Catherine Weiss

Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies

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<0.0001, respectively) and CGI-S (-0.25, p=0.0035, and -0.38, p<0.0001, respectively). Changes from baseline in efficacy endpoints were minimal in the 0.25mg group, while the 1mg group exhibited suboptimal improvement. No relevant moderators were identified. Meta-analysis of the pivotal studies indicates brexpiprazole 2mg and 4mg are effective in treating acute schizophrenia.

Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia

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.

Overview of Short-Term and Long-Term Safety of Brexpiprazole in Patients with Major Depressive Disorder and Inadequate Response to Antidepressant Treatment

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.

Efficacy of Brexpiprazole as Adjunctive Treatment in Major Depressive Disorder With Irritability: Post Hoc Analysis of 2 Pivotal Clinical Studies

To the EditorsIrritability in patients with major depressive disorder (MDD) has been associated with greater overall severity, previous suicide attempts, and suicidal ideations.1 Irritability in MDD is also associated with longer duration of episodes, a more chronic course of illness, impaired funct

Efficacy of Adjunctive Brexpiprazole in Patients with Major Depressive Disorder: A Clinical Overview

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<0.01; 2 mg/day, p<0.01; 3 mg/day, p<0.001; brexpiprazole 1–3 mg/day, p<0.0001). Conclusion: Adjunctive brexpiprazole is an efficacious treatment option for patients with MDD and inadequate response to ADT. ClinicalTrials.gov: NCT00797966; NCT01052077; NCT01360632; NCT01360645.

Efficacy of adjunctive brexpiprazole on the core symptoms of major depressive disorder: A post hoc analysis of two pooled clinical studies

BACKGROUND Patients with major depressive disorder (MDD) who do not adequately respond to antidepressant treatment (ADT) may benefit from adjunctive atypical antipsychotics; however, certain agents target specific symptoms of depression and not the full syndrome. The aim of this analysis was to examine the effects of brexpiprazole, adjunct to ADT, on the core symptoms of MDD, defined using Montgomery-Åsberg Depression Rating Scale (MADRS) items. METHODS This was a post hoc analysis of data from two 6-week, randomized, double-blind studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (n = 1056). Efficacy was assessed using the MADRS core symptom subscale (MADRS6) and individual items (apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts). RESULTS At Week 6, adjunctive brexpiprazole showed a greater effect than adjunctive placebo on the MADRS6 (within-group Cohens d effect sizes: brexpiprazole, 1.05; placebo, 0.71; p < 0.001 between groups) and on each of the six core symptoms (effect sizes: brexpiprazole, 0.64-0.94; placebo, 0.39-0.64; all p < 0.001). At Week 2, adjunctive brexpiprazole already showed a greater effect than adjunctive placebo on the MADRS6, and on five of the core symptoms (all p < 0.01). LIMITATIONS This was a post hoc analysis of studies that were not designed for this purpose. Correction for multiple comparisons was not performed. CONCLUSIONS Brexpiprazole, as adjunct to ADT, produced a statistically significant and clinically meaningful improvement on the core symptoms of MDD. Brexpiprazole is thought to exert its effects in MDD by treating the core symptoms of the disease.

Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder

BackgroundEvidence suggests that nearly half of patients with major depressive disorder (MDD) do not achieve an adequate response to antidepressant treatments (ADTs), which impacts patients’ functioning, quality of life (QoL), and well-being. This patient survey aimed to better understand patient perspectives on the emotional impact of experiencing an inadequate response to ADTs.MethodsAn online survey was conducted in 6 countries with respondents diagnosed with MDD and experiencing an inadequate response to ADTs. The survey was designed to explore how patients felt about their medications and health care provider (HCP). Those indicating they were ‘frustrated’ with their medications and/or HCP were asked to provide reasons for their frustration and its impact on their relationship with their HCP and decisions about their treatment.ResultsOverall, 2096 respondents with MDD and inadequate response to ADT completed the survey. The most frequent emotion reported by patients regarding their medication was frustration (29.8% of respondents) followed by hopeless (27.4%) and apprehensive/anxious/scared (27.4%). Regarding their HCP, patients reported feeling understood (31.6%) and trusting/confident (28.8%) most often; however, 19.2% reported feelings of frustration. Main reasons for frustration with medication were poor symptom control/lack of efficacy (59.3%) and tolerability issues (19.7%), and the main reasons for frustration with their HCP were not feeling heard (22.4%), ineffective treatment (13.5%) and feeling rushed/lack of quality visit (12.5%). The longer the current episode duration and the greater the disruption to daily living, the more likely the respondents experienced feelings of frustration with medication. Feelings of frustration lead to adherence issues, with 33.3 and 27.3% of respondents indicating their frustration with their medication and HCP, respectively, made them want to quit their medication. Approximately one in six patients frustrated with either their medication and/or HCP indicated their frustration had resulted in them not taking their medication regularly. Frustration with their HCP also impacted patient’s confidence in HCPs abilities (34.7%), sharing less information with their HCP (28.9%) as well as missing appointments (17.4%) and medications (14.5%).ConclusionsFeelings of frustration are frequent in patients with inadequate response to ADT and this frustration may impact treatment adherence and the patient-HCP relationship.

Functioning outcomes with adjunctive treatments for major depressive disorder: a systematic review of randomized placebo-controlled studies

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<0.05), as measured by the SDS total or mean score. On the SDS “work/studies” item, only aripiprazole had a statistically significant benefit, in one study out of four. Thus, where a benefit was observed on the SDS total or mean, this was generally driven by improvement on the “social life” and “family life” items. A limitation of the review is that it only considered published literature from one database. Conclusion The SDS, a self-rated functional measure, is informative in acute randomized placebo-controlled studies of adjunctive therapy in patients with MDD and inadequate response to ADT. However, the item that measures work performance may be less relevant to this population than the items that measure social and family life.

Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies.

Objective Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies. Methods Patients 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. Results The 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 (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs. Conclusions Overall, 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.

T50. SYMPTOMATIC AND FUNCTIONAL RESPONSE TO BREXPIP RAZOLE TREATMENT IN PATIENTS WITH ACUTE SCHIZOPHRENIA BY AGE

Abstract Background Atypical antipsychotics are the mainstay of treatment for schizophrenia, and have a meaningful effect on positive symptoms and agitation/aggression. More recently, treatment goals have shifted to target functioning; a cycle of deterioration often occurs in early schizophrenia in which recurring relapse results in decreased functioning. 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 subnanomolar potency. The efficacy of brexpiprazole has been shown in both short- and long-term studies. In this post-hoc analysis from three short-term studies, the proportion of patients achieving symptomatic and functional response was assessed, grouped by age at baseline. Methods Efficacy and functioning data were pooled from three 6-week, double-blind, placebo-controlled studies in hospitalized patients with acute exacerbation of schizophrenia (Vector [NCT01396421]; Beacon [NCT01393613]; and Lighthouse [NCT01810380]), and stratified according to age at baseline (18–35 years; and 36–65 years). For the current analyses, response was defined as reduction in PANSS score of ≥30% from baseline; a CGI-I score of 1 or 2 (much improved or improved); or reduction in PANSS score of ≥30% OR CGI-I score of 1 or 2. Functional response was defined as an increase in PSP total score of at least 10 points. The analyses were conducted using a mixed-model repeated measures (MMRM) approach with all brexpiprazole doses pooled (2-4mg/day). Results 557 patients aged 18–35 years and 857 patients aged 36–65 years were analysed. For patients aged 18–35 years, a statistically significantly greater proportion of brexpiprazole-treated vs placebo-treated patients had symptomatic response after 6 weeks of treatment (PANSS ≥30%: 40.5% vs 28.7%, p<0.01; CGI-I 1 or 2: 39.9% vs 25.4%, p<0.001; PANSS ≥30% OR CGI-I 1 or 2: 46.2% vs 32.3%, p<0.01). Similar results were observed for patients aged 36–65 years (PANSS ≥30%: 48.7% vs 37.6%, p<0.01; CGI-I 1 or 2: 47.1% vs 32.7%, p<0.0001; PANSS ≥30% OR CGI-I 1 or 2: 54.8% vs 41.6%, p<0.001). For patients aged 18–35 years, a statistically significantly greater proportion of brexpiprazole-treated vs placebo-treated patients had functional response after 6 weeks of treatment (PSP 10 points change: 46.3% vs 33.0%, p<0.01); similar results were observed for patients aged 36–65 years (49.2% vs 38.2%, p<0.01). The proportion of patients meeting both symptomatic (using ≥30% PANSS improvement or CGI-I score of 1 or 2) and functional response was statistically significantly greater in brexpiprazole-treated patients vs placebo-treated patients regardless of the age group (18–35 years: 37.4% vs 25.4%, p<0.01; 36–65 years: 41.8% vs 30.2%, p=0.01). Discussion The results of these analyses confirm that 6 weeks of treatment with brexpiprazole results in symptomatic and functional response in acutely ill schizophrenia patients in both younger patients (age 18 to 35 years) as well as older patients (age 36–65).