Brexpiprazole

Approved Indications:

• Schizophrenia
• For the treatment of schizophrenia in adults and adolescents aged ≥13 years.
• Effective in both acute and maintenance phases.
• Major Depressive Disorder (MDD) – Adjunctive Treatment
• Used as an adjunct to antidepressants in adults with MDD who have had an inadequate response to antidepressant therapy alone.

Important Off-Label (Clinically Accepted) Uses:

• Generalized Anxiety Disorder (GAD)
• Under clinical investigation and sometimes used off-label for treatment-resistant GAD.
• Bipolar Depression (Adjunctive)
• Studied as adjunct therapy in bipolar depression, though not officially approved.
• Agitation Associated with Dementia
• Investigated for behavioral symptoms such as agitation in Alzheimer’s disease, though not yet FDA-approved.

Route of Administration: Oral (tablet)

A. Adults

• Schizophrenia:
• Initial dose: 1 mg once daily (days 1–4)
• Target dose: 2 mg once daily (day 5 onward)
• Usual dose range: 2–4 mg once daily
• Maximum dose: 4 mg/day
• Adjunctive Treatment in MDD:
• Initial dose: 0.5 mg or 1 mg once daily
• Target dose: 2 mg once daily
• Maximum dose: 3 mg/day

B. Geriatrics:

• Use lowest effective dose.
• Start with 0.5 mg daily and titrate slowly due to increased sensitivity and fall risk.

C. Renal Impairment:

• For moderate to severe renal impairment (CrCl <60 mL/min):
• Maximum dose: 2 mg/day (in schizophrenia); 1 mg/day (in MDD)

D. Hepatic Impairment:

• For moderate to severe hepatic impairment:
• Maximum dose: 2 mg/day (in schizophrenia); 1 mg/day (in MDD)

E. Pediatric Use:

• Approved for adolescents aged ≥13 years with schizophrenia.
• Start low and titrate slowly under specialist supervision.

Administration Notes:

• May be taken with or without food.
• Dose adjustments required when co-administered with strong CYP3A4 or CYP2D6 inhibitors/inducers.

Brexpiprazole is a serotonin-dopamine activity modulator that exerts its antipsychotic and antidepressant effects by partial agonism at serotonin 5-HT1A and dopamine D2 receptors, and antagonism at serotonin 5-HT2A and noradrenaline alpha-1B/2C receptors. Its partial D2 receptor agonism results in dopaminergic modulation that reduces positive symptoms of schizophrenia while minimizing extrapyramidal symptoms. The serotonin receptor modulation contributes to its antidepressant effects and improved mood regulation. The unique receptor binding profile allows for effective symptom control with a favorable side effect profile.

• Absorption:
• Well absorbed orally with peak plasma concentration (Tmax) at ~4 hours post-dose.
• Absolute bioavailability is approximately 95%.
• Distribution:
• Highly protein bound (~99%).
• Volume of distribution: ~1.6–2.6 L/kg.
• Metabolism:
• Extensively metabolized in the liver via CYP3A4 and CYP2D6 enzymes.
• Produces an active metabolite (DM-3411) with similar receptor affinity but lesser potency.
• Elimination:
• Elimination half-life: ~91 hours (parent compound); ~86 hours (active metabolite).
• Excretion: ~25% in urine and ~46% in feces (mainly as metabolites).

• Pregnancy:
• Not assigned a formal FDA pregnancy category.
• Limited human data; animal studies show potential fetal risks at high doses.
• May cause extrapyramidal and withdrawal symptoms in neonates if used during the third trimester. Use only if clearly needed.
• Lactation:
• Unknown if excreted into human breast milk.
• Due to long half-life and potential adverse effects on the infant (e.g., sedation, EPS), breastfeeding is not recommended during treatment.
• Recommendation:
• Avoid use in pregnancy and lactation unless benefits outweigh risks.

• Primary Class: Atypical Antipsychotic (Second Generation Antipsychotic)
• Sub-class: Dopamine D2 Partial Agonist
• Receptor Activity Profile: Serotonin-dopamine activity modulator

• Known hypersensitivity to brexpiprazole or any component of the formulation
• Severe hepatic impairment without proper dose adjustment
• Concurrent use with strong CYP3A4 inducers in patients on maximum dose
• Use in patients with known history of neuroleptic malignant syndrome without clinical oversight
• Pediatric patients <13 years (safety and efficacy not established)

• Black Box Warning (Suicidality):
• Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults with MDD.
• Elderly with Dementia-Related Psychosis:
• Not approved due to increased risk of death.
• Neuroleptic Malignant Syndrome (NMS):
• Rare but potentially fatal; discontinue immediately if symptoms occur.
• Tardive Dyskinesia:
• Risk increases with long-term use.
• Metabolic Changes:
• Monitor for hyperglycemia, dyslipidemia, and weight gain.
• Orthostatic Hypotension and Syncope:
• Caution in elderly and volume-depleted patients.
• Leukopenia/Neutropenia:
• Monitor complete blood count periodically.
• Seizures:
• Use cautiously in patients with seizure history.

Common Adverse Effects:

• Central Nervous System: Akathisia, headache, insomnia, somnolence, agitation
• Metabolic: Weight gain, increased appetite
• Gastrointestinal: Nausea, dyspepsia
• Cardiovascular: Orthostatic hypotension

Serious/Rare Side Effects:

• Extrapyramidal symptoms (EPS)
• Tardive dyskinesia
• Neuroleptic malignant syndrome
• Suicidal ideation
• Seizures
• Hyperglycemia or new-onset diabetes
• Leukopenia, neutropenia
• Hyponatremia (rare)

Timing and Severity:

• Akathisia and EPS more common during early titration.
• Metabolic changes may develop over weeks to months.

CYP450 Metabolism Involvement:

• Primarily metabolized by CYP3A4 and CYP2D6.

Major Drug-Drug Interactions:

• CYP3A4 Inhibitors (e.g., ketoconazole): Increase brexpiprazole exposure; dose reduction required.
• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): May increase plasma levels.
• CYP3A4 Inducers (e.g., carbamazepine, rifampin): Decrease efficacy; avoid if on maximum dose.
• CNS Depressants (e.g., benzodiazepines, opioids): Additive sedative effect.
• QT-Prolonging Drugs: Caution due to potential additive QT effects.

Alcohol:

• Avoid due to enhanced CNS depression.

• 2023 FDA Update:
• Expanded approval for schizophrenia in adolescents aged ≥13 years.
• Continued surveillance on suicidality and metabolic adverse effects.
• Clinical Guidelines:
• APA and NICE recommend brexpiprazole as an option for treatment-resistant depression as adjunct therapy to SSRIs/SNRIs.
• Acknowledged as an alternative antipsychotic with lower EPS risk.
• Ongoing Trials:
• Evaluating efficacy in agitation in dementia and bipolar depression.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F).
• Humidity Protection: Store in a dry place.
• Light Protection: Protect from direct sunlight and excessive heat.
• Handling: Keep in original packaging; do not remove desiccants.
• Reconstitution/Refrigeration: Not required; available in solid oral tablet form only.