brexpiprazole and Bipolar-Disorder

Are antipsychotic dose equivalents between acute mania and schizophrenia the same?. Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia.. We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%).. Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Haloperidol; Humans; Mania; Olanzapine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task-hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients.

Topics: alpha-Methyltyrosine; Animals; Antimanic Agents; Behavior, Animal; Bipolar Disorder; Cohort Studies; Disease Models, Animal; Dopamine Agonists; Dopamine Plasma Membrane Transport Proteins; Enzyme Inhibitors; Exploratory Behavior; Gene Knockdown Techniques; Locomotion; Mice; Mice, Inbred C57BL; Quinolones; Reproducibility of Results; Thiophenes; Tyrosine 3-Monooxygenase; Valproic Acid

Brexpiprazole is a dopamine/serotonin receptor partial agonist (D. 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).. 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.. 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),. 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.

Topics: Adult; Bipolar Disorder; Dopamine Agonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Quinolones; Serotonin Agents; Thiophenes; Treatment Outcome

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

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

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 D. 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.

Topics: Animals; Behavior, Animal; Bipolar Disorder; Choice Behavior; Disease Models, Animal; Dopamine Agonists; Dopamine Plasma Membrane Transport Proteins; Exploratory Behavior; Female; Gene Knockdown Techniques; Impulsive Behavior; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phenotype; Quinolones; Receptor, Serotonin, 5-HT1A; Risk-Taking; Serotonin Agents; Thiophenes

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