brexpiprazole and Depressive-Disorder--Major

Atypical antipsychotic (AAP) augmentation is an alternative strategy for patients with major depressive disorder (MDD) who had an inadequate response to antidepressant therapy (ADT). We aimed to compare and rank the efficacy and safety of 4 AAPs in the adjuvant treatment of MDD.. We searched randomized controlled trials (RCTs) published and unpublished from the date of databases and clinical trial websites inception to April 30, 2023. The evidence risk of bias (RoB) and certainty are assessed using the Cochrane bias risk tool and grading of recommendations assessment, development, and evaluation (GRADE) framework, respectively. Using network meta-analysis, we estimated summary risk ratios (RRs) or standardized mean difference (SMD) based on the random effects model.. 56 eligible studies comprising 11448 participants were included. In terms of primary efficacy outcome, compared with placebo (PBO), all AAPs had significant efficacy (SMD = -0.40; 95% CI, -0.68 to -0.12 for quetiapine (QTP); -0.35, -0.59 to -0.11 for olanzapine (OLA); -0.28, -0.47 to -0.09 for aripiprazole (ARI) and -0.25, -0.42 to -0.07 for brexpiprazole (BRE), respectively). In terms of acceptability, no significant difference was found, either agents versus agents or agents versus PBO. In terms of tolerability, compared with the PBO, QTP (RR = 0.24; 95% CI,0.11-0.53), OLA (0.30,0.10-0.55), ARI (0.39,0.22-0.69), and BRE (0.37,0.18-0.75) were significantly less well tolerated. 8 (14.2%) of 56 trials were assessed as low RoB, 38 (67.9%) trials had moderate RoB, and 10 (17.9%) had high RoB; By the GRADE, the certainty of most evidence was low or very low.. Adjuvant AAPs had significant efficacy compared with PBO, but treatment decisions must be made to balance the risks and benefits.

Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Adult; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Humans; Network Meta-Analysis; Olanzapine; Quetiapine Fumarate

Brexpiprazole augmentation is an effective treatment strategy for antidepressant-refractory depression, but its optimal dosage remains unclear.. To find the optimal dosage of brexpiprazole as augmentation of other antidepressants.. We searched multiple electronic databases (from inception to September 16th, 2021) to identify double-blind, randomized placebo-controlled fixed-dose trials evaluating brexpiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder not adequately responding to one or more antidepressant treatment. Our outcomes of interest at 8 weeks (range 4-12 weeks) were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects) and acceptability (dropouts for any reason). We performed a random-effects, one-stage dose-effect meta-analysis with restricted cubic splines.. Six studies met the inclusion criteria, including 1671 participants in total. The dose-efficacy curve showed an increase up to doses around 2 mg (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06) and then a decreasing trend through the higher licensed dose up to 3 mg (OR 1.40, 95% CI 0.95-2.08). The shape of the dose-tolerability curve was comparable to that of the efficacy and the dose-acceptability curve showed a monotonic increasing trend but both had wide confidence bands.. One to two milligrams of brexpiprazole as augmentation treatment may achieve an optimal balance between efficacy, tolerability, and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies limit the reliability of the results. Further research is required to validate the findings.

Topics: Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Female; Humans; Male; Quinolones; Randomized Controlled Trials as Topic; Reproducibility of Results; Thiophenes

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D

Topics: Aripiprazole; Depressive Disorder, Major; Dopamine; Dopamine Agonists; Humans; Quinolones; Research; Thiophenes; United States

Mood and psychotic disorders are a group of illnesses that affect behavior and cognition. Schizophrenia is characterized by positive symptoms, such as delusions and hallucinations, as well as negative symptoms. Major depressive disorder (MDD) is a mood disorder that affects the patient's emotions, energy, and motivation. Brexpiprazole works as a partial agonist at serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A. Schizophrenia and MDD have a wide range of risk factors, both biological and environmental. Third generation antipsychotics, which include brexpiprazole, are the latest group of drugs to reach the market, demonstrating efficacy and tolerability. Patients with acute schizophrenia have responded well to brexpiprazole. In this regard, in patients who have MDD plus anxiety symptoms, brexpiprazole can be effective as an adjunctive therapy and can reduce anxiety symptoms. In summary, brexpiprazole has proved to be an effective alternative to typical or first and second-generation atypical antipsychotics.

Topics: Antipsychotic Agents; Depressive Disorder, Major; Humans; Quinolones; Schizophrenia; Thiophenes

Brexpiprazole is a new atypical antipsychotic for schizophrenia management and as adjunct in major depressive disorder (MDD). We searched randomized controlled trials (RCT) to review brexpiprazole efficacy and tolerability in acute management of schizophrenia and MDD using PubMed, EUDRACT, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials. A meta-analysis was conducted using the identified 14 RCT to assess its efficacy using positive and negative syndrome scale (PANSS), clinical global impressions - severity of illness (CGI-S), personal and social performance scale (PSP), Montgomery-Åsberg depression rating scale (MADRS), Sheehan disability scale (SDS) and Hamilton depression rating scale (HDRS17). The mean difference comparing brexpiprazole and placebo were PANSS -4.48, CGI-S -0.23 and PSP 3.24 favoring brexpiprazole. Compared to aripiprazole and quetiapine, brexpiprazole showed similar efficacy. In MDD, brexpiprazole showed efficacy compared to placebo demonstrated by MADRS -1.25, SDS -0.37 and HDRS17 -1.28. Brexpiprazole was associated with side effects including akathisia risk ratio (RR) = 1.72; weight increase RR = 2.74 and somnolence RR = 1.87. Compared to 4 mg, brexpiprazole 2 mg was associated with less risk of akathisia and somnolence. Brexpiprazole demonstrated significant improvements in schizophrenia and MDD and is well-tolerated; however, associated with akathisia and somnolence. These findings will guide psychiatrists and pharmacists in their clinical role for supporting psychiatric patients care.

Topics: Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Humans; Psychiatric Status Rating Scales; Quetiapine Fumarate; Quinolones; Schizophrenia; Thiophenes; Treatment Outcome

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.. 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.. 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.. Brexpiprazole, as adjunct to antidepressant treatments, improved functioning in patients with major depressive disorder and inadequate response to antidepressant treatments.

Topics: Antidepressive Agents; Depressive Disorder, Major; Disability Evaluation; Double-Blind Method; Drug Therapy, Combination; Humans; Prospective Studies; Quinolones; Randomized Controlled Trials as Topic; Serotonin Agents; Single-Blind Method; Thiophenes

This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed.. The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose).. We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50).. Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d.

Topics: Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Humans; Outcome Assessment, Health Care; Quinolones; Randomized Controlled Trials as Topic; Serotonin Agents; Thiophenes

Brexpiprazole is the most recently approved second-generation antipsychotic, which is used as adjunctive therapy to antidepressants for treating major depressive disorder (MDD) with inadequate response. Brexpiprazole shares pharmacological similarities with other second-generation antipsychotics, especially aripiprazole. Area covered: This review provides a detailed overview of the pre-clinical studies of brexpiprazole, followed by a summary of its clinical studies, and a comparison with other antipsychotics in MDD. Brexpiprazole is superior to placebo in reducing depressive symptoms of patients who have had an inadequate response to a standard antidepressant treatment. The efficacy of brexpiprazole is comparable to aripiprazole and quetiapine-XR, but brexpiprazole has demonstrated a lower risk for akathisia than aripiprazole and a lower risk for somnolence than quetiapine-XR. Expert opinion: Given that different studies have used different criteria to define 'treatment-resistance' or 'inadequate-response', an accurate comparison of the efficacy and safety of brexpiprazole with other antipsychotics is difficult. Preclinical data supports the premise that the antidepressant-like effects of antipsychotics are mainly due to their ability to modulate/regulate the monoamine system. Therefore, antipsychotics with similar pharmacodynamic properties like brexpiprazole could also take the 'me too' approach to treating MDD.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Quinolones; Thiophenes

Brexpiprazole was approved for adjunctive treatment of major depressive disorder (MDD) in 2015. Because only a small number of randomized controlled trials have investigated the use of brexpiprazole in MDD, we performed a meta-analysis.. We systematically searched literatures in PubMed, Cochrane Library database, EMBASE, Google Scholar, and clinicaltrials.gov up to January 2016. The primary efficacy measure was the mean change in total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline. Secondary efficacy measures were the mean change in total Hamilton Rating Scale for Depression (17 items) score from baseline and the response (≥50% reduction in MADRS total score) and remission (MADRS total score ≤ 10 with ≥50% reduction) rates.. Four studies fulfilled the inclusion criteria and were included in the analysis. Brexpiprazole showed superior efficacy over placebo with effect sizes (mean differences) of -1.76 (95% confidence interval [CI], -2.45 to -1.07) for MADRS and -1.21 (95% CI, -1.71 to -0.72) for the 17-item Hamilton Rating Scale for Depression. The risk ratios for response and remission were 1.57 (95% CI, 1.29-1.91) and 1.55 (95% CI, 1.22-1.96), respectively. The incidences of discontinuation due to adverse events, akathisia, and weight increase were higher in the brexpiprazole group than in the placebo group, with risk ratios of 3.44 (95% CI, 1.52-7.80), 3.39 (95% CI, 2.08-5.51), and 4.36 (95% CI, 2.45-7.77), respectively, and the incidence of akathisia was related to the brexpiprazole dose.. Although our results suggest that brexpiprazole could be an effective adjunctive agent for MDD, they should be cautiously translated into clinical practice because the meta-analysis was based on only a handful of randomized controlled trials.

Topics: Depressive Disorder, Major; Humans; Quinolones; Serotonin Agents; Thiophenes

To review the pharmacology and clinical data for brexpiprazole in schizophrenia and major depressive disorder (MDD).. An English-language literature search using PubMed and MEDLINE was performed using the term brexpiprazole. All articles containing human clinical trial data published up to September 2016 were evaluated for inclusion as well as information from the manufacturer's product labeling.. Phase 3 trials for brexpiprazole were evaluated. Key in vitro and animal data were incorporated into the pharmacology and pharmacokinetic sections where appropriate.. Four phase 3 trials have evaluated the use of brexpiprazole as a primary therapy for schizophrenia or as an antidepressant adjunct for MDD. For its schizophrenia indication, brexpiprazole was studied in 2 placebo-controlled trials of approximately 1300 patients, with 4 mg of brexpiprazole consistently showing superiority over placebo. For MDD, brexpiprazole was compared with placebo as an adjunct to antidepressants in approximately 1000 patients who had failed trials of 1 to 3 prior antidepressants. The 2-mg and 3-mg dosages of brexpiprazole showed consistent superiority over placebo in the MDD trials. Common treatment emergent adverse effects included akathisia and weight gain.. Brexpiprazole showed efficacy for the treatment of schizophrenia in the range of 2 to 4 mg/d and as an adjunct to antidepressant therapy in MDD when dosed at 2 to 3 mg/d. Advantages of this drug include once-daily dosing, good tolerability, and lack of effect on sexual function. Disadvantages include the lack of long-term safety data and potentially high cost.

Topics: Antidepressive Agents; Antipsychotic Agents; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Quinolones; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Schizophrenia; Thiophenes; Weight Gain

Brexpiprazole (Rexulti(®)) is a serotonin-dopamine activity modulator, with a unique receptor binding profile and low intrinsic D2 activity suggestive of a lower potential than aripiprazole to cause activation-like adverse effects, such as akathisia. The drug was recently approved by the US FDA for adjunctive therapy with antidepressant treatment (ADT) in patients with major depressive disorder (MDD). In two phase III trials, adjunctive oral brexpiprazole 2 or 3 mg once daily was more effective than monotherapy with ADT in improving depressive symptoms in adults with MDD who demonstrated an incomplete response to previous treatment with ADT. Adjunctive brexpiprazole was generally well tolerated in clinical trials, which included treatment periods of up to 52 weeks. Results of ongoing trials should help position the drug in the treatment of MDD. In the meantime, brexpiprazole provides a valid option for patients with persistent symptoms despite standard antidepressant therapy.

Topics: Antidepressive Agents; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Quinolones; Thiophenes

Antipsychotic agents, utilized for the treatment of a range of psychiatric disorders, differ substantially in terms of their pharmacology and adverse effect profiles. Incomplete and variable efficacy, differences in safety-tolerability, and highly heterogeneous response across individuals prompt development of new agents. Brexpiprazole is one of the two most recently introduced antipsychotic agents approved for the treatment of schizophrenia and as an adjunct for treatment of major depressive disorder. Its pharmacology, clinical trial data, and efficacy and side effects in comparison with other antipsychotic agents are discussed. Brexpiprazole is a dopamine D-2 partial agonist with potent activity at the serotonin 5HT1A and 5HT2A and noradrenergic alpha-1B and alpha-2C receptors. Placebo-controlled clinical trials in persons with schizophrenia support its efficacy in treating psychosis and preventing relapse. Short-term clinical trials also support its efficacy as an adjunct to antidepressants in treating major depressive disorder in individuals inadequately responsive to antidepressant treatment alone. Adverse effects include akathisia, gastrointestinal side effects, and moderate weight gain. The recommended oral dose of brexpiprazole is 2-4 mg/day in schizophrenia and 2-3 mg/day as adjunctive treatment in major depression. It must be titrated up to its target dose over 1-2 weeks and is effective in once-daily dosing. How brexpiprazole's unique pharmacological profile will translate into clinically meaningful differences from other antipsychotic agents is unclear. Its place in our antipsychotic armamentarium and potential role in the treatment of schizophrenia and major depressive disorder will be determined by additional clinical data and experience.

Topics: Animals; Depressive Disorder, Major; Humans; Quinolones; Schizophrenia; Thiophenes

To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD).. The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.. All available clinical reports of studies were identified.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.. Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short-term weight gain appears modest; however, more outliers with an increase of ≥ 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident.. Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed.

Topics: Antidepressive Agents; Antipsychotic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Schizophrenia; Thiophenes

Brexpiprazole is a dopamine D₂receptor partial agonist. Compared with aripiprazole, it is more potent at 5-HT1A receptors and displays less intrinsic activity at D₂receptors. Brexpiprazole also has potent antagonistic activity at 5-HT2A as well as alpha-adrenergic receptors. In addition to results from phase II trials, data are available from two pivotal phase III, randomized, placebo-controlled trials of brexpiprazole for the acute treatment of schizophrenia and two pivotal phase III, randomized, placebo-controlled trials of adjunctive brexpiprazole for the acute treatment of major depressive disorder in patients with inadequate response to antidepressant medication treatment. Overall tolerability is promising, with rates of discontinuation due to adverse events lower or slightly higher than that observed for placebo. Although overall akathisia was more commonly observed with brexpiprazole than with placebo, the absolute risk increase attributable to brexpiprazole appears small. Short-term weight gain appears modest; however, outliers with an increase of ≥ 7% of body weight were evident in open-label long-term safety studies.

Topics: Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Receptors, Dopamine D2; Schizophrenia; Thiophenes

Topics: Animals; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin Agents; Thiophenes

Patient-reported outcomes can capture domains that are meaningful to patients, such as life engagement in major depressive disorder (MDD), which reflects life fulfillment, well-being, and participation in valued and meaningful activities. This analysis investigated the effects of brexpiprazole adjunct to antidepressant treatment (ADT) on patient life engagement over the short and long term, using the 10-item Inventory of Depressive Symptomatology Self-Report (IDS-SR. Short-term data were pooled from three 6-week, randomized, double-blind studies of ADT + brexpiprazole 2-3 mg/day versus ADT + placebo in adult outpatients with MDD (DSM-IV-TR criteria) and inadequate response to ADTs. Long-term data were from a 26-52-week, open-label extension study of ADT + brexpiprazole 0.5-3 mg/day.. Over 6 weeks, ADT + brexpiprazole (n = 579) showed greater improvement in IDS-SR. Beyond its efficacy on depressive symptoms, adjunctive brexpiprazole may improve patient life engagement, thereby helping patients with MDD to achieve personally meaningful functional outcomes.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Humans; Self Report; Treatment Outcome

Major depressive disorder (MDD) is a clinically heterogenous condition and its treatment should be individualized according to the presence of particular symptom clusters. The aim of this pooled analysis was to investigate the effects of adjunctive brexpiprazole on different symptom clusters in MDD.. Data were included from four similarly designed, short-term, randomized, double-blind, placebo-controlled studies of adjunctive brexpiprazole in adults with MDD and inadequate response to 2-4 antidepressant treatments (ADTs), including 1 administered by investigators. Mean changes from baseline and Cohen's d effect sizes (ES) versus placebo were determined for the following Montgomery-Åsberg Depression Rating Scale symptom clusters: core, anhedonia, dysphoria, retardation, vegetative, loss of interest, and lassitude.. Over 6 weeks, ADT + brexpiprazole 2 mg (n = 486) showed greater improvement than ADT + placebo (n = 585) for all symptom clusters: core (ES = 0.36; p < 0.0001), anhedonia (ES = 0.43; p < 0.0001), dysphoria (ES = 0.27; p < 0.0001), retardation (ES = 0.32; p < 0.0001), vegetative (ES = 0.29; p < 0.0001), loss of interest (ES = 0.30; p < 0.0001), and lassitude (ES = 0.33; p < 0.0001). Improvements of similar magnitude were observed for ADT + brexpiprazole 2-3 mg (n = 770) versus ADT + placebo (n = 788) (ES = 0.24-0.38; all clusters p < 0.0001). In most cases, improvement over ADT + placebo was observed from Week 1 onwards.. Post hoc analysis with no adjunctive active comparator.. Patients receiving adjunctive brexpiprazole versus adjunctive placebo showed improvements across a range of MDD symptom clusters. Improvements appeared early (generally from Week 1) and were maintained over 6 weeks. These data indicate that adjunctive brexpiprazole may benefit multiple subtypes of patient with MDD and inadequate response to ADTs.

Topics: Adult; Anhedonia; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Fatigue; Humans; Quinolones; Syndrome; Thiophenes; Treatment Outcome

To analyze the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with major depressive disorder (MDD) based on pooled data from 4 short-term studies and 1 long-term extension study.. The short-term studies (June 2011 to November 2016) were randomized, double-blind, placebo-controlled studies in outpatients with MDD (DSM-IV-TR criteria) and inadequate response to 1-3 prior antidepressant treatments (ADTs) plus 1 prospective ADT. Patients were randomized to adjunctive brexpiprazole (fixed or flexible doses in the range of 1-3 mg/d; n = 1,032) or placebo (n = 819) for 6 weeks. The long-term study (October 2011 to May 2017) was a 52-week (amended to 26 weeks), open-label, uncontrolled study of adjunctive brexpiprazole 0.5-3 mg/d (flexible dose; n = 2,938). Mean changes from baseline and categorical shifts in fasting metabolic parameters (cholesterol, triglycerides, and glucose) and body weight were analyzed.. Mean changes from baseline in metabolic parameters were small after 6 weeks (all < 2 mg/dL) and 52 weeks (all < 4 mg/dL, except triglycerides, 15.83 mg/dL) of treatment. In most cases, the incidence of unfavorable shifts in metabolic parameters was lower than the incidence of favorable shifts. Mean body weight increase at last visit in the short-term studies was 1.5 kg with ADT + brexpiprazole and 0.3 kg with ADT + placebo. During long-term treatment, mean body weight increased by 3.8 kg over 58 weeks.. Adjunctive brexpiprazole was associated with small changes in metabolic parameters and moderate weight gain during short- and long-term treatment.. ClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT01360866.

Topics: Adult; Antidepressive Agents; Blood Glucose; Body Weight; Cholesterol; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Quinolones; Thiophenes; Triglycerides

To 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.. The 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.. The 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.. Adjunctive 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.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Quinolones; Serotonin Agents; Thiophenes; Young Adult

Brexpiprazole is currently approved in the United States for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder. In Canada, it is approved for the treatment of schizophrenia. This study evaluated the pharmacokinetics (PK) and safety of brexpiprazole in Japanese patients with schizophrenia. This phase 1 study comprised a 14-day multiple-dose administration of brexpiprazole 1, 4, and 6 mg/day (n = 7, 8, and 6, respectively). Plasma concentrations and PK parameters and the influence of CYP2D6 polymorphisms (intermediate metabolizers [IMs] and extensive metabolizers [EMs]) on PK were evaluated. Adverse events (AEs) were recorded. The C

Topics: Antipsychotic Agents; Area Under Curve; Asian People; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Quinolones; Schizophrenia; Thiophenes

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.. 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 (MADRS. At Week 6, adjunctive brexpiprazole showed a greater effect than adjunctive placebo on the MADRS. This was a post hoc analysis of studies that were not designed for this purpose. Correction for multiple comparisons was not performed.. 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.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Serotonin Agents; Thiophenes; Treatment Outcome

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.

Topics: Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Delivery Systems; Humans; Patient Selection; Quinolones; Serotonin Agents; Thiophenes; Treatment Outcome

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.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Headache; Humans; Male; Middle Aged; Prospective Studies; Psychomotor Agitation; Quetiapine Fumarate; Quinolones; Thiophenes; Treatment Outcome

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.. 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.. 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.. 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.. ClinicalTrials.gov identifier: NCT02196506; EudraCT number: 2014-000062-22​​​.

Topics: Adult; Antidepressive Agents; Anxiety; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Psychiatric Status Rating Scales; Quinolones; Thiophenes; Treatment Outcome; Young Adult

Approximately 50% of patients with major depressive disorder do not respond adequately to their antidepressant treatment, underscoring the need for more effective treatment options. The objective of this study was to investigate the effect of adjunctive brexpiprazole on depressive symptoms in patients with major depressive disorder who were not responding to adjunctive or combination therapy of their current antidepressant treatments with several different classes of agents (NCT02012218).. In this 6-week, open-label, phase 3b study, patients with major depressive disorder who had an inadequate response to ≥1 adjunctive or combination therapy, in addition to history of ≥1 failure to monotherapy antidepressant treatment, were switched to adjunctive brexpiprazole. Efficacy was assessed by change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score. Patient functioning was assessed using the Sheehan Disability Scale and the Cognitive and Physical Functioning Questionnaire. Safety and tolerability were also assessed.. A total of 51/61 (83.6%) patients completed 6 weeks of treatment with adjunctive brexpiprazole. Improvements in depressive symptoms were observed (least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score, -17.3 [P < .0001]) as well as improvements in general and cognitive functioning (mean changes from baseline to week 6: Sheehan Disability Scale, -3.1 [P < .0001]; Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire, -9.2 [P < .0001]). The most common adverse event was fatigue (14.8%); akathisia was reported by 8.2% of patients.. In patients with major depressive disorder who had switched to open-label adjunctive brexpiprazole following inadequate response to previous adjunctive or combination therapy, improvements were observed in depressive symptoms, general functioning, cognitive function, and energy/alertness.

Topics: Antidepressive Agents; Aripiprazole; Bupropion; Central Nervous System Stimulants; Cognition; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Female; Humans; Impulsive Behavior; Male; Middle Aged; Psychiatric Status Rating Scales; Quetiapine Fumarate; Quinolones; Sleep; Thiophenes; Treatment Outcome

Anxiety symptoms are prevalent in major depressive disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). The efficacy and safety of brexpiprazole - a serotonin-dopamine activity modulator - as adjunctive treatment in patients with MDD was recently evaluated in two phase 3 studies. We here present a post-hoc analysis of the efficacy of adjunctive brexpiprazole in patients with MDD and symptoms of anxious distress, defined using proxies for DSM-5 criteria.. Eligible patients were randomized to 2mg brexpiprazole+ADT or placebo+ADT (NCT01360645); or 1mg brexpiprazole+ADT, 3mg brexpiprazole+ADT, or placebo+ADT (NCT01360632), respectively. Patients were defined as having anxious distress if they had ≥2 of the symptoms 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). Primary efficacy endpoint was change in MADRS total score from baseline to Week 6.. 55% of the patients had anxious distress at baseline. Adjunctive brexpiprazole showed greater improvement than adjunctive placebo on the primary efficacy endpoint in both patients with (least square mean difference to placebo+ADT: 2mg+ADT: -2.95, p=0.0023; 3mg+ADT: -2.81, p=0.0027); and without anxious distress (1mg+ADT: -2.37, p=0.0093; 3mg+ADT: -2.23, p=0.0131). Brexpiprazole in patients with anxious distress was not associated with an increased incidence of activating adverse events (e.g., akathisia).. Adjunctive brexpiprazole 2-3mg may be efficacious in reducing depressive symptoms and is well tolerated, in patients with MDD and anxious distress.

Topics: Adult; Antidepressive Agents; Anxiety Disorders; Depression; Depressive Disorder, Major; Dopamine Agonists; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychomotor Agitation; Quinolones; Serotonin Agents; Thiophenes; Treatment Outcome

Major depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study.. Young patients (18-35 years) with MDD (inadequate responders to 1-3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1-3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks.. Depressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, -18.1 [p<0.0001]). Reductions from baseline in Sheehan Disability Scale Score (SDS; LS mean change -11.2 [p<0.0001]) and Work Limitations Questionnaire (WLQ; p<0.0001) indicated improvements in the effects of patients' symptoms on functioning (work/school, social life, and home responsibilities). Changes from baseline in additional measures supported improvements in patient functioning and depression symptoms. The most common adverse events were headache (21.3%), weight increase (17.0%), and somnolence (17.0%); reported rates of akathisia were low (6.4%). Clinically relevant increases in weight (≥7%) occurred in 10.5% of patients.. Open-label design; absence of comparator.. Brexpiprazole may represent an effective therapy for adjunctive treatment strategy of young adults with MDD who are working or studying. The observed improvements in work/school functioning in patients with MDD, whose depression was treated with ADT+brexpiprazole, suggests potential to reduce socioeconomic burden.

Topics: Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Drug Administration Schedule; Drug Therapy, Combination; Employment; Female; Follow-Up Studies; Humans; Male; Psychiatric Status Rating Scales; Quinolones; Students; Thiophenes; Treatment Outcome; Young Adult

To evaluate the effects of adjunctive brexpiprazole on symptoms of irritability in patients with major depressive disorder (MDD).. Patients diagnosed with MDD according to DSM-IV-TR criteria who had inadequate response to antidepressant treatment continued treatment with their current antidepressant for 2 weeks. Patients still having inadequate response, and with irritability, received 6 weeks of open-label treatment with their current antidepressant at the same dose and adjunctive brexpiprazole (target dose: 3 mg/d). Brexpiprazole was discontinued at week 6, and the patients continued with their antidepressant until week 10. Changes from baseline to week 6 and week 6 to week 10 were analyzed.. This study was conducted between October 7, 2013, and July 30, 2014. Fifty-four patients were treated with adjunctive brexpiprazole. At week 6, clinically relevant improvements were observed in Sheehan Irritability Scale total (-21.1) and item 1 (irritable mood) (-3.5) scores, Kellner Symptom Questionnaire total (-24.4) and anger-hostility subscale (-7.7) scores, and 30-item Inventory of Depressive Symptomatology, clinician version (IDS-C₃₀), item 6 (irritable mood) score (-1.2). More (15 patients) stopped than developed (5 patients) anger attacks during treatment, as measured by the Anger Attacks Questionnaire. The Clinical Global Impressions-Severity of Illness score improved (-1.4), as did the depressive symptoms (IDS-C₃₀ total score, -17.8; Kellner Symptom Questionnaire depression subscale score, -7.7; and Montgomery-Asberg Depression Rating Scale total score, -14.2). Irritability symptoms worsened after brexpiprazole discontinuation, assessed at week 10. Adjunctive brexpiprazole was well tolerated.. Adjunctive treatment with brexpiprazole may represent a strategy for patients with MDD and inadequate response to antidepressant treatment who have symptoms of irritability.. ClinicalTrials.gov identifier: NCT01942785.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Irritable Mood; Male; Middle Aged; Outcome Assessment, Health Care; Quinolones; Serotonin Agents; Thiophenes

Major depressive disorder (MDD) with concurrent anxiety symptoms may signal a difficult-to-treat patient. Brexpiprazole is a serotonin-dopamine activity modulator: a partial agonist at 5-HT. Patients with MDD, Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 20, and inadequate response to current ADT received open-label brexpiprazole 1-3 mg day. Of 37 participants enrolled, 32 (86.5%) completed the study. Baseline mean (. These open-label results support the anxiolytic effects of adjunctive brexpiprazole in the treatment of patients with MDD.

Topics: Anxiety; Depressive Disorder, Major; Dopamine Agonists; Drug Therapy, Combination; Female; Humans; Least-Squares Analysis; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotropic Drugs; Quinolones; Serotonin Agents; Thiophenes; Treatment Outcome

Brexpiprazole is a serotonin-dopamine activity modulator. We evaluated the effects of adjunctive treatment with brexpiprazole on sleep disturbances in patients with DSM-IV-TR major depressive disorder (MDD) and inadequate response to antidepressant treatment.. This study was conducted between September 27, 2013, and August 19, 2014. Patients with inadequate response to antidepressant treatment and sleep disturbances continued treatment with their current antidepressant for 2 weeks. Patients still having inadequate response and sleep efficiency less than 85% measured by baseline polysomnography (PSG) received 8-week open-label treatment with their current antidepressant treatment and adjunctive brexpiprazole (target dose: 3 mg/d). Assessments included PSG recordings and scales of insomnia severity, depressive symptoms, and daytime alertness and functioning. Changes from baseline to week 8 were analyzed.. Forty-four patients were treated. Improvements (P < .05) measured by PSG and Consensus Sleep Diary for Morning, respectively, were observed in sleep efficiency (10.4 and 15.4 percentage points), total sleep time (49.0 and 84.5 min), sleep onset latency (-19.7 and -42.6 min), wake-time after sleep onset (-26.4 and -48.0 min), and latency to persistent sleep (-24.9 min, PSG only). Insomnia Severity Index (ISI) total score was improved (-9.2), as was daytime sleepiness (-2.1) as measured by the Epworth Sleepiness Scale (ESS) total score and morning sleepiness (-9.2) as measured by the Bond-Lader Visual Analog Scale (all P < .05). Reaction time was slightly decreased (-0.2 sec-1) by treatment (P < .05). Depressive symptoms improved (Montgomery-Asberg Depression Rating Scale [MADRS]: -16.0 and Clinical Global Impressions-Severity [CGI-S]: -1.8), as did functioning (-8.4) assessed by the Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire (all P < .05). Improvements in depressive symptoms were dependent on sleep (as assessed by ISI) (P < .0001) and improvements in daytime alertness (as assessed by ESS) were dependent on improvements in ISI (P = .009). No new safety concerns were observed compared to previous brexpiprazole studies.. In patients with inadequate response to antidepressant treatment and sleep disturbances treated with adjunctive brexpiprazole, physiologic measures of sleep and daytime alertness were improved.. ClinicalTrials.gov identifier: NCT01942733.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Dopamine Agonists; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Serotonin Agents; Sleep Wake Disorders; Thiophenes; Treatment Outcome

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.. 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.. 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%).. Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs.. ClinicalTrials.gov identifier: NCT01360645.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Thiophenes; Treatment Outcome; Young Adult

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

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Thiophenes; Treatment Outcome; Young Adult

Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect.. Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data.. Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411).. Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Escitalopram; Fluoxetine; Mice; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Swimming

Brexpiprazole (BPZ), which is approved for the treatment of schizophrenia and major depressive disorder, has the potential to meet diverse clinical needs. This study aimed to develop a long-acting injectable (LAI) formulation of BPZ that could provide sustained therapeutic benefits. A library of BPZ prodrugs was screened through esterification, and BPZ laurate (BPZL) was identified as an optimal candidate. To achieve stable aqueous suspensions, a pressure- and nozzle size-controlled microfluidization homogenizer was utilized. The pharmacokinetics (PK) profiles, considering dose and particle size modulation, were investigated following a single intramuscular injection in beagles and rats. BPZL treatment resulted in sustained plasma concentrations above the median effective concentration (EC

Topics: Animals; Antipsychotic Agents; Delayed-Action Preparations; Depressive Disorder, Major; Dogs; Inflammation; Injections, Intramuscular; Rats; Suspensions

Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent 'third'-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Drosophila melanogaster; Electron Transport; Mice

Sleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated efficacy as an adjunct to antidepressant treatment for major depressive disorder (MDD) in adults, with preliminary evidence suggesting greater effectiveness in subgroups of depressed patients with sleep disturbances. This clinical trial aims to evaluate the relationships between changes in sleep-wake and circadian parameters and changes in depressive symptoms following adjunctive brexpiprazole treatment in young adults with MDD and sleep-wake disturbance.. This study is designed as a 16 week (8 weeks active treatment, 8 weeks follow-up) mechanistic, open-label, single-arm, phase IV clinical trial and aims to recruit 50 young people aged 18-30 with MDD and sleep-wake cycle disturbance through an early intervention youth mental health clinic in Sydney, Australia. At baseline, participants will undergo multidimensional outcome assessment and subsequently receive 8 weeks of open-label treatment with brexpiprazole as adjunctive to their stable psychotropic medication. Following 4 weeks of treatment, clinical and self-report measures will be repeated. Ambulatory sleep-wake monitoring will be conducted continuously for the duration of treatment. After 8 weeks of treatment, all multidimensional outcome assessments will be repeated. Follow-up visits will be conducted 4 and 8 weeks after trial completion (including sleep-wake, clinical and self-report assessments). Circadian rhythm biomarkers including salivary melatonin, cortisol and core body temperature will be collected during an in-lab assessment. Additionally, metabolic, inflammatory and genetic risk markers will be collected at baseline and after 8 weeks of treatment.. This trial protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (X19-0417 and 2019/ETH12986, Protocol Version 1-3, dated 25 February 2021). The results of this study, in deidentified form, will be disseminated through publication in peer-reviewed journals, scholarly book chapters, presentation at conferences and publication in conference proceedings.. ACTRN12619001456145.

Topics: Adolescent; Depressive Disorder, Major; Humans; Quinolones; Sleep; Sleep Wake Disorders; Thiophenes; Young Adult

Circadian rhythm disturbances have been reported in patients with major depressive disorder (MDD). Among these is an increased phase angle between peak cortisol concentration and dim-light melatonin onset (DLMO). The aim of this study was to evaluate changes in chronobiologic parameters of sleep in patients with MDD receiving adjunctive brexpiprazole.. This was an interventional, multicenter, open-label, flexible-dose, exploratory study in patients with MDD and inadequate response to antidepressant treatment who were experiencing sleep disturbances. Patients received adjunctive brexpiprazole 2-3 mg/day for 8 weeks. Outcome measures included cortisol and melatonin levels, used to calculate phase angle, and the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN).. The mean (standard error) phase angle between peak cortisol and DLMO increased by 108 (61) minutes from baseline to Week 8 (n = 9). BRIAN Total score changed (improved) by -14.6 (4.6) points from baseline to Week 8 (n = 9). Change in phase angle and BRIAN Total score showed a moderate-to-high correlation (Pearson coefficient: 0.68; 95% confidence limits: 0.04, 0.93; p = 0.040).. This study is limited by its small sample size, and its single-arm, open-label design.. The findings provide a preliminary indication that the phase angle between peak cortisol and DLMO is of interest as a potential biomarker for depression and therapeutic response. Adjunctive brexpiprazole may represent a strategy for correcting circadian dysfunction in patients with MDD and inadequate response to antidepressant treatment. ClinicalTrials.gov identifier: NCT01942733.

Topics: Circadian Rhythm; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Melatonin; Quinolones; Sleep; Thiophenes; Treatment Outcome

A clinical trial often has primary and secondary endpoints and comparisons of high and low doses of a study drug to a control. Multiplicity is not only caused by the multiple comparisons of study drugs versus the control, but also from the hierarchical structure of the hypotheses. Closed test procedures were proposed as general methods to address multiplicity. Two commonly used tests for intersection hypotheses in closed test procedures are the Simes test and the average method. When the treatment effect of a less efficacious dose is not much smaller than the treatment effect of a more efficacious dose for a specific endpoint, the average method has better power than the Simes test for the comparison of two doses versus control. Accordingly, for inferences for primary and secondary endpoints, the matched parallel gatekeeping procedure based on the Simes test for testing intersection hypotheses is extended here to allow the average method for such testing. This procedure is further extended to clinical trials with more than two endpoints as well as to clinical trials with more than two active doses and a control.

Topics: Antidepressive Agents; Clinical Trials, Phase III as Topic; Computer Simulation; Data Interpretation, Statistical; Depressive Disorder, Major; Dose-Response Relationship, Drug; Endpoint Determination; Humans; Models, Statistical; Quinolones; Randomized Controlled Trials as Topic; Research Design; Thiophenes; Treatment Outcome

The purpose of this study was to compare medication adherence, health care utilization, and cost among patients receiving adjunctive treatment for major depressive disorder (MDD) with brexpiprazole, quetiapine, or lurasidone.. Using Truven Health MarketScan® Commercial, Medicaid, and Medicare Supplemental Databases, we identified adults with MDD initiating adjunctive treatment with brexpiprazole, quetiapine, or lurasidone (index atypical antipsychotic [AAP]). We compared medication adherence and persistence measured by proportion of days covered (PDC) and treatment duration of index AAP, all-cause and psychiatric hospital care (hospitalization or emergency department visit), and medical costs during 6-month follow-up. Models performed included logistic regression for hospital care, linear regression for PDC and cost, and Cox proportional hazards regression for time to discontinuation, adjusting for demographic, clinical, and utilization differences during the 6 months before index AAP.. The total sample included 778 brexpiprazole, 626 lurasidone, and 3458 quetiapine therapy initiators. Adjusting for baseline differences, the risk of discontinuation of index AAP was statistically significantly higher for quetiapine than for brexpiprazole (hazard ratio [HR] = 1.13; 95% CI, 1.02-1.25; P = 0.023) and did not differ between lurasidone and brexipiprazole (HR = 1.14; 95% CI, 1.00-1.29; P = 0.054). The adjusted rate of all-cause hospitalization or emergency department visit in the postindex period was lowest for brexpiprazole at 27.4% (95% CI, 24.0%-31.0%), compared with 31.1% (95% CI, 27.3%-35.2%) for lurasidone and 35.3% (95% CI, 33.5%-37.1%) for quetiapine (P< 0.001 for all comparisons). Quetiapine users had increased all-cause costs compared with brexpiprazole users (estimate = $2309; 95% CI, $31-$4587; P = 0.047); all-cause medical costs did not differ between lurasidone and brexpiprazole (estimate = $913; 95% CI, $-2033 -$3859; P = 0.543). Adjusted psychiatric hospital care, psychiatric costs, and PDC did not differ significantly among the groups.. In patients with MDD and a variety of insurance types, brexpiprazole use was associated with statistically significantly lower risks of discontinuation, risk of hospital care (hospitalization and ED visits), and all-cause medical costs compared with adjunctive quetiapine. Differences between brexpiprazole and lurasidone were not statistically significant. These findings suggest that drug choice is associated with subsequent health care utilization and costs.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Depressive Disorder, Major; Emergency Service, Hospital; Female; Health Care Costs; Hospitalization; Humans; Lurasidone Hydrochloride; Male; Medicaid; Medicare; Medication Adherence; Middle Aged; Patient Acceptance of Health Care; Quetiapine Fumarate; Quinolones; Thiophenes; United States; Young Adult

Past studies suggest that brexpiprazole is an effective adjunctive treatment for major depressive disorder and schizophrenia; however, no studies have examined brexpiprazole for bipolar depression. In this study, we examined the effects of brexpiprazole on mood, cognition, and quality of life in outpatients with bipolar depression.. Twenty-one adults with bipolar disorder (most recent episode depressed) and scoring at least a 25 on the Montgomery-Åsberg Depression Rating Scale (MADRS) were recruited. Brexpiprazole was titrated up to 4 mg/day over the 8-week period. Depressive symptoms were measured using MADRS and Inventory of Depressive Symptomatology Self-report (IDS-SR. MADRS and IDS-SR. A limitation to this study is the open-label design.. To our knowledge, this is the first study to examine the effects of brexpiprazole on bipolar depression. We found a significant reduction in depressive symptoms and an increase in quality of life.

Topics: Adult; Antidepressive Agents; Bipolar Disorder; Cognition; Depressive Disorder, Major; Female; Humans; Irritable Mood; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Quality of Life; Quinolones; Thiophenes; Treatment Outcome; Young Adult

Although the sedative and extrapyramidal side effects associated with first-generation antipsychotics are well known, some second-generation antipsychotics are also associated with substantial sedation and activation effects. In this Academic Highlights article, 4 experts on depression from the fields of psychiatry and primary care take a closer look at activation and sedation effects of atypical antipsychotics in patients with MDD. They examine the likelihood of each agent to cause these effects; the impact of these effects on patient functioning, quality of life, and treatment adherence; and the question of whether leveraging activation and sedation to address acute symptoms is ever advisable.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Anxiety Disorders; Aripiprazole; Arousal; Comorbidity; Delayed-Action Preparations; Depressive Disorder, Major; Drug Approval; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Practice Patterns, Physicians'; Quality of Life; Quetiapine Fumarate; Quinolones; Sleep Initiation and Maintenance Disorders; Thiophenes

We sought to characterize the clinical experience of outpatients treated with brexpiprazole after achieving suboptimal outcomes with aripiprazole or bupropion as determined by the treating psychiatric provider.. Case series; inefficacy, intolerability, or other unsatisfactory outcome to previous trial with aripiprazole or bupropion.. The majority of individuals in our sample exhibited tolerability of brexpiprazole. In addition, reduction in mean PHQ-9 scores was observed with brexpiprazole treatment.. The results of our preliminary analysis suggest that a subpopulation of adults who have insufficient outcomes on aripiprazole or bupropion due to intolerability, inefficacy or other unsatisfactory outcome may benefit by switching to brexpiprazole treatment. Larger randomized controlled trials are needed, as well as sophisticated network analysis to further understand efficacy and tolerability differences between atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Bupropion; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; New York; Psychiatric Status Rating Scales; Quinolones; Retrospective Studies; Thiophenes; Treatment Outcome; Young Adult

The study compared all-cause and major depressive disorder (MDD)-related healthcare resource use (HRU) and costs in patients with MDD treated with atypical antipsychotic (AAP) adjunctive therapy early or later in treatment.. Adults with MDD and antidepressant treatment (ADT) who newly initiated adjunctive aripiprazole, brexpiprazole, lurasidone, or quetiapine between October 1, 2014 and September 30, 2015 were identified in the IQVIA Real-World Data Adjudicated Claims database; the index date was the date of the first AAP claim. Patients were stratified into three cohorts: AAP initiated in the first year (Y1); in the second year (Y2); and more than 2 years (Y3) of first ADT use. Within each cohort, HRU and costs were compared between the 12 months before and after the index date. Pre-post changes in HRU and costs were then compared between cohorts.. Five hundred and six (36.7%) patients were categorized as Y1; 252 (18.3%) as Y2; and 622 (45.1%) as Y3. AAP use was associated with significantly decreased rates of all-cause and MDD-related hospitalization and emergency department visits, and increased rates of pharmacy fills and physician office visits; and the magnitude of changes was largest in cohort Y1. Cohort Y1 had the largest reductions in mean (±SD) all-cause medical costs per patient (-$10,496 ± $85,022, p = .015) compared to Y2 (-$2,474 ± $85,022, p = .572) and Y3 (-$472 ± $31,334, p = .823), mainly due to the reduction in hospitalization. After adjusting for differences in baseline characteristics, the largest reductions in hospitalization and medical costs were observed in cohort Y1. Similar increases in all-cause pharmacy costs were seen in all cohorts. A similar trend in costs was observed in MDD-related healthcare services.. AAP treatment was associated with reductions in all-cause and MDD-related medical costs, primarily in decreased hospitalization. The reductions were largest among patients who initiated treatment in the first year.

Topics: Adult; Age Factors; Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Comorbidity; Depressive Disorder, Major; Drug Administration Schedule; Drug Therapy, Combination; Female; Health Expenditures; Health Resources; Health Services; Humans; Insurance Claim Review; Lurasidone Hydrochloride; Male; Middle Aged; Models, Econometric; Quetiapine Fumarate; Quinolones; Residence Characteristics; Retrospective Studies; Sex Factors; Socioeconomic Factors; Thiophenes; Time-to-Treatment

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.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Female; Humans; Longitudinal Studies; Male; Meta-Analysis as Topic; Middle Aged; Quinolones; Randomized Controlled Trials as Topic; Schizophrenia; Thiophenes; Weight Gain

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).. 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-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness (CGI-S), and Social Adaptation Self-Evaluation Scale (SASS).. 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).. 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.

Topics: Aged; Aged, 80 and over; Akathisia, Drug-Induced; Antidepressive Agents; Chemotherapy, Adjuvant; Depressive Disorder, Major; Europe; Fatigue; Female; Humans; Male; Quality of Life; Quinolones; Social Participation; Thiophenes; United States

Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression.. The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission.. The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine.. A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex.. These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.

Topics: Administration, Oral; Amino Acids; Animals; Antidepressive Agents; Brain; Depressive Disorder, Major; Fluoxetine; Ketamine; Male; Mice; Mice, Inbred C57BL; Quinolones; Receptors, N-Methyl-D-Aspartate; Thiophenes

Major depressive disorder (MDD) is a debilitating psychiatric illness with a high cost burden. This analysis evaluates the cost-effectiveness of adjunctive brexpiprazole versus comparator branded adjunctive treatment for MDD and background antidepressant therapy (ADT) alone from a US payer perspective.. An economic model was developed to assess the cost-effectiveness of brexpiprazole versus comparator adjunctive treatment and ADT alone on total direct medical costs using a 6-week cycle time frame for a total of 48 weeks, with treatment response and remission as primary outcomes. The model consisted of 3 parts, 1 to represent the acute treatment phase and 2 to represent the maintenance stage.. In the base-case analysis, brexpiprazole as reference treatment resulted in cost per additional responder ranging from $19,442-$48,745 and cost per additional remitter ranging from $27,196-$71,839 versus comparator treatments over 48 weeks. Sensitivity analyses showed treatment with brexpiprazole was more costly, but more clinically effective in all probabilistic simulations.. This representation of disease natural history over 48 weeks may not account for all possible health states. Resource utilization on treatment was estimated using the resource use data from previous trials, and may overestimate medical costs compared to the real-world setting. Treatment comparators were limited to branded therapies, and head-to-head studies were not available to obtain data inputs.. Compared to other branded adjunctive therapies, brexpiprazole increases response and remission at 6 weeks; medical care cost savings were observed with the use of brexpiprazole. These findings may assist clinicians and formulary decision makers when selecting treatment for MDD.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Cost-Benefit Analysis; Depressive Disorder, Major; Disorders of Excessive Somnolence; Drug Costs; Drug Therapy, Combination; Fatigue; Female; Health Care Costs; Humans; Male; Middle Aged; Models, Economic; Olanzapine; Patient Selection; Quetiapine Fumarate; Quinolones; Serotonin Agents; Thiophenes; Weight Gain; Young Adult

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Irritable Mood; Middle Aged; Quinolones; Thiophenes

Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here.

Topics: Adrenergic alpha-1 Receptor Antagonists; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Thiophenes

The lifetime prevalence of major depressive episodes in the United States is nearly 17%. Clinical trials and clinical effectiveness studies have demonstrated that many patients will fail to achieve remission using traditional monotherapy, contributing to significant morbidity and suffering. Because of this, augmentation strategies have been proposed to improve both treatment response and remission. Areas covered: Brexpiprazole is a second generation antipsychotic (SGA) approved by the US FDA in 2015 as an add-on treatment to an antidepressant medication for the treatment of adults with MDD, based on the results of two large-scale, randomized, placebo-controlled trials. It is thought to exert its antidepressant effect by a partial agonism of both the dopamine D2 and serotonin 5HT1A receptors. In addition, it also has potent antagonistic activity at 5HT2A, α1B and α2 C receptors, which may also contribute to monoamine transmission regulation. Expert Opinion: Overall, the tolerability of brexpiprazole is promising with relatively low rates of side effects and discontinuation rates, thus establishing it as a new option for the treatment of depression.

Topics: Antidepressive Agents; Antipsychotic Agents; Chemotherapy, Adjuvant; Depressive Disorder, Major; Dopamine; Humans; Quinolones; Randomized Controlled Trials as Topic; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT1; Serotonin 5-HT1 Receptor Agonists; Thiophenes; Treatment Outcome

Addition of low doses of the atypical antipsychotic drug brexpiprazole with selective serotonin reuptake inhibitors (SSRIs) could promote antidepressant effect in patients with major depressive disorder although the precise mechanisms underlying the action of the combination are unknown. Combination of low dose of brexpiprazole (0.1 mg/kg) and SSRI fluoxetine (10 mg/kg) could promote a rapid antidepressant effect in social defeat stress model although brexpiprazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling and dendritic spine density in the prefrontal cortex, hippocampus, and nucleus accumbens in the susceptible mice after social defeat stress. Interestingly, TrkB antagonist ANA-12 significantly blocked beneficial effects of combination of brexpiprazole and fluoxetine on depression-like phenotype. These results suggest that BDNF-TrkB signaling plays a role in the rapid antidepressant action of the combination of brexpiprazole and fluoxetine.

Topics: Animals; Antidepressive Agents; Azepines; Behavior, Animal; Benzamides; Brain-Derived Neurotrophic Factor; Dendritic Spines; Depressive Disorder, Major; Disease Models, Animal; Drug Therapy, Combination; Fluoxetine; Male; Mice; Mice, Inbred C57BL; Phenotype; Quinolones; Receptor, trkB; Selective Serotonin Reuptake Inhibitors; Signal Transduction; Thiophenes

Brexpiprazole (also known as OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole. This drug is currently under review by the U.S. Food and Drug Administration as a monotherapy for schizophrenia and an adjunct to antidepressant medication for major depressive disorder. Additional clinical trials include studies of brexpiprazole in attention-deficit/hyperactivity disorder and posttraumatic stress disorder, and for agitation associated with dementia of the Alzheimer's type. Brexpiprazole is an example that illustrates how pharmacological drug diversity may be translated to multipurpose uses.

Topics: Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Depressive Disorder, Major; Humans; Psychomotor Agitation; Quinolones; Schizophrenia; Stress Disorders, Post-Traumatic; Thiophenes

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Depressive Disorder, Major; Dopamine Agonists; Drug Administration Schedule; Drug Interactions; Humans; Piperazines; Quinolones; Schizophrenia; Thiophenes