Treatment Of Acute Schizophrenia Research Articles

Optimal dose for the efficacy of asenapine in patients with schizophrenia: Real-world data.

A meta-analysis of short-term studies revealed no significant differences between the doses of asenapine, 10 and 20 mg/day, in the acute treatment of schizophrenia. However, it should be noted that many patients from clinical practice were excluded, and the dose-response to asenapine in a real-world setting is still unclear. Additionally, the dose-response in the maintenance phase is not clear. This study aimed to evaluate the differences in the efficacy of different asenapine doses in patients with maintenance phase of schizophrenia in a real-world setting. This study conducted post-marketing surveillance of asenapine in clinical settings in Japan. It followed patients diagnosed with schizophrenia who received asenapine for the first time for a maximum of 52 weeks. These patients were divided into two categories based on their average daily asenapine dosage: ≤10 mg/day and >10 mg/day. Asenapine efficacy was assessed by adjusting for patient demographics using multivariate logistic regression analysis, employing the Clinical Global Impression-Global Improvement (CGI-I) scale, which has seven categories. A total of 2774 patients were included in the analysis. Of these, 1689 and 1085 patients were treated with asenapine ≤10 mg/day and >10 mg/day, respectively. The CGI-I improvement rate was significantly higher in the asenapine >10 group (p = 0.012) after adjusting for patient background factors. These results suggest that asenapine doses >10 mg/day may be more effective than 10 mg/day in the treatment of schizophrenia; however, further studies are needed to confirm these findings.

The efficacy of cariprazine in chronic schizophrenia – post hoc analyses of phase II/III clinical trials

IntroductionChronic schizophrenia patients are experiencing persistent and severe illness for more than 15-20 years and are usually suffering from long-term negative symptoms. Cariprazine, a novel D3-D2 partial agonist has been proven to be effective in the treatment of acute schizophrenia, however its ability to treat chronic patients has not been assessed yet.ObjectivesThe primary aim of the present post-hoc analysis is to assess the efficacy of cariprazine in treating patients with chronic schizophrenia (late-stage and residual schizophrenia patients).MethodsData from 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with more than 15 years of schizophrenia were analysed (late-stage patients). Furthermore, schizophrenia patients experiencing predominantly negative symptoms from a 26-week, randomized, double-blind, active-controlled, fixed-flexible-dose trial with an ICD-10 code of F20.5 were analysed post-hoc (residual patients).ResultsAltogether, 414 late stage (286 cariprazine and 128 placebo) and 35 residual (23 cariprazine and 12 risperidone) patients were identified. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference in favour of cariprazine in the late stage (LSMD -6.7, p<0.01) subpopulation compared to placebo. The mean change from baseline in patients with residual schizophrenia in the cariprazine arm was -9.6 on the PANSS-FSNS scale, while -7.9 in the risperidone arm.ConclusionsBased on the results, it seems that cariprazine might be a good treatment option for patients with chronic schizophrenia. Nonetheless, further studies are needed to confirm this.DisclosureI am an employee of Gedeon Richter Plc.

Efficacy and safety of lurasidone in schizophrenia: pooled analysis of European results from double-blind, placebo-controlled 6-week studies.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P < 0.001) and the CGI-Severity score ( P < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters.

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

IntroductionOnset of schizophrenia commonly occurs during late adolescence or early adulthood and is often characterized by greater symptom severity and impairment.ObjectivesTo evaluate the efficacy and safety of lurasidone in the treatment of acute schizophrenia in adolescents and young adults.MethodsThe 4 studies in this pooled analysis used similar study designs. Patients (ages 13-25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with once-daily lurasidone (37 mg, 74 mg, 111 mg, 148 mg). The primary outcome was endpoint change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary measures included the Clinical Global Impression, Severity scale (CGI-S).ResultsThe safety population consisted of 537 patients; 79.1% completed the studies. Treatment with lurasidone was significant (P&lt;0.001) at Week 6 endpoint for change in the PANSS total score, with higher effect sizes (ES) at higher doses (37 mg, 0.53; 74 mg, 0.57; 111 mg, 0.67; 148 mg, 1.35); significance was also observed for change in the CGI-S (37 mg, 0.51; 74 mg, 0.49; 111 mg, 0.57; 148 mg, 1.75). For lurasidone (combined doses), 3 adverse events occurred with a frequency ≥5% (nausea, 13.5%; somnolence, 12.1%; akathisia, 10.1%); 4.8% of patients discontinued due to an adverse event. At LOCF-endpoint, 3.6% of patients had weight gain ≥7%, and 1.5% had weight loss ≥7%. Minimal median changes were observed at endpoint in metabolic lab values.ConclusionsIn adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 37-148 mg/d was a safe, well-tolerated, and effective treatment.DisclosurePresenter is an employee of Sunovion Pharmaceuticals Inc. The study summarized in this Abstract was supported by Funding from Sunovion Pharmaceuticals Inc.

T79. BALANCING EFFECTS WITH SIDE-EFFECTS: EXAMINING COMPARATIVE METABOLIC CONSEQUENCES OF 18 ANTIPSYCHOTICS IN TREATMENT OF SCHIZOPHRENIA USING NETWORK META-ANALYSIS

BackgroundAntipsychotic treatment is associated with metabolic disturbance. However, the relative degree to which metabolic alterations occur in treatment with different antipsychotics remains unclear. Furthermore, predictors of metabolic dysregulation are poorly understood, and association between metabolic-change and change in psychopathology is uncertain.MethodsWe searched Medline, EMBASE and PsychINFO from inception until June 30, 2019. We included blinded randomised controlled trials (RCTs) comparing 18 antipsychotics and placebo in acute-treatment of schizophrenia. We performed frequentist random-effects network meta-analyses (NMAs) to investigate treatment-induced changes in body weight, BMI, total/LDL/HDL-cholesterol, triglycerides, and glucose. We performed meta-regressions to examine relationships between metabolic change and age/gender/ethnicity/baseline-weight/baseline-metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change.ResultsOf 6532 citations, 100 RCTs met inclusion criteria, including 25,952 patients. Median treatment-duration was 6-weeks. According to our NMAs, mean differences for weight-gain compared to placebo ranged from -0.23 (95% CI: -0.83, 0.36) for best (haloperidol) to +3.01kg (1.78, 4.24) for worst (clozapine); for BMI from -0.25 (-0.68, 0.17) for best (haloperidol) to +1.07kg/m2 (0.90, 1.25) for worst (olanzapine); for total-cholesterol from -0.09 (-0.24, 0.07) for best (cariprazine) to +0.56mmol/L (0.26, 0.86) for worst (clozapine); for LDL-cholesterol from -0.13 (-0.21, -0.05) for best (cariprazine) to +0.20mmol/L (0.14, 0.26) for worst (olanzapine); for HDL-cholesterol from +0.05 (0.00, 0.10) for best (brexpiprazole) to -0.10mmol/L (-0.33, 0.14) for worst (amisulpride); for triglycerides from -0.01 (-0.10, 0.08) for best (brexpiprazole) to +0.98mmol/L (0.48, 1.49) for worst (clozapine); for glucose from -0.29 (-0.55, -0.03) for best (lurasidone) to 1.05mmol/L (0.41, 1.70) for worst (clozapine). Greater increases in glucose were predicted by higher baseline-weight (p=0.001) and male-gender (p=0.008). Non-Caucasian ethnicity was associated with greater increases in total-cholesterol (p=0.04). Improvements in symptom severity were associated with increases in weight (rho=0.36, p=0.002), BMI (rho=0.84, p<0.0001), total-cholesterol (rho=0.31, p<0.05), and LDL-cholesterol (rho=0.42, p=0.01), and decreases in HDL-cholesterol (rho= -0.35, p=0.04).DiscussionThere are marked differences between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles. By contrast, compared with placebo, lurasidone and cariprazine respectively reduce fasting glucose and LDL-cholesterol, while aripiprazole and brexpiprazole increase HDL-cholesterol. Baseline weight, male gender, and non-Caucasian ethnicity predict vulnerability to antipsychotic-induced metabolic change. Considering the increased prevalence of metabolic syndrome, cardiovascular disease, and cardiovascular mortality in schizophrenia, these data may be used to inform antipsychotic-prescribing, especially in those at-risk groups we have identified. However, clinical decisions to preferentially use an antipsychotic with fewer metabolic side effects should consider that clinical improvement appears to be associated with development of these side effects.

Optimal doses of antipsychotics may be higher or lower than licensed ranges

A meta‐analysis examining 20 antipsychotic medications used in the acute treatment of schizophrenia has found evidence that licensed doses for some of the drugs are higher or lower than the likely maximum effective dose of the medications. The dose‐response analysis offers important guidance for clinicians treating schizophrenia, according to study authors. Results were published online Dec. 16, 2019, in the American Journal of Psychiatry.

Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis

SummaryBackgroundAntipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment.MethodsWe searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change.FindingsOf 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6–8). Mean differences for weight gain compared with placebo ranged from −0·23 kg (95% CI −0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from −0·25 kg/m2 (−0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from −0·09 mmol/L (−0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26–0·86) for clozapine; for LDL cholesterol from −0·13 mmol/L (−0.21 to −0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to −0·10 mmol/L (−0·33 to 0·14) for amisulpride; for triglycerides from −0·01 mmol/L (−0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from −0·29 mmol/L (−0·55 to −0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=–0·35, p=0·035).InterpretationMarked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.FundingUK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre.

Comparison of the effects of different medications in the treatment of acute onset schizophrenia

Objective To compare the therapeutic effect of different drug in the treatment of schizophrenia in acute stage. Methods From November 2014 to June 2017, 105 patients with acute schizophrenia admitted in Department of Psychiatry of Taiyuan Psychiatric Hospital and Department of Psychiatry of Jiuzhou Dermatological Hospital of Taiyuan were selected in the study.Seventy-five patients were from the Department of Psychiatry, Taiyuan Psychiatric Hospital.Thirty patients were from the Department of Psychiatry, Jiuzhou Dermatology Hospital.The patients were divided into three groups by random number method, with 35 cases in each group.A group was given amisulpride.B group was given olanzapine.C group was given ziprasidone.The PANSS score (positive symptoms, negative symptoms, mental pathological score), curative effect (cured, significantly improved, invalid), adverse events (EPS, akathisia, nausea, rapid heart beat, blurred vision, orthostatic dizziness, weight gain, total adverse events) in the three groups were observed. Results After treatment for 2 weeks, the positive symptoms.negative symptoms, mental pathological score in the three groups were significantly decreased (all P 0.05). There was no statistically significant difference in therapeutic effect among the three groups (P>0.05). The occurrence of EPS of C group was significantly lower than that of B group [14.29%(5/35) vs.40.00%(14/35), χ2=5.851, P 0.05). Conclusion Amisulpride, olanzapine and ziprasidone in the treatment of acute phase of schizophrenia has good early reaction control and late curative effect.The adverse events of ziprasidone is significantly less than the other two drugs.But patients adopt which kind of drugs also need to formulate specific solutions according to individual circumstance. Key words: Schizophrenia; Ammonia sulfonis; Olanzapine; Ziprasidone; Comparative effectivehess research

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses.

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15-44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42-0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3-6 months' duration; trough clozapine level ⩾350-400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.

Efficacy and metabolic effects of lurasidone versus brexpiprazole in schizophrenia: a network meta-analysis.

Aim: To assess the relative efficacy and metabolic effects of lurasidone and brexpiprazole in the acute treatment of schizophrenia. Methods: Five lurasidone and three brexpiprazole trials were identified. In the absence of head-to-head trials, a Bayesian network meta-analysis comparing lurasidone and brexpiprazole was performed. Results: Nonstatistically significant differences in efficacy measures were observed between lurasidone and brexpiprazole. Significant differences favoring lurasidone for weight change (-0.69kg; 95% CrI: -1.22 to -0.15), total cholesterol (-7.60mg/dl; 95% CrI: -13.94 to -1.22), and low-density lipoprotein (-6.58mg/dl; 95% CrI: -12.11 to -1.04) were observed, with a trend indicating half the risk of experiencing ≥7% weight gain. Conclusion: This network meta-analysis suggested that lurasidone had similar efficacy and fewer metabolic effects than brexpiprazole in patients with acute schizophrenia.

F214. PSYCHOLOGICAL INTERVENTIONS FOR POSITIVE SYMPTOMS IN SCHIZOPHRENIA: A NETWORK META-ANALYSIS

BackgroundThere is rising awareness about the need of multi-disciplinary approaches integrating psychological treatments for schizophrenia, but a comprehensive evidence base on their relative efficacy is lacking. Conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, acceptability and tolerability of psychological interventions for schizophrenia.MethodsWe performed a network meta-analysis (which uses both direct and indirect comparisons) of randomized controlled trials on psychological treatments aimed at positive symptoms in the acute treatment of schizophrenia, compared with another psychological intervention or with a no treatment condition (waiting list, treatment as usual). We excluded trials done in patients with predominant negative symptoms, concomitant psychiatric disorders or medical illnesses, and those done in first episode or stable patients. Published and unpublished studies were sought through database searches, trial registries and websites. Study selection and data extraction were conducted by at least two independent reviewers. Our primary outcome is the change in positive symptoms on a validated rating scale. Secondary outcomes include number of dropouts, overall and negative symptoms of schizophrenia, response, relapse, adherence, depression, quality of life, functioning and adverse events. Analyses were conducted in R within a frequentist framework. The risk of bias in studies has been evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using an adaptation of the GRADE framework to NMA, recommended by the Cochrane guidance. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. The protocol of this review has been registered in Prospero (registration number: CRD42017067795).ResultsAfter screening 20196 references for title and abstract and 2555 full text articles, we identified 58 suitable trials, for a total of 3956 participants.Regarding primary outcome positive symptoms, only Cognitive Behavioural Therapy was significantly more effective than treatment as usual, with a standardised mean difference of -0.59 [95% credible interval -1.03; -0.16].The standardised mean differences with 95% credible intervals for other interventions were: Acceptance and Commitment Therapy -0.07 [-2.12; 1.98], Cognitive Therapy -0.18 [-1.92; 1.55], Hallucination Treatment -0.69 [-2.40; 1.01], Metacognitive Therapy -0.26 [-1.16; 0.64], Mindfulness -0.26 [-2.14; 1.62], with heterogeneity tau2 = 0.6942.Data analyses on other outcomes are ongoing.DiscussionWe are going to investigate the possible sources of heterogeneity with the pre-planned subgroup analyses: number of sessions, study duration, individual versus group setting, expertise of the therapist and baseline severity.A network meta-analysis is the only methodology that allows the production of hierarchies of interventions for treatment of schizophrenia. Such hierarchies, saying which treatment is likely to be the best, the second best and so on, are essential for guideline development. The results of this study are therefore likely to provide knowledge of great impact for treatment decisions.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 701717.

Early improvement in PANSS-30, PANSS-8, and PANSS-6 scores predicts ultimate response and remission during acute treatment of schizophrenia.

PANSS-8 and PANSS-6 are derived from the 30-item Positive and Negative Syndrome Scale (PANSS-30). We investigate whether PANSS-8 or PANSS-6 is a reliable, valid, sensitive to change measure, and scalable, and whether early improvement using them can predict response/remission. Data were from 3 trials for 270 schizophrenia inpatients receiving antipsychotics. Internal consistency, validity, sensitivity to change, and scalability using PANSS-30, PANSS-8, and PANSS-6 at each assessment were examined. Early improvement was defined as at least 20% reduction of PANSS-30, PANSS-8, or PANSS-6 scores at week 2. Response was defined as at least 40% reduction of PANSS-30 and remission as a score of PANSS-8 ≤ 3 on each item at endpoint. Receiver operating characteristic analysis was used to determine which rating scale had better discriminative capacity. PANSS-8 and PANSS-6 showed acceptable internal consistency, were highly correlated with PANSS-30, and had sensitivity to change. PANSS-8 and PANSS-6 were scalable at each assessment, except for PANSS-6 at baseline. Early improvement using PANSS-8 or PANSS-6 had comparable predictive values with that of PANSS-30 for response/remission. PANSS-8 and PANSS-6 are clinically useful measures. Early improvement, regardless of whether PANSS-30, PANSS-8, or PANSS-6 is used, is a statistically significant predictor of response/remission.

Cariprazine specificity profile in the treatment of acute schizophrenia: a meta-analysis and meta-regression of randomized-controlled trials.

Cariprazine is a new dopamine D2 and D3 receptor partial agonist antipsychotic. Meta-analytic evidence of efficacy in acute schizophrenia and specific groups of patients is lacking. We carried out a meta-analysis in patients with acute schizophrenia to evaluate the efficacy of cariprazine over placebo and active comparators in overall symptoms, positive and negative symptoms and quality of life. Low and high (≥6 mg/day) doses were tested separately. The possible effect of clinical-demographic modulators was also tested. Four studies (2144 patients) were included. Both high and low cariprazine doses proved superior to placebo in all symptom domains. The standardized mean difference (SMD) to placebo showed a modest impact on overall symptoms compared with meta-analytic results for other antipsychotics (SMD was similar to lurasidone, asenapine, ziprasidone and aripiprazole, but lower than risperidone, quetiapine and olanzapine). The SMD to placebo on negative symptoms was superior to many antipsychotics including aripiprazole, with a slightly more relevant effect of cariprazine low doses. This effect was probably on secondary negative symptoms since the short-term follow-up of the studies included. Meta-regression data further refined the compound clinical profile, suggesting that cariprazine may be particularly useful in young patients with a relatively short duration of disease.

Determination of Iloperidone in Pharmaceuticals by Validated High-Performance Liquid Chromatography

ABSTRACTIloperidone is an antipsychotic drug used for treatment of acute schizophrenia in adults. In this study, a simple and specific method was developed for determination of iloperidone in tablets. The separation was performed on a C18 column using pH 3 20 mM phosphate buffer and acetonitrile as the mobile phase. The optimum conditions were 1 ml/min flow rate, 35°C column temperature, and 2 µL injection volume. Carbamazepine was used as an internal standard. Iloperidone was monitored at 274 nm with a diode array detector. The method was validated according to the literature guidelines and was linear from 0.5 to 100 µg/ml of iloperidone. The detection and quantification limits were 0.0909 and 0.3030 µg/ml, respectively. The method was acceptable in terms of accuracy, precision, specificity, robustness, and stability and employed for the analysis of tablets.

P.3.d.008 - Cariprazine specificity profile in the treatment of acute schizophrenia: a meta-analysis and meta-regression of randomized-controlled trials

The decisions of asset selection and allocation lie at the heart of financial portfolio management. For these challenging tasks, the mathematical programming model of the mean–variance optimization problem proposes to use the concept of diversification. The novel methodology in this article is a representation of the accumulated knowledge of this model from the modern portfolio theory. It is a practical application for portfolio managers to help synthesize the available historical data and to infer rational decisions. The state-of-the-art backtesting methodology integrates the unsupervised machine learning method of clustering analysis into the mean–variance portfolio optimization model. The test results from the proposed novel methodology show that clustering with Euclidean distance measures outperform the results of the benchmark and other specified clustering methods for different datasets, backtesting periods, and temporal scales of major stock indices.

Brain-derived neurotrophic factor serum and plasma levels in the treatment of acute schizophrenia with olanzapine or risperidone: 6-week prospective study

Antipsychotics have been the mainstay of the treatment of schizophrenia, and their potential role in neuroprotection could be related to brain-derived neurotrophic factor (BDNF). So far different effects on both serum and plasma levels of BDNF were reported related to the various antipsychotic treatments. Aim of this study was to investigate the influence of olanzapine or risperidone on both plasma and serum levels of BDNF in patients with acute schizophrenia. For 50 participants with acute episode of schizophrenia both plasma and serum BDNF, along with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression scale, were assessed pretreatment and post treatment – after 6 weeks of either risperidone or olanzapine. Results show that a weak correlation between pretreatment plasma and serum levels of BNDF was found no longer significant after 6 weeks of treatment. Antipsychotics, olanzapine and risperidone showed no significant effect on post treatment plasma and serum levels of BDNF. Pretreatment plasma level of BDNF and PANSS positive subscale were positively correlated. Post treatment serum level of BDNF and Clinical Global Impression were negatively correlated. In conclusion, plasma and serum BDNF levels could be different markers to some extent with regard to clinical symptoms, response to therapy and outcome. The interrelation between serum and plasma BDNF should be established in further studies.

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.

A randomized, double-blind, comparison of the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine versus full-dose olanzapine in the acute treatment of schizophrenia

ObjectiveAntipsychotic polypharmacy is common in clinical practice, but not recommended in guidelines for treating schizophrenia patients. This study aimed to compare the efficacy and safety of low-dose olanzapine plus low-dose trifluoperazine (a first-generation antipsychotic [FGA]) to full-dose olanzapine (a second-generation antipsychotic [SGA]) in the treatment of acute schizophrenia. MethodIn this 6-week, double-blind, fixed-dose study, patients were randomized to receive 5mg/day of olanzapine plus 5mg/day of trifluoperazine or 10mg/day of olanzapine for 6weeks. Efficacy measures, including the Positive and Negative Syndrome Scale (PANSS) and other scales, safety measures, side effect measures, and quality of life were assessed regularly. Response was defined as at least a 30% reduction in the PANSS total score. ResultsBoth groups were similar in: 1) baseline characteristics, 2) score changes in all efficacy measures, safety measures, side effect measures, and quality of life, and 3) response rates at each visit. The polypharmacy group with low-dose olanzapine did not have less weight gain and lower lipid levels than the monotherapy group with full-dose olanzapine. ConclusionPolypharmacy is as efficacious and safe as, but cheaper than, monotherapy in the acute treatment of schizophrenia. Whether our findings can be generalized to other combinations of an appropriate ratio of one FGA to another SGA dosage, which can achieve favorable clinical responses and side effect profiles, needs further investigation.

Starting aripiprazole long-acting-once-a-month early in treatment: why, how and for whom? Expert consensus and practical recommendations by a panel of Italian clinicians

ABSTRACTIntroduction: Aripiprazole long acting once-monthly (AOM) is approved for the treatment of schizophrenia in adults. Despite recent evidence of AOM efficacy in the acute treatment of schizophrenia, it is recommended that AOM should be started once the acute symptoms are controlled and patients are stabilized. However, there currently are no definitive guidelines exactly describing when a patient is to be considered stabilized enough to start AOM and which the patients are for whom an early AOM start is to be preferred.Areas covered: A panel of Italian clinicians experienced with real world use of AOM met to discuss the scenarios where an early (i.e., immediately after controlling the acute symptoms) start of AOM may be suggested. Real life clinical experiences were shared and a consensus was reached.Expert opinion: There are cases when the risks/benefits ratio suggests to start AOM early, i.e. immediately after the acute symptoms have been stabilized, as opposed to starting it several days/weeks after the stabilization of acute symptoms. Clinical pearls, guidelines and opinions are provided.

A Flexible Bayesian Approach to Monotone Missing Data in Longitudinal Studies With Nonignorable Missingness With Application to an Acute Schizophrenia Clinical Trial

We develop a Bayesian nonparametric model for a longitudinal response in the presence of nonignorable missing data. Our general approach is to first specify a working model that flexibly models the missingness and full outcome processes jointly. We specify a Dirichlet process mixture of missing at random (MAR) models as a prior on the joint distribution of the working model. This aspect of the model governs the fit of the observed data by modeling the observed data distribution as the marginalization over the missing data in the working model. We then separately specify the conditional distribution of the missing data given the observed data and dropout. This approach allows us to identify the distribution of the missing data using identifying restrictions as a starting point. We propose a framework for introducing sensitivity parameters, allowing us to vary the untestable assumptions about the missing data mechanism smoothly. Informative priors on the space of missing data assumptions can be specified to combine inferences under many different assumptions into a final inference and accurately characterize uncertainty. These methods are motivated by, and applied to, data from a clinical trial assessing the efficacy of a new treatment for acute schizophrenia. Supplementary materials for this article are available online.