Rexulti for schizophrenia, major depressive disorder, and agitation in Alzheimer's disease

Rexulti is an oral medication containing brexpiprazole, an atypical antipsychotic approved for treating schizophrenia in adults and adolescents 13 years and older, as an add-on therapy to antidepressants for adults with major depressive disorder (MDD), and for managing agitation linked to Alzheimer's disease dementia. It is taken once daily, with or without food.

Rexulti is used for:

• Adjunctive treatment of major depressive disorder (MDD) in adults: It is prescribed alongside antidepressants to help improve symptoms.
• Treatment of schizophrenia: Approved for adults and pediatric patients aged 13 years and older.
• Treatment of agitation associated with dementia due to Alzheimer's disease: Used to manage agitation symptoms in this specific population.

Limitations: Rexulti is not approved as an as-needed ("prn") medication for agitation related to Alzheimer's disease dementia, and its safety and effectiveness in pediatric patients with MDD have not been established.

Brexpiprazole

Brexpiprazole works by modifying the activity of certain chemicals in the brain, particularly dopamine and serotonin receptors. As an atypical antipsychotic, it acts as a partial agonist of dopamine D2 and serotonin 5-HT1A receptors and antagonist of serotonin 5-HT2A receptors, which helps regulate mood, thought processes, and behavior disturbances associated with schizophrenia, depression, and agitation.

Rexulti is taken orally once daily with or without food. Dosage varies by condition and patient factors:

• Major depressive disorder (adults): Start with 0.5 mg or 1 mg daily; titrate weekly to 2 mg daily. Maximum dose is 3 mg daily.
• Schizophrenia in adults: Start 1 mg daily for 4 days; then 2 mg daily for days 5–7; increase to 2–4 mg daily from day 8 based on response. Max dose 4 mg daily.
• Schizophrenia in pediatric patients (13–17 years): Start 0.5 mg daily for 4 days; titrate to 1 mg daily days 5–7; then to 2 mg on day 8; target 2–4 mg daily. Max dose 4 mg daily.
• Agitation associated with Alzheimer's dementia: Start 0.5 mg daily for 7 days; 1 mg daily days 8–14; then 2 mg daily from day 15. Can increase to 3 mg daily after 14 days if tolerated.

Special populations:

• For moderate to severe liver impairment, max doses are lowered to 2 mg daily for MDD or agitation and 3 mg daily for schizophrenia.
• For patients with creatinine clearance under 60 mL/min, the same lowered maximum doses apply.
• Dosage adjustments are required for patients who are CYP2D6 poor metabolizers or those taking CYP3A4 or CYP2D6 inhibitors or inducers. Adjustments include halving or quartering the dosage and slowly increasing if CYP3A4 inducers are added or discontinued.

Rexulti is contraindicated in patients with known hypersensitivity to brexpiprazole or any component of the formulation. Hypersensitivity reactions reported include rash, facial swelling, urticaria, and anaphylaxis.

Important safety warnings include:

• Increased mortality in elderly patients with dementia-related psychosis: Antipsychotics, including Rexulti, increase death risk in these patients. It is not approved for treatment of dementia-related psychosis without agitation associated with Alzheimer’s disease.
• Suicidal thoughts and behaviors: Antidepressants, including when Rexulti is used adjunctively in adults, may increase suicidal ideation in pediatric and young adult patients (up to age 24). Close monitoring is essential, especially early in treatment or when doses change.
• Cerebrovascular adverse reactions: Stroke and transient ischemic attacks have been reported in elderly dementia patients taking antipsychotics.
• Neuroleptic malignant syndrome (NMS): A potentially fatal reaction characterized by fever, muscle rigidity, altered mental status, and autonomic dysfunction. Immediate discontinuation and treatment required if suspected.
• Tardive dyskinesia: Potentially irreversible involuntary movements can develop, often after long-term use; use the lowest effective dose and shortest duration possible.
• Metabolic changes: Monitor for hyperglycemia, diabetes, dyslipidemia, and weight gain during treatment.
• Orthostatic hypotension and syncope: Monitor blood pressure and heart rate, especially in patients with cardiovascular risks.
• Leukopenia, neutropenia, agranulocytosis: Monitor white blood counts in patients with prior low counts.
• Seizures: Use cautiously in patients with seizure history or risks.
• Cognitive and motor impairment: Caution against driving or operating machinery until effects on alertness are known.

Common adverse effects include weight gain, metabolic changes such as elevated blood sugar or cholesterol, and symptoms related to dopamine/serotonin modulation. Serious but less common effects may include neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and leukopenia.

Rexulti’s dosage may need adjustment when used with certain medications affecting liver enzymes:

• CYP2D6 poor metabolizers: Use half the recommended dose.
• Concomitant strong/moderate CYP3A4 inhibitors: Reduce dose by half or quarter (if combined with CYP2D6 inhibition).
• Strong CYP3A4 inducers: Increase dose gradually to double over 1–2 weeks.
• Strong CYP2D6 inhibitors alone: No dose adjustment required for MDD adjunctive treatment.

Dose should be readjusted to original levels if interacting drugs are discontinued.