Objective: To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with inadequate response to ADTs. Method: Patients still depressed despite 1-3 prior ADTs followed by 8 weeks of prospective physician-determined, open-label ADT were randomized (1:1:1) to double-blind brexpiprazole 3 mg/d, brexpiprazole 1 mg/d, or placebo for 6 weeks. The primary efficacy end point was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. The key secondary efficacy end point was change in Sheehan Disability Scale mean score. The Hochberg procedure corrected for multiplicity. The efficacy population comprised all patients who had ≥ 1 dose of study drug with baseline and ≥ 1 postrandomization MADRS scores; the efficacy population per final protocol consisted of efficacy population patients meeting amended criteria for inadequate response throughout the 8-week prospective ADT. The study was conducted between June 2011 and September 2013. Results: In the efficacy population per final protocol, brexpiprazole 3 mg (n = 213) showed a greater improvement in MADRS total score versus placebo (n = 203; −8.29 vs −6.33; P = .0079), whereas brexpiprazole 1 mg did not (n = 211; −7.64 vs −6.33; P = .0737). The brexpiprazole groups showed comparable improvement in SDS mean score versus placebo (least squares [LS] mean difference: [1 mg] −0.49, P = .0158; [3 mg] −0.48, P = .0191). The most frequent adverse events were akathisia (4.4%, 13.5%, 2.3%), headache (9.3%, 6.1%, 7.7%), and weight increase (6.6%, 5.7%, 0.9%) in brexpiprazole 1-mg, 3-mg, and placebo groups, respectively. Mean changes from baseline in Abnormal Involuntary Movement Scale (LS mean difference = 0.08, P = .0141) and Barnes Akathisia Rating Scale (LS mean difference = 0.17, P = .0001) total scores were significantly greater with brexpiprazole 3 mg versus placebo. causing loss of productivity and increased mortality. 3 Although numerous antidepressant treatments (ADTs) are available, a significant minority of people suffering from MDD do not respond to first-line therapies.6,7 Treatment options following inadequate ADT response include changing to another ADTeither within the same class or in another ADT class-or augmenting ADT with another medication, such as a second-generation antipsychotic. 6,8 In the United States, adjunctive aripiprazole and quetiapine are currently approved in MDD, while olanzapine combined with fluoxetine is approved for patients with treatment-resistant depression. Although efficacy has been established in many randomized controlled trials, tolerability profiles of these agents limit their clinical use.9,10 Side effects vary between medications but most commonly include akathisia for aripiprazole, increased appetite/weight gain for olanzapine-fluoxetine combination, and excessive sedation for quetiapine. 11Weight gain can be a particularly ominous side effect because it...

Brexpiprazole at dosages of 2 and 4 mg/day demonstrated statistically significant efficacy compared with placebo and good tolerability for patients with an acute schizophrenia exacerbation.

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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​​​.