Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify® ). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti® ), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.

An open-label, positron emission tomography study of the striatal D2/D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

PURPOSE: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg. METHODS: Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. RESULTS: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. CONCLUSION: By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT00805454 December 9, 2008.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). DESIGN: Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). SETTING: Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. PARTICIPANTS: Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. INTERVENTION: Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed. RESULTS: In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. CONCLUSIONS: Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

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.

The safety and tolerability of aripiprazole once-monthly as maintenance treatment for bipolar I disorder: A double-blind, placebo-controlled, randomized withdrawal study.

BACKGROUND: Aripiprazole once-monthly 400 mg (AOM 400), an atypical long-acting injectable antipsychotic, has demonstrated efficacy and safety in maintenance treatment of bipolar I disorder (BP-I). We further assess safety and tolerability and characterize adverse events (AEs) across the duration of aripiprazole exposure. METHODS: Patients with BP-I were stabilized on oral aripiprazole (2-8 weeks), AOM 400 (12-28 weeks), followed by 1:1 randomization of patients meeting stability criteria to a 52-week, double-blind, placebo-controlled withdrawal phase. Treatment-emergent AEs (TEAEs) were collected across study phases. AEs were counted in a phase if they were drug-related and continued from the baseline of that phase. A separate analysis on new-onset akathisia was conducted. RESULTS: Among TEAEs occurring in ≥10% of patients during all study phases were akathisia (23.3%) and weight increased (10.6%). Median time to akathisia onset was 20 days after starting oral aripiprazole; median duration was 29 days for the first occurrence; 21/168 patients (12.5%) reporting akathisia experienced >1 episode. Episodes of new-onset akathisia decreased over time, with few events reported in the randomized phase. Weight gain was minimal with oral aripiprazole, generally starting within 3 months after the first AOM 400 injection, and appearing to plateau at 36 weeks. The mean weight gain within any study phase was ≤1.0 kg. Potentially clinically significant changes in metabolic parameters were uncommon. LIMITATIONS: Patients on placebo had AOM 400 exposure before randomization. CONCLUSION: These findings suggest that AEs with AOM 400 treatment were time-limited and support AOM 400 as a well-tolerated maintenance treatment of BP-I.

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​​​.

The effects of brexpiprazole and aripiprazole on body weight as monotherapy in patients with schizophrenia and as adjunctive treatment in patients with major depressive disorder: an analysis of short-term and long-term studies.

The aim of this analysis was to explore the effects of brexpiprazole and aripiprazole on body weight when used as monotherapy to treat schizophrenia and as adjunctive treatment to antidepressant treatment (ADT) for major depressive disorder (MDD) in short-term (4/6 weeks) and long-term (≤52 weeks) studies. Body weight data were obtained from the clinical studies of each drug (brexpiprazole and aripiprazole), in schizophrenia and adjunctive treatment of MDD. Data were pooled and analyzed to assess the mean change in body weight and to determine the incidence of a clinically relevant change in body weight from baseline (≥7% increase or decrease, at any time) in each treatment group. The overall weight profiles for brexpiprazole and aripiprazole in the short-term and long-term treatment of schizophrenia, and MDD (adjunctive to ADT), were similar. In short-term schizophrenia studies, the mean weight increase was 1.2 kg for brexpiprazole and 0.6 kg for aripiprazole. In short-term MDD studies (adjunctive to ADT), the mean weight increase was 1.5 kg for brexpiprazole and 1.6 kg for aripiprazole. In the long-term schizophrenia studies, at week 52, the mean weight increase was 2.1 kg for brexpiprazole and 3.0 kg for aripiprazole. In long-term MDD studies (adjunctive to ADT), at week 52, the mean weight increase was 3.2 kg for brexpiprazole and 4.0 kg for aripiprazole. Clinically relevant increases or decreases in body weight were also similar for brexpiprazole and aripiprazole. Overall, in the treatment of schizophrenia, and in adjunctive treatment of MDD, brexpiprazole and aripiprazole have a similar effect on body weight over the course of 1 year.

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.

Symptoms and functioning with aripiprazole once-monthly injection as maintenance treatment for bipolar I disorder.

BACKGROUND: Effects of maintenance treatment with aripiprazole once-monthly 400mg (AOM 400) on symptoms and functioning were assessed in adults with bipolar I disorder (BP-I) after a manic episode. METHODS: Patients were stabilized on oral aripiprazole, cross-titrated to AOM 400, then randomized in a 52-week, double-blind, placebo-controlled, withdrawal phase. Prespecified secondary outcomes are reported: time to hospitalization for mood episode, Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Bipolar scale, Functioning Assessment Short Test (FAST), and Brief Quality of Life in Bipolar Disorder questionnaire. Time to hospitalization for mood episode was analyzed using log-rank test and changes from baseline using mixed model for repeated measures or analysis of covariance. RESULTS: AOM 400 significantly increased time to hospitalization for any mood episode versus placebo (P=0.0002). YMRS total scores decreased with oral aripiprazole; improvements were maintained with AOM 400. After randomization, YMRS scores changed little with AOM 400 but worsened with placebo (P=0.0016), and MADRS scores, already low at trial initiation, did not differ between groups. FAST score improvements were maintained with AOM 400 but not placebo (P=0.0287). LIMITATIONS: Results are generalizable to patients with BP-I stabilized on aripiprazole following a manic episode. CONCLUSIONS: Patients with BP-I experiencing an acute manic episode exhibited symptomatic and functional improvements during stabilization with oral aripiprazole and AOM 400 that were maintained with continued AOM 400 treatment but not placebo. AOM 400 is the first once-monthly long-acting injectable antipsychotic to demonstrate efficacy in maintenance treatment of the manic phase of BP-I.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS: Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).

Aripiprazole Once-Monthly in the Treatment of Acute Psychotic Episodes in Schizophrenia: Post Hoc Analysis of Positive and Negative Syndrome Scale Marder Factor Scores.

BACKGROUND: Long-acting injectable antipsychotics are treatment options for acute and long-term treatment of patients with schizophrenia. In a previously published 12-week randomized, double-blind, placebo-controlled clinical trial of patients with schizophrenia experiencing an acute psychotic episode, aripiprazole once-monthly 400 mg (AOM 400) produced significantly greater improvement than placebo on the primary endpoint, Positive and Negative Syndrome Scale (PANSS) total score at week 10. METHODS: To examine the efficacy of AOM 400 across a broader representation of schizophrenia symptoms, including agitation, a post hoc analysis of this trial was carried out to assess the change in PANSS Marder factor domains (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression) and the PANSS excited component (equivalent to Marder factor domain uncontrolled hostility/excitement plus the tension item) by comparing differences in change from baseline between AOM 400 and placebo using a mixed model for repeated measures. RESULTS: The differences between treatment and placebo for all factors were statistically significant, with improvements seen as early as week 1 or 2, and maintained through week 12. Thus, AOM 400, supplemented with oral aripiprazole in the first 2 weeks, showed significantly greater efficacy versus placebo in acutely ill patients with schizophrenia in all 5 Marder illness domains, as well as in agitation as conceptualized by the PANSS excited component score. CONCLUSIONS: These findings indicate that AOM 400 is efficacious across the spectrum of schizophrenia symptoms in acutely ill patients, with implications for both short-term and, by extension, long-term patient outcomes.

Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) as maintenance treatment for bipolar I disorder (BP-I). METHODS: In a double-blind, placebo-controlled, 52-week randomized withdrawal study conducted from August 2012 to April 2016, patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and AOM 400 and then randomized to AOM 400 or placebo. The primary end point was time from randomization to recurrence of any mood episode. Other end points included proportion of patients with recurrence of any mood episode and recurrence by mood episode type. RESULTS: Of 266 randomized patients, 64 (48.1%) of 133 in the AOM 400 group and 38 (28.6%) of 133 in the placebo group completed the study. AOM 400 significantly delayed the time to recurrence of any mood episode compared with placebo (hazard ratio: 0.45; 95% CI, 0.30 to 0.68; P < .0001). Significantly fewer patients (P < .0001) experienced recurrence of any mood episode with AOM 400 (35/132; 26.5%) compared with placebo (68/133; 51.1%), with the effects observed predominantly on manic episodes (P < .0001). Patients were not depressed at study entry, and between-group differences in depressive episodes were not significant (P < .864). The treatment-emergent adverse events (incidence > 5%) that were reported at higher rates with AOM 400 than placebo were weight increase, akathisia, insomnia, and anxiety. CONCLUSIONS: AOM 400 delayed the time to and reduced the rate of recurrence of mood episodes and was generally safe and well tolerated. These findings support the use of AOM 400 for maintenance treatment of BP-I. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01567527.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration.

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.

Efficacy and Safety of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia: a Randomized, Double-Blind, Placebo-Controlled Study.

Background: Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia. Methods: Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1-4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase. Those patients who met stability criteria for 12 weeks were randomized 1:1 to double-blind maintenance treatment with either brexpiprazole (at their stabilization dose) or placebo for up to 52 weeks. The primary efficacy endpoint was the time from randomization to impending relapse. Safety and tolerability were also assessed. Results: A total of 524 patients were enrolled, 202 of whom were stabilized on brexpiprazole and randomized to brexpiprazole (n=97) or placebo (n=105). Efficacy was demonstrated at a prespecified interim analysis (conducted after 45 events), and so the trial was terminated early. The final analysis showed that time to impending relapse was statistically significantly delayed with brexpiprazole treatment compared with placebo (P<.0001, log-rank test). The hazard ratio for the final analysis was 0.292 (95% confidence interval: 0.156, 0.548); mean dose at last visit, 3.6mg. The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (P<.0001). During the maintenance phase, the incidence of adverse events was comparable to placebo. Conclusions: or patients with schizophrenia already stabilized on brexpiprazole, maintenance treatment with brexpiprazole was efficacious, with a favorable safety profile.

Effects of aripiprazole once-monthly on symptoms of schizophrenia in patients switched from oral antipsychotics.

OBJECTIVE: To assess the effects of aripiprazole once-monthly 400 mg (AOM 400) on clinical symptoms and global improvement in schizophrenia after switching from an oral antipsychotic. METHODS: In a multicenter, open-label, mirror-image, naturalistic study in patients with schizophrenia (>1 year, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), changes in efficacy measures were assessed during prospective treatment (6 months) with AOM 400 after switching from standard-of-care oral antipsychotics. During prospective treatment, patients were cross-titrated to oral aripiprazole monotherapy (1-4) weeks followed by open-label AOM 400 (24 weeks). Mean change from baseline of the open-label AOM 400 phase in Positive and Negative Syndrome Scale (PANSS) scores (total, positive and negative subscales) and Clinical Global Impression-Severity (CGI-S) scores; mean CGI-Improvement (CGI-I) score; and proportion of responders (≥30% decrease from baseline in PANSS total score or CGI-I score of 1 [very much improved] or 2 [much improved]) were assessed. RESULTS: PANSS and CGI-S scores improved from baseline (P<0.0001) and CGI-I demonstrated improvement at all time points. By the end of the study, 49.0% of patients were PANSS or CGI-I responders. CONCLUSIONS: In a community setting, patients with schizophrenia who were stabilized at baseline and switched to AOM 400 from oral antipsychotics showed clear improvements in clinical symptoms.

Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants.

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 treatment-related 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.

Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study.

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. CONCLUSIONS: Brexpiprazole 3 mg demonstrated efficacy versus placebo in the efficacy population per final protocol. Both doses of brexpiprazole were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360632.

Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: The efficacy, safety, and tolerability of brexpiprazole and placebo were compared in adults with acute schizophrenia. METHOD: This was a multicenter, randomized, double-blind, placebo-controlled study. Patients with schizophrenia experiencing an acute exacerbation were randomly assigned to daily brexpiprazole at a dosage of 0.25, 2, or 4 mg or placebo (1:2:2:2) for 6 weeks. Outcomes included change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint measure), Clinical Global Impressions Scale (CGI) severity score (key secondary endpoint measure), and other efficacy and tolerability measures. RESULTS: The baseline overall mean PANSS total score was 95.2, and the CGI severity score was 4.9. Study completion rates were 62.2%, 68.1%, and 67.2% for patients in the 0.25-, 2-, and 4-mg brexpiprazole groups, respectively, versus 59.2% in the placebo group. At week 6, compared with placebo, brexpiprazole dosages of 2 and 4 mg produced statistically significantly greater reductions in PANSS total score (treatment differences: -8.72 and -7.64, respectively) and CGI severity score (treatment differences: -0.33 and -0.38). The most common treatment-emergent adverse event for brexpiprazole was akathisia (2 mg: 4.4%; 4 mg: 7.2%; placebo: 2.2%). Weight gain with brexpiprazole was moderate (1.45 and 1.28 kg for 2 and 4 mg, respectively, versus 0.42 kg for placebo at week 6). There were no clinically or statistically significant changes from baseline in lipid and glucose levels and extrapyramidal symptom ratings. CONCLUSIONS: 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.

Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies.

OBJECTIVES: To further characterize the clinical profile of long-term treatment with aripiprazole once-monthly 400 mg (AOM 400) by examining patient-centered outcomes in adults with schizophrenia. METHODS: Data are from 2 separate studies: a 52-week, multicenter, randomized, double-blind, placebo-controlled study and a 38-week, multicenter, randomized, double-blind, active-controlled study that evaluated the clinical profile of AOM 400 as maintenance treatment in patients with schizophrenia. The studies were conducted from July 2008 through February 2011 and from September 2008 through August 2012, respectively. Both studies included the Drug Attitude Inventory (DAI), the Medication Adherence Questionnaire (MAQ), the Patient Satisfaction with Medication Questionnaire, and a resource utilization and hospitalization form as prespecified patient-centered endpoints. RESULTS: A total of 710 patients entered the oral stabilization phase in the 52-week study, and 403 patients were randomized to double-blind treatment. The corresponding sample sizes in the 38-week study were 842 and 662, respectively. In both studies, mean DAI and MAQ scores remained stable across all treatment phases; mean changes from baseline during the double-blind phase were not significantly different between treatment arms. Treatment satisfaction remained high throughout both studies, and most patients reported no or fewer side effects with AOM 400 relative to their prior medication. Most patients did not have unscheduled outpatient visits or hospitalizations throughout the studies. CONCLUSIONS: Data from 2 randomized, double-blind studies indicated that patient perceptions about treatment satisfaction, side effects, and medication adherence were maintained in patients with schizophrenia receiving maintenance treatment with AOM 400. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00705783, NCT00706654.