, myalgia, flu-like symptoms
• Psychological symptoms: Irritability, anxiety, mood instability, crying spells
• Neurological symptoms: Dizziness, concentration difficulties

If withdrawal symptoms become severe: 1, 3

• Return to the previous well-tolerated dose
• Slow the taper further by extending each dose reduction phase to 2-4 weeks
• Consider 10% monthly reductions for patients on bupropion longer than 1 year 1

Critical Safety Considerations

Do NOT abruptly discontinue bupropion 450mg. The maximum dose carries seizure risk, and gradual tapering minimizes both seizure risk and withdrawal symptoms. 2, 4 The most serious adverse effect of bupropion is seizures, which is why doses must be gradually titrated and tapered. 4

Monitor monthly during the taper for: 1

• Withdrawal symptom severity
• Mood changes and suicidal ideation
• Return of depressive symptoms
• Sleep disturbances and anxiety

Common Pitfalls to Avoid

Do not mistake withdrawal symptoms for depression relapse. 3, 5 Withdrawal symptoms typically emerge within 1-4 days of dose reduction and are self-limiting, whereas relapse develops more gradually over weeks. If symptoms emerge immediately after dose reduction and include physical manifestations (dizziness, flu-like symptoms), this suggests withdrawal rather than relapse.

Do not rush the transition. Although bupropion lacks serotonergic effects, allowing adequate time for each dose reduction (minimum 1-2 weeks per step) significantly reduces withdrawal symptom severity. 1, 6

Do not start sertraline before completing the bupropion taper. While pharmacologically safe to overlap, starting sertraline during bupropion tapering makes it impossible to distinguish which medication is causing any emerging side effects or whether symptoms represent bupropion withdrawal. 7

Timeline Expectations

The entire transition will require 5-6 weeks minimum: 1

• 2 weeks at 300mg
• 2 weeks at 150mg
• 3-5 days washout
• Begin sertraline titration

Patients on bupropion for extended periods (>1 year) may require slower tapers extending to 8-12 weeks total. 1