What are the approved uses, dosing recommendations, and potential side effects of Rexulti (brexpiprazole)?

Rexulti (Brexpiprazole): Approved Uses, Dosing, and Side Effects

Rexulti (brexpiprazole) is FDA-approved for three specific indications: adjunctive treatment of major depressive disorder in adults, treatment of schizophrenia in adults and adolescents ≥13 years, and treatment of agitation associated with Alzheimer's disease dementia. 1

Approved Indications and Dosing

Major Depressive Disorder (Adjunctive Therapy)

• Starting dose: 0.5-1 mg once daily
• Target dose: 2 mg once daily
• Maximum dose: 3 mg once daily
• Titrate gradually based on response and tolerability 1

Schizophrenia

Adults:

• Starting dose: 1 mg once daily
• Target dose: 2-4 mg once daily
• Maximum dose: 4 mg once daily 1

Adolescents (13-17 years):

• Starting dose: 0.5 mg once daily
• Target dose: 2-4 mg once daily
• Maximum dose: 4 mg once daily 1

Agitation Associated with Alzheimer's Disease Dementia

• Starting dose: 0.5 mg once daily
• Target dose: 2 mg once daily
• Maximum dose: 3 mg once daily
• Note: Not approved for PRN (as-needed) use 1

Recent evidence suggests that brexpiprazole 2 mg provides optimal therapeutic benefit for agitation in Alzheimer's disease, with significant improvements in Cohen-Mansfield Agitation Inventory scores (mean difference: -5.88 compared to placebo), though it may take 6-12 weeks to separate from placebo 2, 3.

Administration Guidelines

• Take once daily with or without food 1
• Titration is essential - start low and increase gradually over 1-2 weeks to minimize side effects 4, 5
• For schizophrenia: typical titration is 1 mg/day initially, increase to 2 mg/day on Days 5-7, then to 4 mg/day on Day 8 if needed 4

Dosage Adjustments

Hepatic Impairment

• Moderate to severe hepatic impairment (Child-Pugh ≥7):
  • Maximum 2 mg daily for MDD or Alzheimer's agitation
  • Maximum 3 mg daily for schizophrenia 1

Renal Impairment

• CrCl <60 mL/min:
  • Maximum 2 mg daily for MDD or Alzheimer's agitation
  • Maximum 3 mg daily for schizophrenia 1

Drug Interactions

Strong CYP2D6 or CYP3A4 inhibitors: Reduce dose by half 1

Strong/moderate CYP2D6 AND CYP3A4 inhibitors together: Reduce dose to one-quarter 1

Strong CYP3A4 inducers: Double the dose over 1-2 weeks 1

Important exception: For MDD patients, no dose adjustment needed with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) as this was already factored into clinical trials 1

Side Effects Profile

Most Common Adverse Effects

In Major Depressive Disorder (≥5% and twice placebo rate):

• Weight gain
• Somnolence/drowsiness
• Akathisia (restlessness, need to move) - occurs in 8.6% vs placebo, NNH=15 5

In Schizophrenia (≥4% and twice placebo rate):

• Weight gain 1
• Akathisia - occurs in 5.5% vs 4.6% placebo, NNH=112 (not statistically significant) 5

In Adolescents with Schizophrenia:

• Extrapyramidal symptoms (difficulty moving, slow movement)
• Tremors
• Abnormal eye movements
• Muscle stiffness 1

In Alzheimer's Agitation:

• Nasopharyngitis
• Dizziness 1

Weight and Metabolic Effects

Weight gain is modest in short-term studies:

• Approximately 10% of patients gain ≥7% body weight (vs 4% placebo, NNH=17) 4
• However, more outliers with significant weight gain appear in long-term (52-week) studies 4, 5
• Monitor weight regularly; consider discontinuation if >5% weight loss occurs 1

Metabolic monitoring required:

• Check blood glucose before starting and periodically during treatment
• Monitor lipid levels (cholesterol, triglycerides) before starting and periodically
• Effects on glucose and lipids are generally small 4, 5

Serious Warnings and Precautions

BLACK BOX WARNINGS:

1. Increased mortality in elderly patients with dementia-related psychosis - Rexulti is NOT approved for dementia-related psychosis without agitation specifically due to Alzheimer's disease 1

2. Suicidal thoughts and behaviors - Increased risk in children, adolescents, and young adults (≤24 years) taking antidepressants. Close monitoring essential, especially during initial months and dose changes 1

Neurological Side Effects

Neuroleptic Malignant Syndrome (NMS) - rare but potentially fatal:

• High fever
• Muscle rigidity
• Confusion
• Changes in pulse, blood pressure, heart rate, breathing
• Increased sweating
• Requires immediate discontinuation and emergency care 1

Tardive Dyskinesia:

• Uncontrolled movements of face, tongue, or body
• May be irreversible even after stopping medication
• Can start after discontinuation
• Consider discontinuation if clinically appropriate 1

Extrapyramidal symptoms: Lower risk compared to typical antipsychotics, but can occur, especially at higher doses 4

Cardiovascular Effects

• Orthostatic hypotension and syncope - may feel dizzy or faint when standing up
• Increased fall risk, especially in elderly
• Monitor blood pressure and heart rate 1

Cerebrovascular events: Increased risk of stroke and transient ischemic attacks in elderly patients with dementia 1

Hematological Effects

• Leukopenia, neutropenia, agranulocytosis possible
• Perform complete blood counts in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia
• Consider discontinuation if clinically significant WBC decline occurs 1

Behavioral and Psychiatric Effects

Compulsive behaviors:

• Pathological gambling
• Compulsive sexual urges
• Compulsive shopping
• Binge eating
• Consider dose reduction or discontinuation if these emerge 1

Depression worsening: May worsen pre-existing depression or cause new-onset depression (~1% incidence). Counsel patients before starting 1

Other Important Side Effects

• Seizures: Use cautiously in patients with seizure history or conditions lowering seizure threshold 1
• Cognitive and motor impairment: Caution when operating machinery 1
• Difficulty swallowing: May cause aspiration 1
• Temperature regulation problems: May feel too warm; avoid overheating and dehydration 1
• Gastrointestinal effects: Diarrhea, nausea (especially in elderly, may lead to dehydration requiring hospitalization) 1

Contraindications

Absolute contraindication: Known hypersensitivity to brexpiprazole or any component - reactions include rash, facial swelling, urticaria, anaphylaxis 1

Clinical Pearls

• Discontinuation rates due to adverse events are generally low: 3% vs 1% placebo in MDD trials (NNH=53) 5
• Minimal prolactin elevation - advantage over some other antipsychotics 4, 5
• No clinically relevant QTc prolongation 4, 5
• Efficacy in schizophrenia: Response rate 45.5% vs 31% placebo (NNT=7); relapse prevention NNT=4 4, 5
• Efficacy in MDD: Response rate 23.2% vs 14.5% placebo (NNT=12) 5
• For Alzheimer's agitation: Benefits appear greatest in patients with severe agitation/aggression, but onset is delayed (6-12 weeks) 3

Pharmacology

Brexpiprazole is a serotonin-dopamine activity modulator acting as:

• Partial agonist at dopamine D2 and serotonin 5-HT1A receptors
• Antagonist at serotonin 5-HT2A receptors
• Antagonist at noradrenergic α1B and α2C receptors
• Compared to aripiprazole: more potent at 5-HT1A receptors, less intrinsic activity at D2 receptors 6, 7, 4