Objective: To assess the efficacy, tolerability, and safety of brexpiprazole as adjunctive therapy to antidepressant treatments (ADTs) in adults with major depressive disorder (as defined by DSM-IV-TR criteria) and inadequate response to ADTs. Method: Patients with historical inadequate response to 1-3 ADTs were enrolled. All patients entered a prospective 8-week phase on physician-determined, open-label ADT. Those with inadequate response were randomized to ADT + brexpiprazole 2 mg/d or ADT + placebo for 6 weeks. The study was conducted between July 2011 and May 2013. The primary efficacy end point was change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The key secondary end point was change from baseline to week 6 in Sheehan Disability Scale (SDS) mean score. The efficacy population comprised all patients who had ≥ 1 dose of study drug in the double-blind phase and both baseline and ≥ 1 postrandomization MADRS scores. The efficacy population per final protocol included patients from the efficacy population who met amended randomization criteria of inadequate response throughout prospective treatment. Results: Brexpiprazole (n = 175) reduced mean MADRS total score versus placebo (n = 178) at week 6 in the efficacy population per final protocol (−8.36 vs −5.15, P = .0002). Brexpiprazole improved SDS mean score versus placebo (−1.35 vs −0.89, P = .0349). The most common treatmentrelated adverse events were weight gain (brexpiprazole, 8.0%; placebo, 3.1%) and akathisia (7.4% vs 1.0%). Conclusions:Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs. Trial Registration: ClinicalTrials.gov identifier: NCT01360645 J Clin Psychiatry 2015;76(9):1224-1231 dx.doi.org/10.4088/JCP.14m09688 © Copyright 2015 Effective treatment of patients with major depressive disorder (MDD) not responding adequately to first-line antidepressant treatment (ADT) remains an important unmet need.1,2 For inadequate response to an optimized trial of first-line ADT, current guidelines recommend switching ADT, adding a second ADT or adding adjunctive therapy with a non-ADT. 1,3 Adjunctive second-generation antipsychotic therapies such as olanzapine, 4 quetiapine, 5,6 and aripiprazole 7 are associated with significant improvements in treatment response and remission; however, their side effect profile may limit use in clinical practice. 8,9 Prominent side effects vary from drug to drug, 10,11 ie, weight gain with olanzapine, 12 sedation with quetiapine, 5 and akathisia with aripiprazole. 7 Thus, there is ongoing interest in identifying adjunctive strategies that offer the rapid efficacy of antipsychotics while reducing frequency and burden of side effects.Serotoninergic (5-HT), dopaminergic (D), and noradrenergic systems appear to play important roles in ADT mechanisms of action. 13,14 Brexpiprazole is a rationally designed serotonindopamine activity modulator, with partial agonism at...

ClinicalTrials.gov identifier: NCT02196506; EudraCT number: 2014-000062-22​​​.

Adjunctive brexpiprazole 2-3 mg/day improved symptoms of depression compared with adjunctive placebo in patients with MDD and an inadequate response to ADTs, and was well tolerated with no unexpected side effects.

Objective:Brexpiprazole is a serotonin-noradrenaline-dopamine agent that binds with high affinity to multiple serotonin, norepinephrine and dopamine receptors. In particular, Brexpiprazole is a partial agonist at dopamine D2/D3 and 5-HT1A receptors and an antagonist at 5-HT2A and norepinephrine alpha1B receptors.We assessed the efficacy and safety of brexpiprazole versus placebo as adjunctive therapy to anti-depressant therapy (ADT) in subjects with MDD who demonstrated inadequate response to ADT.Methods:This trial had 3 phases: a screening phase (7-28 days); a prospective phase (Phase A): 8-week, single-blind placebo plus an investigator-determined, open-label ADT; a randomized phase (Phase B): 6-week, double-blind, adjunctive brexpiprazole (2 mg/day) vs. placebo in patients with an inadequate response to ADT.The primary efficacy endpoint was the change from the end of Phase A (Week 8) to the end of Phase B (Week 14) in MADRS Total Score. The key secondary endpoint was the change in mean SDS score. Other secondary endpoints were mean change in CGI-S, IDS-R, HAMD and HAMA.Results:Of 379 randomized patients, completion rates at Week 14 were high (92.9%). Statistically significant improvements in mean MADRS Total score were observed for subjects receiving adjunctive brexpiprazole 2mg/day compared with placebo (p=0.0001) at endpoint. In addition, on all secondary endpoints Brexpiprazole showed a statistically significant advantage over placebo.Commonly reported adverse events in the brexpiprazole group (>5% and more than twice placebo) were weight gain (8.0%), akathisia (7.4%).Conclusions:Brexpiprazole was effective and well tolerated as adjunctive treatment for MDD patients with an inadequate response to ADT.