Discontinue Brexpiprazole (Rexulti) First
In an adult with major depressive disorder who is stable on both brexpiprazole and vortioxetine without active psychotic symptoms, discontinue brexpiprazole first. The antidepressant (vortioxetine/Trintellix) should be maintained as the foundational treatment, while the augmenting antipsychotic can be safely tapered and removed.
Rationale Based on Medication Roles
Apply the Augmentation-First Principle
When a patient takes two medications targeting the same disorder, remove the augmenting agent first while maintaining the primary medication. This principle comes from pediatric psychopharmacology guidelines but applies equally to adults: the medication added to boost response should be discontinued before the foundational treatment 1.
Brexpiprazole was FDA-approved specifically as adjunctive therapy to antidepressants for MDD—it functions as an augmenting agent, not a primary antidepressant 2, 3. Vortioxetine is a standalone antidepressant with multimodal serotonergic activity that serves as the primary treatment 2.
The STAR*D trial demonstrated that augmentation strategies (including antipsychotics) can be successfully withdrawn after achieving remission, with the primary antidepressant maintained for relapse prevention 1.
Consider Long-Term Safety Profiles
Atypical antipsychotics carry greater long-term metabolic and neurological risks than antidepressants. Brexpiprazole causes clinically significant weight gain (≥7% in 10.5% of patients), increases in triglycerides, and carries risk for tardive dyskinesia and akathisia—though lower than other antipsychotics 4, 3, 5, 6.
Antidepressants like vortioxetine have more favorable long-term safety profiles with lower metabolic burden and no risk of extrapyramidal symptoms 1.
Guidelines recommend keeping the medication with the least long-term side effect potential when both medications provide equivalent benefit 1.
Tapering Protocol for Brexpiprazole
Gradual Dose Reduction Strategy
Taper brexpiprazole slowly over 2–4 weeks minimum to avoid withdrawal symptoms and rebound worsening of depressive symptoms 1. Although antipsychotics generally require gradual withdrawal, brexpiprazole's relatively short half-life necessitates careful monitoring 4.
Reduce the dose by 25–50% every 1–2 weeks while monitoring for symptom recurrence 7. For example, if taking 2 mg daily, reduce to 1 mg for 1–2 weeks, then 0.5 mg for 1–2 weeks before complete discontinuation 7.
If moderate-to-severe withdrawal symptoms or depressive symptom return develops, pause the taper at the current dose for 1–2 weeks before resuming 7.
Critical Monitoring Parameters
Assess for return of depressive symptoms weekly during the taper and for 4–8 weeks after complete discontinuation 1. Depression symptoms may not re-emerge immediately but can appear weeks to months after the last dose 1.
Monitor specifically for akathisia, restlessness, and extrapyramidal symptoms during the taper, as abrupt antipsychotic discontinuation can precipitate dyskinesias and parkinsonian symptoms 1.
Watch for suicidal ideation during the first 1–2 months after any medication change, as this period carries the highest risk 1, 7.
Maintain Vortioxetine as Foundational Treatment
Duration of Continuation Therapy
Continue vortioxetine for a minimum of 4–9 months after achieving stable remission for a first depressive episode 1.
For recurrent depression (≥2 episodes), maintain vortioxetine for ≥1 year or longer, as relapse risk rises to 70% after two episodes and 90% after three episodes 7.
If Symptoms Return During Brexpiprazole Taper
Do not immediately restart brexpiprazole if mild depressive symptoms emerge—first optimize the vortioxetine dose and add cognitive-behavioral therapy (CBT), which demonstrates superior efficacy to medication alone 1.
If significant symptom return occurs despite these measures, re-escalate brexpiprazole to the previous effective dose rather than switching to a different augmentation strategy 7.
Common Pitfalls to Avoid
Do not discontinue both medications simultaneously—this creates unnecessary risk of relapse and makes it impossible to determine which medication was providing benefit 1.
Do not abruptly stop brexpiprazole without tapering, as this increases risk of withdrawal dyskinesias and symptom rebound 1.
Do not assume stability at 4 weeks means the taper is complete—continue monitoring for 2–3 months after full discontinuation, as mood disorders can relapse with delayed onset 1.
Do not restart brexpiprazole at the first sign of mild symptom fluctuation—allow 2–4 weeks to determine if symptoms stabilize, as transient mood changes are common during medication adjustments 7.