Serotonin-dopamine Activity Modulator Research Articles

A Review of Recent Advances in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed.As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

1.2 Flexible-Dose Brexpiprazole as Maintenance Treatment in Adolescents With Schizophrenia: A Long-Term, Multicenter, Open-Label Study

Schizophrenia disease characteristics and symptomatic changes have been demonstrated to be similar between adolescents and adults. However, the risk-benefit profile of currently available antipsychotics appears to be less favorable in adolescents with schizophrenia than adults, due to high rates of adverse events (AEs) and treatment discontinuation. The efficacy and safety of brexpiprazole (a serotonin-dopamine activity modulator) for the treatment of schizophrenia have been demonstrated in adult patients aged 18 to 65 years.

In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole

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.

Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human

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.

P.855Efficacy and safety of lurasidone in adolescents and young adults with schizophrenia: pooled analysis of double-blind, placebo-controlled 6-week studies

Second-generation antipsychotics have demonstrated efficacy for patients with schizophrenia but are associated with wide-ranging side effects. Brexpiprazole, a serotonin-dopamine activity modulator, has demonstrated efficacy in adult patients with schizophrenia. This paper provides an overview of the safety and tolerability of brexpiprazole in patients with schizophrenia through examination of pooled safety data from one Phase 2 and two Phase 3 6-week, short-term studies, and two open-label, 52-week, long-term studies.In the short-term studies, there were no reports of treatment-emergent adverse events (TEAEs) with an incidence ≥ 5% and twice that of placebo in patients treated with brexpiprazole 2–4 mg. In the long-term studies, TEAEs reported by ≥ 5% of patients were schizophrenia (10.7%), insomnia (8.0%), weight increase (7.7%), headache (6.0%), and agitation (5.2%). Akathisia rates were low in the short- (5.8%, pooled brexpiprazole group) and long-term studies (4.6%). Sedation rates were low in the short- (2.3%, pooled brexpiprazole group) and long-term studies (0.9%). Mean body weight increase was 1.1 kg in both short- and long-term studies.For all studies, changes from baseline to last visit in laboratory parameters, electrocardiogram values, and vital signs were small and not clinically relevant. Changes in lipid profiles or other metabolic parameters were also small. Collectively, these studies suggest that brexpiprazole was well tolerated, with a favorable safety profile that does not exhibit significant rates of important adverse events that can be seen with existing antipsychotics (akathisia, sedation, weight gain, or QTc prolongation), and therefore may provide a useful treatment option for patients with schizophrenia.ClinicalTrials.gov: NCT00905307; NCT01396421; NCT01393613; NCT01649557; NCT01397786.

M191. EFFECT OF BREXPIPRAZOLE ON ENGAGEMENT IN PATIENTS WITH SCHIZOPHRENIA: POST-HOC ANALYSIS OF THREE STUDIES

BackgroundIn schizophrenia, a patient’s quality of life and level of psychosocial functioning is dependent on two key domains: the severity of their psychotic symptoms, and the side effects of antipsychotic medication. In addition, people with schizophrenia experience motivation deficits, thus patient engagement is a key component of successful schizophrenia treatment outcomes.The present analyses investigated the effect of brexpiprazole (a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all at similar potency) on patient engagement. The concept of patient engagement stems from the collective post-marketing experience with brexpiprazole, and has been established in patients with MDD and an inadequate response to antidepressant treatments treated with adjunctive brexpiprazole.To explore the concept of engagement in schizophrenia, 11 out of the 30 items in the Positive and Negative Syndrome Scale (PANSS) were identified as relevant to capture patient improvement and well-being beyond an improvement of the core symptoms of schizophrenia.MethodsThe studies [Vector (NCT01396421), Beacon (NCT01393613) and Lighthouse (NCT01810380)] included patients aged 18–65 years experiencing an acute exacerbation of schizophrenia (DSM-IV-TR criteria), and who would benefit from hospitalization or continued hospitalization. Eligible patients were randomized to 6 weeks treatment with placebo or brexpiprazole ranging from doses of 0.25 to 4 mg/day depending on the study. The primary efficacy analysis in all three studies was the mean change in PANSS Total score from baseline (randomization) to Week 6. The PANSS was administered at weekly intervals.Items N1, N2, N3, N4, N5, N6, G6, G7, G13, G15, and G16 were selected from the PANSS as relevant items to capture patient engagement.In the present analysis, data were pooled for patients allocated to placebo and to a brexpiprazole dose in the range of 2–4 mg. Mean changes from baseline on the selected PANSS items were analyzed using a mixed model repeated measures approach. A Principal Component Analysis (PCA) was performed to validate whether changes in the selected items clustered together. Standardized effect sizes were also calculated.ResultsIn the short-term studies, the PANSS scale was completed at baseline by a total of 1,378 patients, brexpiprazole 2–4 mg (n=863); placebo (n=515). At Week 6, an improvement (p<0.05) was observed on 10 out of the 11 selected items from the PANSS scale, with LS mean differences versus placebo in the range of -0.11 to -0.24.The PCA showed that the majority of the selected items cluster together, confirming the importance of the selected items for patient engagement/re-engagement with their lives. The standardized effect size for brexpiprazole versus placebo was -0.31 for the combined 11 selected items and of a similar magnitude as the effect size of the PANSS Total score (-0.32).Discussion11 items from the PANSS scale were selected to capture patient re-engagement. The clustering, as shown by the PCA, validated the selection of the specific engagement items. The results of these exploratory post-hoc analyses suggest that treatment with brexpiprazole, in addition to improving symptoms of schizophrenia, has the potential to also improve patient well-being and engagement with life.

Brexpiprazole as an augmentation agent to antidepressants in treatment resistant major depressive disorder

ABSTRACTIntroduction: Approximately 50% of adults with major depressive disorder (MDD) who receive a first-line antidepressant treatment, at an appropriate dose, do not achieve an adequate response. Brexpiprazole is a novel serotonin-dopamine activity modulator in the second generation/atypical antipsychotic class that was approved by the United States Food & Drug Administration in 2015 for use as an adjunctive agent in the treatment of MDD inadequately responsive to antidepressant treatment. In general, second generation/atypical antipsychotics are widely used in the treatment of treatment resistant depression with brexpiprazole providing preliminary evidence for broad-spectrum efficacy across multiple domains affected by MDD, providing a basis for further elucidating its mechanistic effects to inform novel drug discovery.Areas covered: The review herein presents the evidence base for the use of brexpiprazole as an augmentation agent to antidepressants in individuals with treatment resistant MDD, including its efficacy, safety, and tolerability profile.Expert opinion: Brexpiprazole has been demonstrated to be effective and safe to use as an augmentation agent to antidepressant treatment among individuals with treatment resistant MDD due to its considerably improved tolerability profile when compared to other second generation/atypical antipsychotics; however, it is important to exercise clinical judgment when selecting disparate augmentation agents on a case-by-case basis weighing individual risks versus benefits

Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction.

Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression.

In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile

ABSTRACTFrom 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.

In silico, in vitro and in vivo metabolite identification of brexpiprazole using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Brexpiprazole is a novel serotonin-dopamine activity modulator approved by the USFDA in July 2015 for the treatment of schizophrenia and as an adjunctive therapy with other antidepressants for major depressive disorder in adults. However, limited numbers of metabolites are reported in the literature for brexpiprazole. Our prime intent behind this study is to revisit metabolite profiling of brexpiprazole and to identify and characterize all possible in vitro and in vivo metabolites. Firstly, the site of metabolism for brexpiprazole was predicted by a Xenosite web predictor model. Secondly, in vitro metabolite profiling was performed by incubating the drug individually with rat liver microsomes, human liver microsomes and rat S9 fraction at 37°C for 1 h in incubator shaker. Finally, for in vivo metabolite identification, a 50 mg kg-1 dose of brexpiprazole was administered to male Sprague-Dawley rats and the presence of various metabolites was confirmed in rat plasma, urine and feces. The predicted atomic site of metabolism was obtained as a color gradient by the Xenosite web predictor tool and, from this study, probable metabolites were listed. In total, 14 phase I and 2 phase II metabolites were identified and characterized in the in vitro and in vivo matrices using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/QTOF-MS/MS). The majority of metabolites were found in the sample incubated with human liver microsomes and in rat urine, while in the other matrices only a few metabolites were detected. All the 16 metabolites were identified and characterized using UHPLC/QTOF-MS/MS. The study revealed that brexpiprazole is metabolized via hydroxylation, glucuronidation, S-oxidation, N-oxidation, dioxidation, oxidative deamination, N-dealkylation, etc.

Preclinical pharmacological profiles and clinical efficacy of the novel antipsychotic drug brexpiprazole (REXULTI® Tablets 1 mg, 2 mg)

Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as 〝Serotonin- dopamine Activity Modulator (SDAM)〟 that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.

O7.5. LONG-TERM SAFETY AND TOLERABILITY OF BREXPIPRAZOLE IN PATIENTS WITH SCHIZOPHRENIA

BackgroundLong-term maintenance treatment is recommended to control the symptoms of schizophrenia1,2; therefore, safety monitoring for longer than the period required to treat an acute exacerbation is warranted. The aim of the present study (Lighthouse extension; NCT01810783) was to assess the long-term safety and tolerability of open-label treatment with brexpiprazole (flexible dose 1–4 mg/day) in adult patients with schizophrenia. Brexpiprazole is a serotonin-dopamine activity modulator that acts as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at the 5-HT2A and noradrenaline α1B/2C receptors, all with subnanomolar potency. Brexpiprazole is approved in the US as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) and in the US, Australia and Canada as monotherapy for treatment of schizophrenia.MethodsPatients rolled over into this 52-week open-label study from a randomized, double-blind, placebo-controlled, active referenced, Phase 3 study (Lighthouse3; NCT01810380). The primary endpoint was safety and tolerability. Efficacy was assessed as an exploratory endpoint using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions – Severity of illness (CGI-S) and Improvement (CGI-I) scales, and the Personal and Social Performance (PSP) scale. Changes from baseline were analyzed using a mixed model repeated measurements (MMRM) approach.Results210 patients were enrolled, and 101 (48.3%) completed the study. The mean and mean modal doses of brexpiprazole were 3.07mg/day and 3.18mg/day, respectively; at last visit, 50% of the patients received 4mg/day. Among patients who took ≥1 dose of brexpiprazole, the incidence of discontinuation due to treatment-emergent adverse events (TEAEs) was 17.2%. TEAEs with an incidence of ≥5.0% were schizophrenia (worsening of the underlying disease; 11.5%), weight increase (10.5%), headache (8.6%), and insomnia (8.1%). Most TEAEs were mild or moderate in severity. The mean increase in body weight from baseline to Week 52 was 2.6kg (observed cases [OC]) and 19.6% of patients had a weight increase ≥7% at any time during the study. There were no clinically relevant findings for either metabolic parameters (lipids and glucose), or for events related to ECGs, vital signs, extrapyramidal symptoms, or prolactin. Patients’ symptoms and functioning showed continual improvement; at Week 52, mean change from baseline in PANSS was -6.8 (95% confidence interval [CI]: -9.3, -4.2); CGI-S: -0.4 (95%CI: -0.5, -0.2); and PSP: 4.2 (95%CI: 2.2, 6.1). The CGI-I score at Week 52 was 2.8 (95%CI: 2.6, 3.1). The percentage of responders (reduction of ≥30% from baseline in PANSS total score or a CGI-I score of 1 [very much improved] or 2 [much improved]) increased throughout the study, from 16% (OC and last observation carried forward [LOCF]) at Week 1 to 48% (OC) and 35% (LOCF) at Week 52.DiscussionTreatment with open-label brexpiprazole 1–4 mg/day was generally well tolerated for up to 52 weeks in patients with schizophrenia. Further, long-term treatment with brexpiprazole was associated with continued improvement in efficacy measures and functional outcomes.

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

BackgroundAtypical antipsychotics are the mainstay of treatment for schizophrenia, and have a meaningful effect on positive symptoms and agitation/aggression. More recently, treatment goals have shifted to target functioning; a cycle of deterioration often occurs in early schizophrenia in which recurring relapse results in decreased functioning.Brexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all at subnanomolar potency. The efficacy of brexpiprazole has been shown in both short- and long-term studies. In this post-hoc analysis from three short-term studies, the proportion of patients achieving symptomatic and functional response was assessed, grouped by age at baseline.MethodsEfficacy and functioning data were pooled from three 6-week, double-blind, placebo-controlled studies in hospitalized patients with acute exacerbation of schizophrenia (Vector [NCT01396421]; Beacon [NCT01393613]; and Lighthouse [NCT01810380]), and stratified according to age at baseline (18–35 years; and 36–65 years). For the current analyses, response was defined as reduction in PANSS score of ≥30% from baseline; a CGI-I score of 1 or 2 (much improved or improved); or reduction in PANSS score of ≥30% OR CGI-I score of 1 or 2. Functional response was defined as an increase in PSP total score of at least 10 points. The analyses were conducted using a mixed-model repeated measures (MMRM) approach with all brexpiprazole doses pooled (2-4mg/day).Results557 patients aged 18–35 years and 857 patients aged 36–65 years were analysed. For patients aged 18–35 years, a statistically significantly greater proportion of brexpiprazole-treated vs placebo-treated patients had symptomatic response after 6 weeks of treatment (PANSS ≥30%: 40.5% vs 28.7%, p<0.01; CGI-I 1 or 2: 39.9% vs 25.4%, p<0.001; PANSS ≥30% OR CGI-I 1 or 2: 46.2% vs 32.3%, p<0.01). Similar results were observed for patients aged 36–65 years (PANSS ≥30%: 48.7% vs 37.6%, p<0.01; CGI-I 1 or 2: 47.1% vs 32.7%, p<0.0001; PANSS ≥30% OR CGI-I 1 or 2: 54.8% vs 41.6%, p<0.001). For patients aged 18–35 years, a statistically significantly greater proportion of brexpiprazole-treated vs placebo-treated patients had functional response after 6 weeks of treatment (PSP 10 points change: 46.3% vs 33.0%, p<0.01); similar results were observed for patients aged 36–65 years (49.2% vs 38.2%, p<0.01).The proportion of patients meeting both symptomatic (using ≥30% PANSS improvement or CGI-I score of 1 or 2) and functional response was statistically significantly greater in brexpiprazole-treated patients vs placebo-treated patients regardless of the age group (18–35 years: 37.4% vs 25.4%, p<0.01; 36–65 years: 41.8% vs 30.2%, p=0.01).DiscussionThe results of these analyses confirm that 6 weeks of treatment with brexpiprazole results in symptomatic and functional response in acutely ill schizophrenia patients in both younger patients (age 18 to 35 years) as well as older patients (age 36–65).

Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine.

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

Clinical role of brexpiprazole in depression and schizophrenia.

Brexpiprazole, a serotonin–dopamine activity modulator, is the second D2 partial agonist to come to market and has been approved for the treatment of schizophrenia and as an adjunctive treatment in major depressive disorder. With less intrinsic activity than aripiprazole at the D2 receptor and higher potency at 5-HT2A, 5-HT1A, and α1B receptors, the pharmacological properties of brexpiprazole suggest a more tolerable side effect profile with regard to akathisia, extrapyramidal dysfunction, and sedation. While no head-to-head data are currently available, double-blind placebo-controlled studies show favorable results, with the number needed to treat (NNT) vs placebo of 6–15 for response in acute schizophrenia treatment and 4 for maintenance. NNT is 12 for response and 17–31 for remission vs placebo in major depression. In schizophrenia trials, treatment-emergent adverse effects (TEAEs) and discontinuation rates due to TEAEs were lower in treatment groups vs placebo (7.1%–9.2% vs 14.7%, respectively). Meanwhile, discontinuation rates due to TEAEs in depression studies were higher in treatment groups vs placebo (1.3%–3.5% vs 0–1.4%, respectively) and appeared dose dependent. Rates of akathisia are lower compared to those with aripiprazole and cariprazine, weight gain is more prominent than with aripiprazole, cariprazine, or ziprasidone, and sedation is less than with aripiprazole but more than with cariprazine. Brexpiprazole target dosing is 2–4 mg in schizophrenia and 2 mg in depression augmentation. Dose adjustments should be considered in hepatic or renal dysfunction and/or in poor cytochrome P450 2D6 metabolizers. While brexpiprazole represents an exciting second entry for D2 partial agonists with positive studies thus far, direct head-to-head comparisons will shed more light on the efficacy and side effect profile of brexpiprazole.

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

Bipolar disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient's quality of life, better treatments are needed. Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3 and 5-HT1A receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania. The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the behavioral pattern monitor (BPM) and Iowa gambling task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively. DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice. Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model.

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

Background: Many patients with major depressive disorder (MDD) do not respond adequately to first-line antidepressant treatment (ADT). Adjunctive treatment with second-generation antipsychotics has demonstrated efficacy for patients with MDD, but is limited by tolerability and safety issues. The recently introduced serotonin-dopamine activity modulator, brexpiprazole, has demonstrated efficacy as an adjunctive treatment for MDD. Objective/Method: We report tolerability and safety results for adjunctive brexpiprazole from four 6-week short-term (ST; pooled phase 2 and 3, placebo-controlled) and two 52-week long-term (LT; pooled, openlabel) studies. Results: Approximately 90% of patients completed the ST studies, and 48.8% of patients completed the LT studies. In the ST studies, 2.9% of patients discontinued because of an adverse event (AE); in the LT studies, 14.1% of patients discontinued because of an AE. In the ST and LT studies, the most frequently reported treatment-emergent AEs (TEAEs) were akathisia (8.6% and 10.0%, respectively) and weight gain (7.3% and 25.5%, respectively). Rates of sedation and somnolence were low (ST and LT: sedation, 0.8% and 3.7%, respectively; somnolence, 3.4% and 9.4%, respectively). In the ST and LT studies, brexpiprazole was associated with small changes in metabolic parameters and moderate weight increase. Conclusions: Collectively, these data suggest brexpiprazole is well tolerated as an adjunctive treatment for MDD.

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

Second-generation antipsychotics have demonstrated efficacy for patients with schizophrenia but are associated with wide-ranging side effects. Brexpiprazole, a serotonin-dopamine activity modulator, has demonstrated efficacy in adult patients with schizophrenia. This paper provides an overview of the safety and tolerability of brexpiprazole in patients with schizophrenia through examination of pooled safety data from one Phase 2 and two Phase 3 6-week, short-term studies, and two open-label, 52-week, long-term studies.In the short-term studies, there were no reports of treatment-emergent adverse events (TEAEs) with an incidence≥5% and twice that of placebo in patients treated with brexpiprazole 2–4mg. In the long-term studies, TEAEs reported by ≥5% of patients were schizophrenia (10.7%), insomnia (8.0%), weight increase (7.7%), headache (6.0%), and agitation (5.2%). Akathisia rates were low in the short- (5.8%, pooled brexpiprazole group) and long-term studies (4.6%). Sedation rates were low in the short- (2.3%, pooled brexpiprazole group) and long-term studies (0.9%). Mean body weight increase was 1.1kg in both short- and long-term studies.For all studies, changes from baseline to last visit in laboratory parameters, electrocardiogram values, and vital signs were small and not clinically relevant. Changes in lipid profiles or other metabolic parameters were also small. Collectively, these studies suggest that brexpiprazole was well tolerated, with a favorable safety profile that does not exhibit significant rates of important adverse events that can be seen with existing antipsychotics (akathisia, sedation, weight gain, or QTc prolongation), and therefore may provide a useful treatment option for patients with schizophrenia.ClinicalTrials.gov: NCT00905307; NCT01396421; NCT01393613; NCT01649557; NCT01397786.

Brexpiprazole as adjunctive treatment of major depressive disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials

BackgroundAnxiety symptoms are prevalent in major depressive disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). The efficacy and safety of brexpiprazole – a serotonin-dopamine activity modulator – as adjunctive treatment in patients with MDD was recently evaluated in two phase 3 studies. We here present a post-hoc analysis of the efficacy of adjunctive brexpiprazole in patients with MDD and symptoms of anxious distress, defined using proxies for DSM-5 criteria. MethodsEligible patients were randomized to 2mg brexpiprazole+ADT or placebo+ADT (NCT01360645); or 1mg brexpiprazole+ADT, 3mg brexpiprazole+ADT, or placebo+ADT (NCT01360632), respectively. Patients were defined as having anxious distress if they had ≥2 of the symptoms tension (MADRS item 3 score ≥3), restlessness (IDS item 24 score ≥2), concentration (MADRS item 6 score ≥3), or apprehension (HAM-D item 10 score ≥3). Primary efficacy endpoint was change in MADRS total score from baseline to Week 6. Results55% of the patients had anxious distress at baseline. Adjunctive brexpiprazole showed greater improvement than adjunctive placebo on the primary efficacy endpoint in both patients with (least square mean difference to placebo+ADT: 2mg+ADT: −2.95, p=0.0023; 3mg+ADT: −2.81, p=0.0027); and without anxious distress (1mg+ADT: −2.37, p=0.0093; 3mg+ADT: −2.23, p=0.0131). Brexpiprazole in patients with anxious distress was not associated with an increased incidence of activating adverse events (e.g., akathisia). ConclusionsAdjunctive brexpiprazole 2–3mg may be efficacious in reducing depressive symptoms and is well tolerated, in patients with MDD and anxious distress.

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

Brexpiprazole, a serotonin-dopamine activity modulator, is a partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency. Efficacy of brexpiprazole was evaluated in patients with acutely exacerbated schizophrenia in three short-term, randomized, double-blind, placebo-controlled studies.In a Phase 2 study, patients were randomized to brexpiprazole 0.25mg (fixed dose), 1.0±0.5mg, 2.5±0.5mg, 5.0±1mg (flexible-dose ranges), placebo, or aripiprazole 15±5mg. In two Phase 3 studies, patients were randomized to fixed-dose brexpiprazole 0.25mg, 1mg, 2mg, or 4mg, or placebo. For this review, brexpiprazole 2mg and 4mg arms from the Phase 3 studies were combined. Primary efficacy endpoint was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at week 6; key secondary endpoint was change in Clinical Global Impression-Severity of illness (CGI-S) score at week 6. Primary outcome moderator analyses explored effects of sex, age, race, and illness duration.There were no statistically significant differences vs. placebo in the Phase 2 brexpiprazole and aripiprazole groups for primary and key secondary endpoints. Combined brexpiprazole 2mg (n=359) and 4mg (n=359) were superior to placebo (n=358) in change in PANSS total score (least square mean difference from placebo: −5.46, p=0.0004, and −6.69, p<0.0001, respectively) and CGI-S (−0.25, p=0.0035, and −0.38, p<0.0001, respectively). Changes from baseline in efficacy endpoints were minimal in the 0.25mg group, while the 1mg group exhibited suboptimal improvement. No relevant moderators were identified.Meta-analysis of the pivotal studies indicates brexpiprazole 2mg and 4mg are effective in treating acute schizophrenia.