Efficacy of Brexpiprazole as Adjunctive Treatment in Major Depressive Disorder With Irritability

To the Editors: I rritability in patients with major depressive disorder (MDD) has been associated with greater overall severity, previous suicide attempts, and suicidal ideations. Irritability in MDD is also associated with longer duration of episodes, a more chronic course of illness, impaired functioning, and less favorable outcomes. Irritability is a symptom often addressed with the use of an antipsychotic as adjunctive therapy to antidepressant treatment (ADT). The adverse effects profile of atypical antipsychotics, however, may limit their use in clinical practice. Aripiprazole is associated with activating adverse effects, including akathisia and anxiety, whereas quetiapine is associated with sedation. Brexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all at similar potencies. Brexpiprazole was approved in 2015 in the United States for the treatment of schizophrenia and for use as an adjunctive therapy to antidepressants for the treatment of MDD. Here we assess the efficacy of adjunctive brexpiprazole in patients with MDD and irritability, comparing brexpiprazole to placebo as adjunctive therapy to ADT in patients with and without self-rated irritability, using pooled data from the 2 similarly designed randomized, double-blind, placebocontrolled, pivotal phase 3 studies. Briefly, each study included a screening phase, an 8-week single-blind prospective phase, and a 6-week double-blind randomized treatment phase. Patients aged 18 to 65 years diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision with a single or recurrent nonpsychotic episode of MDD of 8 weeks or more duration were recruited. Patients