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PURPOSE/BACKGROUND Evidence supports use of adjunctive atypical antipsychotics in major depressive disorder (MDD). Impaired sexual functioning is common in MDD and may be worsened by antipsychotic adverse effects. We evaluated the effect of brexpiprazole on prolactin and sexual functioning in patients with MDD. METHODS/PROCEDURES In short-term studies, patients received adjunctive brexpiprazole 1, 2, or 3 mg or placebo. The long-term study was a flexible-dose (0.5-3 mg/d) open-label extension (OLE). Change from baseline and shifts in prolactin status and prolactin-related treatment-emergent adverse events (TEAEs) were assessed. Sexual functioning was assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire. FINDINGS/RESULTS Median changes in prolactin levels from baseline to week 6 in short-term studies were as follows: brexpiprazole, 5.99 ng/mL (females) and 1.61 ng/mL (males); placebo, -0.15 ng/mL (females) and -0.08 ng/mL (males).Median changes from baseline to week 52 in the OLE were as follows: 0.27 ng/mL (females) and 0.27 ng/mL (males). Prolactin levels in patients with baseline prolactin greater than 1× upper limit of normal values tended to decrease over time.The proportion of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies for both sexes was low (0%-0.3%) and did not differ from placebo: OLE, 0.5% (females) and 0.8% (males).In short-term studies, the incidence of prolactin-related TEAEs was 3.1% for brexpiprazole and 0.7% for placebo (OLE, 3.1%). There were overall numerical improvements from baseline in sexual functioning for females and males after short- and long-term brexpiprazole treatment, with statistically significant improvements for brexpiprazole versus placebo in females on the items 'interest in sex' (-0.19; 95% confidence interval [CI], -0.33 to -0.05; P = 0.0074), 'sexually aroused' (-0.17; 95% CI, -0.30 to -0.03; P = 0.0154), and 'overall sexual satisfaction' (-0.16; 95% CI, -0.30 to -0.03; P = 0.0184). IMPLICATIONS/CONCLUSIONS There were small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, low incidences of prolactin-related TEAEs, and modest improvements in sexual functioning with adjunctive brexpiprazole in MDD.

Purpose Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD). Patients and Methods In a phase 2a, flexible-dose, single-blind study, 41 male patients (aged 18‒55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200‒300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18‒60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score. Results In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (P

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.

Objective:We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.Methods:Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.Results:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].Conclusion:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.

ObjectiveTo compare the tolerability and efficacy of different antipsychotic cross-titration schedules, using data from a brexpiprazole study (Equator; NCT01668797).MethodsPatients with schizophrenia were cross-titrated from other antipsychotics to brexpiprazole monotherapy in a 1–4 week open-label conversion phase, then entered a single-blind brexpiprazole treatment phase. Patients were stratified into four “conversion groups,” according to the amount of time spent in the conversion phase. Discontinuation rates, treatment-emergent adverse events (TEAEs), and efficacy (Positive and Negative Syndrome Scale [PANSS]) were compared between conversion groups.ResultsOf the 404 patients treated with brexpiprazole, the majority (72.0%) spent 22–33 days in the conversion phase. Discontinuation rates due to lack of efficacy or adverse events were low in all conversion groups. Of the 292 patients who successfully switched and completed 8 weeks of brexpiprazole treatment, most were converted to brexpiprazole over 22–33 days (80.1%), and fewer were converted over 1–7 days (2.4%), 8–14 days (6.5%), or 15–21 days (11.0%). The incidence of TEAEs over 8 weeks was lower among those converted over 22–33 days (44.4%) than in other conversion groups (62.5–84.2%), although low patient numbers with shorter conversion times limit the generalizability of this finding. Each conversion group showed comparable improvement in PANSS total score from baseline.ConclusionThe majority of patients were cross-titrated to brexpiprazole over a period of 22–33 days, by investigators’ choice. Additional data on shorter conversions may help clinicians to choose a switching paradigm that best meets their patients’ needs.

ObjectiveTo evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design.MethodsThe study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1–3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks.ResultsThe primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (−0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group.ConclusionAdjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.

Background Brexpiprazole is a serotonin–dopamine activity modulator with efficacy in acute schizophrenia and relapse prevention. The aim of this Phase 3, multicenter study was to assess the long-term safety, tolerability, and efficacy of treatment with brexpiprazole flexible-dose 1–4 mg/d. Methods Patients rolled over into this 52-week open-label study (amended to 26 weeks towards the end) from 3 randomized, double-blind, placebo-controlled Phase 3 studies. De novo patients, not part of the previous studies, were also enrolled. The primary outcome variable was the frequency and severity of treatment-emergent adverse events. Efficacy was assessed as a secondary objective using the Positive and Negative Syndrome Scale and the Personal and Social Performance scale. Results A total of 1072 patients was enrolled (952 for 52 weeks and 120 for 26 weeks), 47.4% of whom completed the study. Among patients who took at least one dose of brexpiprazole, 14.6% discontinued due to treatment-emergent adverse events, most commonly schizophrenia (8.8%) and psychotic disorder (1.5%). Treatment-emergent adverse events with an incidence of ≥5% were schizophrenia (11.6%), insomnia (8.6%), weight increased (7.8%), headache (6.4%), and agitation (5.4%). Most treatment-emergent adverse events were mild or moderate in severity. The mean increase in body weight from baseline to week 26 was 1.3 kg and to week 52 was 2.1 kg. There were no clinically relevant findings related to prolactin, lipids, and glucose, or QT prolongation. On average, patients’ symptoms and functioning showed continual improvement. Conclusions Treatment with brexpiprazole 1–4 mg/d was generally well tolerated for up to 52 weeks in patients with schizophrenia. ClinicalTrials.gov identifier NCT01397786 (https://clinicaltrials.gov/show/NCT01397786).

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).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.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%).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.

Objective Patients with major depressive disorder (MDD) with inadequate response to antidepressant treatment (ADT) may suffer a prolonged loss of functioning. This review aimed to determine if self-rated functional measures are informative in randomized placebo-controlled studies of adjunctive therapy in patients with MDD and inadequate response to ADT. Methods This was a systematic literature review of articles in any language from the MEDLINE database published between January 1990 and March 2017. Eligible studies met the following criteria: patients with MDD; inadequate response to at least one ADT; adjunctive therapy (pharmacological or otherwise) to ADT; placebo control group; randomized controlled trial or a post hoc analysis of a randomized controlled trial; reported a self-rated functioning scale. Study characteristics and functioning efficacy data were extracted. Results A total of 2,090 discrete records were screened, 293 full-text articles were assessed for eligibility, and 26 studies were included. All studies were acute (6–12 weeks) except for one 52-week study. The only self-rated functioning scale used in the included studies was the Sheehan Disability Scale (SDS). Of the 13 adjunctive agents identified, aripiprazole, brexpiprazole, edivoxetine, and risperidone improved functioning versus placebo (p

Paroxetine and sertraline are the only FDA approved drugs for treatment of posttraumatic stress disorder (PTSD). Although both drugs show better outcomes than placebo, not all patients benefit from treatment. We examined predictors and latent classes of SSRI treatment response in patients with PTSD. Symptom severity was measured over a 12-week period in 390 patients suffering from PTSD treated with open-label sertraline or paroxetine and a double-blinded placebo. First, growth curve modeling (GCM) was used to examine population-level predictors of treatment response. Second, growth mixture modeling (GMM) was used to group patients into latent classes based on their treatment response trajectories over time and to investigate predictors of latent class membership. Gender, childhood sexual trauma, and sexual assault as index trauma moderated the population-level treatment response using GCM. GMM identified three classes: fast responders, responders with low pretreatment symptom severity and responders with high pretreatment symptom severity. Class membership was predicted based on time since index trauma, severity of depression, and severity of anxiety. The study shows that higher severity of comorbid disorders does not result in an inferior response to treatment and suggests that patients with longer time since index trauma might particularly benefit from treatment with sertraline or paroxetine.

Background: Many patients with major depressive disorder (MDD) do not respond adequately to first-line antidepressant treatment (ADT). Adjunctive treatment with second-generation antipsychotics has demonstrated efficacy for patients with MDD, but is limited by tolerability and safety issues. The recently introduced serotonin-dopamine activity modulator, brexpiprazole, has demonstrated efficacy as an adjunctive treatment for MDD. Objective/Method: We report tolerability and safety results for adjunctive brexpiprazole from four 6-week short-term (ST; pooled phase 2 and 3, placebo-controlled) and two 52-week long-term (LT; pooled, openlabel) studies. Results: Approximately 90% of patients completed the ST studies, and 48.8% of patients completed the LT studies. In the ST studies, 2.9% of patients discontinued because of an adverse event (AE); in the LT studies, 14.1% of patients discontinued because of an AE. In the ST and LT studies, the most frequently reported treatment-emergent AEs (TEAEs) were akathisia (8.6% and 10.0%, respectively) and weight gain (7.3% and 25.5%, respectively). Rates of sedation and somnolence were low (ST and LT: sedation, 0.8% and 3.7%, respectively; somnolence, 3.4% and 9.4%, respectively). In the ST and LT studies, brexpiprazole was associated with small changes in metabolic parameters and moderate weight increase. Conclusions: Collectively, these data suggest brexpiprazole is well tolerated as an adjunctive treatment for MDD.

Objective: To summarize efficacy data from two phase 2 and two phase 3 short-term, multicenter, randomized, double-blind, placebo-controlled studies of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (MDD) with inadequate response to ADTs. Methods: Patients with MDD who were inadequate responders to 1–3 prior ADTs entered an 8-week single-blind prospective treatment phase on physician-determined ADT. Patients with inadequate response throughout the prospective treatment phase were randomized to receive either placebo or brexpiprazole (phase 2: flexible dosage 0.15–3.0 mg/day; phase 3: fixed-dosages 1, 2, or 3 mg/day) as adjunctive treatment to their ADT. The primary endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. Results: Phase 2 studies suggested brexpiprazole doses of 1–3 mg/day were effective as an adjunctive therapy. These observations were confirmed across the two phase 3 studies utilizing a pooled placebo group versus brexpiprazole 1, 2, and 3 mg/day and a pooled analysis of all four studies (brexpiprazole 1–3 mg/day). Greater improvements were observed in MADRS total score with brexpiprazole+ADT versus placebo+ADT (1 mg/day, p

ObjectiveReview efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.MethodsPatients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.ResultsThe efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (pConclusionsOverall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.

Second-generation antipsychotics have demonstrated efficacy for patients with schizophrenia but are associated with wide-ranging side effects. Brexpiprazole, a serotonin-dopamine activity modulator, has demonstrated efficacy in adult patients with schizophrenia. This paper provides an overview of the safety and tolerability of brexpiprazole in patients with schizophrenia through examination of pooled safety data from one Phase 2 and two Phase 3 6-week, short-term studies, and two open-label, 52-week, long-term studies.In the short-term studies, there were no reports of treatment-emergent adverse events (TEAEs) with an incidence≥5% and twice that of placebo in patients treated with brexpiprazole 2–4mg. In the long-term studies, TEAEs reported by ≥5% of patients were schizophrenia (10.7%), insomnia (8.0%), weight increase (7.7%), headache (6.0%), and agitation (5.2%). Akathisia rates were low in the short- (5.8%, pooled brexpiprazole group) and long-term studies (4.6%). Sedation rates were low in the short- (2.3%, pooled brexpiprazole group) and long-term studies (0.9%). Mean body weight increase was 1.1kg in both short- and long-term studies.For all studies, changes from baseline to last visit in laboratory parameters, electrocardiogram values, and vital signs were small and not clinically relevant. Changes in lipid profiles or other metabolic parameters were also small. Collectively, these studies suggest that brexpiprazole was well tolerated, with a favorable safety profile that does not exhibit significant rates of important adverse events that can be seen with existing antipsychotics (akathisia, sedation, weight gain, or QTc prolongation), and therefore may provide a useful treatment option for patients with schizophrenia.ClinicalTrials.gov: NCT00905307; NCT01396421; NCT01393613; NCT01649557; NCT01397786.

Background Hyperprolactinemia is an undesirable effect of most antipsychotics because of D2-receptor blockade. We assessed the effect of the D2-receptor partial agonist brexpiprazole on prolactin, based on pooled data from three 6-week, randomized, placebo-controlled studies and two open-label extension studies in patients with schizophrenia. Methods In the short-term studies, patients received 0.25, 1, 2, 4 mg brexpiprazole or placebo; or flexible-dose brexpiprazole (2-4 mg/d), placebo, or active reference. The extension studies were 52-week, flexible-dose (1-4 mg/d) studies. We studied changes from baseline and shifts in prolactin status in patients with normal or elevated prolactin levels at baseline, and prolactin-related treatment-emergent adverse events (TEAEs). Results Median changes from baseline to week 6 in brexpiprazole-treated patients in short-term studies were as follows: 3.63 ng/mL (females), 0.26 ng/mL (males); placebo: -2.15 ng/mL (females), -1.08 ng/mL (males).Median changes from baseline to week 52 in long-term studies were 0.60 ng/mL (females) and 0.18 ng/mL (males). Prolactin levels in patients with baseline values greater than 1× upper limit of normal tended to decrease over time regardless of previous treatment.The proportions of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies were as follows: 1.5% (females), 1.6% (males); placebo: 3.6% (females), 3.4% (males). Corresponding figures in long-term studies were 5.3% (females) and 2.0% (males).In short-term studies, the incidence of prolactin-related TEAEs was 1.8% for brexpiprazole and 0.6% for placebo. In long-term studies, the incidence of prolactin-related TEAEs was 1.7%. Conclusions Small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, and low incidence of prolactin-related TEAEs were observed after treatment with brexpiprazole.

Background Patients with major depressive disorder and inadequate response to antidepressant treatments may experience a prolonged loss of functioning. This post hoc analysis aimed to determine the effect of adjunctive brexpiprazole on functioning in such patients. Methods A pooled analysis of data from the 6-week, randomized, double-blind treatment phases of 6 studies of adjunctive brexpiprazole (2 and 3 mg/d in fixed-dose studies; 1–3 mg/d in flexible-dose studies) vs placebo in patients with major depressive disorder and inadequate response to antidepressant treatments (NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT00797966, NCT01052077). Functioning was measured by change in Sheehan Disability Scale score from baseline to week 6. Results Considering Sheehan Disability Scale mean score across all 6 studies (n = 2066 randomized), the least squares mean difference between antidepressant treatments + brexpiprazole and antidepressant treatments + placebo at week 6 was −0.40 (95% CI: −0.56, −0.23; P < .0001). Antidepressant treatments + brexpiprazole showed a greater benefit than antidepressant treatments + placebo on the social life (−0.45; −0.63, −0.27; P < .001) and family life (−0.50; −0.70, −0.31; P < .001) items but not on the work/studies item (−0.16; −0.38, 0.06; P = .16). Pooled analyses of just the (1) fixed-dose, (2) flexible-dose, and (3) Phase 3 studies showed the same pattern of benefits for antidepressant treatments + brexpiprazole. Conclusions Brexpiprazole, as adjunct to antidepressant treatments, improved functioning in patients with major depressive disorder and inadequate response to antidepressant treatments.

Objectives The 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). Methods Elderly 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-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness (CGI-S), and Social Adaptation Self-Evaluation Scale (SASS). Results Of 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). Conclusions Long-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.

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.

The objective of this study was to evaluate the efficacy, safety and tolerability of brexpiprazole versus placebo in adults with acute schizophrenia. This was a 6-week, multicenter, placebo-controlled double-blind phase 3 study. Patients with acute schizophrenia were randomized to brexpiprazole 1, 2 or 4 mg, or placebo (2:3:3:3) once daily. The primary endpoint was changed from baseline at week 6 in Positive and Negative Syndrome Scale (PANSS) total score; the key secondary endpoint was Clinical Global Impressions-Severity (CGI-S) at week 6. Brexpiprazole 4 mg showed statistically significant improvement versus placebo (treatment difference: -6.47, p=0.0022) for the primary endpoint. Improvement compared with placebo was also seen for the key secondary endpoint (treatment difference: -0.38, p=0.0015), and on multiple secondary efficacy outcomes. Brexpiprazole 1 and 2mg also showed numerical improvements versus placebo, although p>0.05. The most common treatment-emergent adverse events were headache, insomnia and agitation; incidences of akathisia were lower in the brexpiprazole treatment groups (4.2%-6.5%) versus placebo (7.1%). Brexpiprazole treatment was associated with moderate weight gain at week 6 (1.23-1.89 kg versus 0.35 kg for placebo); there were no clinically relevant changes in laboratory parameters and vital signs. In conclusion, brexpiprazole 4 mg is an efficacious and well-tolerated treatment for acute schizophrenia in adults. Clinical Trials.gov NCT01393613; BEACON trial.

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-Asberg 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​​​.

Despite advances in clinical trial design, failure rates near 80% in phase 2 and 50% in phase 3 have recently been reported. The challenges to successful drug development are particularly acute in central nervous system trials such as for pain, schizophrenia, mania, and depression because high-placebo response rates lessen assay sensitivity, diminish estimated treatment effect sizes, and thereby decrease statistical power. This paper addresses the importance of rigorous patient selection in major depressive disorder trials through an enhanced enrichment paradigm. This approach led to a redefinition of an ongoing, blinded phase 3 trial algorithm for patient inclusion (1) to eliminate further randomization of transient placebo responders and (2) to exclude previously randomized transient responders from the primary analysis of the double blind phase of the trial. It is illustrated for a case study for the comparison between brexpiprazole + antidepressant therapy and placebo + antidepressant therapy. Analysis of the primary endpoint showed that efficacy of brexpiprazole versus placebo could not be established statistically if the original algorithm for identification of placebo responders was used, but the enhanced enrichment approach did statistically demonstrate efficacy. Additionally, the enhanced enrichment approach identified a target population with a clinically meaningful treatment effect. Through its successful identification of a target population, the innovative enhanced enrichment approach enabled the demonstration of a positive treatment effect in a very challenging area of depression research.

The efficacy of brexpiprazole across a spectrum of schizophrenia symptoms was evaluated in patients with acute schizophrenia in 2 short-term 6-week studies and in a long-term 52-week maintenance study using the 5 previously validated PANSS-derived Marder factors.[1–3] The analysis was performed on the pooled data from two 6-week, double-blind, placebo-controlled studies of patients with schizophrenia who were randomly assigned to fixed once-daily doses of brexpiprazole 2 mg (n = 359), 4 mg (n = 359), or placebo (n = 358; NCT01396421 and NCT01393613), and in one 52-week, double-blind, placebo-controlled study with patients randomized to bexpiprazole (1–4 mg; n = 97) and placebo, n = 105 [NCT01668797]). The maintenance study included a stabilization phase in which patients needed to be stable on brexpiprazole for at least 12 weeks before randomization to brexpiprazole or placebo. In the short-term studies, brexpiprazole 4 mg and 2 mg were each superior to placebo in change from baseline in PANSS Total score at Week 6 (least square mean difference [LSMD] versus placebo: −6.69, < .0001 and −5.46, = .0004, respectively). The LSMD versus placebo at Week 6 was also significant (

Study objectivesSymptoms of anxiety are prevalent in Major Depressive Disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). In MDD, anxiety symptoms can be assessed as ‘anxious distress’ (new DSM-5 specifier) or ‘anxious depression’ (score ≥7 on the HAM-D anxiety/somatization factor). Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors – all at similar potency. Brexpiprazole is approved in the US for treatment ofschizophrenia, and as adjunctive treatment in MDD. The objective of this post-hoc analysis was to assess the efficacy of brexpiprazole as adjunct to ADT in patients with MDDand anxiety symptoms, using these two definitions of anxiety.MethodsData were pooled from three randomized, double-blind, placebo-controlled studies with similar designs (Pyxis – NCT01360645; Polaris – NCT01360632; Sirius – NCT02196506). In each study, patients with MDD and an inadequate response to 1–3 ADTs received single-blind ADT for 8 weeks. Patients with inadequate response throughout this prospective phase were randomized to receive either ADT+brexpiprazole (2mg in Pyxis and Sirius; 1mg or 3 mg in Polaris) or ADT+placebo for 6 weeks. Proxies used to categorize patients as having ‘anxious distress’ included a score of ≥2 on the following symptoms at randomization: tension (MADRS item 3 score ≥3); restlessness (IDS item 24 score ≥2); concentration (MADRS item 6 score ≥3); or apprehension (HAM-D item 10 score ≥3). Scores on the items of the HAM-D anxiety/somatization factor at randomization (baseline) were used to identify patients with ‘anxious depression’. Efficacy was assessed as the change in MADRS total score from baseline to Week 6. Statistical analysis used a Mixed Model Repeated Measure approach using pooled brexpiprazole doses.ResultsAfter 8 weeks of prospective ADT monotherapy, 57.6% (n=797/1,383) of patients met the criteria for anxious distress, and 48.5% (n=671/1,383) for anxious depression. The mean MADRS total score was 29.0 for patients with anxious distress in the adjunctive brexpiprazole (n=462) group and 29.1 in the placebo (n=327) group; while those with anxious depression were 28.9 (brexpiprazole; n=384) and 28.6 (placebo; n=282). Compared to those receiving placebo, patients with both anxious distress and anxious depression who received adjunctive brexpiprazole showed a greater improvement in MADRS total score (LS mean difference -2.38, p=0.0001 and -1.68, p=0.012, respectively). These improvements, compared to placebo, were similar to those in patients who had not met the criteria for anxious distress (-1.40, p=0.023) or anxious depression (-2.17, pConclusionAdjunctive brexpiprazole may be efficacious in reducing depressive symptoms both in patients with or without symptoms of anxiety.Funding AcknowledgementsThe studies were funded by H. Lundbeck A/S and Otsuka Pharmaceutical Development & Commercialization, Inc.

BackgroundEffective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).MethodsIn the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.ResultsA total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).ConclusionThis post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S

Brexpiprazole, a serotonin-dopamine activity modulator, is a partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency. Efficacy of brexpiprazole was evaluated in patients with acutely exacerbated schizophrenia in three short-term, randomized, double-blind, placebo-controlled studies.In a Phase 2 study, patients were randomized to brexpiprazole 0.25mg (fixed dose), 1.0±0.5mg, 2.5±0.5mg, 5.0±1mg (flexible-dose ranges), placebo, or aripiprazole 15±5mg. In two Phase 3 studies, patients were randomized to fixed-dose brexpiprazole 0.25mg, 1mg, 2mg, or 4mg, or placebo. For this review, brexpiprazole 2mg and 4mg arms from the Phase 3 studies were combined. Primary efficacy endpoint was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at week 6; key secondary endpoint was change in Clinical Global Impression-Severity of illness (CGI-S) score at week 6. Primary outcome moderator analyses explored effects of sex, age, race, and illness duration.There were no statistically significant differences vs. placebo in the Phase 2 brexpiprazole and aripiprazole groups for primary and key secondary endpoints. Combined brexpiprazole 2mg (n=359) and 4mg (n=359) were superior to placebo (n=358) in change in PANSS total score (least square mean difference from placebo: −5.46, p=0.0004, and −6.69, p

This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia.Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study.57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration120-135 mEq/L) at 16 sites.Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance.Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations.Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03).There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating.Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.

The efficacy, safety, and tolerability of brexpiprazole and placebo were compared in adults with acute schizophrenia.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.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.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.

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.

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