Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study

Hobart, Mary; Skuban, Aleksandar; Zhang, Peter; Hefting, Nanco; Augustine, Carole; Brewer, Claudette; Sanchez, Raymond; McQuade, Robert D.

doi:10.1080/03007995.2018.1430220

Cited by 53 publications

(69 citation statements)

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“…Compared to the BUP/SAM phase II study [14], MADRS response and remission rates were lower in both FORWARD studies. A similar phenomenon was observed in the recent Delphinus study where, following 6 weeks of therapy, response and remission rates were 10.5% and 6.8%, respectively, for adjunctive brexpiprazole and 8.1% and 2.0% for adjunctive quetiapine, compared with 6.8% and 4.4% for ADT plus placebo [38]. Like the FORWARD studies, Delphinus identified nonresponders to ADT prior to randomization to active adjunctive treatment and incorporated measures of masking to ensure investigators were unaware of the timing of treatment initiation.…”

Section: Discussionsupporting

confidence: 84%

“…Increasing placebo response rates in outpatient depression studies observed over the past several decades have made it more difficult to detect antidepressant efficacy and determine effect size [35,36]. For example, several recently completed phase III studies of new adjunctive agents for MDD, including agents with known efficacy, have failed to meet primary endpoints [37][38][39][40][41][42][43]. While some studies were considered supportive of a therapeutic effect [38,40], the majority found no evidence of efficacy [37,39,42,43], highlighting the challenge encountered in clinical trials, especially outpatient studies, for new antidepressant treatments.…”

Section: Discussionmentioning

confidence: 99%

“…For example, several recently completed phase III studies of new adjunctive agents for MDD, including agents with known efficacy, have failed to meet primary endpoints [37][38][39][40][41][42][43]. While some studies were considered supportive of a therapeutic effect [38,40], the majority found no evidence of efficacy [37,39,42,43], highlighting the challenge encountered in clinical trials, especially outpatient studies, for new antidepressant treatments. To minimize the risk of excessive placebo response rates, the FORWARD-4 and FORWARD-5 studies were conducted utilizing SPCD as a strategy to increase statistical power in smaller sample sizes [44,45] and enhance signal detection [14,45,46].…”

Section: Discussionmentioning

confidence: 99%

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Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

et al. 2018

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The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallelcomparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/ SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

et al. 2018

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“…Brexpiprazole is a serotonin–dopamine activity modulator that acts as a partial agonist at serotonin 5‐HT 1A and dopamine D 2 receptors and as an antagonist at serotonin 5‐HT 2A and noradrenaline α 1B/2C receptors, all with subnanomolar potency . The efficacy and safety of brexpiprazole as adjunctive treatment to ADT over 6 weeks has been demonstrated in 4 studies in adult patients (aged 18‐65 years) with MDD . Brexpiprazole is approved in the USA as an adjunctive therapy to antidepressants for the treatment of adults with MDD, and in the USA, Canada, Australia, and Japan as monotherapy for the treatment of adults with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…7 The efficacy and safety of brexpiprazole as adjunctive treatment to ADT over 6 weeks has been demonstrated in 4 studies in adult patients (aged 18-65 years) with MDD. [8][9][10][11] Brexpiprazole is approved in the USA as an adjunctive therapy to antidepressants for the treatment of adults with MDD, and in the USA, Canada, Australia, and Japan as monotherapy for the treatment of adults with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Adjunctive brexpiprazole for elderly patients with major depressive disorder: An open‐label, long‐term safety and tolerability study

Lepola

Hefting

Zhang

et al. 2018

Int J Geriat Psychiatry

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ObjectivesThe objective of this study was to evaluate the long‐term safety and tolerability of flexible‐dose brexpiprazole adjunct to antidepressant treatment (ADT) in elderly patients with major depressive disorder (MDD).MethodsElderly patients (≥65 years) with MDD and inadequate response to ≥1 ADT during the current episode were recruited to a 26‐week, interventional, open‐label study (NCT02400346) at outpatient centers in the USA and Europe. All patients received brexpiprazole 1 to 3 mg/day adjunct to their current ADT. Safety outcomes included adverse events (AEs), movement disorder scales, and standard safety assessments (vital signs, laboratory safety parameters, physical examination, electrocardiograms). Exploratory efficacy outcomes included the Montgomery–Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions‐Severity of Illness (CGI‐S), and Social Adaptation Self‐Evaluation Scale (SASS).ResultsOf the 132 treated patients, 88 (66.7%) completed the study and 44 (33.3%) withdrew, including 24 who withdrew because of AEs (18.2%). Overall, 102 patients (77.3%) experienced ≥1 treatment‐emergent AE (TEAE), which were mostly mild or moderate in severity. Treatment‐emergent AEs with the highest incidence were fatigue (15.2%) and restlessness (12.9%). The most common TEAE leading to withdrawal was fatigue (3.0%). No consistent clinically relevant findings were seen with regard to movement disorder scales or standard safety assessments. Mean (standard error) efficacy score changes from baseline to week 26 were: MADRS total, −14.5 (0.9); CGI‐S, −1.8 (0.1); and SASS, 3.2 (0.5).ConclusionsLong‐term (26‐week) treatment with adjunctive brexpiprazole was generally well tolerated in elderly patients with MDD and inadequate response to prior ADT. Improvements were observed in depressive symptoms and social functioning.

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Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

et al. 2021

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IMPORTANCEThe placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear.OBJECTIVE To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators. DATA SOURCESSearches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021. STUDY SELECTION Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm. DATA EXTRACTION AND SYNTHESIS Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed. MAIN OUTCOMES AND MEASURES The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I 2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks. RESULTS Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooledplacebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (β = −0.12; 95% CI, −0.23 to −0.01, P = .03). The Egger test result was not significant for small studies' effects. (continued) Key Points Question What is the placebo effect magnitude in different treatment modalities used for management of patients with treatment-resistant depression? Findings In this systematic review and meta-analysis of 3228 patients with treatment-resistant depression in 50 randomized clinical trials, the placebo effect size was large and consistent across treatment modalities. Response and remission rates associated with placebo effect were comparable across modalities.Meaning The findings of this study suggest a placebo effect size benchmark may be used to interpret the findings of past and future clinical trials.

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Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study

Abstract: 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.

Cited by 53 publications

References 28 publications

Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

Adjunctive brexpiprazole for elderly patients with major depressive disorder: An open‐label, long‐term safety and tolerability study

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

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