Brexpiprazole: Clinical Overview and Prescribing Considerations
FDA-Approved Indications
Brexpiprazole is FDA-approved for two specific indications: monotherapy treatment of schizophrenia in adults and adjunctive treatment (added to antidepressants) for major depressive disorder in adults. 1
Pharmacological Profile
Brexpiprazole is classified as a third-generation antipsychotic (also called a serotonin-dopamine activity modulator) that acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A and adrenergic alpha1B and alpha2C receptors. 2, 3 Compared to aripiprazole, brexpiprazole displays more potent activity at 5-HT1A receptors and less intrinsic activity at D2 receptors, which may translate to a different side effect profile. 3, 4
Dosing Algorithms
For Schizophrenia
Start brexpiprazole at 1 mg once daily on Days 1-4, increase to 2 mg daily on Days 5-7, then titrate to the target dose of 2-4 mg daily on Day 8 based on clinical response and tolerability. 1 The maximum recommended dose is 4 mg daily. 1
- Administer once daily with or without food 1
- The recommended target dose range is 2-4 mg/day 1, 3
- Once symptoms improve, continue the same dose indefinitely, as 70% of patients with schizophrenia require long-term or lifetime medication. 5
For Major Depressive Disorder (Adjunctive)
Start at 0.5 mg or 1 mg once daily, titrate to 1 mg daily, then increase to the target dose of 2 mg daily based on clinical response, with weekly titration intervals. 1 The maximum recommended dose is 3 mg daily. 1
- The recommended target dose is 2 mg/day 1, 6
- Periodically reassess to determine continued need for treatment 1
Dose Adjustments for Special Populations
For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum dose is 2 mg daily for MDD and 3 mg daily for schizophrenia. 1
For patients with renal impairment (CrCl <60 mL/minute), the maximum dose is 2 mg daily for MDD and 3 mg daily for schizophrenia. 1
For CYP2D6 poor metabolizers or patients taking strong CYP2D6 or CYP3A4 inhibitors, administer half the recommended dose. 1 For patients who are CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, or patients taking both strong/moderate CYP2D6 and CYP3A4 inhibitors, administer one-quarter of the recommended dose. 1
For patients taking strong CYP3A4 inducers, double the recommended dose over 1-2 weeks. 1
Efficacy Data
Schizophrenia
In pooled acute schizophrenia trials, 45.5% of patients receiving brexpiprazole 2-4 mg/day were responders versus 31.0% for placebo, yielding a number needed to treat (NNT) of 7. 3, 6 In a 52-week relapse prevention study, significantly fewer patients relapsed with brexpiprazole compared to placebo (13.5% vs. 38.5%), resulting in an NNT of 4. 3, 6
Major Depressive Disorder
When pooling results from two Phase III MDD trials at doses of 1-3 mg, 23.2% of brexpiprazole-treated patients were responders versus 14.5% for placebo, yielding an NNT of 12. 6 Meta-analysis showed mean difference improvements on MADRS of -1.25, SDS of -0.37, and HDRS17 of -1.28 compared to placebo. 7
Side Effect Profile and Management
Common Adverse Effects
The most common adverse event in schizophrenia trials (≥4% and at least twice the rate of placebo) is weight gain. 1, 3 Approximately 10% of patients receiving brexpiprazole 1-4 mg/day gained ≥7% body weight from baseline compared to 4% for placebo, resulting in a number needed to harm (NNH) of 17. 3
Akathisia occurred in 5.5% of patients with schizophrenia receiving brexpiprazole 1-4 mg/day versus 4.6% for placebo (NNH of 112), but was more common in MDD trials at 8.6% (NNH of 15). 3, 6, 7
Other common side effects include somnolence and gastrointestinal effects. 4, 7
Critical Side Effect Management
If akathisia develops, lower the brexpiprazole dose, switch to another antipsychotic, add a benzodiazepine, or add a beta-blocker. 5
If parkinsonism develops, lower the dose, switch medications, or add an anticholinergic agent. 5
Monitor for tardive dyskinesia periodically, as risk increases with treatment duration; if moderate to severe tardive dyskinesia develops, treat with a VMAT2 inhibitor. 5
Metabolic Monitoring
Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain throughout treatment. 1 Effects on glucose and lipids were small in clinical trials, and minimal effects on prolactin were observed. 3, 6
Cardiovascular Monitoring
Monitor heart rate and blood pressure, particularly in patients with known cardiovascular or cerebrovascular disease and those at risk for dehydration or syncope, due to risk of orthostatic hypotension. 1
No clinically relevant effects on ECG QTc interval were evident in trials. 3, 6
Hematologic Monitoring
Perform complete blood counts in patients with pre-existing low white blood cell count or history of leukopenia or neutropenia; consider discontinuing brexpiprazole if a clinically significant decline in WBC occurs without other causative factors. 1
Critical Prescribing Considerations
Black Box Warnings
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death; brexpiprazole is not approved for this population. 1
Antidepressants, including brexpiprazole when used adjunctively for MDD, increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients; closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts. 1
When NOT to Prescribe
Do not start brexpiprazole for personality traits or prodromal symptoms alone without at least one week of psychotic symptoms causing distress or functional impairment. 5, 8
Known hypersensitivity to brexpiprazole or any of its components is a contraindication. 1
Specific Clinical Scenarios
For patients with schizophrenia who remain at substantial suicide risk despite brexpiprazole treatment, switch to clozapine, as clozapine is specifically recommended for reducing suicide attempts. 5
For patients with persistent aggressive behavior despite other treatments, consider clozapine. 5
Important Pitfalls to Avoid
Do not increase brexpiprazole dose or add additional antipsychotics to treat amotivation or negative symptoms, as antipsychotics do not markedly improve these domains; implement psychosocial interventions instead. 5, 9
Do not mistake sedation or extrapyramidal symptoms for primary negative symptoms—these require dose reduction or medication switch, not dose increase. 5
Avoid antipsychotic polypharmacy except after a failed clozapine trial. 2, 9
Mandatory Adjunctive Interventions
For Schizophrenia
Combine brexpiprazole with cognitive-behavioral therapy for psychosis (CBTp) to address persistent symptoms and improve functioning. 5
Provide psychoeducation about the illness, medications, and warning signs of relapse. 5
Offer supported employment services to facilitate return to work or vocational functioning. 5
Implement coordinated specialty care programs for first-episode psychosis. 5
Provide assertive community treatment for patients with history of poor engagement, frequent relapse, homelessness, or legal difficulties. 5
For Major Depressive Disorder
Continue the antidepressant medication that brexpiprazole is augmenting; brexpiprazole is approved only as adjunctive therapy, not monotherapy, for MDD. 1
Additional Warnings
Use cautiously in patients with a history of seizures or conditions that lower the seizure threshold. 1
Warn patients about potential for cognitive and motor impairment; use caution when operating machinery. 1
Monitor for pathological gambling and other compulsive behaviors; consider dose reduction or discontinuation if these emerge. 1
Be aware of increased risk of cerebrovascular adverse reactions (stroke, transient ischemic attack) in elderly patients with dementia-related psychosis. 1
Monitor for neuroleptic malignant syndrome; manage with immediate discontinuation and close monitoring if it occurs. 1