A Randomized, Placebo-Controlled Study of the Efficacy and Safety of Fixed-Dose Brexpiprazole 2 mg/d as Adjunctive Treatment of Adults With Major Depressive Disorder

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

doi:10.4088/jcp.17m12058

Cited by 59 publications

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“…Supporting the findings of four individual short-term studies [9][10][11][12], the present analysis of pooled data shows that adjunctive brexpiprazole 2-3 mg/day improves symptoms of depression compared with adjunctive placebo in patients with MDD and an inadequate response to ADTs. The magnitude of the benefit for adjunctive brexpiprazole over adjunctive placebo was 2.15 points, which is above the minimum clinically important difference for MADRS Total score (estimated at around 2 points) [21,22].…”

Section: Discussionsupporting

confidence: 82%

“…Each of the studies had a similar design. For a full description of the study designs, patients and outcomes, please refer to the individual study publications [9][10][11][12].…”

Section: Study Design and Patientsmentioning

confidence: 99%

“…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 /α 2C receptors, all with subnanomolar affinity [8]. The efficacy and safety of brexpiprazole as adjunctive treatment to ADT over 6 weeks have been demonstrated in four Phase 3 studies in adult patients with MDD and inadequate response to ADTs [9][10][11][12]. Brexpiprazole is approved in various countries and regions, including the United States, Canada, Australia, Japan, and the European Union, for the treatment of schizophrenia in adults.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies

Thase

Zhang

Weiss

et al. 2019

Expert Opinion on Pharmacotherapy

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Background: There is a need for effective, safe and well-tolerated pharmacotherapies for patients with major depressive disorder (MDD) who have inadequate response to antidepressant treatments (ADTs). This analysis aimed to summarize the short-term efficacy and safety of adjunctive brexpiprazole in adults with MDD. Research design and methods: A pooled analysis of data from the 6-week, randomized, double-blind treatment phases of four studies of adjunctive brexpiprazole 1-3 mg/day versus placebo in outpatients with MDD and inadequate response to ADTs (n = 1,853). Efficacy was measured by Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and safety by treatment-emergent adverse events (TEAEs). Results: ADT + brexpiprazole 2-3 mg/day showed greater improvement in MADRS Total score from baseline to Week 6 than ADT + placebo (least squares mean difference: −2.15; confidence limits: −2.82, −1.48; p < 0.0001; Cohen's d effect size: 0.33). TEAEs with incidence ≥5% with ADT + brexpiprazole 1-3 mg/day were akathisia (8.0% versus 2.6% with ADT + placebo), headache (5.8% versus 6.0%), and weight increased (5.8% versus 1.6%). Conclusions: Adjunctive brexpiprazole is an efficacious and well-tolerated treatment option for adult patients with MDD and inadequate response to ADTs. Study limitations included a lack of active comparator.

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Section: Discussionsupporting

confidence: 82%

“…Each of the studies had a similar design. For a full description of the study designs, patients and outcomes, please refer to the individual study publications [9][10][11][12].…”

Section: Study Design and Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies

Thase

Zhang

Weiss

et al. 2019

Expert Opinion on Pharmacotherapy

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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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A Randomized, Placebo-Controlled Study of the Efficacy and Safety of Fixed-Dose Brexpiprazole 2 mg/d as Adjunctive Treatment of Adults With Major Depressive Disorder

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

Cited by 59 publications

References 0 publications

Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies

Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term 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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A Randomized, Placebo-Controlled Study of the Efficacy and Safety of Fixed-Dose Brexpiprazole 2 mg/d as Adjunctive Treatment of Adults With Major Depressive Disorder

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

Cited by 59 publications

References 0 publications

Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies

Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term 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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Abstract: ClinicalTrials.gov identifier: NCT02196506; EudraCT number: 2014-000062-22.