What is the safest way to taper off venlafaxine (Effexor) in an adult with bipolar II disorder and moderate depressive symptoms who has previously trialed lamotrigine, brexpiprazole (Rexulti), lurasidone (Latuda), cariprazine (Vraylar) and is currently taking metoprolol and bupropion (Wellbutrin)?

Venlafaxine Taper Protocol in Bipolar II Disorder with Concurrent Bupropion and Metoprolol

In a patient with bipolar II disorder taking bupropion and metoprolol, venlafaxine should be tapered gradually over 4–6 weeks using 37.5 mg decrements every 5–7 days, while maintaining mood stabilization with an evidence-based agent such as lamotrigine or quetiapine throughout the taper. 1

Critical Pre-Taper Requirements

Before initiating the venlafaxine taper, you must address the underlying bipolar II disorder with appropriate mood stabilization:

• Do not taper venlafaxine without concurrent mood stabilizer coverage, because antidepressant monotherapy in bipolar disorder increases the risk of mood destabilization, rapid cycling, and hypomanic episodes. 2, 3
• Quetiapine (150–300 mg daily) or lamotrigine (titrated to 200 mg daily) are first-line options for bipolar II depression and should be initiated or optimized before beginning the venlafaxine taper. 4, 5
• Lithium (therapeutic level 0.6–1.0 mEq/L) is another first-line choice supported by decades of observational data in bipolar II disorder, though acute depression efficacy is less robust than quetiapine or lamotrigine. 6, 5

Evidence-Based Taper Schedule

The FDA label for venlafaxine explicitly warns that abrupt discontinuation produces withdrawal symptoms; therefore, a structured taper is mandatory:

• Week 1–2: Reduce venlafaxine by 37.5 mg every 5–7 days (e.g., from 150 mg to 112.5 mg, then to 75 mg). 1
• Week 3–4: Continue 37.5 mg decrements every 5–7 days (e.g., 75 mg to 37.5 mg, then to discontinuation). 1
• If moderate-to-severe withdrawal symptoms emerge (dizziness, anxiety, irritability, sensory disturbances), hold the current dose for 1–2 weeks before resuming the taper. 7
• Total taper duration should span 4–6 weeks minimum to minimize discontinuation syndrome, which includes dizziness, nausea, headache, irritability, and "brain zaps." 1

Monitoring During the Taper

• Assess mood stability weekly during the first month using standardized scales (e.g., PHQ-9 for depression, Mood Disorder Questionnaire for hypomania) to detect early destabilization. 7, 1
• Monitor specifically for hypomanic symptoms (decreased need for sleep, increased energy, impulsivity, rapid speech) because antidepressant withdrawal can unmask underlying bipolar instability. 2, 1
• Watch for suicidal ideation at every contact during the first 1–2 months, as the FDA black-box warning for venlafaxine emphasizes heightened suicide risk during treatment changes. 1
• Check blood pressure weekly because venlafaxine discontinuation can cause transient blood pressure fluctuations, and this patient is already on metoprolol for cardiovascular management. 7, 1

Managing Bupropion During the Taper

• Continue bupropion at the current dose throughout the venlafaxine taper, as bupropion monotherapy is insufficient for bipolar II disorder but may provide adjunctive benefit for residual depressive symptoms once a mood stabilizer is established. 3, 8
• Bupropion does not require dose adjustment during venlafaxine taper because there are no significant pharmacokinetic interactions between these agents. 7
• If depressive symptoms worsen during the taper, optimize the mood stabilizer dose (e.g., increase quetiapine to 300 mg or lamotrigine to 200 mg) rather than increasing bupropion, because antidepressant escalation in bipolar disorder risks mood destabilization. 3, 5

Metoprolol Considerations

• Metoprolol does not require adjustment during venlafaxine taper, as venlafaxine does not significantly inhibit CYP2D6 at therapeutic doses and metoprolol clearance will not be affected. 7
• Monitor for rebound hypertension or tachycardia during the first 2 weeks of venlafaxine taper, as discontinuation of SNRIs can transiently elevate sympathetic tone. 1

Common Pitfalls to Avoid

• Do not taper venlafaxine faster than 37.5 mg every 5–7 days, as more rapid tapers markedly increase discontinuation syndrome severity. 1
• Do not rely on bupropion alone for mood stabilization after venlafaxine discontinuation, because bupropion lacks antimanic efficacy and is not recommended as monotherapy in bipolar disorder. 2, 3
• Do not add another antidepressant after venlafaxine discontinuation without concurrent mood stabilizer coverage, as this perpetuates the risk of antidepressant-induced mood destabilization. 2, 5
• Do not assume the patient is "stable" on bupropion alone simply because they have not had a recent manic episode; bipolar II disorder requires ongoing mood stabilizer therapy to prevent depressive recurrence and hypomanic episodes. 4, 5

Post-Taper Management

• After venlafaxine discontinuation, continue the mood stabilizer indefinitely (lithium, lamotrigine, or quetiapine) as maintenance therapy, because bipolar II disorder has a 70–90% relapse risk without prophylactic treatment. 4, 5
• Reassess the need for bupropion 4–8 weeks after venlafaxine discontinuation, as some patients achieve adequate symptom control with mood stabilizer monotherapy and can avoid polypharmacy. 7, 5
• If residual depressive symptoms persist despite optimized mood stabilizer therapy, consider adjunctive lamotrigine (if not already used) or lurasidone rather than reintroducing an SNRI or SSRI. 4, 5