Topiramate and Metformin Are Effective Add-On Treatments in Controlling Antipsychotic-Induced Weight Gain: A Systematic Review and Network Meta-Analysis

Abstract

Background: Antipsychotic drugs may lead to side effects such as obesity, diabetes, dyslipidemia, and cardiovascular disease. The current systematic review and network meta-analysis analyzes and provides an update on the clinical performance of these add-ons in comparison to placebo on body weight and body mass index (BMI) reductions.Methods: A comprehensive literature search was performed on electronic databases: PubMed (1946-), Embase (1974-), Cochrane library (1992-), and OpenGrey (2000-) until 31 July 2018. Network meta-analyses, comparing the body weight change, BMI change and withdrawn due to adverse events of different pharmacological add-ons, was performed using a multivariate meta-regression model with random-effects, adopting a frequentist approach. To rank the prognosis for all add-ons, we used surface under the cumulative ranking (SUCRA) values.Outcomes: From 614 potential studies identified, 27 eligible studies (n = 1,349 subjects) were included. All the studies demonstrated low to moderate risk of bias. For the analysis of body weight change, all add-ons except Ranitidine showed significant weight reductions comparing to placebo. The effectiveness rank based on SUCRA results from highest to lowest was Sibutramine, Topiramate, Metformin, Reboxetine, Ranitidine, and placebo. A similar pattern was seen for BMI change. The analysis of safety outcome did not detect significantly increased withdrawn number from the add-ons. Current evidence showed relatively good tolerance and safety of using the pharmacological add-ons.Interpretation: Topiramate and Metformin are effective add-on treatments in controlling antipsychotic-induced weight gain, comparing to placebo. They are well tolerated in short-term period. Although Sibutramine has the highest rank of the effectiveness, its license has been withdrawn in many countries due to its adverse effects. Hence, Sibutramine should not be adopted to treat antipsychotic-induced weight gain.

Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials

“…Thus, blood lactate concentration, serum B 12 levels and folate levels should be regularly screened for patients with schizophrenia when they received metformin treatment 2 . Several meta-analyses 11,13,[29][30][31][32][33][34][35][36][37] had examined antipsychotic-induced body weight and metabolic abnormalities in schizophrenia, however, only a small number of them with comparatively smaller sample size meta-analyzed dyslipidemia as a secondary outcome 33,35,37 . This meta-analysis only included double-blind RCTs examining adjunctive metformin for dyslipidemia in schizophrenia, together with a large sample size increase the robustness and reliability of meta-analytic findings.…”

“…Both international (PubMed, Cochrane Library, Psy-cINFO, and EMBASE) and Chinese (Chinese Journal Net, and WanFang) databases were independently searched to obtain relevant published RCTs by three investigators (WLJ, DBC, and FY) from their commencement dates to October 22, 2018, using the search terms as follows: ("metformin"[MeSH] OR metformin OR Dimethylbiguanidine OR Dimethylguanylguanidine OR Glucophage) AND ("dyslipidemias"[MeSH] OR Dyslipidemias OR Dyslipidemia OR Dyslipoproteinemias OR Dyslipoproteinemia OR metabolic OR lipid OR fats OR Hypolipidemic Agents OR cholesterol OR HDL OR LDL OR lipoprotein OR triglyceride OR adiponectin OR ghrelin OR leptin OR resistin OR chemerin OR omentin OR apelin or adipocytokine OR adipokine) AND ("schizophrenia"[Mesh] OR schizophrenic disorder OR disorder, schizophrenic OR schizophrenic disorders OR schizophrenia OR dementia praecox). The references of relevant reviews 11,13,[29][30][31][32][33][34][35][36][37] were also searched manually to avoid missing publications.…”

“…Some reviews and meta-analyses 11,13,[29][30][31][32][33][34][35][36][37] have examined the efficacy and safety of adjunctive metformin for antipsychotics-related weight gain and metabolic abnormalities in schizophrenia. However, the primary outcome in most meta-analyses was weight gain, rather than dyslipidemia, and some meta-analyses included open-label studies, which deviate from the standardized recommendations 38 .…”

Outcomes and safety of concomitant topiramate or metformin for antipsychotics-induced obesity: A randomized controlled trial

“…For example, sibutramine, reboxetine, bupropion, orlistat, liraglutide, uoxetine, metformin, topiramate, and antagonism of the histamine 2 (H2) receptor, etc. were also reported to have signi cant effects on weight gain compared to placebo, [5][6][7][8] whereas, some previous studies' results were not consistent each other, even there are some con icting reports. 9 Metformin,a biguanide drug approved for treatment of type 2 diabetes, has been extensively studied for use of weight gain in the absence of diabetes in typically developing children.…”

“…[15][16][17] And it holds some promise as an adjunctive therapy for both overweight and treatment of psychotic symptoms. 5 Topiramate has the strongest mean weight loss compared with placebo, metformin, H2 receptor antagonists, and norepinephrine reuptake inhibitors in some reviews 5,8,18,19 although it has some adverse events which are possibly uncommon. Whereas, the effect of topiramate on patients with obesity caused by SGAs varied in different studies, some of the studies were either smaller samples or lack of placebo-controlled trial, or reported as other researches' additional results, and did not exactly infer the effects of topiramate on weight loss.…”