What is Rexulti (Brexpiprazole)?
Rexulti (brexpiprazole) is an atypical antipsychotic medication FDA-approved for two specific indications: as monotherapy for schizophrenia in adults and as adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults. 1
Pharmacological Classification and Mechanism
Brexpiprazole is classified as a third-generation atypical antipsychotic and functions as a serotonin-dopamine activity modulator 2, 3. Its unique receptor profile includes:
- Partial agonist at dopamine D2 receptors (with less intrinsic activity than aripiprazole) 3
- Partial agonist at serotonin 5-HT1A receptors (more potent than aripiprazole at these receptors) 3
- Antagonist at serotonin 5-HT2A receptors 2
- Antagonist at noradrenergic alpha-1B and alpha-2C receptors 2, 3
This pharmacological profile distinguishes brexpiprazole from other antipsychotics through its partial dopamine receptor agonist activity, placing it in the same category as aripiprazole but with distinct receptor binding characteristics 4.
FDA-Approved Indications and Dosing
For Schizophrenia
- Recommended dose range: 2-4 mg/day 1, 3
- Titration schedule: Start with 1 mg/day, increase to 2 mg/day on Days 5-7, then to 4 mg/day on Day 8 3
- Administration: Once daily dosing 5
For Major Depressive Disorder (Adjunctive)
- Recommended dose: 2 mg/day (range 2-3 mg/day) 5, 6
- Titration: Must be titrated up to target dose over 1-2 weeks 6
Clinical Efficacy Data
Schizophrenia
- Acute treatment: Pooled responder rates of 46% for brexpiprazole 2-4 mg/day versus 31% for placebo, yielding a number needed to treat (NNT) of 7 3, 5
- Relapse prevention: In a 52-week maintenance study, 13.5% relapsed on brexpiprazole versus 38.5% on placebo, with an NNT of 4 3, 5
Major Depressive Disorder (Adjunctive)
- Response rates: 23.2% of patients receiving brexpiprazole were responders versus 14.5% for placebo, yielding an NNT of 12 5
Safety and Tolerability Profile
Common Adverse Effects
The most common side effects include 1, 3:
- Weight gain (approximately 10% of patients gained ≥7% body weight versus 4% on placebo, NNH of 17) 3
- Akathisia (5.5% in schizophrenia trials versus 4.6% placebo, NNH of 112; 8.6% in MDD trials with NNH of 15) 3, 5
- Sleepiness, drowsiness, and fatigue 1
- Dizziness and orthostatic hypotension 1
- Common cold symptoms 1
Metabolic Effects
- Short-term weight gain is modest, but more outliers with ≥7% body weight increase were evident in 52-week open-label studies 3, 5
- Minimal effects on glucose and lipids 3, 5
- Minimal prolactin elevation 3, 5
Cardiovascular Safety
Serious Warnings
Brexpiprazole carries warnings for 1:
- Compulsive behaviors (gambling, sexual urges, shopping, binge eating)
- Low white blood cell count (requires monitoring during first few months)
- Orthostatic hypotension and falls
- Seizures
- Temperature regulation problems
- Difficulty swallowing (aspiration risk)
Clinical Context and Positioning
Brexpiprazole represents a third-generation antipsychotic with a potentially favorable metabolic profile compared to some second-generation agents like olanzapine and clozapine 4. The American Psychiatric Association emphasizes that treatment selection should be based on individual drug pharmacodynamic profiles and patient-specific factors rather than generational classification 7, 4.
Key Clinical Considerations
- Discontinuation rates due to adverse events were lower for brexpiprazole versus placebo in schizophrenia trials 5
- For MDD, only 3% discontinued due to adverse events versus 1% on placebo (NNH of 53) 5
- Head-to-head comparisons with other antipsychotics in real-world settings are needed to fully establish its place in clinical practice 5