Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown efficacy in 2 phase-III acute trials for each indication.1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors,7 which could mean better tolerability.
Clinical implications
Schizophrenia is heterogeneous, and individual response and tolerability to antipsychotics vary greatly8; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant therapy9; brexpiprazole represents another agent for patients whose depressive symptoms persist after standard antidepressant treatment.
Variables that limit the use of antipsychotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favorable side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.
How it works
In addition to a subnanomolar binding affinity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhibits similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antagonist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.7
Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) receptors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antagonist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).
Brexpiprazole’s pharmacodynamic profile differs from other available antipsychotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelioration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.6
Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is relatively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brexpiprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.
In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.
Exposure, as measured by maximum concentration and area under the concentration curve, is dose proportional.
Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brexpiprazole shows little or no inhibition of CYP450 isozymes.
Efficacy
FDA approval for brexpiprazole for schizophrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.1-6 These studies are described in Table 2.2-5
Schizophrenia. The primary outcome measure for the acute schizophrenia trials was change on the Positive and Negative Syndrome Scale (PANSS) total scores from baseline to 6-week endpoint. Statistically significant reductions in PANSS total score were observed for brexpiprazole dosages of 2 mg/d and 4 mg/d in one study,2 and 4 mg/d in another study.3 Responder rates also were measured, with response defined as a reduction of ≥30% from baseline in PANSS total score or a Clinical Global Impressions-Improvement score of 1 (very much improved) or 2 (much improved).2,3 Pooling together the available data for the recommended target dosage of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 phase-III studies, 45.5% of patients responded to the drug, compared with 31% for the pooled placebo groups, yielding a number needed to treat (NNT) of 7 (95% CI, 5-12).6
Although not described in product labeling, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symptoms and impending relapse in patients with schizophrenia.10 Time from randomization to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).
Major depressive disorder. The primary outcome measure for the acute MDD studies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the randomized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inadequate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.