What is Rexulti (Brexpiprazole)?
Rexulti (brexpiprazole) is an atypical antipsychotic medication FDA-approved for two specific indications: as adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults, and for the treatment of schizophrenia in adults. 1
Pharmacological Classification and Mechanism
Brexpiprazole is classified as a third-generation antipsychotic and functions as a serotonin-dopamine activity modulator. 2 It works through a unique receptor profile:
- Partial agonist at dopamine D2 receptors and serotonin 5-HT1A receptors 3, 4
- Antagonist at serotonin 5-HT2A receptors and noradrenergic alpha-1B and alpha-2C receptors 3, 5
- Compared to aripiprazole (another D2 partial agonist), brexpiprazole displays less intrinsic activity at D2 receptors and higher potency at 5-HT1A receptors, which theoretically translates to a more favorable tolerability profile regarding akathisia and extrapyramidal symptoms 3, 6
FDA-Approved Indications and Dosing
For Schizophrenia:
- Recommended dose range: 2-4 mg once daily 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
For Major Depressive Disorder (Adjunctive):
- Recommended dose: 2 mg once daily 7
- Used as an add-on to antidepressant therapy in patients with inadequate response to antidepressants alone 1, 5
Clinical Efficacy
Schizophrenia Treatment:
- In acute schizophrenia trials, pooled responder rates were 46% for brexpiprazole 2-4 mg/day versus 31% for placebo, yielding a number needed to treat (NNT) of 7 3, 7
- For relapse prevention, 13.5% relapsed on brexpiprazole versus 38.5% on placebo over 52 weeks, with an NNT of 4 3, 7
Major Depressive Disorder (Adjunctive):
- 23.2% of patients were responders versus 14.5% for placebo, yielding an NNT of 12 7
Common Adverse Effects and Safety Profile
The most commonly encountered adverse event is weight gain (incidence ≥4% and at least twice the rate of placebo). 1, 3 Other important side effects include:
- Akathisia (restlessness, feeling need to move): 5.5% in schizophrenia trials versus 4.6% placebo (NNH of 112), and 8.6% in MDD trials (NNH of 15) 3, 7
- Sleepiness, drowsiness, and fatigue 1
- Dizziness and orthostatic hypotension (decreased blood pressure when standing) 1
- Common cold symptoms 1
Weight and Metabolic Effects:
- Approximately 10% of patients gained ≥7% body weight in short-term trials (versus 4% on placebo, NNH of 17) 3
- More significant weight gain outliers observed in 52-week open-label studies 3, 7
- Minimal effects on prolactin and small effects on glucose and lipids 3, 7
Serious Warnings:
- Risk of falls due to sedation, dizziness, and orthostatic hypotension 1
- Seizures (convulsions) 1
- Compulsive behaviors including gambling, sexual urges, shopping, and binge eating 1
- Low white blood cell count (monitoring recommended during first few months) 1
- Difficulty swallowing that can cause aspiration 1
Important Clinical Considerations
Discontinuation rates due to adverse events were generally favorable: 7.1-9.2% for brexpiprazole versus 14.7% for placebo in schizophrenia trials, though rates were slightly higher in depression trials (1.3-3.5% versus 0-1.4% placebo) and appeared dose-dependent. 6, 7
No clinically relevant effects on ECG QTc interval were observed, which is an important safety consideration. 3, 7
The medication is available as oral tablets in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. 1