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SUMMARYAripiprazole, 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.

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.

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.

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., “Dopamine‐system stabilizer” activity of aripiprazole.

Mizue Ichinose,1,2 Itaru Miura,1 Sho Horikoshi,1,3 Shinnosuke Yamamoto,1,4 Keiko Kanno-Nozaki,1 Kenya Watanabe,5 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 3Department of Psychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 4Department of Psychiatry, Fukushima Red Cross Hospital, Fukushima, Japan; 5Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru MiuraDepartment of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, JapanTel +81-24-547-1331Fax +81-24-548-6735Email itaru@fmu.ac.jpObjective: Although switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia.Methods: The antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters.Results: Switching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p< 0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores.Conclusion: Switching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.Keywords: brexpiprazole, extrapyramidal symptoms, EPS, homovanillic acid, prolactin, schizophrenia, switching

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.

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.

While the prognosis of patients with schizophrenia has dramatically improved after the advent of chlorpromazine, the antipsychotics currently available are so numerous that it has become a challenge for psychiatrists to choose from among these drugs for each patient presenting for care. In addition, while numerous studies show that an effective antipsychotic should be continued indefinitely to prevent relapses or worsening, many patients appear to have difficulty remaining on any drug thus initiated. Brexpiprazole, a dopamine D2 receptor partial agonist, appears to provide a unique profile that has much to offer in this light. Specifically, this novel drug is potentially better suited for long-term use, with decreased risk of extrapyramidal side effects, hyperprolactinemia, weight gain, psychosis, insomnia, akathisia, nausea/vomiting or restlessness, thus potentially facilitating patients' reintegration into society. Indeed, brexpiprazole has been shown in randomized, double-blind, placebo-controlled trials to have proven efficacy not only in improving the symptoms of schizophrenia but in preventing relapses. It is also suggested in both short- and long-term studies that brexpiprazole offers a favorable safety and tolerability profile. This review also includes a proposed treatment algorithm incorporating brexpiprazole, based on the clinical trial results available, as well as on the authors' clinical experience, where brexpiprazole may be best used as a drug of first choice for the treatment of schizophrenia. Thus, overall, brexpiprazole appears to play a more significant role in the treatment of schizophrenia than other antipsychotics.

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.

PURPOSE/BACKGROUND Extensive research has been conducted comparing the metabolic characteristics of older second-generation antipsychotics (SGAs); minimal data exist comparing the long-term metabolic effects of SGAs approved in the last 10 years. METHODS/PROCEDURES A retrospective chart review of patients treated with brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone (newer SGAs) for at least 6 weeks at an outpatient psychiatric practice was conducted. Patients treated with olanzapine, an older SGA, were included as a comparator. Metabolic characteristics were collected at baseline, approximately 6 weeks, 12 weeks, and for up to 12 months. FINDINGS/RESULTS Of the newer SGAs, there were statistically significant increases in patients' average weight at 12 weeks and 1 year or less with brexpiprazole (2.48 lb, P = 0.02; 5.97 lb, P = 0.01) and iloperidone (4.54 lb, P < 0.01; 5.13 lb, P = 0.02). Brexpiprazole and iloperidone resulted in significant increases in body mass index, up to a 0.90-kg/m2 average increase in patients taking brexpiprazole at 1 year or less. Minimal weight gain was seen with cariprazine (4.25 lb, P = 0.42) and asenapine (1.80 lb, P = 0.62) at 1 year or less after treatment initiation. Although not statistically significant, lurasidone showed an average weight loss of up to 0.60 lb at 1 year or less (P = 0.56). IMPLICATIONS/CONCLUSIONS Although some weight gain was seen with the newer SGAs, all demonstrated significantly favorable metabolic characteristics compared with olanzapine. Monitoring of weight and metabolic parameters remain important in patients treated with SGAs.

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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

Background. Cariprazine is a new piperazine derivative atypical antipsychotic, like aripiprazole and brexpiprazole. It has been approved for treating schizophrenia in many countries and has recently been included on the List of Essential Medicines in Russia. Unlike most other atypical antipsychotics, it shows high in vivo occupancy of dopamine D2 and D3 receptors at clinically relevant doses. In animal models, cariprazine has demonstrated dopamine D3 receptor- dependent pro-cognitive and anti-anhedonic effects, suggesting its potential for treating negative symptoms. This review summarizes the efficacy of cariprazine in the treatment of negative symptoms of schizophrenia. Methods. A literature search of databases covering international and Russian journals, for articles published between 1st January 2010 and 1stJune 2020. Results. Cariprazine demonstrated at least comparable efficacy in the treatment of schizophrenia symptoms to active comparators including risperidone, olanzapine or aripiprazole. The drug has a good safety profile. It appeared to be associated with a lower risk of metabolic syndromes and most extrapyramidal symptoms. The positive effect of cariprazine on the negative symptoms of schizophrenia may be associated with the elimination of secondary negative symptoms. However, of all the atypical antipsychotics to date, only cariprazine has a convincingly, methodologically robust proven advantage over risperidone in eliminating the predominant negative symptoms of schizophrenia. Yet only four studies have investigated the effect of cariprazine on the negative symptoms of schizophrenia. There is a lack of research into its direct impact on emotional-volitional disorders, anhedonia, cognitive symptoms and personality changes. However, there is evidence to suggest cariprazine is effective in treatment-resistant cases, but this requires further confirmation. Conclusion. Cariprazine is an effective and well-tolerated agent for the treatment of schizophrenia and may be effective in cases where other antipsychotics have failed. Cariprazine has been shown to have a positive effect on negative symptoms. Further studies are needed to collect more data on long-term treatment of schizophrenia and especially negative symptoms.

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, 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.

A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days’ post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal–amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.

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; pConclusions: Brexpiprazole is an efficacious and well-tolerated treatment for schizophrenia in patients with more severe, and less severe, symptoms.

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.

The substantive delay (often 4-6 weeks) between the commencement of an antidepressant and any discernible improvement in depressive symptoms is an ongoing concern in the management of depressive disorders. This delay incurs the risk of cessation of medication, self-harm/suicide and ongoing 'damage' to the brain caused by the illness. Both historically and now, off-label polypharmacy has been used in clinical practice in an attempt to facilitate both immediate- and long-term relief from symptoms. While somewhat effective, this strategy was unregulated and associated with severe adverse side effects for patients. In this article we proffer an alternative paradigm to achieve a more rapid antidepressant response by conceptualising the gap in terms of windows of response. The Windows of Antidepressant Response Paradigm (WARP) frames treatment response as windows of time in which a clinical response can be expected following initiation of an antidepressant. The paradigm defines three distinct windows-the immediate-response window (1-2 days), fast-response window (up to 1 week) and slow-response window (from 1 week onwards). Newer agents such as rapid-acting antidepressants are considered to act within the immediate-response window, whereas atypical antipsychotic augmentation strategies are captured within the fast-response window. The slow-response window represents the delay experienced with conventional antidepressant monotherapy. Novel agents such as esketamine and brexpiprazole are discussed as examples to better understand the clinical utility of WARP. This framework can be used to guide research in this field and aide the development of newer, more effective antidepressant agents as well as providing a strategy to guide the prescription of multiple agents in clinical practice.

Objective To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). Design Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). Setting Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. Participants Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. Intervention Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5–2 mg/day or placebo (1:1) for 12 weeks. Measurements Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29–203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression – Severity of illness (CGI-S) as related to agitation. Safety was also assessed. Results In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, −3.77; confidence limits, –7.38, –0.17; t(316) = –2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; −3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5–2 mg/day did not achieve statistical superiority over placebo (–2.34; –5.49, 0.82; t(230) = −1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (−5.06; −8.99, −1.13; t(144) = −2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (−0.16; −0.39, 0.06; t(337) = −1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5–2 mg/day in Study 2 (−0.31; −0.55, −0.06; t(222) = −2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5–2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. Conclusions Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

The objective of this study was to identify the factors associated with brexpiprazole discontinuation after initiating brexpiprazole in patients with schizophrenia or schizoaffective disorder. All patients with schizophrenia or schizoaffective disorder who were started on brexpiprazole in our institution between May 2018 and April 2019 were retrospectively screened. The continuation rate of brexpiprazole during a follow-up period of 16 weeks was examined. Multivariate Cox regression analysis was conducted to identify predictors of brexpiprazole discontinuation. During the follow-up period, 52 out of 120 patients (43.4%) discontinued brexpiprazole. Thirty-three subjects discontinued due to a lack of efficacy, eight more due to intolerability and a further 11 for other reasons. The continuation rate of brexpiprazole among patients who were previously on high-dose antipsychotics (chlorpromazine-equivalent doses > 800 mg) was significantly lower than that in those who were previously on low-dose antipsychotics (chlorpromazine-equivalent doses ≤ 800 mg). The Cox regression analysis showed that only having been subject to a high dose of their previous antipsychotics was independently associated with an increased risk of brexpiprazole discontinuation (P < 0.001). Patients who were previously on high-dose antipsychotics discontinued brexpiprazole mainly due to inefficacy. Previous high-dose antipsychotic therapy is an independent risk factor for brexpiprazole discontinuation in patients with schizophrenia or schizoaffective disorder.

Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.

Purpose of review Over the last ten years, the treatment of psychosis has seen a near explosion of creative development in both novel agents and new delivery modalities. The current review summarizes these developments over the past decade (2011-2020). We performed a systematic review utilizing PubMed and PsychInfo with the aim of identifying all the RCT and related analyses in adults with psychosis (schizophrenia and mania). Recent findings We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery methods: subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M1 and M4 muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis.

BackgroundBorderline personality disorder is associated with impaired quality of life and has a number of untoward public health associations. There is no established first-line pharmacological treatment for borderline personality disorder, and available options are not suitable for all individuals.AimsTo evaluate brexpiprazole, which has effects on the dopaminergic and serotonergic systems, for the reduction of borderline personality disorder symptoms.MethodEighty adults with borderline personality disorder were recruited for a randomised, double-blind placebo-controlled study. Participants received 12-week treatment with brexpiprazole (1 mg/day for 1 week, then increasing to 2 mg/day) or placebo in a parallel design. The primary efficacy outcome measure was the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). Safety data were collected. Effects of active versus placebo treatment were characterised with linear repeated measures models.ResultsThere was a significant interaction between treatment and time on the ZAN-BPD scale (P = 0.0031), solely because of differentiation specifically at week 12. Brexpiprazole was generally well tolerated. Secondary measures did not result in statistically significant differences from placebo.ConclusionsBrexpiprazole appears to have some possible effect on borderline personality disorder symptoms, but further studies are needed because of the significant effects evident, specifically at the final time point. These findings also need to be viewed cautiously, given the small sample size, large drop-out rate and robust placebo response.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To investigate the efficacy, tolerability, acceptability, and safety of brexpiprazole as monotherapy or adjunct treatment in the acute‐ and long‐term treatment of major depression.

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

Introduction Patients with major depressive disorder (MDD) incur high costs, despite established treatment options. Adding an atypical antipsychotic (AAP) to antidepressant therapy has shown to reduce depressive symptoms in MDD, but it remains unclear with which adjunctive AAP to initiate. As economic burden is one factor that can influence treatment selection, this study's objective was to evaluate the impact of adjunctive AAP choice on psychiatric costs and healthcare utilization in MDD. Materials and methods This retrospective cohort study analyzed de-identified data from: (1) IBM® MarketScan® Commercial (C), Medicare Supplemental (MS), and MarketScan Multi-State Medicaid (M) Databases, and (2) Optum® Clinformatics® Datamart. Adult MDD patients were included if they had: initiated adjunctive AAPs during study identification period (7/1/15-9/30/16 MarketScan C/MS, and Optum; 7/1/15-6/30/16 MarketScan M), and ≥12 months of continuous enrollment before (baseline) and after (follow-up) first treatment date. Models included generalized linear models (GLMs) for psychiatric costs (total inpatient and outpatient services, excluding outpatient pharmacy costs), and a two-part model (logistic regression for psychiatric hospitalizations, GLM for psychiatric hospitalization costs among hospitalized patients); models were adjusted for baseline characteristics. Results The final study sample consisted of 10,325 patients (7657 aripiprazole, 1219 brexpiprazole, 827 lurasidone, 622 quetiapine). Using brexpiprazole as reference, lurasidone and quetiapine users had $1662 and $3894 higher psychiatric costs, respectively. Psychiatric costs were not statistically significantly different between aripiprazole and brexpiprazole (p>0.05). Quetiapine users had $15,159 (p 0.05). Conclusion In MDD, brexpiprazole users had significantly lower psychiatric costs than lurasidone and quetiapine users, and significantly lower psychiatric hospitalization risk than quetiapine users. Adjunctive AAP choice may impact subsequent healthcare costs and utilization in MDD.

Introduction The use of the blonanserin patch (BLO-P) for schizophrenia treatment was approved in Japan in 2019. This systematic review of trials in Japan assessed the efficacy and safety profile of BLO-P compared with other antipsychotics. Methods The systematic review included 6-week, double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with acute schizophrenia. Pooled data for patients receiving BLO-P 40 and 80 mg/day (BLO-P40+80) were compared with pooled data for patients receiving asenapine 10 and 20 mg/day (ASE10+20) and data for those receiving brexpiprazole 2 mg/day (BRE2) and paliperidone extended-release 6 mg/day (PAL-ER6). Results All the investigated treatments were superior to placebo in reducing the Positive and Negative Syndrome Scale (PANSS) total score; the Hedges’ g values (95% confidence interval) for BLO-P40+80, ASE10+20, BRE2, and PAL-ER6 were−0.40 (−0.58,−0.22),−0.61 (−0.79,−0.42),−0.33 (−0.60,−0.07), and−0.69 (−0.93,−0.45), respectively. There were differences among the antipsychotics in the incidence of various individual adverse events. Discussion BLO-P40+80 may have a good efficacy/safety/tolerability profile for the treatment of patients with acute schizophrenia.

Purpose Brexpiprazole is an oral atypical antipsychotic (OAA) for the treatment of schizophrenia (SCZ). This study compared all-cause and psychiatric inpatient hospitalization and medical costs in adult patients with SCZ newly treated with brexpiprazole versus other US Food and Drug Administration–approved OAAs in a real-world setting. Methods This retrospective cohort study analyzed data from: (1) the IBM MarketScan Commercial and Medicare Supplemental databases, and the MarketScan Multi-State Medicaid database; and (2) the de-identified Optum Clinformatics Datamart. Adult patients were identified if they had SCZ and initiated either brexpiprazole or another OAA during the study identification period (July 1, 2015, to September 30, 2016, for MarketScan Commercial and Medicare Supplemental and for Optum; July 1, 2015, to June 30, 2016, for MarketScan Multi-State Medicaid) and had ≥12 months of continuous enrollment before (baseline) and after (follow-up) the first treatment date. Linear regression analyses were performed to test associations between treatment groups (brexpiprazole vs another OAA) and costs (total and medical); negative binomial regression models were used to estimate number of hospitalizations per year, adjusting for baseline characteristics and medication adherence to index treatment during the 12-month follow-up. Findings The final study sample consisted of 6254 patients with SCZ: 176 initiated brexpiprazole; 391, ziprasidone; 453, paliperidone; 523, lurasidone; 786, aripiprazole; 1234, quetiapine; 1264, olanzapine; and 1427, risperidone. Controlling for baseline characteristics and medication adherence, the adjusted number of hospitalizations (both all-cause and psychiatric), all-cause total costs, and all-cause medical costs did not differ across groups. Brexpiprazole users had the lowest mean psychiatric costs among all OAA users ($12,013; 95% bootstrap CI, 7488–16,538). Compared with brexpiprazole users, paliperidone (incidence rate ratio [95% CI], 1.52 [1.05–2.19]; P = 0.027) and quetiapine (incidence rate ratio [95% CI], 1.47 [1.04–2.07]; P = 0.029) users had more psychiatric hospitalizations per year. Paliperidone had higher psychiatric costs than brexpiprazole (total, $32,066 [95% bootstrap CI, 28,779–35,353] vs $23,851 [18,907–28,795]; medical, $19,343 [16,294–22,392] vs $12,013 [7488–16,538]). Psychiatric medical costs were also $6744 higher in olanzapine users (95% bootstrap CI, 1694–11,795; P = 0.009) than in brexpiprazole users. Implications Patients with SCZ treated with brexpiprazole had fewer psychiatric hospitalizations and lower psychiatric costs than those treated with paliperidone. Differences in the number of all-cause hospitalizations and medical costs among treatments were not statistically significant. Although treatment decisions are driven by a number of factors (eg, clinical circumstances and drug costs), choice of OAA may affect health care costs.

The objective of this study (NCT01854944) was to assess D(2)/D(3), 5-HT(1A), 5-HT(2A) and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [(11)C]-(+)-PHNO to measure D(2) and D(3) receptor occupancy and [(11)C]CUMI101 to measure 5-HT(1A) occupancy; Cohort 2 received [(11)C]MDL100907 for 5-HT(2A) occupancy and [(11)C]DASB for SERT occupancy; Cohort 3 underwent scanning with [(11)C]-(+)-PHNO and [(11)C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28–55 years), participated in this study. Dose dependency was observed at D(2) receptors, with occupancies reaching 64 ± 8% (mean +/− SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D(3) receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT(2A) receptors. Negligible occupancy (

Purpose Major depressive disorder (MDD) is a chronic mental disorder with a substantial clinical and economic burden. Despite the efficacy of adjunctive atypical antipsychotics (AAP) for augmentation in patients with major depressive disorder (MDD) who failed first-line antidepressant therapy (ADT), little is known of the impact of AAP choices on healthcare resource use and costs in real-world practice. Therefore, this study compared real-world healthcare utilization and costs in patients with MDD treated with brexpiprazole or extended-release (XR) quetiapine as adjunctive treatment to ADT. Patients and methods Adults with MDD starting adjunctive treatment with brexpiprazole (n=844) or extended-release (XR) quetiapine (n=688) were identified in the adjudicated health plan claims data (07/2014 - 09/2016). Resource use and healthcare costs in the 6 months following treatment initiation were compared between non-matched populations, and between propensity score-matched groups, and by multivariable regression analyses. Results During follow-up, unadjusted all-cause hospitalization (6.6% vs 12.5%) and ED visits (17.0% vs 27.5%) were lower with brexpiprazole compared to quetiapine XR (both p

Adherence to prescribed antipsychotics is an ongoing problem. Traditionally, estimates of adherence have been made from patient interviews, pill counting and blood testing. A number of methods for the analysis of antipsychotics in blood have been reported for both therapeutic drug monitoring and postmortem testing for toxicity. This report details a dilute and shoot method for the analysis of 19 different antipsychotics and metabolites. The method takes advantage of earlier reports demonstrating unique, prevalent urine metabolites for aripiprazole, brexpiprazole, haloperidol and lurasidone to enhance sensitivity for these analytes. With a fast analysis time and minimal sample preparation, this method can be used for quantitation of antipsychotics in urine. Finally, this method has been used to test samples for over a year with the results summarized in this report. While further improvements are certainly possible, this method is selective and sensitive for this group of important compounds.

Background/aim Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. Materials and methods YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. Results Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. Conclusion Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.

Background: There is a need for effective, safe and well-tolerated pharmacotherapies for patients with major depressive disorder (MDD) who have inadequate response to antidepressant treatments (ADT...

From the perspective of psycho-oncology, antipsychotics are widely used for patients with cancer. Although some antipsychotic drugs have anti-tumor effects, these antipsychotic drugs are not applicable for cancer patients because of their severe side effects. Brexpiprazole, a novel serotonin-dopamine modulator with an improved side effect profile, was developed as a drug that is structurally and pharmacologically related to aripiprazole, which was reported to have anti-cancer effects. However, it remains unknown whether brexpiprazole has anti-cancer effects. In this study, we examined whether brexpiprazole has anti-tumor effects in cancer cells and cancer stem cells (CSCs) of glioblastoma, pancreatic cancer, and lung cancer. Brexpiprazole suppressed cell growth and induced cell death in the cancer cells and the CSCs, and decreased the CSC properties of the CSCs. Brexpiprazole did not exert any cytotoxic effects on non-cancer cells at the anti-cancer effect-inducing concentration. In the cancer cells and the CSCs, brexpiprazole reduced the expression of survivin, an anti-apoptotic protein, whose reduction sensitizes tumor cells to chemotherapeutic reagents. In the preclinical model in which pancreatic CSCs were subcutaneously implanted into nude mice, brexpiprazole suppressed tumor growth, in addition to reducing the expression of Sox2, a marker for CSCs, and survivin. This suggests that brexpiprazole is a promising antipsychotic drug with anti-tumor effects and an improved safety profile.

To critically review the current landscape of literature on cardiotoxicity of “new-generation antipsychotics,” defined as those approved by the Food and Drug Administration in the last 10 years. There is a paucity of data regarding the cardiovascular risks of these medications. Based on the investigations that have been published, iloperidone appears to be the greatest risk of corrected QT prolongation followed by asenapine whereas lurasidone, cariprazine, and brexpiprazole were not found to have significant effects on corrected QT. However, the evidence was low quality. In terms of metabolic effects, asenapine, iloperidone, cariprazine, and brexpiprazole all had mild to moderate effects whereas lurasidone had no significant effects observed. Further investigation is warranted for all of these medications to better understand their cardiovascular effects.

BACKGROUND: Akathisia is a common and distressing movement disorder that can be associated with the use of antipsychotics. It is characterized by a subjective (inner restlessness) and an objective (excessive movements) component. Akathisia can have a negative impact on clinical outcome and even lead to treatment discontinuation. Although medication-induced akathisia is more commonly associated with the use of first-generation antipsychotics (FGAs), it also occurs with second-generation antipsychotics (SGAs), including the newly approved antipsychotics (NAPs) asenapine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Until now, no meta-analysis has been published on the risk of akathisia for all NAPs, as monotherapy or adjunctive treatment, in patients with a severe mental illness. OBJECTIVE: The primary objectives of this systematic review and meta-analysis were to (i) compare akathisia incidence rates of the NAPs, as monotherapy or adjunctive treatment, in adult patients with a severe mental illness (i.e., schizophrenia, bipolar disorder, or major depressive disorder), using data from published and unpublished randomized controlled trials; and (ii) examine the role of several study characteristics explaining differences in akathisia incidence rates between studies. METHODS: A systematic literature search, using the PubMed, EMBASE, and Cochrane Library databases (until October 2018), was conducted for English-language placebo- as well as active-controlled clinical trials, including subjective (percentage of patients reporting akathisia) and/or scale-defined medication-induced akathisia incidence rates with NAPs (as monotherapy or as adjunctive treatment) in adult patients with schizophrenia, bipolar disorder, or major depressive disorder. Additional unpublished clinical trials were identified through the ClinicalTrials.gov electronic database. Two meta-analyses (incidence rates and odds ratio [OR] [placebo vs. active] of medication-induced akathisia with NAPs) were performed to obtain an optimal estimation of akathisia risks of adult patients with a severe mental illness under these treatment conditions and to assess the role of study characteristics. RESULTS: Two hundred and thirteen reports were selected as potentially eligible for our meta-analysis. Of these, 48 met the inclusion criteria. Eight records, identified through the ClinicalTrials.gov database and cross-referencing, and which fulfilled the inclusion criteria, were added, resulting in a total of 56 records (iloperidone = 5, asenapine = 11, lurasidone = 15, brexpiprazole = 13, cariprazine = 12). The estimated weighted mean incidence rate of akathisia was 7.7% (95% confidence interval [CI] 6.5-9.1), with estimates being 3.9% (95% CI 2.4-6.3) for iloperidone, 6.8% (95% CI 5.1-9.0) for asenapine, 10.0% (95% CI 7.4-13.5) for brexpiprazole, 12.7% (95% CI 10.1-16.1) for lurasidone, and 17.2% (95% CI 13.4-22.1) for cariprazine. After Tukey-adjustment for multiple testing, the incidence rate of akathisia was significantly (p

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.

Background: Brexpiprazole and aripiprazole are atypical antipsychotics that act as partial agonists at the dopamine D2 receptor. No head-to-head trial comparing brexpiprazole and aripiprazole in the treatment of schizophrenia is available. Here, we carry out a systematic review and comparison of the efficacy and safety of brexpiprazole and aripiprazole in schizophrenia treatment.Methods: We employed an indirect meta-analysis to determine effect sizes from randomised placebo-controlled trials with brexpiprazole and aripiprazole in the acute treatment of schizophrenia. We compared responder rates, incidences of adverse events and serious adverse events, the number needed to treat (NNT) for response, number needed to harm (NNH) for adverse events or treatment discontinuation, and likelihood to be helped or harmed (LHH) as efficacy and safety indices of the two drugs. Results: Five studies for each drug were included in the analysis. Similar risk differences vs. placebo were observed for responder rates under brexpiprazole (10.2%, p = 0.0015) and aripiprazole (10.3%, p = 0.0003). Higher incidences of adverse events and serious adverse events were seen under aripiprazole compared with brexpiprazole, however, the risk differences were not statistically significant. The NNT for response was 11 for both substances. For brexpiprazole compared with placebo, we did not find an increase of adverse events (NNH = 27, not significant), however, we found an increased number of adverse events for aripiprazole versus placebo (NNH = 17, p < 0.05). For both drugs, benefits were encountered more often than harms, with an LHH for any adverse event of 2.41 for brexpiprazole and 1.56 for aripiprazole, respectively. Conclusions: The likelihood to be helped rather than harmed was greater with brexpiprazole compared to aripiprazole for the total rate of adverse events (ratio of brexpiprazole LHH/aripiprazole LHH = 1.54).

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.

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, This retrospective study sought to compare the treatment continuation rates of asenapine and brexpiprazole while examining the specific factors that affect both the continuation rates and clinical efficacy of brexpiprazole in patients with schizophrenia. Results show that brexpiprazole had a significantly higher treatment continuation rate compared to asenapine. Moreover, patients who were older, had a lower CGI‐severity of illness score, and those for whom the drug was initiated as an outpatient, had a higher continuation rate. Meanwhile, disease duration, CGI‐S scale, and continuation duration all significantly affected the clinical efficacy of brexpiprazole.

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 D3 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.

Hiroaki Okayasu,1 Takahiro Shinozaki,1 Yumiko Takano,1 Norio Sugawara,1 Kumiko Fujii,2 Norio Yasui-Furukori,1 Yuji Ozeki,2 Kazutaka Shimoda1 1Department of Psychiatry, Dokkyo Medical University, Tochigi, Japan; 2Department of Psychiatry, Shiga University of Medical Science, Shiga, JapanCorrespondence: Hiroaki Okayasu Tel +81 282-86-1111Email hokayasu@dokkyomed.ac.jpPurpose: Antipsychotic drugs have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect marker for proarrhythmic risk. Recently, improved methods, namely, QT dispersion (QTD), QTD ratio (QTDR), T wave peak-to-end interval (Tp-e), Tp-e/QT ratio and Tp-e/QTc ratio, have been regarded as proarrhythmic risk markers. We attempted to reevaluate the risk of sudden cardiac death due to antipsychotics use by measuring these improved evaluation methods.Patients and Methods: We retrospectively evaluated QTc, QTD, QTDR, Tp-e, Tp-e/QT ratio and Tp-e/QTc ratio from the medical records of 410 patients with schizophrenia diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, or 5th Edition. Information on drugs administered was obtained from medical records. We investigated the correlation between each index on ECG and medication, such as antipsychotics, prescribed to participants with linear regression analysis. We also compared each index between 235 healthy controls and 235 patients matched for age and sex.Results: Positive correlations between QTc and levomepromazine and brexpiprazole were identified. Levomepromazine and lithium were positively correlated with QTD. Levomepromazine, quetiapine, asenapine, clozapine and carbamazepine were positively correlated with QTDR. Levomepromazine, olanzapine, brexpiprazole and lithium were positively correlated with Tp-e. Olanzapine, brexpiprazole and lithium were positively correlated with the Tp-e/QT ratio. Olanzapine, brexpiprazole and lithium were positively correlated with Tp-e/QTc ratio. Significant differences in all indexes were noted between the patients and healthy controls.Conclusion: According to our results, the prediction of the risk of sudden cardiac death by each index was inconsistent. We should evaluate the predictive factor of ventricular arrhythmia according to various electrocardiogram indexes because QTc alone could not identify the risk of sudden cardiac death.Keywords: antipsychotic drugs, sudden cardiac death, electrocardiogram, QT prolongation, QT dispersion, T peak-to-end interval

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=“disagree” and 9=“agree”). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

The successful treatment of schizophrenia entails improvement across a spectrum of symptoms. The aim of this post hoc analysis was to characterize the short- and long-term effects of brexpiprazole on Positive and Negative Syndrome Scale (PANSS) ‘Marder factors.’ Data were included from three 6-week, randomized, double-blind, placebo-controlled studies; a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study; and two 52-week open-label extension (OLEx) studies—all in schizophrenia (DSM-IV-TR criteria). Patients receiving oral brexpiprazole were dosed at 2–4 mg/day (short-term studies) or 1–4 mg/day (long-term studies). At Week 6, least squares mean differences (LSMDs, with 95% confidence limits [CLs]) for brexpiprazole (n = 868) vs placebo (n = 517) were: Positive symptoms: −1.55 (−2.30, −0.80), P < .0001, Cohen’s d effect size (ES) = 0.27; Negative symptoms: −1.12 (−1.63, −0.61), P < .0001, ES = 0.29; Disorganized thought: −1.26 (−1.78, −0.74), P < .0001, ES = 0.32; Uncontrolled hostility/excitement: −0.76 (−1.15, −0.37), P = .0002, ES = 0.26; Anxiety/ depression: −0.56 (−0.91, −0.22), P = .0014, ES = 0.22. At last visit of the maintenance study, LSMDs (95% CLs) for brexpiprazole (n = 96) vs placebo (n = 104) were: Positive symptoms: −3.44 (−4.99, −1.89), P < .0001, ES = 0.62; Negative symptoms: −1.23 (−2.52, 0.07), P = .063, ES = 0.27; Disorganized thought: −1.69 (−2.81, −0.56), P = .0035, ES = 0.42; Uncontrolled hostility/excitement: −1.26 (−2.12, −0.39), P = .0046, ES = 0.41; Anxiety/depression: −0.72 (−1.47, 0.03), P = .061, ES = 0.27. In the OLEx studies, improvements were maintained over 58 (6 + 52) weeks of brexpiprazole treatment. In conclusion, these data suggest that brexpiprazole treats the continuum of schizophrenia symptoms, in the short- and long-term. Trial Registration: Data used in this post hoc analysis came from ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, NCT01810783.

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. 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.