How is Brexiprazole used in clinical practice?

Brexiprazole in Clinical Practice

Primary Indications and Positioning

Brexiprazole is FDA-approved for two primary indications: treatment of schizophrenia in adults and adolescents (13-17 years), and as adjunctive therapy for major depressive disorder (MDD) in adults. 1

Schizophrenia Treatment

• Brexiprazole should be used as monotherapy at 2-4 mg/day for schizophrenia, following the standard treatment algorithm where it serves as a first-line atypical antipsychotic option. 2, 1
• The medication is initiated with gradual titration over 1-2 weeks to reach the target dose, administered once daily. 1, 3
• In acute schizophrenia trials, brexiprazole 2-4 mg/day demonstrated a response rate of 45.5% versus 31.0% for placebo, yielding a number needed to treat (NNT) of 7. 4
• For relapse prevention in stabilized patients, brexiprazole 1-4 mg/day significantly delayed time to relapse (13.5% vs 38.5% for placebo), with an NNT of 4. 4, 5

Major Depressive Disorder (Adjunctive Treatment)

• Brexiprazole is indicated as adjunctive therapy at 2-3 mg/day for MDD in patients with inadequate response to standard antidepressant therapy alone. 1, 3
• In pooled MDD trials, adjunctive brexiprazole achieved a 23.2% response rate versus 14.5% for placebo, with an NNT of 12. 4
• The medication should only be added after establishing inadequate response to at least one antidepressant trial. 1

Pharmacological Profile and Mechanism

• Brexiprazole functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptors. 5, 6
• Critically, brexiprazole displays less intrinsic activity at D2 receptors compared to aripiprazole, which translates to a lower propensity for activating adverse events and extrapyramidal symptoms. 5
• The drug also demonstrates potent activity at noradrenergic α1B and α2C receptors, contributing to its unique clinical profile. 3, 6

Safety and Tolerability Profile

Common Adverse Effects

• The most common adverse reactions in adults include weight gain, akathisia, headache, somnolence, and insomnia (≥5% incidence). 1
• In pediatric patients (13-17 years), the most common adverse reactions are weight gain, somnolence, headache, akathisia, and nasopharyngitis. 1

Akathisia

• Akathisia occurred in 5.5% of patients in acute schizophrenia trials and 8.6% in MDD trials. 4
• The NNH for akathisia was non-significant (112) in schizophrenia but modest at 15 in MDD patients. 4
• Akathisia risk is dose-dependent: the 2 mg dose is associated with less akathisia compared to 4 mg. 7

Metabolic Effects

• Short-term weight gain appears modest, though more outliers with ≥7% body weight increase were evident in 52-week open-label studies. 4
• Effects on glucose and lipids were small and not clinically significant. 4, 5
• Minimal effects on prolactin were observed. 4

Discontinuation Rates

• Overall discontinuation rates due to adverse events were lower for brexiprazole versus placebo in schizophrenia trials. 4
• In MDD trials, 3% of brexiprazole-treated patients versus 1% of placebo-treated patients discontinued due to adverse events (NNH = 53). 4

Dosing and Administration

Schizophrenia

• Recommended dose: 2-4 mg once daily. 1, 3
• Titration schedule: Start at lower doses and increase gradually over 1-2 weeks to target dose. 1, 3

Major Depressive Disorder (Adjunctive)

• Recommended dose: 2 mg once daily (may increase to 3 mg if needed). 1, 3
• Titration to target dose should occur over 1-2 weeks. 3

Critical Clinical Considerations

Warnings and Precautions

• Black box warning: Increased mortality in elderly patients with dementia-related psychosis. 1
• Black box warning: Suicidal thoughts and behaviors in adolescents and young adults. 1
• Potential for somnolence and sedation—patients should be cautioned about operating hazardous machinery until they know how brexiprazole affects them. 1
• Monitor for neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, and seizures. 1

Monitoring Requirements

• Before initiating treatment, measure BMI, waist circumference, blood pressure, HbA1c, glucose, lipids, prolactin, liver function, and ECG. 2
• Monitor glucose at 4 weeks after initiation; BMI, waist circumference, and blood pressure weekly for 6 weeks. 2
• Repeat all parameters at 3 months, then annually. 2

Comparative Positioning

• Brexiprazole demonstrates similar efficacy to aripiprazole and quetiapine in head-to-head comparisons for schizophrenia. 7
• The lower intrinsic D2 receptor activity compared to aripiprazole theoretically provides advantages in terms of reduced activating side effects and extrapyramidal symptoms. 5
• Brexiprazole offers a favorable profile regarding cognitive performance, sleep patterns, and affective symptoms with lower risk of metabolic complications compared to many other second-generation antipsychotics. 6

Place in Treatment Algorithm

Schizophrenia

• Brexiprazole can be considered as a first-line atypical antipsychotic, particularly in patients where metabolic side effects or akathisia are concerns. 2
• If first-line treatment fails after 4-6 weeks, switch to another atypical antipsychotic rather than adding agents. 2
• Brexiprazole should not be used as part of polypharmacy regimens except in treatment-resistant cases after clozapine trials. 2

Major Depressive Disorder

• Use only after establishing inadequate response to at least one adequate antidepressant trial. 1
• Consider as an alternative to other augmentation strategies in patients who have not responded to standard antidepressant monotherapy. 4