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Objective Brexpiprazole is a serotonin-noradrenaline-dopamine agent that binds with high affinity to multiple serotonin, norepinephrine and dopamine receptors. In particular, Brexpiprazole is a partial agonist at dopamine D2/D3 and 5-HT1A receptors and an antagonist at 5-HT2A and norepinephrine alpha1B receptors. We assessed the efficacy and safety of brexpiprazole versus placebo as adjunctive therapy to anti-depressant therapy (ADT) in subjects with MDD who demonstrated inadequate response to ADT. Methods This trial had 3 phases: a screening phase (7-28 days); a prospective phase (Phase A): 8-week, single-blind placebo plus an investigator-determined, open-label ADT; a randomized phase (Phase B): 6-week, double-blind, adjunctive brexpiprazole (2 mg/day) vs. placebo in patients with an inadequate response to ADT. The primary efficacy endpoint was the change from the end of Phase A (Week 8) to the end of Phase B (Week 14) in MADRS Total Score. The key secondary endpoint was the change in mean SDS score. Other secondary endpoints were mean change in CGI-S, IDS-R, HAMD and HAMA. Results Of 379 randomized patients, completion rates at Week 14 were high (92.9%). Statistically significant improvements in mean MADRS Total score were observed for subjects receiving adjunctive brexpiprazole 2mg/day compared with placebo (p=0.0001) at endpoint. In addition, on all secondary endpoints Brexpiprazole showed a statistically significant advantage over placebo. Commonly reported adverse events in the brexpiprazole group (>5% and more than twice placebo) were weight gain (8.0%), akathisia (7.4%). Conclusions Brexpiprazole was effective and well tolerated as adjunctive treatment for MDD patients with an inadequate response to ADT.

Objective Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia. Methods Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening. Results 710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p Conclusions Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.

Objective Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia. Methods Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed. Results 710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p 5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders. Conclusions ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia 1 .

Objective Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day). Methods Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint. Results At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea. Conclusions The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.

Objective Evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) initiation in patients stabilized on oral antipsychotics other than aripiprazole. Previous pivotal Phase III trials have evaluated initiating ARI-OM in patients stabilized on oral aripiprazole 1 . Methods Eligible patients were treated with oral atypical antipsychotics other than aripiprazole with a history of oral aripiprazole tolerability. The study included a screening phase (30 days) and a treatment phase (28 days). Patients were stabilized per investigator's judgment for ≥14 days on risperidone, olanzapine, quetiapine, or ziprasidone, before administration of ARI-OM (400 mg). Current oral antipsychotic was co-administered with ARI-OM for 2 weeks to determine safety and tolerability of a single ARI-OM dose following treatment initiation. Safety assessments were adverse events (AEs); extrapyramidal symptoms (EPSs) using standard objective rating scales; Columbia-Suicide Severity Rating Scale; clinical laboratory measures; and weight changes. Results 60 patients initiated ARI-OM, while continuing treatment for ≤2 weeks with oral risperidone (n=24), quetiapine (n=28), ziprasidone (n=5) or olanzapine (n=3). Treatment-emergent (TE) AEs (≥5%) were fatigue, injection-site pain, and restlessness (risperidone); insomnia, dystonia, injection-site pain, and toothache (quetiapine); and muscle spasm, tooth abscess, and toothache (ziprasidone). Prior olanzapine did not cause any AEs. Incidence of TE-EPSs were similar in all groups ( Conclusions The AE profile of patients receiving ARI-OM concomitant with oral atypical antipsychotics other than aripiprazole was consistent with prior reports 1 .

ObjectiveEvaluate the time-course, severity and resolution patterns of adverse events (AEs) occurring with long-term aripiprazole treatment for irritability associated with autistic disorder.MethodsParticipants were treated with aripiprazole in a 52-week, open-label, flexibly dosed (2–15 mg/day) study. Subjects had either completed one of two 8-week randomised trials or were de novo. AEs with an incidence of ≥10% were evaluated by incidence, peak first onset, severity, percent resolved and time to resolution.ResultsA total of 330 subjects entered open-label treatment; 199 completed 52 weeks. Mean dose for the population stabilised at around 10 mg/day after approximately 4 months. Thirteen AEs had an incidence of ≥10%; most were mild or moderate in severity. Vomiting, diarrhoea and headache had an early first onset and tended to resolve fairly quickly.Sedation, fatigue and insomnia also appeared early and resolved in a majority of cases, but not as quickly. Increased appetite appeared early (followed by increased weight) and fewer weight-related AEs resolved. More than half of the subjects increased their weight by at least one percentile category rank; nevertheless, only a small proportion of subjects with normal baseline metabolic or glucose measures had a treatment-emergent, clinically relevant laboratory abnormality. Nasopharyngitis, upper respiratory infection, cough, nasal congestion and pyrexia all had peak onset at variable times during the study, resolving in nearly all cases, with short time to resolution.ConclusionAEs were mostly mild or moderate and of variable duration. Increased weight was observed.

ObjectivesThe safety and tolerability of aripiprazole as adjunctive treatment was examined in patients with major depressive disorder (MDD) without psychotic features who had a major depressive episode and who did not respond adequately to standard antidepressant therapy (ADT).MethodsData from three identical short-term, double-blind, placebo-controlled studies (CN138139, CN138163, CN138165) were pooled. After a prospective phase with placebo plus ADT, patients without adequate response entered a 6-week, double-blind phase with placebo or aripiprazole plus ADT. Safety endpoints included death, serious adverse events (SAEs), treatment-emergent adverse events (AEs), Simpson-Angus Scale (SAS), Barnes Akathisia Global Clinical Assessment, Abnormal Involuntary Movement Scale (AIMS), clinical laboratory tests, vital signs and electrocardiograms.ResultsIn total, 538 patients were randomized to adjunctive placebo and 547 to adjunctive aripiprazole. AEs with an incidence ≥5% and at least twice the rate of placebo were akathisia (adjunctive aripiprazole, 22.7%; adjunctive placebo, 4.1%), restlessness (12.4% vs 2.2%), fatigue (8.6% vs 4.3%), insomnia (8.2% vs 3.2%), vision blurred (6.2% vs 1.5%), somnolence (5.9% vs 2.6%), and constipation (4.9% vs 2.4%). AEs that had a treatment difference of ≥2% included akathisia, somnolence, sedation, dizziness, disturbance in attention, extrapyramidal disorder, restlessness, insomnia, constipation, dyspepsia, fatigue, feeling jittery, vision blurred, weight increased, and dyspnea. SAEs occurred in 0.7% of patients in each treatment group. There were no deaths during the studies.ConclusionsIn this pooled analysis of patients with MDD and an inadequate response to ADT, adjunctive aripiprazole showed consistently high study completion rates and low discontinuation rates resulting from adverse events.

AimsTo evaluate the efficacy of aripiprazole as adjunctive treatment in patients with major depressive disorder (MDD) without psychotic features and an inadequate response to standard antidepressant therapy (ADT).MethodsData were collected from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165). After a single-blind prospective phase with placebo plus ADT, patients with inadequate response were randomized to 6-weeks’ treatment with adjunctive aripiprazole or placebo. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score during the double-blind phase. Secondary endpoints were response (≥50% reduction in MADRS total score), remission (MADRS total score ≤10 and ≥50% reduction in MADRS total score), and mean change in Hamilton Depression Rating Scale (HAM-D17) total score.ResultsIn all three studies, adjunctive aripiprazole was associated with a significantly greater reduction in MADRS total score than adjunctive placebo, with a treatment difference ranging between -3.73 and -2.84 (p≤0.001 in each study). Response and remission rates with adjunctive aripiprazole (32.4-46.6% and 25.4-36.8%, respectively) were also significantly higher than with adjunctive placebo (17.4-26.6% [p< 0.05 in each study] and 15.2-18.9% [p< 0.05 in each study]). Mean change in HAM-D17 total score ranged from -7.64 to -6.77 with adjunctive aripiprazole and from -5.12 to -4.41 with adjunctive placebo (p< 0.001 for each study).ConclusionsResults of the three studies indicate that treatment with adjunctive aripiprazole and ADT is effective in improving the symptoms of MDD in patients who have had an inadequate response to ADT.

PurposeTo evaluate the safety of aripiprazole as adjunctive treatment in major depressive disorder (MDD) without psychotic features within different patient subgroups.MethodsData were pooled from three multicentre, randomized, double-blind, placebo-controlled studies (CN138-139, CN138-163 and CN138-165). Patients who did not respond adequately to an 8-week course of standard ADT were randomized to receive adjunctive aripiprazole or placebo for a further 6 weeks. To assess differences in the adverse events (AE) profile of aripiprazole for demographic subgroups, the incidence of AEs was presented for the pooled placebo-controlled MDD studies by gender, age, and race. An odds ratio (OR) estimate was calculated and the ORs compared across all categories using the Breslow-Day test for AEs with incidence ≥5% in the pooled aripiprazole group.ResultsIn total, 14.3% of aripiprazole-treated patients and 12.5% of placebo-treated patients discontinued treatment. Treatment-emergent AEs were reported by 65.4% and 82.3% in the adjunctive placebo and adjunctive aripiprazole groups, respectively. Most aripiprazole-related AEs were, however, mild to moderate in severity. With the exception of blurred vision, which occurred in white patients only (p=0.002), there were no significant differences in the incidence of treatment-emergent AEs across different age groups, racial groups or between the genders in the aripiprazole- and placebo-treated groups.ConclusionAdjunctive aripiprazole was generally well tolerated and most treatment-emergent AEs were of mild to moderate severity. The AEs profile of adjunctive aripiprazole did not show significant variation in relation to age, gender or race, compared with that of placebo.

AimsTo conduct a subgroup analysis of the efficacy of adjunctive aripiprazole as treatment in patients with major depressive disorder (MDD) who demonstrated an inadequate response to standard antidepressant therapy (ADT).MethodsData were pooled from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165) with an 8-week phase of placebo plus ADT and a 6-week double-blind phase with ADT plus adjunctive placebo or aripiprazole. Only MDD patients without psychotic features were eligible for entry. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score in the double-blind phase. Subgroup analyses of the primary efficacy endpoint were performed for age, race, ethnicity, MADRS response, number and choice of previous ADTs, episode duration, and use of selective serotonin re-uptake inhibitors (SSRI).ResultsCompared with the adjunctive placebo group, adjunctive aripiprazole was associated with greater reductions in MADRS total score in all subgroups. Mean change in MADRS total score ranged from -10.71 to -5.89 with adjunctive aripiprazole and -7.57 to -4.10 with adjunctive placebo. No statistically significant treatment-by-subgroup interaction effects were observed for any subgroup except gender (p=0.039). This difference is, however, primarily because of results from study CN138-139 results; consistent results between men and women were reported in CN138-163 and CN138-165.ConclusionsPooled data indicate that in patient populations with similar baseline characteristics, treatment with adjunctive aripiprazole and ADT is efficacious in improving the symptoms of MDD in subgroups of patients having an inadequate response to ADT.

ObjectiveTo evaluate the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in bipolar mania.MethodsCompleters of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to monotherapy were followed up over 46-weeks on open-label aripiprazole plus lithium (ARI+LI) or valproate (ARI+VAL).Results283 (ARI+LI n=108; ARI+VAL n=175) patients entered and 146 (ARI+LI n=55; ARI+VAL n=91) completed the 46-week extension. Safety results for both combinations were consistent with the known tolerability profile of aripiprazole, lithium and valproate. No clinically significant changes in lipids or glucose were observed with either ARI+LI or ARI+VAL. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI+LI and 2.0 (0.4) kg with ARI+VAL. Temporal analysis of the time of first onset of adverse events showed that akathisia and insomnia tended to occur early in treatment, with few new cases in patients previously treated with aripiprazole during the 6-week study.Significant improvements from baseline in YMRS total score and MADRS total score were sustained over the 52 weeks with both ARI+LI and ARI+VAL treatment.Mean reduction from baseline at Week 52 LOCF[95%CI], p value vs baselineARI+LIARI+VALYMRS total score-16.5 [-18.1; -14.8], p-17.6 [-18.9; -16.3] pMADRS total score-1.7 [-3.3; -0.1] p-2.7 [-4.0; -1.4] pConclusionsLong-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well-tolerated. Improvements in manic and depressive symptoms observed during the first 6 weeks of treatment were maintained.

Purpose:To evaluate the efficacy and safety of aripiprazole monotherapy as acute and continuation therapy for acute bipolar I mania.Methods:Patients with acute bipolar I mania were randomized (1:1:1) to double-blind aripiprazole (15–30 mg/day; n=155), placebo (n=165) or lithium (900–1500 mg/day; n=160) for 3 weeks. At the end of Week 3, patients randomized to placebo were blindly switched to aripiprazole. Key efficacy outcome measures were mean change from baseline in YMRS Total score at Week 3 (LOCF; primary endpoint) and Week 12.Results:Improvements in YMRS Total scores from baseline were significantly greater versus placebo as early as Day 2 with aripiprazole (p=0.003) and Day 7 with lithium (p=0.040; LOCF). At Week 3, improvements from baseline in mean YMRS Total scores were significantly greater with aripiprazole (–12.96; p