Brexpiprazole: mechanism of action, pharmacokinetics, application and side effect

General Description

Brexpiprazole is a medication used for the treatment of schizophrenia and as an adjunctive therapy for major depressive disorder (MDD). It interacts with multiple monoaminergic receptors, acting as a partial agonist at 5-HT1A and D₂ receptors, and an antagonist at other receptors. Brexpiprazole has a long half-life and undergoes metabolism primarily by CYP3A4 and CYP2D6 enzymes. It can increase serum concentrations when used with CYP3A4 inhibitors and may require dose adjustments in poor CYP2D6 metabolizers. Common side effects include nausea, constipation, headache, and weight gain. Rare but serious side effects include NMS, tardive dyskinesia, and serotonin syndrome. Brexpiprazole shows efficacy in alleviating symptoms of schizophrenia and MDD.

Figure 1. Tablet of brexpiprazole

Mechanism of action

Brexpiprazole exhibits its pharmacological effects through its interaction with multiple monoaminergic receptors. In addition to dopamine D₂ receptors, it also has affinity for serotonin 5-HT₁A, 5-HT₂A, 5-HT2B, and 5-HT7 receptors, as well as norepinephrine, histamine H₁, and muscarinic M₁ receptors. Specifically, brexpiprazole acts as a partial agonist at the 5-HT1A and D₂ receptors with similar potency. It also functions as a partial agonist at the D3 receptor. However, it acts as an antagonist at the remaining receptors mentioned above. This unique combination of receptor interactions contributes to the complex mechanism of action of brexpiprazole. By modulating these various receptor systems, brexpiprazole can exert its therapeutic effects in the treatment of certain psychiatric conditions. ¹

Pharmacokinetics

Brexpiprazole is an orally administered medication with peak plasma concentrations reached within four hours. It has a long terminal half-life of 86-91 hours and undergoes metabolism primarily by cytochrome P450 (CYP) enzymes, specifically CYP3A4 and CYP2D6. Concomitant use of strong CYP3A4 inhibitors, like ketoconazole, can increase brexpiprazole’s serum concentrations, while inducers such as rifampicin may decrease its concentrations. Therefore, adjustment of the brexpiprazole dose is necessary when used concurrently with these medications. Patients who are poor CYP2D6 metabolisers may require a dose reduction. Brexpiprazole can be taken with or without food. The recommended starting dose is 1 mg, which should be titrated to a target dose of 2-4 mg over eight days based on individual response and tolerability. For individuals with moderate-severe hepatic or renal impairment, the maximum daily dose is 3 mg. ²

Applications

Brexpiprazole is clinically used for the treatment of certain psychiatric conditions. It has been approved for the management of schizophrenia and as an adjunctive therapy for MDD. In the treatment of schizophrenia, brexpiprazole helps alleviate symptoms such as hallucinations, delusions, disorganized thinking, and negative symptoms. By acting as a partial agonist at dopamine D₂ receptors and serotonin 5-HT₁A receptors, it helps to regulate the imbalances of these neurotransmitters in the brain. Furthermore, brexpiprazole has shown efficacy as an adjunctive treatment for MDD. When added to an antidepressant, it can help improve mood, reduce feelings of sadness, and increase interest in daily activities. The mechanism behind its effectiveness in MDD involves its partial agonism at 5-HT₁A receptors, which can modulate serotonin levels. ^{1, 3}

Side effect

Common side effects of brexpiprazole include nausea, stomach discomfort, constipation, headache, drowsiness, insomnia, restlessness, and weight gain. These effects are relatively common and may affect more than 1 in 10 individuals taking the medication. Less common side effects can include dizziness, tremors, dyskinesia, visual disturbances, increased heart rate, orthostatic hypotension, dry mouth, increased appetite, disturbances in sexual function, and abnormal dreams. Although uncommon, these side effects may still be experienced by some individuals. Rare but serious side effects that require immediate medical attention include neuroleptic malignant syndrome (NMS), which presents with high fever, muscle stiffness, confusion, and changes in blood pressure and heart rate. Tardive dyskinesia, characterized by repetitive, involuntary movements, and serotonin syndrome, a potentially life-threatening condition with symptoms such as agitation, hallucinations, rapid heartbeat, increased body temperature, and tremors, are also rare but important to be aware of. ⁴

Reference

1. Fornaro M, Fusco A, Anastasia A, Cattaneo CI, De Berardis D. Brexpiprazole for treatment-resistant major depressive disorder. Expert Opin Pharmacother, 2019, 20(16):1925-1933.

2. Markovic M, Gallipani A, Patel KH, Maroney M. Brexpiprazole. Ann Pharmacother, 2017, 51(4):315-322.

3. Brexpiprazole for schizophrenia. Aust Prescr, 2017, 40(5):197-198.

4. Lobo MC, Whitehurst TS, Kaar SJ, Howes OD. New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics. Neurosci Biobehav Rev, 2022, 132:324-361.