Brexpiprazole: A New Antipsychotic Following in the Footsteps of Aripiprazole.

Abstract

doses were well tolerated and that daily doses of 2 mg and 4 mg, but not 0.5 mg, were effective. This study provides a comprehensivepictureofshort-termefficacyandtolerability in relation to placebo, but in the absence of an active comparator it is difficult to predict whether brexpiprazole has meaningful advantages or disadvantages compared with existing agents. Brexpiprazole arrives at a time when many of the existing second-generation agents, including aripiprazole, have become generic—this shift toward generic agents has had a significant impact on current and projected health care budgets (2). Brexpiprazole, like aripiprazole, is a partial agonist at dopamineD2receptors.ByactivatingD2receptorstoalesser degreethanendogenousdopamine,partialagonistslowerthe ceilingformaximalD2transmissionwhileincreasingactivity at hypoactive D2receptors. The intentis toachieve a balance such that D2 receptors are activated sufficiently to prevent neurologic side effects (extrapyramidal symptoms) and hyperprolactinemia while avoiding excessive D2 activity, which would compromise antipsychotic efficacy and might produce side effects associated with D2 agonism. An earlier unsuccessful D2 partial agonist, bifeprunox, had greater intrinsic activityat D2receptors than aripiprazole and was less effective than existing antipsychotics while producing nausea and vomiting attributable to D2 receptor activation (3). It might be expected that aripiprazole, as a partial agonist, alsowouldbelesseffectivethanotherantipsychoticsthatare D2antagonists;however,thelimitedavailabledatafromheadto-head comparisons suggests that aripiprazole resides in the middle of the pack of second-generation antipsychotics in terms of efficacy (4). Aripiprazole is essentially free of hyperprolactinemia and extrapyramidal symptoms, but nausea,insomnia,andrestlessness,whichmaybesymptomsofD2 agonism, can complicate early treatment in some patients. The relative intrinsic D2 activity of brexpiprazole was 43% compared with 61% for aripiprazole, 84% for bifeprunox, and 100% for dopamine as determined by the maximum inhibitory effect on forksolin-induced cAMP in human D2-expressing cells (5). This level of D2 activity places brexpiprazole between aripiprazole and D2 antagonist antipsychotics. All else being equal, one would predict that brexpiprazolewouldpossessanintermediatelevelofefficacy and risk for extrapyramidal symptoms and prolactin elevation. However, unlike aripiprazole, brexpiprazole also has a high affinity for serotonin 5-HT1a receptors, where it is a partial agonist, and for 5-HT2a and alpha 1b and 2c adrenoceptors, where it is a potent antagonist (5). This profile makesbrexpiprazolemoresimilartoothersecond-generation antipsychotics than is aripiprazole and might reduce risk for extrapyramidal symptomsand improve efficacy, although this remains to be established. The efficacy of 2- and 4-mg/day dosages of brexpiprazole in this study was robust despite a relatively large placebo