Meta-analysis of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other atypical antipsychotics

IntroductionAsenapine is an FDA-approved atypical antipsychotic (AAP) indicated in adults for treatment of schizophrenia.ObjectivePresent meta-analyses of asenapine vs placebo and other antipsychotics in acute schizophrenia.AimFurther demonstrate the efficacy of asenapine in acute schizophrenia.MethodsPANSS total score changes from baseline to week 6 were assessed using last observation carried forward (LOCF) and mixed model for repeated measures (MMRM). Comparisons of asenapine and antipsychotics vs placebo were obtained from 4 placebo-controlled asenapine studies. Head-to-head comparisons among AAPs assessed in the same trials (including those for which no direct comparisons are available) were conducted with network meta-analyses using a published database (Leucht et al, Am J Psychiatry 2009;166:152–166) of 74 studies updated with data from 5 AAP-controlled asenapine trials.ResultsPANSS change from baseline with asenapine exceeded that of placebo (LOCF: 3.7 [95% CI, 1.5–5.9], P = 0.001; MMRM: 4.1 [95% CI, 1.6–6.5], P = 0.001), a treatment effect comparable to other antipsychotics (LOCF: 4.1 [95% CI, 1.7–6.5], P = 0.001; MMRM: 4.6 [95% CI, 1.9–7.3], P = 0.001). Head-to-head network meta-analysis reported comparable efficacy with asenapine and other AAPs; PANSS differences ranged from 3.9 points better than ziprasidone (95% CI, 0.3–7.4) to 2.9 points worse than olanzapine (95% CI, -5.-0.1).DiscussionThese meta-analyses demonstrate superiority of asenapine over placebo in acute schizophrenia, with treatment effects of asenapine at least comparable to antipsychotics used in the same studies. Further, the network meta-analysis suggests the efficacy of asenapine for acute schizophrenia is comparable to that of established AAPs.

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Efficacy and tolerability of pharmacological interventions on metabolic disturbance induced by atypical antipsychotics in adults: A systematic review and network meta-analysis

Journal of Psychopharmacology ◽

10.1177/02698811211035391 ◽

2021 ◽

pp. 026988112110353

Author(s):

Yewei Wang ◽

Dandan Wang ◽

Jie Cheng ◽

Xinyu Fang ◽

Yan Chen ◽

...

Keyword(s):

Body Weight ◽

Atypical Antipsychotics ◽

Randomized Clinical Trials ◽

Weighted Mean Difference ◽

Meta Analysis ◽

Metabolic Disturbance ◽

Pharmacological Interventions ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Meta Analyses

Background: There have been a few systematic reviews and conventional meta-analyses reporting effect of drugs on metabolic disturbance induced by atypical antipsychotics (AAPs). However, few of them provided sufficient and comprehensive comparisons between pharmacological interventions. Aims: We aimed to qualitatively compare drugs’ effect on AAPs-induced metabolic abnormalities by using network meta-analysis (NMA). Methods: We searched PubMed, EMBASE, Web of Science, Cochrane Controlled Register of Trials (CENTRAL), and PsycINFO on March 26, 2019. Of 5889 records identified, 61 randomized clinical trials including 3467 participants were included. We estimated weighted mean difference (WMD) and odds ratio (OR) using NMA. We assessed the risk of bias of individual studies with the Review Manager 5.3. Primary outcomes included change of body weight and body mass index (BMI). Secondary outcomes included change of other cardiometabolic risk factors, acceptability, and tolerability. Results: For body weight, topiramate (WMD −5.4, 95% CI −7.12 to −3.68), zonisamide (−3.44, 95% CI −6.57 to −0.36), metformin (−3.01, 95% CI −4.22 to −1.83), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (−3.23, 95% CI −5.47 to −0.96), and nizatidine (−2.14, 95% CI −4.01 to −0.27) were significantly superior to placebo. Results regarding to BMI were similar to that of body weight. With respect to tolerability, only topiramate (OR 24, 95% CI 3.15 to 648) was inferior to placebo. Conclusions: Considering both efficacy and tolerability, evidence from this NMA indicates zonisamide, metformin, GLP-1RAs, and nizatidine in adults should be the first-line treatment for alleviating AAPs-induced weight gain or elevated BMI.

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Interval estimation of the overall treatment effect in random-effects meta-analyses: Recommendations from a simulation study comparing frequentist, Bayesian, and bootstrap methods

10.31219/osf.io/5zbh6 ◽

2020 ◽

Author(s):

Frank Weber ◽

Guido Knapp ◽

Anne Glass ◽

Günther Kundt ◽

Katja Ickstadt

Keyword(s):

Literature Review ◽

Random Effects ◽

Simulation Study ◽

Treatment Effect ◽

Profile Likelihood ◽

Meta Analysis ◽

Artery Bypass ◽

Interval Length ◽

Interval Estimators ◽

Meta Analyses

There exists a variety of interval estimators for the overall treatment effect in a random-effects meta-analysis. A recent literature review summarizing existing methods suggested that in most situations, the Hartung-Knapp/Sidik-Jonkman (HKSJ) method was preferable. However, a quantitative comparison of those methods in a common simulation study is still lacking. Thus, we conduct such a simulation study for continuous and binary outcomes, focusing on the medical field for application.Based on the literature review and some new theoretical considerations, a practicable number of interval estimators is selected for this comparison: the classical normal-approximation interval using the DerSimonian-Laird heterogeneity estimator, the HKSJ interval using either the Paule-Mandel or the Sidik-Jonkman heterogeneity estimator, the Skovgaard higher-order profile likelihood interval, a parametric bootstrap interval, and a Bayesian interval using different priors. We evaluate the performance measures (coverage and interval length) at specific points in the parameter space, i.e. not averaging over a prior distribution. In this sense, our study is conducted from a frequentist point of view.We confirm the main finding of the literature review, the general recommendation of the HKSJ method (here with the Sidik-Jonkman heterogeneity estimator). For meta-analyses including only 2 studies, the high length of the HKSJ interval limits its practical usage. In this case, the Bayesian interval using a weakly informative prior for the heterogeneity may help. Our recommendations are illustrated using a real-world meta-analysis dealing with the efficacy of an intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting.

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Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽

10.1161/circ.133.suppl_1.p260 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

James S Floyd ◽

Colleen Sitlani ◽

Christy L Avery ◽

Eric A Whitsel ◽

Leslie Lange ◽

...

Keyword(s):

Repeated Measures ◽

Qt Interval ◽

Association Studies ◽

Meta Analysis ◽

Small Sample ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

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A Bayesian Network Meta-analysis of Add-on Drug Therapies Specific for Pulmonary Arterial Hypertension

Annals of Pharmacotherapy ◽

10.1177/1060028019888760 ◽

2019 ◽

Vol 54 (5) ◽

pp. 423-433 ◽

Cited By ~ 1

Author(s):

Maja Petrovič ◽

Igor Locatelli

Keyword(s):

Pulmonary Arterial Hypertension ◽

Combination Therapy ◽

Arterial Hypertension ◽

Meta Analysis ◽

Phosphodiesterase Type 5 Inhibitors ◽

Number Of Patients ◽

All Cause Mortality ◽

Pulmonary Arterial ◽

Meta Analyses ◽

Better Than

Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.

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Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis

European Child & Adolescent Psychiatry ◽

10.1007/s00787-019-01425-2 ◽

2019 ◽

Vol 29 (9) ◽

pp. 1195-1205

Author(s):

Celso Arango ◽

Daisy Ng-Mak ◽

Elaine Finn ◽

Aidan Byrne ◽

Antony Loebel

Keyword(s):

Weight Gain ◽

Literature Review ◽

Atypical Antipsychotic ◽

Systematic Literature Review ◽

Atypical Antipsychotics ◽

Meta Analysis ◽

Similar Efficacy ◽

Binary Outcomes ◽

Schizophrenia Spectrum Disorders ◽

Credible Intervals

AbstractThis network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (− 7.95, 95% CrI − 11.76 to − 4.16) and CGI-S (− 0.44, 95% CrI − 0.67 to − 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (− 3.62 kg, 95% CrI − 4.84 kg to − 2.41 kg), quetiapine (− 2.13 kg, 95% CrI − 3.20 kg to − 1.08 kg), risperidone (− 1.16 kg, 95% CrI − 2.14 kg to − 0.17 kg), asenapine (− 0.98 kg, 95% CrI − 1.71 kg to − 0.24 kg), and paliperidone ER (− 0.85 kg, 95% CrI − 1.57 kg to − 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10–0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08–0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical antipsychotics.

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Linear mixed model better than repeated measures analysis

European Journal of Ophthalmology ◽

10.1177/1120672119890518 ◽

2019 ◽

Vol 30 (6) ◽

pp. NP1-NP2 ◽

Cited By ~ 1

Author(s):

Işıl Kutluturk Karagoz ◽

Berhan Keskin ◽

Flora Özkalaycı ◽

Ali Karagöz

Keyword(s):

Mixed Models ◽

Repeated Measures ◽

Mixed Model ◽

Linear Mixed Model ◽

Linear Time ◽

Case Series ◽

Model Fit ◽

Repeated Measures Analysis ◽

Technical Issues ◽

Better Than

We have some criticism regarding some technical issues. Mixed models have begun to play a pivotal role in statistical analyses and offer many advantages over more conventional analyses regarding repeated variance analyses. First, they allow to avoid conducting multiple t-tests; second, they can accommodate for within-patient correlation; third, they allow to incorporate not only a random coefficient, but also a random slope, typically ‘linear’ time in longitudinal case series when there are enough data and patients’ trajectories vary a lot and improving model fit.

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Bivariate Random-effects Meta-analysis of Sensitivity and Specificity with SAS PROC GLIMMIX

Methods of Information in Medicine ◽

10.3414/me09-01-0001 ◽

2010 ◽

Vol 49 (01) ◽

pp. 54-64 ◽

Cited By ~ 33

Author(s):

J. Menke

Keyword(s):

Sensitivity And Specificity ◽

Random Effects ◽

Mixed Model ◽

Linear Mixed Model ◽

Meta Analysis ◽

Empirical Evaluation ◽

Test Accuracy ◽

Random Effects Model ◽

Operating Characteristics ◽

Meta Analyses

Summary Objectives: Meta-analysis allows to summarize pooled sensitivities and specificities from several primary diagnostic test accuracy studies. Often these pooled estimates are indirectly obtained from a hierarchical summary receiver operating characteristics (HSROC) analysis. This article presents a generalized linear random-effects model with the new SAS PROC GLIMMIX that obtains the pooled estimates for sensitivity and specificity directly. Methods: Firstly, the formula of the bivariate random-effects model is presented in context with the literature. Then its implementation with the new SAS PROC GLIMMIX is empirically evaluated in comparison to the indirect HSROC approach, utilizing the published 2 x 2 count data of 50 meta-analyses. Results: According to the empirical evaluation the meta-analytic results from the bivariate GLIMMIX approach are nearly identical to the results from the indirect HSROC approach. Conclusions: A generalized linear mixed model with PROC GLIMMIX offers a straightforward method for bivariate random-effects meta-analysis of sensitivity and specificity.

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How should systematic reviewers handle conference abstracts? A view from the trenches

Systematic Reviews ◽

10.1186/s13643-019-1188-0 ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 18

Author(s):

Roberta W. Scherer ◽

Ian J. Saldanha

Keyword(s):

Systematic Reviews ◽

Treatment Effect ◽

Meta Analysis ◽

Good Practice ◽

Effect Estimate ◽

Main Body ◽

Unpublished Studies ◽

Study Results ◽

Meta Analyses ◽

Positive Results

Abstract Background While identifying and cataloging unpublished studies from conference proceedings is generally recognized as a good practice during systematic reviews, controversy remains whether to include study results that are reported in conference abstracts. Existing guidelines provide conflicting recommendations. Main body The main argument for including conference abstracts in systematic reviews is that abstracts with positive results are preferentially published, and published sooner, as full-length articles compared with other abstracts. Arguments against including conference abstracts are that (1) searching for abstracts is resource-intensive, (2) abstracts may not contain adequate information, and (3) the information in abstracts may not be dependable. However, studies comparing conference abstracts and fully published articles of the same study find only minor differences, usually with conference abstracts presenting preliminary results. Other studies that have examined differences in treatment estimates of meta-analyses with and without conference abstracts report changes in precision, but usually not in the treatment effect estimate. However, in some cases, including conference abstracts has made a difference in the estimate of the treatment effect, not just its precision. Instead of arbitrarily deciding to include or exclude conference abstracts in systematic reviews, we suggest that systematic reviewers should consider the availability of evidence informing the review. If available evidence is sparse or conflicting, it may be worthwhile to search for conference abstracts. Further, attempts to contact authors of abstracts or search for protocols or trial registers to supplement the information presented in conference abstracts is prudent. If unique information from conference abstracts is included in a meta-analysis, a sensitivity analysis with and without the unique results should be conducted. Conclusions Under given circumstances, it is worthwhile to search for and include results from conference abstracts in systematic reviews.

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The clinical significance of atypical antipsychotics

Acta Neuropsychiatrica ◽

10.1017/s0924270800034323 ◽

1991 ◽

Vol 3 (4) ◽

pp. 55-60 ◽

Cited By ~ 1

Author(s):

J.A. Den Boer ◽

H.G.M. Westenberg ◽

J.W. Louwerens ◽

C.J. Slooff

Keyword(s):

Tardive Dyskinesia ◽

Clinical Significance ◽

Atypical Antipsychotic ◽

Atypical Antipsychotics ◽

Antipsychotic Drugs ◽

Extrapyramidal Symptoms ◽

Pharmacological Profile ◽

Double Blind ◽

Acute Schizophrenia ◽

Concise Review

SummaryA concise review is given of the importance of the atypical antipsychotic drugs clozapine, sulpiride, remoxipride and raclopride. Both the concept of atypicality and the pharmacological profile of these compounds is discussed. The newly developed atypical antipsychotic remoxipride has been studied in several double blind studies. In virtually all of these studies a reduced propensity for the induction of extrapyramidal symptoms was found.These findings implicate that atypical antipsychotics may also not induce tardive dyskinesia. In addition to the treatment of acute schizophrenia, these compounds might be of use in the treatment of treatment resistent schizophrenia (clozapine), tardive dyskinesia and psychosis during the course of Parkinson's disease.

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Influence of motivational placebo-related factors on the effects of exercise treatment in depressive adolescents

European Child & Adolescent Psychiatry ◽

10.1007/s00787-021-01742-5 ◽

2021 ◽

Author(s):

Heidrun Lioba Wunram ◽

Stefanie Hamacher ◽

Max Oberste ◽

Susanne Neufang ◽

Luisa Belke ◽

...

Keyword(s):

Repeated Measures ◽

Adolescent Depression ◽

Protective Factor ◽

Mixed Model ◽

Rating Scale ◽

Motivational Factors ◽

Related Factors ◽

Exercise Treatment ◽

Meta Analyses ◽

Induced Changes

AbstractRecent meta-analyses reveal a moderate effect of physical activity (PA) in the treatment of adolescent depression. However, not only the underlying neurobiological mechanisms, also the influences of placebo-related motivational factors (beliefs and expectancies in sporting, enjoyment and prior sports experiences), are still unclear. Based on the data of our prior study “Mood Vibes”, we hypothesized that placebo-inherent factors like positive prior sports experiences and motivational factors, (positive beliefs, expectancies, and enjoyment related to PA), would increase the effects of an add-on exercise-therapy in juvenile depression. From 64 included depressed adolescents, 41 underwent an intensive add-on PA-therapy. Motivational factors were assessed using sport-specific scales. The changes in depression scores under treatment were rated by self-rating scale (German “Childhood Depression Inventory”, (DIKJ)). A mixed model for repeated measures (MMRM) was used to analyze the effects of the different motivational variates on DIKJ. While prior sports experiences had no impact, motivational factors showed a significant effect on PA-induced changes in DIKJ scores (p = 0.002). The demotivated participants improved less, whereas it was sufficient to be neutral towards sporting to benefit significantly more. Motivational placebo-related factors (beliefs, expectancies and enjoyment regarding PA) affected the outcomes of an exercise treatment in depressed adolescents. Yet, a neutral mindset was sufficient to profit more from PA. Prior sporting in the sense of positive conditioning and as a protective factor did not play a role. Knowledge about these influences could in a second step help to develop tailored therapies.

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