What is the recommended treatment approach for an adult patient with a history of mental health issues, such as schizophrenia, bipolar disorder, or major depressive disorder, using Brexpiprazole (atypical antipsychotic medication)?

Brexpiprazole Treatment Approach for Adult Psychiatric Disorders

Brexpiprazole is FDA-approved as adjunctive therapy to antidepressants for major depressive disorder and as monotherapy for schizophrenia in adults, with recommended dosing of 2 mg/day for MDD and 2-4 mg/day for schizophrenia, initiated at 1 mg/day and titrated over 5-8 days. 1

FDA-Approved Indications and Positioning

Brexpiprazole is specifically indicated for two conditions in adults only 1:

• Adjunctive treatment to antidepressants for major depressive disorder (not monotherapy)
• Monotherapy for schizophrenia

Brexpiprazole is NOT approved for bipolar disorder, dementia-related psychosis, or pediatric populations. 1 The FDA boxed warning explicitly states increased mortality risk in elderly patients with dementia-related psychosis and increased suicidal thoughts in pediatric/young adult patients. 1

Dosing Algorithm by Indication

For Major Depressive Disorder (Adjunctive Therapy)

Starting dose: 0.5-1 mg/day 1

• Target dose: 2 mg/day 1, 2
• Maximum dose: 3 mg/day 1
• Titration schedule: Increase to target over 1-2 weeks 3

The number needed to treat (NNT) for response in MDD is 12, with 23.2% responders on brexpiprazole versus 14.5% on placebo. 4

For Schizophrenia (Monotherapy)

Starting dose: 1 mg/day 1, 2

• Increase to 2 mg/day on Days 5-7 2
• Increase to 4 mg/day on Day 8 if needed 2
• Target dose range: 2-4 mg/day 1, 2
• Maximum dose: 4 mg/day 1

The NNT for response in acute schizophrenia is 7 (45.5% responders versus 31.0% placebo), and for relapse prevention the NNT is 4 (13.5% relapse versus 38.5% placebo). 4

Mandatory Pre-Treatment Assessment

Before initiating brexpiprazole, document the following 5:

• Baseline metabolic parameters: Weight, BMI, waist circumference, blood pressure, fasting glucose, lipid panel
• Baseline movement assessment: Document any preexisting abnormal movements to distinguish from medication-induced effects 6
• Target symptoms: Use standardized rating scales 5
• Medical history: Screen for cardiovascular disease, seizure history, hepatic/renal impairment 1

Dose Adjustments for Special Populations

Hepatic Impairment

Moderate to severe hepatic impairment: Maximum 2 mg/day for MDD, 3 mg/day for schizophrenia 1

Renal Impairment

CrCl <60 mL/minute: Maximum 2 mg/day for MDD, 3 mg/day for schizophrenia 1

CYP2D6 Poor Metabolizers and Drug Interactions

• Strong CYP2D6 or CYP3A4 inhibitors: Administer half the recommended dose 1
• Strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors: Administer one-quarter of the recommended dose 1
• CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer one-quarter of the recommended dose 1

Monitoring Schedule During Treatment

Metabolic Monitoring 5

• Fasting glucose: Baseline, 4 weeks, 3 months, then annually
• Weight, BMI, waist circumference, blood pressure: At each visit
• Lipid panel: Baseline, 3 months, then annually

Movement Disorder Monitoring

Monitor for akathisia (NNH = 15 for MDD, NNH = 112 for schizophrenia) and tardive dyskinesia at each visit. 4 Discontinue if tardive dyskinesia develops. 1

Expected Adverse Effects and Management

Common Adverse Effects

Most common (≥5% and twice placebo rate): Weight gain, somnolence, akathisia 1

Weight gain profile: Approximately 10% of patients gain ≥7% body weight in short-term trials (NNH = 17), with more outliers in 52-week studies. 2, 4 This is more prominent than aripiprazole or cariprazine but less than olanzapine. 7

Akathisia rates: 5.5% in schizophrenia trials versus 4.6% placebo; 8.6% in MDD trials. 4 Lower than aripiprazole and cariprazine. 7

Serious Warnings

• Orthostatic hypotension and syncope: Monitor blood pressure, especially in patients with cardiovascular disease 1
• Seizures: Use cautiously in patients with seizure history 1
• Neuroleptic malignant syndrome: Discontinue immediately if suspected 1
• Pathological gambling and compulsive behaviors: Consider dose reduction or discontinuation 1

Determining Treatment Adequacy

Minimum trial duration: 4-6 weeks at therapeutic doses before declaring treatment failure 5

Before switching medications, verify 5:

1. Medication adherence through pill counts or pharmacy records
2. Adequate dosing within therapeutic range
3. No interfering drug interactions

If inadequate response after 6-8 weeks: Switch to a different antipsychotic with a different receptor profile. 5

Critical Pitfalls to Avoid

• Never use brexpiprazole in dementia-related psychosis due to increased mortality risk 1
• Never use as monotherapy for MDD—it is only approved as adjunctive therapy 1
• Never use in pediatric populations—safety and efficacy not established 1
• Never declare treatment failure before completing 4-6 week trials at adequate doses with confirmed adherence 5
• Never use clozapine before trying at least two other antipsychotics (one should be atypical) 6
• Never neglect psychosocial interventions—combine pharmacotherapy with psychoeducation, structured programs, and continuity of care 6, 5

Discontinuation Considerations

For schizophrenia, first-episode patients should receive maintenance treatment for 1-2 years after initial episode due to relapse risk. 6 The decision to lower doses or attempt medication-free trials must balance side effect minimization against increased relapse risk. 6

Discontinuation rates due to adverse events were lower than placebo in schizophrenia trials (7.1-9.2% versus 14.7%) but higher in MDD trials (1.3-3.5% versus 0-1.4%), appearing dose-dependent. 7