BREXI 2

Indications

• Schizophrenia
• Adjunctive treatment of major depressive disorder

Dosage

Children: The safety and efficacy of brexpiprazole in children and adolescents have not been established. Refer to the BNF for Children for guidance on paediatric dosing.

Adults: The dosage of brexpiprazole in adults typically starts at 0.5 to 1 mg once daily, with adjustments made based on clinical response and tolerability, not exceeding 4 mg per day.

Mechanism of action

The exact mechanism of action of brexpiprazole in psychiatric disorders is not fully understood. However, it is believed to exert its therapeutic effects through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, alongside antagonist activity at serotonin 5-HT2A receptors. This dual action allows brexpiprazole to modulate dopaminergic and serotonergic neurotransmission, which is significant in the pathophysiology of schizophrenia and depression.

Pharmacodynamics

Brexpiprazole is effective in managing symptoms associated with psychiatric disorders, such as cognitive deficits and mood disturbances. It has a high affinity for multiple monoaminergic receptors, including 5-HT1A, 5-HT2A, dopamine D2, and noradrenergic α receptors. Its partial agonism at D2 receptors allows it to stabilize dopamine activity, enhancing cognitive functions and improving affective symptoms while minimizing the risk of extrapyramidal side effects commonly associated with full D2 agonists.

Pharmacokinetics

Brexpiprazole is well absorbed following oral administration, with peak plasma concentrations typically reached within 4 to 5 hours. The drug is extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP3A4 and CYP2D6. Its elimination half-life is approximately 91 hours, allowing for once-daily dosing. The drug is primarily excreted as metabolites in urine and feces.

Adverse effects

• Weight gain
• Sedation
• Akathisia
• Insomnia
• Anxiety
• Nausea
• Vomiting
• Constipation
• Dizziness

Interactions

• CYP2D6 inhibitors may increase brexpiprazole levels
• CYP3A4 inducers may decrease brexpiprazole levels
• Use with caution in combination with other central nervous system depressants

Precautions

• Monitor for worsening of depression or emergence of suicidal thoughts
• Use with caution in patients with a history of seizures
• Assess metabolic parameters regularly due to potential weight gain

Pregnancy

Brexpiprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, as there is limited data on its safety.

Breast-feeding

Brexpiprazole is excreted in human milk. Caution should be exercised when administering to a nursing woman.

Storage

Store at room temperature, away from excess heat and moisture. Keep out of reach of children.

Formulations

• Tablets

Mechanism of action

Although the exact mechanism of action of brexpiprazole in psychiatric disorders has not been fully elucidated, the efficacy of brexpiprazole may be attributed to combined partial agonist activity at 5-HT_1A and dopamine D2 receptors, and antagonist activity at 5-HT_2A receptors. Brexpiprazole binds to these receptors with subnanomolar affinities. These therapeutic targets have been implicated in psychiatric conditions such as schizophrenia and depression. Partial D2 receptor agonism allows the drug to stimulate D2 receptors under low dopamine conditions, while attenuating their activation when dopamine levels are high. Partial agonism at 5-HT_1A receptors may be tied to improved memory function and cognitive performance. Antagonism at α-adrenergic receptors has also been implicated in schizophrenia and depression.

Pharmacodynamics

Brexpiprazole is an atypical antipsychotic agent used to ameliorate the symptoms of psychiatric conditions, such as cognitive deficits and affective symptoms. Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT_1A (0.12 nM), 5-HT_2A (0.47 nM), 5-HT_2B (1.9 nM), 5-HT₇ (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α_1A (3.8 nM), α_1B (0.17 nM), α_1D (2.6 nM), and α_2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT_1A, D2, and D3 receptors and as an antagonist at 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A, α_1B, α_1D, and α_2C receptors. Brexpiprazole also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic M1 receptor (67% inhibition at 10 µM).