Metabolic side effects of antipsychotic drugs in individuals with schizophrenia during medium- to long-term treatment: protocol for a systematic review and network meta-analysis of randomized controlled trials

Johannes Schneider-Thoma,Georgia Salanti,John M Davis,Dongfang Wang,Wulf-Peter Hansen,Spyridon Siafis,Angelika Kapfhammer,Irene Bighelli,Stefan Leucht,Hui Wu

doi:10.1186/s13643-021-01760-z

Abstract

BackgroundAntipsychotic drugs and especially the newer compounds are known to cause metabolic side effects. However, a comprehensive comparison of the different substances regarding their propensity to cause metabolic side effects in medium- to long-term treatment of schizophrenia is lacking.MethodsWe will conduct a systematic review and network meta-analysis (NMA). We will include randomized controlled trials (RCTs) in which participants received either placebo or an antipsychotic (i.e. placebo-controlled trials and head-to-head comparisons of drugs). We will include studies in individuals with schizophrenia or related disorders (such as schizophreniform or schizoaffective disorders) at any stage of the disease (acute episode; maintenance phase). We will include studies with a duration of more than 3 months (medium- to long-term treatment). The primary outcome will be the change in body weight. Secondary outcomes will be the further metabolic parameters: fastening glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides. We will search for eligible studies (independent of the publication status) in Cochrane Schizophrenia Group’s Study-Based Register of Trials, which is compiled by regular searches in trial registries and multiple electronic databases from their inception onwards including MEDLINE, EMBASE and PsycINFO. Additionally, we will search previously published systematic reviews and websites of pharmaceutical companies for eligible studies. At least two reviewers will independently conduct the process of study selection and data extraction. We will use the Cochrane Risk of Bias 2 tool to evaluate the risk of bias in studies. We will conduct random-effects NMA within a Bayesian framework to synthesize all evidence for each outcome. We will conduct sensitivity and subgroup analyses to assess the robustness of the findings and to explore heterogeneity. The confidence in the results will be evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework.DiscussionThis systematic review and network meta-analysis will provide a synthesis of the existing evidence from RCTs how antipsychotic drugs differ in terms of metabolic side effects during medium- to long-term treatment. The findings have the potential to influence the choice of antipsychotic medication made by individuals with schizophrenia and their physicians.Systematic review registrationPROSPERO CRD42020175414

Highlights

Antipsychotic drugs and especially the newer compounds are known to cause metabolic side effects
This systematic review and network meta-analysis will provide a synthesis of the existing evidence from Randomized controlled trial (RCT) how antipsychotic drugs differ in terms of metabolic side effects during medium- to long-term treatment
This network meta-analysis will examine the differences in metabolic side effects of antipsychotic drugs during medium- to long-term treatment of individuals with schizophrenia

Summary

Methods

This systematic review and network meta-analysis is registered in the PROSPERO database (registration number: CRD42020175414). Data analysis Characteristics of the included studies We will generate descriptive statistics of study characteristics (by study and overall), describing important clinical or methodological variables, such as age, gender, ethnicity, baseline metabolic parameters, lifetime exposure to antipsychotics (if not available, duration of illness will be used as a proxy), antipsychotic dose, blinding, use of enriched design, sponsorship and study duration. That means that trial participants who fulfil the inclusion criteria are likely to be randomized to any of the studies of interest (i.e. jointly randomizable) and that the observed comparisons do not differ with respect to the distribution of effect modifiers We will assess this assumption epidemiologically by comparing the distribution of potential effect modifiers across studies grouped by comparison [43], namely age, sex, baseline weight, antipsychotic dose and study duration. Assessment of the confidence in the evidence from NMA We will evaluate the confidence in estimates of the primary outcome with the framework Confidence in Network Meta-Analysis (CINeMA) [53, 54], implemented in a web application [55]

Discussion

Background

Objective

55. CINeMA