What is the recommended initial dosage and monitoring approach for Rexulti (brexpiprazole) in an adult patient with schizophrenia, bipolar disorder, or major depressive disorder and no significant medical history?

Rexulti (Brexpiprazole) Initiation Protocol

Direct Recommendation for Initial Dosing

For adults with schizophrenia, start brexpiprazole at 1 mg orally once daily on Days 1-4, then increase to 2 mg once daily on Days 5-7, with the option to increase to the target dose of 2-4 mg daily on Day 8 based on clinical response and tolerability. 1

For adults with major depressive disorder (as adjunctive therapy), start brexpiprazole at 0.5 mg or 1 mg orally once daily, titrate to 1 mg once daily, then increase to the target dosage of 2 mg once daily at weekly intervals based on clinical response and tolerability. 1

Indication-Specific Dosing Algorithms

Schizophrenia in Adults

• Days 1-4: 1 mg once daily 1
• Days 5-7: 2 mg once daily 1
• Day 8 onward: 2-4 mg once daily (target dose range) 1
• Maximum dose: 4 mg once daily 1
• Target therapeutic dose: 2-4 mg/day demonstrates statistically significant and clinically meaningful improvements in overall symptomatology and psychosocial functioning 2

Major Depressive Disorder (Adjunctive Treatment)

• Week 1: 0.5 mg or 1 mg once daily 1
• Week 2: Titrate to 1 mg once daily 1
• Week 3 onward: Increase to target dose of 2 mg once daily 1
• Maximum dose: 3 mg once daily 1
• Target therapeutic dose: 2 mg/day is the recommended target for adjunctive treatment 1, 3

Administration Details

• Timing: Once daily, with or without food 1
• Titration rationale: Gradual dose escalation at weekly intervals minimizes adverse effects while achieving therapeutic benefit 1, 4
• Response assessment: Allow at least 4-6 weeks at target dose before concluding treatment failure 4

Baseline Monitoring Requirements Before Initiation

Obtain these measurements before starting brexpiprazole:

• Body mass index (BMI) and waist circumference 5
• Blood pressure 5
• Fasting glucose or HbA1c 5
• Fasting lipid panel 5
• Electrocardiogram (ECG) 5
• Liver function tests 5
• Complete blood count if patient has pre-existing low white blood cell count or history of leukopenia/neutropenia 1

Follow-Up Monitoring Schedule

First 6 Weeks

• Weekly: BMI, waist circumference, and blood pressure 5
• Week 4: Repeat fasting glucose 5

After 3 Months

• Repeat all baseline metabolic measures 5

Ongoing Maintenance

• Annually: BMI, waist circumference, blood pressure, HbA1c or fasting glucose, lipid panel 5

Dosage Modifications for Special Populations

Hepatic Impairment (Moderate to Severe, Child-Pugh ≥7)

• MDD: Maximum 2 mg once daily 1
• Schizophrenia: Maximum 3 mg once daily 1

Renal Impairment (CrCl <60 mL/min)

• MDD: Maximum 2 mg once daily 1
• Schizophrenia: Maximum 3 mg once daily 1

CYP2D6 Poor Metabolizers

• Administer half of the recommended dosage 1
• If also taking strong/moderate CYP3A4 inhibitors, administer a quarter of the recommended dosage 1

Concomitant Strong CYP2D6 or CYP3A4 Inhibitors

• Administer half of the recommended dosage 1
• Exception: For MDD patients taking strong CYP2D6 inhibitors (paroxetine, fluoxetine), no dosage adjustment needed as this was factored into clinical trial dosing 1

Concomitant Strong/Moderate CYP2D6 AND CYP3A4 Inhibitors

• Administer a quarter of the recommended dosage 1

Concomitant Strong CYP3A4 Inducers

• Double the recommended dosage over 1-2 weeks 1
• When inducer is discontinued, reduce brexpiprazole to original level over 1-2 weeks 1

Expected Efficacy Outcomes

Schizophrenia

• Acute treatment: Number needed to treat (NNT) of 7 for response vs. placebo (45.5% responders vs. 31.0% placebo) 6
• Maintenance/relapse prevention: NNT of 4 (13.5% relapse vs. 38.5% placebo) 6
• Brexpiprazole 1-4 mg/day significantly delays time to relapse in stabilized patients 2

Major Depressive Disorder (Adjunctive)

• Response: NNT of 12 vs. placebo (23.2% responders vs. 14.5% placebo) 6
• Adjunctive brexpiprazole 2-3 mg once daily is more effective than antidepressant monotherapy in patients with incomplete response to previous antidepressant treatment 3

Tolerability Profile and Common Adverse Effects

Most Common Adverse Effects

• Schizophrenia: Weight gain (≥4% incidence, at least twice placebo rate) 1
• MDD: Weight increased, somnolence, and akathisia (≥5% incidence, at least twice placebo rate) 1
• Akathisia rates: 5.5% in schizophrenia trials, 8.6% in MDD trials 6
• Akathisia NNH: Non-significant (112) for schizophrenia, modest NNH of 15 for MDD 6

Discontinuation Rates Due to Adverse Events

• Schizophrenia: Lower in brexpiprazole groups (7.1-9.2%) vs. placebo (14.7%) 4
• MDD: Higher in brexpiprazole groups (1.3-3.5%) vs. placebo (0-1.4%), appearing dose-dependent 4
• Overall NNH for discontinuation in MDD: 53 (3% brexpiprazole vs. 1% placebo) 6

Metabolic Effects

• Weight gain: Moderate, with more outliers showing ≥7% body weight increase in 52-week open-label studies 6
• Glucose and lipids: Small, not clinically significant changes 2, 6
• Prolactin: Minimal effects 6

Cardiovascular Effects

• QT interval: Small changes, not clinically significant, with no clinically relevant effects on ECG QT interval 2, 6

Pharmacological Rationale for Tolerability

Brexpiprazole displays less intrinsic activity at D2 receptors than aripiprazole, coupled with actions at 5-HT1A, 5-HT2A, and noradrenaline α1B receptors that are at least as potent as its action at D2 receptors, predicting lower propensity for activating adverse events and extrapyramidal symptoms. 2

With higher potency at 5-HT2A, 5-HT1A, and α1B receptors compared to aripiprazole, brexpiprazole's pharmacological properties suggest a more tolerable side effect profile regarding akathisia, extrapyramidal dysfunction, and sedation. 4

Critical Safety Warnings

Boxed Warnings

• Elderly patients with dementia-related psychosis: Increased risk of death; brexpiprazole is NOT approved for this population 1
• Suicidal thoughts and behaviors: Antidepressants increase risk in pediatric and young adult patients; closely monitor all patients for clinical worsening and emergence of suicidal thoughts 1
• Pediatric MDD: Safety and effectiveness not established in pediatric patients with MDD 1

Other Important Warnings

• Neuroleptic malignant syndrome: Manage with immediate discontinuation and close monitoring 1
• Tardive dyskinesia: Discontinue if clinically appropriate 1
• Orthostatic hypotension and syncope: Monitor heart rate and blood pressure, especially in patients with cardiovascular/cerebrovascular disease 1
• Seizures: Use cautiously in patients with history of seizures or conditions lowering seizure threshold 1
• Pathological gambling and other compulsive behaviors: Consider dose reduction or discontinuation 1
• Leukopenia, neutropenia, agranulocytosis: Perform CBC in patients with pre-existing low WBC or history of leukopenia/neutropenia 1

Common Pitfalls to Avoid

• Rapid titration: Avoid escalating dose faster than recommended weekly intervals, as this increases risk of akathisia and other activating adverse effects 1, 4
• Premature discontinuation: Allow minimum 4-6 weeks at target therapeutic dose before concluding treatment failure 4
• Ignoring CYP interactions: Failure to adjust dose for CYP2D6 poor metabolizers or concomitant CYP inhibitors/inducers can lead to subtherapeutic or toxic levels 1
• Inadequate metabolic monitoring: Missing baseline or follow-up metabolic assessments increases risk of undetected weight gain, hyperglycemia, or dyslipidemia 5, 1
• Using in dementia-related psychosis: This is contraindicated due to increased mortality risk 1