Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports.

Published on Aug 25, 2021in BMC Medicine8.775
· DOI :10.1186/S12916-021-02062-W
Alexander Hodkinson11
Estimated H-index: 11
(NIHR: National Institute for Health Research),
Evangelos Kontopantelis2
Estimated H-index: 2
(University of Manchester)
BACKGROUND Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries). METHODS We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556. RESULTS Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity. CONCLUSION IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.
Background Clinical study reports (CSRs) have been increasingly utilised within academic research in recent years. European Medicines Agency (EMA) Policy 0070 ‘Phase 1,’ which came into effect in January 2015, requires the publication of regulatory documents such as CSRs from central applications in an anonymised format. EMA Policy 0070 requires sponsors to demonstrate careful consideration of data utility within anonymised CSRs published within the scope of the policy, yet the concept of data u...
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#2Adriani Nikolakopoulou (University of Bern)H-Index: 23
Last. Stefan Leucht (TUM: Technische Universität München)H-Index: 106
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Summary Background Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials. Methods We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, M...
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Background Although risperidone is increasingly used for behavioral indications in children, the associated adverse events (AEs) are not well defined in this population.
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Reporting bias is a major threat to the validity and credibility of systematic reviews. This article outlines the rationale for accessing clinical study reports and other regulatory documents (regulatory data) as a means of addressing reporting bias and identifies factors that may help decide whether (or not) to include regulatory data in systematic reviews. The article also describes the origins and current state of regulatory data access and summarises a survey of current systematic reviewers'...
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The Yale University Open Data Access (YODA) Project has facilitated access to clinical trial data since 2013. The purpose of this article is to provide an overview of the Project, describe key decisions that were made when establishing data sharing policies, and suggest how our experience and the experiences of our first two data generator partners, Medtronic, Inc. and Johnson & Johnson, can be used to enhance other ongoing or future initiatives.
#1Alexander HodkinsonH-Index: 11
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Clinical study reports (CSRs) are produced for marketing authorisation applications. They often contain considerably more information about, and data from, clinical trials than corresponding journal publications. Use of data from CSRs might help circumvent reporting bias, but many researchers appear to be unaware of their existence or potential value. Our survey aimed to gain insight into the level of familiarity, understanding and use of CSRs, and to raise awareness of their potential within th...
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#2Orestis Efthimiou (University of Bern)H-Index: 22
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Summary Background Acutely occurring, life-threatening side-effects of antipsychotic drugs might contribute to the reduced life expectancy observed in patients with severe mental disorders. We aimed to assess this hypothesis by doing a systematic review and meta-analysis of deaths occurring in placebo-controlled trials of antipsychotic drugs. Methods For this systematic review and meta-analysis, we included randomised controlled trials comparing second-generation antipsychotics with placebo acro...
BACKGROUND: Individual patient data (IPD) meta-analysis allows for the exploration of heterogeneity and can identify subgroups that most benefit from an intervention (or exposure), much more successfully than meta-analysis of aggregate data. One-stage or two-stage IPD meta-analysis is possible, with the former using mixed-effects regression models and the latter obtaining study estimates through simpler regression models before aggregating using standard meta-analysis methodology. However, a com...
#1Maria Petropoulou (UoI: University of Ioannina)H-Index: 6
#2Dimitris Mavridis (UoI: University of Ioannina)H-Index: 33
When we synthesize research findings via meta-analysis, it is common to assume that the true underlying effect differs across studies. Total variability consists of the within-study and between-study variances (heterogeneity). There have been established measures, such as I2 , to quantify the proportion of the total variation attributed to heterogeneity. There is a plethora of estimation methods available for estimating heterogeneity. The widely used DerSimonian and Laird estimation method has b...
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Background Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty.
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