What are the recommended starting dose, titration schedule, contraindications, common adverse effects, and monitoring parameters for Rexulti (brexpiprazole) in adults with schizophrenia or as adjunctive therapy for major depressive disorder?

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Rexulti (Brexpiprazole) Prescribing Guide

Starting Dose and Titration

For schizophrenia, start brexpiprazole at 1 mg once daily, increase to 2 mg on days 5–7, then to 4 mg on day 8 if needed; for major depressive disorder as adjunctive therapy, start at 0.5–1 mg daily and titrate to the target dose of 2 mg over 1–2 weeks. 1

Schizophrenia Dosing

  • Initial dose: 1 mg once daily 1
  • Day 5–7: Increase to 2 mg once daily 1
  • Day 8 onward: May increase to 4 mg once daily based on response 1, 2
  • Target dose range: 2–4 mg once daily 1, 2
  • Maximum dose: 4 mg once daily 1

Major Depressive Disorder (Adjunctive) Dosing

  • Initial dose: 0.5 mg or 1 mg once daily 1
  • Target dose: 2 mg once daily 1, 3
  • Maximum dose: 3 mg once daily 1
  • Titration: Increase gradually over 1–2 weeks to target dose 3

Administration Details

  • Administer once daily with or without food 1
  • No need for food restrictions or timing requirements 1

Dose Adjustments for Special Populations

Hepatic Impairment

  • Moderate to severe hepatic impairment: Maximum 2 mg daily for MDD; maximum 3 mg daily for schizophrenia 1

Renal Impairment

  • CrCl <60 mL/min: Maximum 2 mg daily for MDD; maximum 3 mg daily for schizophrenia 1

Drug Interactions Requiring Dose Adjustment

  • Strong CYP2D6 or CYP3A4 inhibitors: Administer half the usual dose 1
  • Strong/moderate CYP2D6 plus strong/moderate CYP3A4 inhibitors: Administer one-quarter the usual dose 1
  • CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer one-quarter the usual dose 1
  • Strong CYP3A4 inducers: Double the usual dose and adjust based on clinical response 1
  • Note: For MDD patients on strong CYP2D6 inhibitors (paroxetine, fluoxetine), no dose adjustment needed 1

Contraindications

The only absolute contraindication is known hypersensitivity to brexpiprazole or any component of the formulation. 1

Common Adverse Effects

Schizophrenia

  • Weight gain: Most common adverse effect (≥4% and at least twice placebo rate) 1
  • Approximately 10% of patients on 1–4 mg daily gained ≥7% body weight (vs. 4% placebo), yielding NNH of 17 2
  • Akathisia: 5.5% for brexpiprazole 1–4 mg vs. 4.6% placebo (NNH = 112, not statistically significant) 2, 4

Major Depressive Disorder (Adjunctive)

  • Weight gain: ≥5% incidence and at least twice placebo rate 1
  • Somnolence: ≥5% incidence and at least twice placebo rate 1
  • Akathisia: ≥5% incidence and at least twice placebo rate; 8.6% in MDD trials (NNH = 15) 1, 4
  • Discontinuation due to adverse events: 3% brexpiprazole vs. 1% placebo (NNH = 53) 4

Metabolic Effects

  • Small effects on glucose and lipids observed 2, 4
  • Significant increases in triglycerides noted across studies 5
  • More weight outliers (≥7% increase) evident in 52-week open-label studies 2, 4

Other Notable Effects

  • Minimal prolactin elevation 2, 4
  • No clinically relevant QTc prolongation 2, 4
  • Gastrointestinal side effects reported 3

Monitoring Parameters

Baseline Assessment

  • Weight and BMI 1
  • Fasting glucose and HbA1c 1
  • Lipid panel (fasting triglycerides and cholesterol) 1
  • Blood pressure 1
  • Complete blood count if pre-existing low WBC or history of leukopenia/neutropenia 1
  • Pregnancy test in women of childbearing potential 1

Ongoing Monitoring

  • Weight and BMI: Monitor regularly; significant weight gain warrants intervention 1
  • Glucose and lipids: Periodic monitoring, especially in patients with diabetes risk factors 1
  • Blood pressure and heart rate: Monitor for orthostatic hypotension, particularly early in treatment 1
  • Movement disorders: Assess for akathisia, tardive dyskinesia, and extrapyramidal symptoms at each visit 1
  • CBC: Continue monitoring if baseline abnormalities present; discontinue if clinically significant WBC decline occurs without other cause 1
  • Suicidal ideation: Close monitoring in MDD patients, especially early in treatment and during dose changes 1

Critical Warnings and Precautions

Black Box Warnings

  • Increased mortality in elderly patients with dementia-related psychosis: Brexpiprazole is NOT approved for this population 1
  • Suicidal thoughts and behaviors: Increased risk in pediatric and young adult patients treated with antidepressants; close monitoring required 1
  • Safety not established in pediatric MDD 1

Serious Adverse Reactions

  • Cerebrovascular events: Increased risk of stroke and TIA in elderly patients with dementia-related psychosis 1
  • Neuroleptic malignant syndrome: Manage with immediate discontinuation and close monitoring 1
  • Tardive dyskinesia: Risk increases with duration of treatment and total cumulative dose; discontinue if clinically appropriate 1
  • Metabolic changes: Monitor for hyperglycemia/diabetes, dyslipidemia, and weight gain 1
  • Pathological gambling and compulsive behaviors: Consider dose reduction or discontinuation if these emerge 1
  • Orthostatic hypotension and syncope: Monitor in patients with cardiovascular/cerebrovascular disease or risk of dehydration 1
  • Leukopenia, neutropenia, agranulocytosis: Perform CBC in at-risk patients; consider discontinuation if significant WBC decline 1
  • Seizures: Use cautiously in patients with seizure history or conditions lowering seizure threshold 1
  • Cognitive and motor impairment: Caution when operating machinery 1

Clinical Efficacy Data

Schizophrenia

  • Acute treatment: 45.5% responders with brexpiprazole 2–4 mg vs. 31% placebo (NNT = 7) 4
  • Relapse prevention: 13.5% relapsed on brexpiprazole vs. 38.5% on placebo over 52 weeks (NNT = 4) 4

Major Depressive Disorder (Adjunctive)

  • Response rate: 23.2% responders with brexpiprazole 1–3 mg vs. 14.5% placebo (NNT = 12) 4
  • Demonstrated efficacy on MADRS (mean difference -1.25), SDS (-0.37), and HDRS17 (-1.28) compared to placebo 6

Common Pitfalls and Clinical Pearls

Avoid These Mistakes

  • Do not start at target dose: Titration is required to minimize adverse effects, particularly akathisia 1, 2
  • Do not exceed 4 mg daily in schizophrenia or 3 mg daily in MDD: Higher doses increase adverse effects without additional benefit 1
  • Do not use in dementia-related psychosis: Black box warning for increased mortality 1
  • Do not forget dose adjustments: Hepatic/renal impairment and drug interactions require dose reduction 1

Optimize Tolerability

  • Lower doses (2 mg) associated with less akathisia and somnolence compared to 4 mg in schizophrenia 6
  • Gradual titration over 1–2 weeks reduces early adverse effects 3
  • Monitor weight closely: Early intervention for weight gain improves long-term metabolic outcomes 1

When to Consider Brexpiprazole

  • Schizophrenia patients requiring acute treatment with favorable metabolic and EPS profile compared to some other atypicals 2, 5
  • MDD patients with inadequate response to 1–3 antidepressants where adjunctive antipsychotic is appropriate 5, 4
  • Patients at high risk for metabolic syndrome where modest weight gain profile may be advantageous 2

References

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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