Adjunctive Brexpiprazole 1 and 3 mg for Patients With Major Depressive Disorder Following Inadequate Response to Antidepressants

Abstract

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...

Adjunctive Brexpiprazole in Patients With Major Depressive Disorder and Irritability

“…The antidepressant effects observed in the current study are also consistent with the results of previous clinical studies, 10,11 which have shown that brexpiprazole is efficacious as adjunctive treatment in adult patients with MDD who had an inadequate response to antidepressant treatment. The tolerability of the compound in this study is also consistent with previous clinical studies, which have revealed that the compound is safe and well tolerated, with low rates of sedating (eg, somnolence, sedation) and activating (eg, akathisia, restlessness, anxiety, insomnia) side effects, 10,11 although the incidence of akathisia observed here (20.4%) was higher than those previously reported from the pivotal studies (1 mg: 4.4%; 2 mg: 7.4%; and 3 mg: 13.5%).…”

“…Assessment used to measure changes in levels of irritability, impulsivity, anger, and hostility included the Sheehan Irritability Scale, 18 Sheehan Irritability Scale item 1 (irritable mood), and IDS-C 30 item 6 (irritable mood) to measure irritability; Monetary Choice Questionnaire 19 and Barratt Impulsiveness Scale, version 11,20 to measure impulsivity; and patient-rated Kellner Symptom Questionnaire 21 angerhostility subscale score and Anger Attacks Questionnaire 4 to measure anger and hostility. The Anger Attacks Questionnaire is a patient-rated scale developed to assess the presence of distinct forms of anger attacks over a period of time.…”

“…2 Brexpiprazole (OPC-34712) is a partial agonist at serotonin 5-HT 1A and dopamine D 2 receptors and an antagonist at serotonin 5-HT 2A and norepinephrine α 1B/2C receptors, all with similar subnanomolar binding affinity. 9 Clinical studies 10,11 demonstrated that brexpiprazole was efficacious as adjunctive treatment in adult patients with MDD who had an inadequate response to antidepressant treatment. In addition, brexpiprazole was safe and well-tolerated, with low rates of sedating (eg, somnolence, sedation) and activating (eg, akathisia, restlessness, anxiety, insomnia) side effects.…”

“…In addition, brexpiprazole was safe and well-tolerated, with low rates of sedating (eg, somnolence, sedation) and activating (eg, akathisia, restlessness, anxiety, insomnia) side effects. 10,11 The aim of this interventional, open-label, flexible-dose, exploratory study was to evaluate changes in irritability, anger, and other impulsivity-related behaviors, as well as depressive symptoms, in patients with MDD who were treated with adjunctive brexpiprazole. In addition, the safety and tolerability of brexpiprazole were assessed.…”

Symptoms of Anxiety and Irritability in Patients with Major Depressive Disorder

“…The study designs and selection criteria have been described in previous publications [14][15][16][17][18]. Briefly, each study included an 8-week, open-label treatment phase with an ADT (phase A) followed by a randomized, double-blind treatment phase with the adjunct antipsychotic or placebo (phase B).…”