Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania.

BACKGROUND: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). AIMS: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). METHODS: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies. RESULTS: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p = 0.8797; study 081: -1.62 (-3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). CONCLUSIONS: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Adjunctive Therapy in Adults With Major Depressive Disorder.

BACKGROUND: Long-term treatment is recommended in major depressive disorder (MDD) to prevent relapse and to restore functioning. The aim of this study (Orion; NCT01360866) was to assess the long-term safety, tolerability, and efficacy of open-label treatment with adjunctive brexpiprazole in adult patients with MDD. METHODS: Patients rolled over into this 52-week study (amended to 26 weeks) from 3 randomized, double-blind, placebo-controlled studies. Patients received brexpiprazole 0.5 to 3 mg/d (flexible dose) adjunct to their current antidepressant treatment. The primary outcome variable was the frequency and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed as a secondary objective using clinical rating scales. RESULTS: A total of 2944 patients were enrolled (1547 for 52 weeks, 1397 for 26 weeks), of whom 1895 (64.4%) completed the study. The TEAEs with incidence of 5% or greater were weight increase (17.7%), somnolence (8.0%), headache (7.2%), akathisia (6.7%), increased appetite (6.3%), insomnia (6.3%), fatigue (6.1%), viral upper respiratory tract infection (5.4%), and anxiety (5.2%). Most TEAEs were mild or moderate in severity. The mean increase in body weight was 2.7 kg to week 26 and 3.2 kg to week 52; 25.8% of patients had a weight increase of 7% or greater at any postbaseline visit. There were no clinically relevant findings related to extrapyramidal symptoms, prolactin, lipids, or glucose. Patients' symptoms and functioning showed continual improvement. CONCLUSIONS: Adjunctive treatment with open-label brexpiprazole 0.5 to 3 mg/d was generally well tolerated for up to 52 weeks in patients with MDD and was associated with continued improvement in efficacy measures and functional outcomes.

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.

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole as adjunct to antidepressant treatment (ADT) in adults with major depressive disorder (MDD) and inadequate response to ADTs. METHODS: Outpatients with inadequate response to 1-3 ADTs during their current depressive episode (DSM-IV-TR criteria) were administered prospective, open-label ADT. Those patients with inadequate response to prospective ADT were randomized to double-blind, adjunctive brexpiprazole 2 mg/d or placebo. The primary efficacy end point was the change from baseline (randomization) to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Key secondary efficacy end points were the change in Sheehan Disability Scale (SDS) mean score for all patients and the change in MADRS total score for subgroups with minimal response to prospective ADT and DSM-5-defined anxious distress. The study was conducted from July 2014 to May 2016. RESULTS: Adjunctive brexpiprazole (n = 191) improved MADRS total score from baseline to week 6 versus placebo (n = 202; least squares mean difference [95% confidence limits]: -2.30 [-3.97, -0.62]; P = .0074). There was no separation between groups for the SDS mean score (-0.22 [-0.66, 0.23]; P = .33). Adjunctive brexpiprazole also improved MADRS total score versus placebo in the subgroups with minimal response to prospective ADT (-2.25 [-4.23, -0.27]; P = .026) and anxious distress (-2.98 [-5.24, -0.72]; P = .0099). Treatment with adjunctive brexpiprazole was well tolerated with no unexpected side effects. CONCLUSIONS: This study adds to the substantial body of evidence for the efficacy and tolerability of brexpiprazole as adjunctive treatment in patients with MDD and inadequate response to ADTs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02196506; EudraCT number: 2014-000062-22​​​.

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

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole as adjunctive treatment in adults with major depressive disorder (MDD) and an inadequate response to prior antidepressant treatment (ADT). METHODS: Patients with a current major depressive episode after prior treatment with 1-3 ADTs entered an 8- or 10-week prospective treatment phase in which they received double-blind placebo adjunct to open-label ADT. Inadequate responders were randomized (2:2:1) to brexpiprazole 2-3 mg/day, placebo, or quetiapine extended-release (XR) 150-300 mg/day, adjunct to the same ADT, for 6 weeks. The primary efficacy endpoint was the change from baseline (randomization) to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The key secondary efficacy endpoint was the change in Sheehan Disability Scale (SDS) mean score. RESULTS: Adjunctive brexpiprazole showed a greater improvement in MADRS total score than adjunctive placebo (least squares mean difference [95% confidence interval] = -1.48 [-2.56, -0.39]; p = .0078), whereas adjunctive quetiapine XR did not separate from placebo (-0.30 [-1.63, 1.04]; p = .66). Adjunctive brexpiprazole failed to separate from placebo on the SDS mean score (-0.23 [-0.52, 0.07]; p = .13), but did improve functioning on two of the three SDS items (family life and social life). The most frequent treatment-emergent adverse events in patients receiving brexpiprazole were akathisia (6.1%), somnolence (5.6%), and headache (5.6%). CONCLUSIONS: 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.

A multicenter, open-label, pilot study evaluating the functionality of an integrated call center for a digital medicine system to optimize monitoring of adherence to oral aripiprazole in adult patients with serious mental illness.

BACKGROUND: Medication nonadherence is common in the treatment of serious mental illness (SMI) and leads to poor outcomes. The digital medicine system (DMS) objectively measures adherence with oral aripiprazole in near-real time, allowing recognition of adherence issues. This pilot study evaluated the functionality of an integrated call center in optimizing the use of the DMS. MATERIALS AND METHODS: An 8-week, open-label, single-arm trial at four US sites enrolled adults with bipolar I disorder, major depressive disorder, and schizophrenia on stable oral aripiprazole doses and willing to use the DMS (oral aripiprazole + ingestible event marker [IEM], IEM-detecting skin patch, and software application). Integrated call-center functionality was assessed based on numbers and types of calls. Ingestion adherence with prescribed treatment (aripiprazole + IEM) during good patch wear and proportion of time with good patch wear (days with ≥80% patch data or detected IEM) were also assessed. RESULTS: All enrolled patients (n=49) used the DMS and were included in analyses; disease duration overall approached 10 years. For a duration of 8 weeks, 136 calls were made by patients, and a comparable 160 calls were made to patients, demonstrating interactive communication. The mean (SD) number of calls made by patients was 2.8 (3.5). Approximately half of the inbound calls made by patients occurred during the first 2 weeks and were software application- or patch-related. Mean ingestion adherence was 88.6%, and corresponding good patch wear occurred on 80.1% of study days. CONCLUSION: In this pilot study, the integrated call center facilitated DMS implementation in patients with SMI on stable doses of oral aripiprazole. In clinical practice, the call center and the DMS will facilitate objective measurement of adherence and potentially improve rates of adherence in patients with SMI.