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AbstractObjectiveMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYPatients with schizophrenia value improved life engagement, a term that describes positive health aspects across emotional, physical, social, and cognitive domains. This post hoc analysis of clinical trial data aimed to investigate the effect of brexpiprazole on patient life engagement in schizophrenia over the short and long term.Data were pooled from three 6-week, randomized, double-blind, placebo-controlled clinical trials (ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380; N = 1385) and two 52-week, open-label extension studies (NCT01397786, NCT01810783; N = 408) of brexpiprazole in adults with schizophrenia. Patient life engagement was measured using a subset of 14 Positive and Negative Syndrome Scale items (score range: 14 [best] to 98 [worst]) that has previously demonstrated content validity. Mean score changes and response rates (based on minimal clinically important difference estimates of ≥5 and ≥10 points) were calculated.Greater improvement in patient life engagement from baseline to Week 6 was observed for brexpiprazole 2–4 mg/day (least squares mean [standard error] change: −8.3 [0.3]; n = 868) versus placebo (−5.7 [0.4]; n = 517), with a least squares mean difference of −2.58 (95% confidence interval: −3.57 to −1.58; p < 0.001; Cohen’s d effect size: 0.28). These improvements were maintained over 58 weeks on brexpiprazole 1–4 mg/day (n = 399). At Week 6, response rates among patients treated with brexpiprazole versus placebo were 71.6% versus 58.0% (≥5-point improvement; p < 0.001) and 43.5% versus 32.8% (≥10-point improvement; p < 0.001). At Week 58 (n = 179), response rates among patients treated with brexpiprazole were 90.5% (≥5-point improvement) and 78.2% (≥10-point improvement).Beyond its efficacy on psychotic symptoms, brexpiprazole has the potential to improve patient life engagement – an important patient-centered outcome in schizophrenia.Schizophrenia is a serious mental disorder in which people may hear, see, or believe things that do not exist. Most people with schizophrenia hope to become more engaged with life, as well as to improve their schizophrenia symptoms. Being engaged with life means feeling happy and hopeful, having energy and motivation, being interested and involved in activities, and being alert and thinking clearly. This study investigated if brexpiprazole, a medicine for schizophrenia and some other medical conditions, can help to improve patients’ engagement with life. The researchers looked at data from over a thousand people with schizophrenia across five previously completed clinical trials. To measure ‘patient life engagement’, the researchers used data from a questionnaire filled in by doctors during their meetings with the patients. The results showed that, on average, people taking brexpiprazole (rather than a ‘placebo’ tablet) became more engaged with life over the first 6 weeks of treatment. For some people who kept taking brexpiprazole, these improvements lasted for over a year. This means that brexpiprazole may help people with schizophrenia to become more engaged with life, as well as improving their schizophrenia symptoms. [ABSTRACT FROM AUTHOR]

Background: A 12-week randomized controlled trial demonstrated that brexpiprazole is efficacious for treating agitation in patients with dementia due to Alzheimer's disease. Objective: To assess the long-term safety and tolerability of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease. Methods: This 12-week, active-treatment (oral brexpiprazole 2 or 3 mg/day) extension trial ran from October 2018–September 2022 at 66 sites in Europe/US. Patients with agitation in dementia due to Alzheimer's disease in a care facility/community-based setting who completed the randomized trial were eligible (N = 259 enrolled/analyzed for safety; 88.4% completed). Stable Alzheimer's disease medications were permitted. The primary safety endpoint was the frequency and severity of treatment-emergent adverse events (TEAEs). Change in Cohen-Mansfield Agitation Inventory (CMAI) total score was an exploratory efficacy endpoint. Results: Mean (SD) age was 74.3 (7.6) years, 145 patients (56.0%) were female, and 248 (95.8%) were White. TEAEs were reported by 67 patients (25.9%), most commonly headache (3.5%) and fall (2.3%). Most TEAEs were mild or moderate in severity; 5 patients (1.9%) reported a severe TEAE, including 3 severe falls attributed to tripping, misjudging sitting, or dehydration. Twelve patients (4.6%) discontinued due to TEAEs. No patients died. Mean CMAI total score improved by 9.1 points over 12 weeks. Conclusions: Considering the randomized and extension trials together, brexpiprazole 2 or 3 mg was generally well tolerated for up to 24 weeks in elderly patients with agitation associated with dementia due to Alzheimer's disease. Patients showed continued improvement in agitation. ClinicalTrials.gov identifier: NCT03594123 (registration date: July 11, 2018). [ABSTRACT FROM AUTHOR]

Antipsychotics such as phenothiazines, pimozide, flupentixol and brexpiprazole have been shown to have good antitumor effects. Brexpiprazole, the successor to aripiprazole, has a better safety profile. Brexpiprazole promotes the death of tumor cells by inhibiting the proliferation of tumor stem cells, resolving the resistance of tumor cells to EGFR-TKIs, and promoting the sensitivity of tumor cells to chemotherapeutic agents, thus inhibiting the development of colorectal, lung, glioblastoma, pancreatic, and gastric cancers. This review focuses on the antitumor effects of antipsychotic drugs, especially the inhibitory effect of brexpiprazole on tumor cells, aiming to provide a theoretical basis for antipsychotic drugs in antitumor field. [ABSTRACT FROM AUTHOR]

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I2 = 19%) and at 2 mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I2 = 0%) over 12 weeks. Brexpiprazole at any dose and 2 mg also showed benefit in the Clinical Global Impression − Severity of illness (CGI-S) score as related to agitation over 12 weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I2 = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I2 = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I2 = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole. Prospero registry: CRD42023486694. [ABSTRACT FROM AUTHOR]

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence‐based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady‐state concentration)–response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure–response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease–drug–dropout models were developed using patient‐level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure–response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure–response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13‐17 years with schizophrenia. [ABSTRACT FROM AUTHOR]

Aim: Brexpiprazole is the first FDA‐approved treatment for agitation associated with dementia due to Alzheimer's disease. Agitation in Alzheimer's dementia (AAD) occurs in high prevalence and is a great burden for patients and caregivers. Efficacy, safety, and tolerability of brexpiprazole were demonstrated in the AAD clinical trials. To demonstrate the agitation‐ameliorating effect of brexpiprazole in animals, we evaluated brexpiprazole in two AAD mouse models. Methods: The resident–intruder test was conducted in 5‐ to 6‐month‐old Tg2576 mice, given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally 1 h before the test. Locomotor activity was measured in 6‐month‐old APPSL‐Tg mice given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally the evening before the start of locomotor measurement for 3 days. Results: In the resident–intruder test, Tg2576 mice showed significantly higher attack number and shorter latency to first attack compared to non‐Tg mice. In the Tg mice, brexpiprazole treatment (0.03 mg/kg) significantly delayed the latency to first attack and showed a trend toward a decrease in attack number. APPSL‐Tg mice (≧6 months old) showed significantly higher locomotion during dark period Phase II (Zeitgeber time [ZT] 16–20) and Phase III (ZT20‐24) compared to non‐Tg mice, correlating with the clinical observations of late afternoon agitation in Alzheimer's disease. Brexpiprazole treatment (0.01 and 0.03 mg/kg) significantly decreased hyperlocomotion during the Phase III in APPSL‐Tg mice. Conclusion: The suppression of attack behavior and the reduction of nocturnal hyperlocomotion in these Tg mice may be indicative of the therapeutic effect of brexpiprazole on AAD, as demonstrated in the clinical trials. [ABSTRACT FROM AUTHOR]

A novel antipsychotic medication named brexpiprazole (BRX) is currently employed for the treatment of schizophrenia and other psychotic disorders. Because BRX's molecular structure includes a benzothiophene ring, it natively fluoresces. To detect BRX with precision and speed, a flow injection-fluorometric method, which is both sensitive and selective, is recommended. The fluorescence detection was conducted at 364 nm following excitation at 326 nm to capture the strong intrinsic fluorescence of BRX. The carrier solution employed was a mixture of phosphate buffer (pH 4, 10 mM) and acetonitrile (50: 50, v/v), with a flow rate of 0.5 mL min− 1. The calibration curve, based on peak areas, exhibited linearity within the concentration range of 20–350 ng mL− 1, with a remarkable correlation coefficient (r2) of 0.9999. The limit of quantitation was 9.7 ng mL− 1, and the limit of detection was found to be 3.2 ng mL− 1. This method was applied to quantify BRX in Neopression® tablets, achieving recovery within an acceptable range without interference from the tablet's additives. Additionally, the proposed approach was successfully utilised to quantify the drug in spiked human plasma. The approach underwent validation following ICH requirements. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes. Methods: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1–2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5–2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables. Results: Of 122 enrolled patients, 120 (98.4%) were treated (mean [ SD ] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR10 Life Engagement subscale score (baseline mean [ SD ]: 16.1 [4.7]; change [95% confidence interval]: −8.11 [−9.34, −6.88]; p < 0.001) and IDS-SR total score (baseline mean [ SD ]: 41.3 [9.8]; change [95% confidence interval]: −17.38 [−20.08, −14.68]; p < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue (n = 13, 10.8%), headache (n = 13, 10.8%), insomnia (n = 12, 10.0%), nausea (n = 9, 7.5%), tremor (n = 8, 6.7%), and weight increase (n = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean (SD) change in body weight from baseline to last visit was +1.9 (3.4) kg. Conclusions: Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04830215. [ABSTRACT FROM AUTHOR]

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13‐17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure–response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13‐17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model‐based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13‐17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long‐term open‐label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Dual disorders (DDs) involve the coexistence of a substance use disorder (SUD) with another mental illness, often from the psychotic and affective categories. They are quite common in clinical practice and present significant challenges for both diagnosis and treatment. This study explores the effectiveness of brexpiprazole, a third-generation antipsychotic, in an Italian sample of individuals diagnosed with schizophrenia spectrum disorder and a comorbid SUD. Methods: Twenty-four patients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and enrolled in several Italian hospitals, underwent a psychometric assessment at baseline (T0) and one month (T1) after starting brexpiprazole treatment administered at a mean dosage of 2 mg/day. Results: Brexpiprazole demonstrated significant reductions in psychopathological burden (Positive and Negative Syndrome Scale/PANSS total score: p < 0.001). Positive (p = 0.003) and negative (p = 0.028) symptoms, substance cravings (VAS craving: p = 0.039), and aggression (MOAS scale: p = 0.003) were notably reduced. Quality of life improved according to the 36-item Short Form Health Survey (SF-36) subscales (p < 0.005). Conclusions: This study provides initial evidence supporting brexpiprazole's efficacy and safety in this complex patient population, with positive effects not only on psychopathology and quality of life, but also on cravings. Further studies involving larger cohorts of subjects and extended follow-up periods are needed. [ABSTRACT FROM AUTHOR]

Aim: This systematic review and frequentist network meta‐analysis used random‐effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants. Methods: Outcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non‐response rate; the non‐remission rate; all‐cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain. Results: A literature search identified three double‐blind, randomized, placebo‐controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible‐dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day. Conclusions: Overall BRE showed similar utility to ARI and a good risk–benefit balance. [ABSTRACT FROM AUTHOR]

This study aims to analysis adverse drug events (ADE) related to Brexpiprazole from the third quarter of 2015 to the first quarter of 2023 from FAERS database. The ADE data related to Brexpiprazole from 2015 Q3 to 2023 Q1 were collected. After standardizing the data, a variety of signal quantification techniques, including ROR, PRR, BCPNN, and MGPS were used for analysis. Among the 8559 ADE reports with Brexpiprazole as the primary suspected drug, 178 preferred terms (PT) of adverse reactions spanning 27 different system organ classes (SOC) were identified. Specifically, Metabolism and nutrition disorders and Reproductive system and breast disorders were unique adverse reactions to Brexpiprazole, with the latter not mentioned in the official drug label. Moreover, uncommon but significantly strong ADE signals, such as Egocentrism, Pharmacophobia, and Compulsions were observed. Notably, Tardive dyskinesia (n = 317, ROR 103.87, PRR 102.21, IC 6.21, EBGM 96.17) and Extrapyramidal disorder (n = 104, ROR 31.17, PRR 31.00, IC 4.57, EBGM 30.44) exhibited relatively high occurrence rates and signal strengths. Additionally, Lactation disorder (n = 6, ROR 48.09, PRR 48.07, IC 2.63, EBGM 46.71) and Breast discharge (n = 10, ROR 23.18, PRR 23.17, IC 2.94, EBGM 22.86) were observed, both presenting strong ADE signals. Brexpiprazole poses risks of various adverse reactions while providing therapeutic effects. In clinical applications, practitioners should closely monitor occurrences of Psychiatric disorders, Metabolism and nutrition disorders, Reproductive system and breast disorders, and other events. • From 2015 Q3 to 2023 Q1, 8,559 ADE reports with Brexpiprazole were identified, spanning 27 different SOC with 178 PTs. • Unique adverse reactions to Brexpiprazole included Metabolism and nutrition disorders and Reproductive system and breast disorders. • Tardive dyskinesia and Extrapyramidal disorder exhibited high occurrence rates and signal strengths. [ABSTRACT FROM AUTHOR]

Aims: Inadequate antidepressant response interrupts effective treatment of major depressive disorder (MDD). The BLESS study evaluates the dosage, efficacy, and safety of brexpiprazole adjunctive therapy in Japanese patients with inadequate antidepressant therapy (ADT) response. Methods: This placebo‐controlled, randomized, multicenter, parallel‐group phase 2/3 study randomized Japanese MDD patients (Hamilton Rating Scale for Depression 17‐item total score ≥ 14; historical inadequate response to 1–3 ADTs) with inadequate response to 8‐week single‐blind, prospective SSRI/SNRI treatment to 6‐week adjunctive treatment with brexpiprazole 1 mg, 2 mg, or placebo. The primary endpoint was change in Montgomery‐Åsberg Depression Rating Scale (MADRS) total score from baseline. Secondary endpoints included MADRS response, remission rate, and Clinical Global Impression‐Improvement score. Safety was comprehensively evaluated, especially regarding antipsychotic adverse events (AEs). Results: Of 1194 screened patients, 740 were randomized and 736 (1 mg, n = 248; 2 mg, n = 245; placebo, n = 243) had ≥1 baseline/post‐baseline MADRS total score. The LSM (SE) change from baseline in MADRS total score at Week 6 by MMRM analysis was −8.5 (0.47) with brexpiprazole 1 mg, −8.2 (0.47) with brexpiprazole 2 mg, and −6.7 (0.47) with placebo (placebo‐adjusted LSM difference [95% CI]: 1 mg, −1.7 [−3.0, −0.4]; P = 0.0089; 2 mg, −1.4 [−2.7, −0.1]; P = 0.0312). Secondary efficacy results supported the primary endpoint. Brexpiprazole was generally well tolerated. Conclusion: Brexpiprazole 1 mg daily was an appropriate starting dose and both 1 mg and 2 mg daily were effective and well tolerated as adjunctive therapy for Japanese MDD patients not adequately responsive to ADT. [ABSTRACT FROM AUTHOR]

Objective To observe the effect of brexpiprazole on cholesterol synthesis in colorectal cancer cell lines HCT116 and SW620, and to explore its mechanism. Methods HCT116 and SW620 cells in the logarithmic growth phase were divided into the brexpiprazole group and control group, respectively. Cells in the brexpiprazole group were add⁃ ed with medium containing 20 μmol/L brexpiprazole, while cells in the control group were added with equal amount of me⁃ dium. After the cells were cultured for 24 h, the total cholesterol (TC） in the cells was detected by microplate assay. Hu⁃ man 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR） mRNA and human 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1） mRNA were detected by real-time fluorescence quantitative PCR. HMGCR, HMGCS1, p-PI3K, p-AKT, and SREBP2 proteins were detected by Western blotting. Results The TC levels of HCT116 and SW620 cells were lower in the brexpiprazole group than in the control group (both P<0. 05). The relative expression levels of HMGCR mRNA and HMGCS1 mRNA in HCT116 and SW620 cells in the brexpiprazole group were lower than those in the control group (all P< 0. 05). The relative protein expression levels of HMGCR, HMGCS1, p-PI3K, p-AKT and SREBP2 in HCT116 and SW620 cells of the brexpiprazole group were lower than those of the control group (all P<0. 05). Conclusion Brexpipra⁃ zole inhibits intracellular cholesterol synthesis in HCT116 and SW620 cells possibly by inhibiting the protein expression of PI3K/Akt-SREBP2 signaling pathway. [ABSTRACT FROM AUTHOR]

Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations. These instructions are variable and rarely based on dedicated studies in people with obesity. This review briefly discusses the current clinical use of body measurements to guide chronic dosing instructions and highlights the need for obesity‐specific dosing instructions when the half‐life of a drug is prolonged (typically through increased volume of distribution) in people with obesity. Examples of drugs with apparent opportunities for either ramp‐up, loading, or washout instructions for patients based on body mass index are identified, specifically for vortioxetine, posaconazole, and brexpiprazole. We call for inclusion of people with obesity in clinical studies as a special subpopulation during drug development and propose the use of body mass index to guide dosing decisions among these patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of this review is to analyse the literature regarding studies centred on the clinical outcome of individuals affected by schizophrenia and treated with various antipsychotics, and then switched to orally administered partial D2-dopamine agonists (PD2A): Aripiprazole (ARI), brexpiprazole (BREX) or cariprazine (CARI). Method: A PubMed literature search was performed on 16 February 2021, and updated on Jan 26, 2022 for literature on antipsychotic switching in individuals affected by schizophrenia. Literature was included from 2002 onward. Six strategies were defined: Abrupt, gradual and cross-taper switch, and 3 hybrid strategies. The primary outcome was all-cause discontinuation rate per switch strategy per goal medication. Results: In 10 reports on switching to ARI, 21 studies with different strategies were described, but there were only 4 reports and 5 strategies on switching to BREX. Only one study about CARI was included, but it was not designed as a switch study. The studies are difficult to compare due to differences in methodology, previous antipsychotic medication, doses of the introduced P2DA and study duration. Conclusion: This analysis did not reveal evidence for a preferable switching strategy. A protocol should be developed which defines optimal duration, instruments to be used, and the timing of the exams. [ABSTRACT FROM AUTHOR]

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off‐label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose–exposure between adults and adolescents aged 13‐17 years following oral daily doses of brexpiprazole 1‐4 mg, indicating that the target brexpiprazole dose of 2‐4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13‐17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents. [ABSTRACT FROM AUTHOR]

The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of patients and caregivers. Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of amnestic dementia in the geriatric population. Pathophysiology of AD is widely attributed to aggregation of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau proteins. Initial treatment modalities aimed to increase brain perfusion in a non-specific manner. Subsequent therapy focused on rectifying neurotransmitter imbalance in the brain. Newer drugs modify the progression of the disease by acting against aggregated Aβ plaques. However, not all drugs used in therapy of AD have been granted approval by the United States Food and Drug Administration (FDA). This review categorizes and summarizes the FDA-approved drugs in the treatment of AD in a manner that would make it a convenient reference for researchers and practicing physicians alike. Drugs that mitigate symptoms of dementia may be categorized into mitigators of Behavioral and Psychological Symptoms of Dementia (BPSD), and mitigators of cognitive decline. BPSD mitigators include brexpiprazole, an atypical antipsychotic with a once-daily dosage suited to treat agitation in dementia patients, and suvorexant, an orexin receptor antagonist used to treat sleep disturbances. Cognitive decline mitigators include cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine and glutamate inhibitors such as memantine. Donepezil is the most commonly prescribed drug. It is cheap, well-tolerated, and may be prescribed orally once daily, or as a transdermal patch once weekly. It increases ACh levels, enhances oligodendrocyte differentiation and also protects against Aβ toxicity. However, regular cardiac monitoring is required due to reports of cardiac conduction side effects. Rivastigmine requires a twice-daily oral dosage or once-daily replacement of transdermal patch. It has fewer cardiac side effects than donepezil, but local application-site reactions have been noted. Galantamine, in addition to improving cognitive symptoms in a short span of time, also delays the development of BPSDs and has minimal drugdrug interactions by virtue of having multiple metabolic pathways. However, cardiac conduction disturbances must be closely monitored for. Memantine, a glutamate regulator, acts as an anti-Parkinsonian agent and an antidepressant, in addition to improving cognition and neuroprotection, and requires a once-daily dosage in the form of immediate-release or sustained-release oral tablets. Disease-modifying drugs such as aducanumab and lecanemab reduce the Aβ burden. Both act by binding with fibrillary conformations of Aβ plaques in the brain. These drugs have a risk of causing amyloid-related imaging abnormalities, especially in persons with ApoE4 gene. Aducanumab is administered once every 4 weeks and lecanemab once every 2 weeks. The decision on the choice of the drug must be made after considering the availability of drug, compliance of patient (once-daily vs. multiple doses daily), cost, specific comorbidities, and the risk-benefit ratio for the particular patient. Other non-pharmacological treatment modalities must also be adopted to have a holistic approach toward the treatment of AD. [ABSTRACT FROM AUTHOR]

Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics. D2 partial agonists share many pharmacological and clinical properties D2 partial agonists differ in several important respects from D2 antagonists D2 partial agonists should be considered a discrete class of antipsychotics [ABSTRACT FROM AUTHOR]

This graphical abstract was created by Adobe Photoshop 2020 containing the rat and muscle materials from BioRender.com. [Display omitted] 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 50) for 2 ∼ 3 weeks, without exhibiting an initial burst release. Histological examination of foreign body reaction (FBR) in rats revealed the morphological evolution of an inflammation-mediated drug depot, confirming the sustained release mechanism of BPZL. These findings provide strong support for the further development of a ready-to-use LAI suspension of BPZL, which could potentially enhance treatment outcomes, improve patient adherence, and address the clinical challenges associated with long-term regimens of schizophrenia spectrum disorders (SSD). [ABSTRACT FROM AUTHOR]

Using natural language processing (NLP) technology to analyze and organize textual information in psychiatric electronic medical records can identify undiscovered factors associated with treatment discontinuation. This study aimed to evaluate brexpiprazole treatment continuation rate and factors affecting brexpiprazole discontinuation using a database that employs the MENTAT® system with NLP technology. This retrospective observational study evaluated patients with schizophrenia who were newly initiated on brexpiprazole (April 18, 2018-May 15, 2020). The first prescriptions of brexpiprazole were followed up for 180 days. Factors associated with brexpiprazole discontinuation were assessed using structured and unstructured patient data (April 18, 2017-December 31, 2020). The analysis population comprised 515 patients; mean (standard deviation) age of patients was 48.0 (15.3) years, and 47.8 % were male. Using Kaplan-Meier analysis, the cumulative brexpiprazole continuation rate at 180 days was 29 % (estimate: 0.29; 95 % confidence interval, 0.25–0.33). Univariate Cox proportional hazards analysis identified 16 variables independently associated with brexpiprazole discontinuation. Multivariate analysis identified eight variables associated with treatment discontinuation: variables with hazard ratio <1 were the presence of physical complications, longer hospitalization duration, and maximum chlorpromazine-equivalent dose of antipsychotics of >200 to ≤400 mg/day vs ≤200 mg/day in the past year; variables with hazard ratio >1 were previous electroconvulsive therapy, availability of key contact person information, a history of crime committed/reported, increase in brexpiprazole dose to 2 mg in >28 days, and appearance/worsening of symptoms other than positive symptoms. In conclusion, we identified potential new factors that may be associated with brexpiprazole discontinuation, which may improve the treatment strategy and continuation rate in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Brexpiprazole is an atypical antipsychotic drug widely used in Japan for the treatment of schizophrenia. Previous studies have investigated the therapeutic effects of some antipsychotics on sleep variables; however, to our knowledge, the effects of brexpiprazole on sleep architecture have not been examined in patients with schizophrenia. Therefore, we aimed to exploratorily investigate the effect of brexpiprazole on sleep variables measured by polysomnography in patients with schizophrenia. Methods: This study included 10 patients with schizophrenia who were originally treated with haloperidol alone. Sleep variables of the participants were measured using polysomnography. After excluding those who did not meet the study criteria, seven patients (five men and two women; mean age [SD], 59.0 [10.0] years) were eligible for further analysis. Polysomnography was repeated at 4 weeks after the participants were prescribed brexpiprazole in addition to haloperidol. We compared the sleep architecture of the participants, measured using polysomnography, before and after taking brexpiprazole. Results: Add‐on brexpiprazole significantly prolonged rapid eye movement latency, increased the duration and percentage of stage N2 and stage N3 sleep (min, %), and decreased the duration and percentage of stage rapid eye movement sleep (min, %) at a significance level of nominal p < 0.05. Conclusion: Although not significant after correcting for multiple comparisons, the present results showed that add‐on brexpiprazole could alter the sleep architecture of patients with schizophrenia. Future studies are warranted to replicate these findings and to further investigate the beneficial influence of brexpiprazole on sleep. [ABSTRACT FROM AUTHOR]

Aim: 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. Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

SUMMARY: Aripiprazole, brexpiprazole and cariprazine are partial dopamine (and serotonin) agonists developed as novel antipsychotics. This article discusses their pharmacology, evidence on their licensed and off-licence uses (including psychosis, mania, bipolar depression, Tourette syndrome and autism spectrum disorder) and side-effects. In schizophrenia, they have a low risk of Parkinsonism or hyperprolactinaemia, cause modest increases in body weight and are of moderate efficacy. [ABSTRACT FROM AUTHOR]

Increased prescribing of antipsychotics and availability of new antipsychotics has resulted in increased exposures in children. Current data on aripiprazole, brexpiprazole, and cariprazine are limited. This was a retrospective database study utilizing the National Poison Data System from 2015 through 2021. We included cases of single substance exposures to aripiprazole, brexpiprazole, cariprazine, or lumateperone in children ages 0 to 5 years old with follow-up to a known outcome. Key outcomes were medical outcomes, clinical effects, and level of care if treated in a healthcare facility. There were 3,573 aripiprazole, 137 brexpiprazole, 249 cariprazine, and one lumateperone exposure over the period. Primary outcomes were evaluated in 2,655 cases (2,390 aripiprazole, 96 brexpiprazole, and 169 cariprazine). Fifty-one percent were male and 77% were between 0 and 2 years old. Moderate effect was coded in 16.6% of aripiprazole, 23% of brexpiprazole, and 12% of cariprazine exposures. Major effect was coded in 0.6% of aripiprazole, 1% of brexpiprazole, and 2.4% of cariprazine exposures. Duration of symptoms was mostly between 8 and 24 h for 34.6% of aripiprazole, 30% of brexpiprazole, and 32% of cariprazine exposures. Over 60% of the children seen in a health care facility were discharged from the emergency department. The lowest doses resulting in at least a moderate effect and admission to a health care facility was 0.46 mg/kg for aripiprazole, 2.1 mg/kg for brexpiprazole, and 1.9 mg/kg for cariprazine. Important clinical effects included central nervous system depression, tremors, tachycardia, agitation, and vomiting. Reported ingestions of aripiprazole, brexpiprazole, or cariprazine may result in neurologic symptoms like central nervous system depression or seizures in children. The prolonged duration of symptoms resulted in admission for at least a day for many cases. Further research should address optimal monitoring time and location for these exposures. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Limitations: Post hoc analysis with no adjunctive active comparator.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Brexpiprazole augmentation is an effective treatment strategy for antidepressant‐refractory depression, but its optimal dosage remains unclear. Aims: To find the optimal dosage of brexpiprazole as augmentation of other antidepressants. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT 1A and dopamine D 2 receptor agonist activity and serotonin 5-HT 2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this meta-analysis was to compare the efficacy and safety profile of low-dose brexpiprazole (< 2 mg/d) compared to placebo and standard-dose brexpiprazole (2– 4 mg/d). Patients and Methods: We identified relevant studies pertaining to the specific purpose of our meta-analysis by searching PubMed, Web of Science, Embase, Cochrane library, and PsycINFO using the search terms "schizophrenia" or "schizophrenic" AND "brexpiprazole" or "REXULTI". We systematically reviewed all randomized controlled trials (RCTs) comparing low-dose brexpiprazole with placebo. Primary efficacy outcomes were the PANSS total score change and response rate. Primary safety outcomes were total treatment discontinuation rate, and total serious adverse events (SAEs). Risk ratios (RR) and standardized mean differences (SMDs) were pooled implementing a random effect model. Results: Four RCTs (2178 patients) were included for effect assessment of low-dose brexpiprazole treatment on the patients with acute schizophrenia. Low-dose brexpiprazole was not superior to placebo (SMD = − 0.11, 95% CI = − 0.23, 0.02, P = 0.10, I2 = 0%), and significantly inferior to standard-dose brexpiprazole (SMD = 0.15, 95% CI = 0.03, 0.26, P = 0.01, I2 = 0%) for PANSS total score change. Low-dose brexpiprazole did not result in significant difference for response rate when compared to placebo and standard-dose brexpiprazole (RR = 1.16, 95% CI = 0.95, 1.41, P = 0.14, I2 = 25%; RR = 0.92, 95% CI = 0.76, 1.12, P = 0.40, I2 = 38%, respectively). For ratio of total discontinuation, low-dose brexpiprazole did not exhibit significant difference when compared to placebo (RR = 0.95, 95% CI = 0.81, 1.11, P = 0.53, I2 = 0%) and standard-dose brexpiprazole group (RR = 1.11, 95% CI = 0.95, 1.29, P = 0.19, I2 = 0%). Total SAEs in low-dose brexpiprazole group did not differ significantly from placebo and standard-dose brexpiprazole group (RR = 0.96, 95% CI = 0.52, 1.80, P = 0.90, I2 = 0%; RR = 1.29, 95% CI = 0.65, 2.57, P = 0.47, I2 = 26%, respectively). Conclusion: The results indicated that low-dose brexpiprazole may be not superior for improving the efficacy and safety for acute schizophrenia compared to placebo and standard-dose brexpiprazole, and may cause additional risk of increasing body weight. Therefore, using low-dose brexpiprazole in acute schizophrenia patients may be not recommended. [ABSTRACT FROM AUTHOR]

Several atypical antipsychotics exert mood-stabilising effects via the modulation of various monoamine receptors and intracellular signallings. Recent pharmacodynamic studies suggested that tripartite synaptic transmission can contribute to the pathophysiology of schizophrenia and mood disorders, their associated cognitive impairment, and several adverse reactions to atypical antipsychotics. Therefore, to explore the mechanisms underlying the antidepressive mood-stabilising and antipsychotic effects of brexpiprazole (Brex), we determined the effects of subchronic administration of therapeutically relevant concentrations/doses of Brex on the protein expression of 5-HT receptors, connexin43, cAMP levels, and intracellular signalling in cultured astrocytes and rat hypothalamus using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. Subchronic administration of a therapeutically relevant concentration of Brex (300 nM) downregulated both 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors, in addition to phosphorylated Erk (pErk), without affecting phosphorylated Akt in the astroglial plasma membrane. Subchronic administration of 300 nM Brex decreased and increased phosphorylated AMPK and connexin43, respectively, in the astroglial cytosol fraction. A therapeutically relevant concentration of Brex acutely decreased the astroglial cAMP level, whereas, under the inhibition of 5-HT1AR, Brex did not affect astroglial cAMP levels. However, the 5-HT7R-agonist-induced increased astroglial cAMP level was inhibited by Brex. In contrast to the in vitro study, systemic subchronic administration of effective doses of Brex (3 and 10 mg/kg/day for 14 days) increased the cAMP level but did not affect phosphorylated AMPK in the rat hypothalamus. These results suggest several complicated pharmacological features of Brex. Partial 5-HT1AR agonistic action predominates in the low range of therapeutically relevant concentrations of Brex, whereas in the high range, 5-HT7R inverse agonist-like action is overlapped on the 5-HT1A agonistic action. These unique suppressive effects of Brex on 5-HT7R play important roles in the clinical features of Brex regarding its antidepressive mood-stabilising actions. [ABSTRACT FROM AUTHOR]

Serotonin‐dopamine activity modulators (SDAMs) have been approved as an adjunctive treatment to antidepressants in patients with inadequate response. These drugs have been proposed to have a beneficial effect on cognition, sleep‐related problems, and other affective symptoms in patients with depression. Previous studies have shown inconsistent evidence and have not reported a pooled effect of the 2 drugs of this class: aripiprazole and brexpiprazole. This meta‐analysis evaluated the effect of augmentation with SDAM drugs in patients with major depression. The meta‐analysis protocol was made as per Preferred Reporting Items for Systematic Reviews and Meta‐Analysis Protocol guidelines and registered in the International Prospective Register of Ongoing Systematic Reviews. The PubMed/MEDLINE, Cochrane Clinical Trial registry, and EudraCT databases were searched with prespecified search terms. A random‐effects meta‐analysis was performed using the meta package in R software. Fifteen studies were included in this meta‐analysis. The random‐effects model analysis observed a pooled effect of 1.55 (95%CI, 1.32‐1.84; prediction interval, 0.95‐2.55, z = 5.19 [P <.0001]) for remission between the SDAM and placebo groups. A pooled effect of 1.58 (95%CI, 1.37‐1.83; prediction interval, 1.00–2.51, z = 6.34 [P <.0001]) for adverse events and 0.72 (95%CI, 0.48‐1.08; prediction interval, 0.46‐1.12; z = −1.58 [P =.113]) for serious adverse events was observed. No significant publication bias was noticed. The quality of the evidence was rated as high. Adjunct SDAM increased remission in patients and had no significant effect on serious adverse events compared to placebo. Therefore, we conclude that SDAM drugs can be an effective and safe antidepressant augmentation strategy in patients with major depressive disorder. [ABSTRACT FROM AUTHOR]

• Several new agents reduce psychotic symptoms without direct action on D2 receptors. • Cariprazine, pimavanserin and roluperidone may treat negative symptoms. • Some data suggest roluperidone, xanomeline and BI425809 improve cognitive symptoms. • Partial D2 agonists and low D2 affinity drugs could benefit treatment resistance. • Novel agents have low rates of both extra-pyramidal and metabolic side effects. Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial data and tolerability of novel medications to representative antipsychotics. Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses. Initial studies indicate pimavanserin and roluperidone improve negative symptoms. Ulotaront and xanomeline showed efficacy for positive and negative symptoms of schizophrenia in phase II trials. BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal. [ABSTRACT FROM AUTHOR]

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m2) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole‐body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal‐weight (body mass index 18‐25 kg/m2) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic simulations demonstrated significant differences in the time to effective concentrations between obese and normal‐weight individuals within metabolizer groups according to the label‐recommended titration. Simulations using an alternative dosing strategy of 1 week of twice‐daily dosing in obese EMs or 2 weeks of twice‐daily dosing in obese poor metabolizers, followed by a return to once‐daily dosing, yielded more consistent plasma concentrations between normal‐weight and obese patients without exceeding the area under the plasma concentration–time curve observed in the normal‐weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole. [ABSTRACT FROM AUTHOR]

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label‐recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole‐body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time to effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label‐recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower minimum concentrations during the dosing interval than CYP2D6 EMs. Simulations using an alternative dosing strategy of twice‐daily dosing (as opposed to once daily) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the area under the plasma concentration–time curve observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a reevaluation of steady‐state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs. [ABSTRACT FROM AUTHOR]

Brexpiprazole is a new antipsychotic that belongs to dopamine receptor partial agonists (DRPA). We present seven case studies that represent prosperous use of brexpiprazole in complex treatment of schizophrenia. Not only psychiatrists but patients appreciate weight loss, absence of sedation, akathisia, neuroleptic dysphoria and return to society, study or working activities together with improvement of positive and negative symptoms with brexpiprazole treatment. The case studies documented that brexpiprazole is not exchangeable with other antipsychotics. Brexpiprazole meants enrichment of treatment, because patients might reach the functional remision of schizophrenia and substantial quality of life improvement. [ABSTRACT FROM AUTHOR]

Aripiprazole has been associated with impulse control symptoms (ICS). Recently, two drugs with similar pharmacological features have become available: cariprazine and brexpiprazole. All of them interact with the D 3 receptor, which plays a role in cerebral circuits involved in reward pathways. The objective of this study was to analyze whether a disproportionate number of cases of ICS are reported for cariprazine or brexpiprazole in EudraVigilance. A case/non-case study was conducted to assess the association between ICS and these antipsychotics, calculating reporting odds ratios (RORs) from their respective approval date to Nov 17, 2020. First, cases involving cariprazine or brexpiprazole were compared with those involving all other drugs. Second, to reduce the risk of confounding by indication, the RORs for cariprazine and brexpiprazole were compared with other antipsychotics. Besides, to evaluate a possible notoriety bias, a sensitivity analysis excluding aripiprazole was performed. Seven cases of ICS were reported for cariprazine and another seven for brexpiprazole. The ROR for cariprazine was 28.3 (95% confidence interval [CI], 13.4–59.8) and 33.4 (15.8–70.1) in the case of brexpiprazole. Nonetheless, this association disappeared for cariprazine when compared with other antipsychotics drugs. However, when excluding aripiprazole from the analysis, a safety signal emerged. Although our study is the first to suggest an association between cariprazine, brexpiprazole and ICS, these results should only be considered as exploratory in the context of safety signal detection. Further, well designed observational analytical studies will be needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest. [ABSTRACT FROM AUTHOR]

Objectives: To determine the long‐term safety of switching to brexpiprazole from aripiprazole or non‐aripiprazole dopamine antagonists. Methods: Post‐hoc analysis of 56‐week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4‐week switching period with further titration (1–4 mg/day) allowed during the 52‐week, open‐label period. Major assessment items: total/low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc). Results: 84/186 (45.2%) patients (aripiprazole, 32.9%; non‐aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL‐/HDL‐cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non‐aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non‐aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non‐aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval. Conclusions: Switching to brexpiprazole is associated with a low long‐term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms. [ABSTRACT FROM AUTHOR]

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

Introduction: The current study sought to compare the treatment continuation rates of asenapine and brexpiprazole while specifically investigating the factors influencing this index and the clinical efficacy of brexpiprazole. Methods: Retrospective study on patients with schizophrenia who were prescribed either asenapine (n = 73) or brexpiprazole (n = 136), as part of their routine medical care. Results: The treatment continuation rates for asenapine and brexpiprazole were 19.0% and 38.6% at 52 weeks, with that of brexpiprazole found to be significantly higher than that of asenapine (p =.002). Moreover, age was found to be a significant factor affecting the treatment continuation rate for brexpiprazole (p =.03). Additionally, patients with a longer continuation duration had significantly lower Clinical Global Impression‐Severity of Illness (CGI‐S) scale scores compared to those who discontinued early (p =.04). The continuation rate was also significantly higher for those who began using the drug as outpatients compared to those first administered the drug as inpatients (p =.04). Furthermore, disease duration, CGI‐S scale, and continuation duration significantly affected the clinical efficacy of brexipiprazole (p <.05 for all). Conclusions: The continuation rate for brexpiprazole increases as the age of the patient increases, as disease severity decreases, and if the patient first uses the drug as an outpatient. Shorter disease duration and longer drug administration may lead to improved clinical efficacy. These results suggest that brexpiprazole is an effective treatment option for maintenance therapy of schizophrenia. [ABSTRACT FROM AUTHOR]

Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug–drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in vitro investigation. Brexpiprazole exhibited weak inhibitory effects (IC50 >13 μmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 μmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes. Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 μmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low. Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 μmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates. These in vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of brexpiprazole were investigated in the in vitro and in vivo. The total body clearance of brexpiprazole in rat and monkey was 2.32 and 0.326 L/h/kg, respectively, after intravenous administration, and oral availability was 13.6% and 31.0%, respectively. Dose-dependent exposures were observed at dose ranges between 1–30 mg/kg in the rat and 0.1–3 mg/kg in the monkey. Brexpiprazole distributed widely to body tissues, and Vd,z were 2.81 and 1.82 L/kg in rat and monkey, respectively. The serum protein binding of brexpiprazole was 99% or more in animals and human. Uniform distribution character among the species was suggested by a traditional animal scale-up method. A common main metabolite, DM-3411 was found in animals and humans in the metabolic reactions with the liver S9 fraction. CYP3A4 and CYP2D6 were predominantly involved in the metabolism. The affinity of DM-3411 for D2 receptors was lower than that of brexpiprazole, and neither DM-3411 nor any metabolites with affinity other than M3 were detected in the brain, demonstrating that brexpiprazole is only involved in the pharmacological effects. Overall, brexpiprazole has a simple pharmacokinetic profile with good metabolic stability, linear kinetics, and no remarkable species differences with regard to metabolism and tissue distribution. [ABSTRACT FROM AUTHOR]

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

Background: 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.Methods: 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).Results: 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).Limitations: This study is limited by its small sample size, and its single-arm, open-label design.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Purpose: This study was performed to assess the long-term efficacy, safety, and tolerability of brexpiprazole in elderly Japanese patients with schizophrenia. Methods: This is a post hoc analysis of a previous open-label study conducted over 56 weeks which consisted of two consecutive phases: a 4-week switching period and a 52-week open-label period. Mean change in the Positive and Negative Syndrome Scale (PANSS) total score, response rates, number and incidence of treatment-emergent adverse events (TEAEs), and other safety parameters were analyzed using descriptive statistics based on age group (elderly, ≥ 65 and non-elderly, < 65). Results: This post hoc analysis included 208 de novo patients of which 33 were elderly. The continuation rate in elderly patients was 54.5%, and the mean daily dose and treatment duration of brexpiprazole in elderly patients at week 56 were similar to those of non-elderly patients. The mean change in the PANSS total score from the baseline to week 56 was − 13.8 in elderly patients and this improvement was maintained throughout the open-label phase. This outcome was comparable to that of the non-elderly patients (− 9.0). The incidence rate of TEAEs was 97.0% in elderly patients and 82.3% in non-elderly patients. Most of the TEAEs were either mild (75.8%) or moderate (18.2%) in severity in the elderly patients and the incidence of TEAEs leading to discontinuation was lower in elderly (9.1%) than in non-elderly patients (13.1%). The most commonly observed adverse events in elderly patients were nasopharyngitis (30.3%) and worsening of schizophrenia (27.3%). The safety profiles in both groups were similar. Conclusion: Brexpiprazole was shown to be safe and effective in the treatment of elderly Japanese patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The treatment of patients with severe schizophrenia symptoms can be complicated and expensive.Aims: The purpose of this study was to evaluate the short- and long-term effects of brexpiprazole in patients with schizophrenia presenting with severe symptoms.Methods: Data were pooled from three six-week, randomized, double-blind, placebo-controlled studies and two 52-week, open-label extension studies. In the short-term studies, 1405 patients received placebo or brexpiprazole 2-4 mg/day; 412 brexpiprazole-treated patients rolled over into the long-term studies and received brexpiprazole 1-4 mg/day. More severe symptoms were defined as a Positive and Negative Syndrome Scale Total score >95 (median score at baseline). Outcomes included change in Positive and Negative Syndrome Scale Total and Personal and Social Performance scale scores.Results: Brexpiprazole improved Positive and Negative Syndrome Scale Total score over 6 weeks among more severely ill patients, with a least squares mean difference versus placebo of -6.76 (95% confidence limits: -9.80, -3.72; p<0.0001; Cohen's d: 0.43). Brexpiprazole also improved Personal and Social Performance scale score over 6 weeks in more severely ill patients (least squares mean difference: 4.38; limits: 2.14, 6.62; p=0.0001; Cohen's d: 0.38). Improvement of functioning was greatest in the 'Self-care' domain, followed by 'Personal and social relationships'. Among less severely ill patients, brexpiprazole was superior to placebo on Positive and Negative Syndrome Scale Total and Personal and Social Performance scale at Week 6. Improvements were maintained over 58 weeks. No new safety or tolerability concerns were observed.Conclusions: Brexpiprazole is an efficacious and well-tolerated treatment for schizophrenia in patients with more severe, and less severe, symptoms. [ABSTRACT FROM AUTHOR]

A post hoc analysis was performed using data obtained over eight weeks from 200 Japanese patients with schizophrenia who were switched to brexpiprazole monotherapy in a long‐term treatment study. The 8‐week period comprised of a 4‐week switching phase and a 4‐week post‐switch phase. For the antipsychotic switching schedule, brexpiprazole was first administered at 1 mg/day and increased to 2 mg/day by the end of week 4. Concurrently, the previous antipsychotic(s) was/were tapered gradually from the start of week 3 and discontinued by the end of week 4. Brexpiprazole could then be increased up to 4 mg/day according to the CGI‐I criteria. At week 8, 1.8%, 23.2%, 25.0%, and 50% of patients were administered daily brexpiprazole doses of 1, 2, 3, and 4 mg, respectively. The discontinuation rate at week 8 was 17.0%. The major reasons for discontinuation were consent withdrawal (9.5%), occurrence of adverse events (5.5%), and physician's decision (2.0%). Commonly reported adverse events were nasopharyngitis (13.5%), schizophrenia (9.0%), insomnia (6.5%), headache (5.5%), and akathisia (5.5%). The discontinuation rate was 4.9% for patients who were switched from aripiprazole as the primary antipsychotic and 25.4% for those who were switched from other antipsychotics. Owing to the serious adverse events that led to treatment discontinuation, careful switching to brexpiprazole is necessary in patients who previously used olanzapine as their primary antipsychotic. [ABSTRACT FROM AUTHOR]

Rationale: What is the difference between aripiprazole and brexpiprazole? Objectives: This systematic review, network meta-analysis of randomized trials evaluated the efficacy and safety/tolerability of aripiprazole and brexpiprazole for treating acute schizophrenia. Methods: We searched Scopus, MEDLINE, and Cochrane Library from inception until May 22, 2019. The response rate was set as the primary outcome. Other outcomes were discontinuation rate and incidence of individual adverse events. The risk ratio (RR) and 95% credible interval (95%CrI) were calculated. Results: Fourteen studies were identified (n = 3925). Response rates of both aripiprazole and brexpiprazole were superior to that of the placebo (RR [95%CrI]: aripiprazole = 0.84 [0.78, 0.92], brexpiprazole = 0.84 [0.77, 0.92]). Aripiprazole and brexpiprazole were associated with a lower incidence of all-cause discontinuation (0.80 [0.71, 0.89], 0.83 [0.72, 0.95]), adverse events (0.67 [0.47, 0.97], 0.64 [0.46, 0.94]), and inefficacy (0.56 [0.40, 0.77], 0.68 [0.48, 0.99]) compared with the placebo. Although brexpiprazole was associated with a lower incidence of schizophrenia as an adverse event compared with the placebo (0.57 [0.37, 0.85]), aripiprazole and brexpiprazole were associated with a higher incidence of weight gain compared with the placebo (2.12 [1.28, 3.68], 2.14 [1.35, 3.42]). No significant differences were found in other individual adverse events, such as somnolence, akathisia, extrapyramidal symptoms, and dizziness between aripiprazole or brexpiprazole and placebo. Any outcome between aripiprazole and brexpiprazole were not different. Conclusions: Differences in short-term efficacy and safety for acute schizophrenia were not apparent between aripiprazole and brexpiprazole. Future studies are warranted to evaluate whether there are differences in the long-term outcome between treatments. [ABSTRACT FROM AUTHOR]

Background: Long‐term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic. Methods: The maximum D2 receptor density (Bmax) and apomorphine (a D2 receptor agonist)‐induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for Bmax, 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine‐induced hyperlocomotion and (±)‐2,5‐dimethoxy‐4‐iodoamphetamine hydrochloride (DOI: a 5‐HT2A receptor agonist)‐induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. Results: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti‐apomorphine‐induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the Bmax and apomorphine‐induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine‐induced hyperlocomotion and also DOI‐induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine‐induced hyperlocomotion. Conclusion: Brexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5‐HT2A receptors after a repeated administration of risperidone. [ABSTRACT FROM AUTHOR]