Efficacy of Brexpiprazole as Adjunctive Treatment in Major Depressive Disorder With Irritability: Post Hoc Analysis of 2 Pivotal Clinical Studies

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To the Editors
Irritability in patients with major depressive disorder (MDD) has been associated with greater overall severity, previous suicide attempts, and suicidal ideations.1 Irritability in MDD is also associated with longer duration of episodes, a more chronic course of illness, impaired functioning, and less favorable outcomes.2–4 Irritability is a symptom often addressed with the use of an antipsychotic as adjunctive therapy to antidepressant treatment (ADT).5 The adverse effects profile of atypical antipsychotics, however, may limit their use in clinical practice.6 Aripiprazole is associated with activating adverse effects, including akathisia and anxiety,7 whereas quetiapine is associated with sedation.8 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.9 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, placebo-controlled, pivotal phase 3 studies.10,11 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 had to have inadequate response, defined as less than 50% reduction in Massachusetts General Hospital Antidepressant Treatment Response Questionnaire score to an adequate treatment course of 1 to 3 ADTs administered for 6 weeks or more. Eligible patients also had Hamilton Depression Rating Scale (HAM-D17)12 total scores 18 or higher at screening and at start of the prospective treatment phase. Patients were randomized to treatment if they had an inadequate response throughout the prospective treatment phase defined as a HAM-D17 score 14 or higher, less than 50% reduction from start of prospective phase in HAM-D17, as well as less than 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS)13 total score between start of prospective phase and each visit, and a Clinical Global Impression–Improvement (CGI-I) score 3 or higher at each visit. Based on their self-assessment of irritability during the preceding week on Inventory of Depressive Symptomatology–Self-Report (IDS-SR) item 6 at randomization, patients were categorized as “with irritability” (IDS item 6 score ≥ 1) or “without irritability” (IDS item 6 score = 0) with IDS-SR scores being defined as follows14: 0, does not feel irritable; 1, feels irritable less than half the time; 2, feels irritable more than half the time; and 3, feels extremely irritable virtually all of the time. High level of irritability was defined as IDS-SR item 6 scores of 2 or higher. Patients were randomized to 2 mg brexpiprazole + ADT or placebo + ADT (1:1 ratio) or 1 mg brexpiprazole + ADT, 3 mg brexpiprazole + ADT, or placebo + ADT (1:1:1 ratio) in the 2 studies, respectively. The primary efficacy end point was change in MADRS total score from baseline, and efficacy analyses with pooled placebo groups in patients with and without irritability were conducted with a mixed model for repeated measures methodology as previously reported.10,11 Of the 987 patients who were randomized and fulfilled inadequate response criteria throughout the prospective ADT treatment phase, 811 (82.2%) reported irritability at baseline. At baseline, patients with and without irritability showed similar characteristics (mean age, 44.
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