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Systematic review

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Glucagon-like peptide-1 receptor-agonists for antipsychotic-associated cardio-metabolic risk factors: a systematic review and individual participant data meta-analysis.

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Journal Diabetes, obesity & metabolism
Year 2019
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OBJECTIVE: Patients with schizophrenia have higher cardio-metabolic risk, partially from antipsychotic-induced weight-gain. Glucagon-like-peptide-1 receptor-agonists (GLP-1RAs) may reduce antipsychotic-associated weight-gain, however, safety and efficacy in schizophrenia has not been systematically reviewed. MATERIALS AND METHODS: We systematically searched PubMed/EMBASE/PsycINFO/Cochrane, using the search terms "(antipsychotic and GLP-1RA)". Individual participant data from studies randomizing patients to GLP-1RA or control were meta-analysed. Primary outcome was difference in body weight between GLP-1RA and control; secondary outcomes included cardio-metabolic parameters and adverse drug reactions (ADRs). Multiple linear regression was conducted including sex, age, psychosis severity, metabolic parameter, ADRs, and GLP-1RA-agent. RESULTS: Three studies (exenatide once-weekly=2; liraglutide once-daily=1) provided participant-level data (n=164, age=40.0±11.1years, weight=105.8±20.8kg). After 16.2±4.0 weeks of treatment, weight loss was 3.71 kg (95% CI=2.44-4.99 kg) greater for GLP-1RA vs. control (p<0.001), number-needed-to-treat ≥5% weight-loss=3.8 (95%CI=2.6-7.2). Waist, BMI, HbA1c, fasting-glucose and visceral-adiposity were each significantly lower with GLP-1RA. Sex, age, psychosis severity, nausea, any ADR, and GLP-1RA-agent did not significantly impact outcomes. Weight loss with GLP-1RAs was greater for clozapine-/olanzapine-treated patients (n=141) than other antipsychotics (n=27) (4.70kg, 95%CI=3.13-6.27 vs 1.5kg 95%CI=-1.47-4.47) (p<0.001). Nausea was more common with GLP-1RAs than control (53.6% vs 27.5%, p=0.002, number-needed-to-harm=3.8). CONCLUSION: GLP-1RAs are effective and tolerable for antipsychotic-associated weight-gain, particularly clozapine-/olanzapine-treated patients. With few included patients, further studies are required before making routine use recommendations for GLP-1RAs. This article is protected by copyright. All rights reserved.

Systematic review

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Combination of Metformin and lifestyle intervention for antipsychotic-related weight gain: A meta-analysis of randomized controlled trials.

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Journal Pharmacopsychiatry
Year 2019
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INTRODUCTION: Weight gain is a common antipsychotic (AP)- related adverse drug reaction (ADR) that can increase the risk of cardiovascular diseases and premature mortality. This meta-analysis examined the efficacy and tolerability of combining metformin and lifestyle intervention for AP-related weight gain in schizophrenia. METHODS: Randomized controlled trials (RCTs) with meta-analyzable data were searched and retrieved by 2 independent investigators. RevMan software (version 5.3) was used to synthesize data, and to calculate the standardized or weighted mean differences and risk ratio with their 95 % confidence intervals. RESULTS: Six RCTs (n = 732) were included and meta-analyzed. The metformin and lifestyle combination (MLC) group had significant reduction in weight and body mass index compared with the metformin group, lifestyle group, and placebo group. There was less frequent weight gain of ≥ 7 % in the MLC group over placebo. No other group differences in ADRs, total psychopathology, and all-cause discontinuation were found. In terms of study quality, 5 RCTs were open-labelled, 1 RCT had low risk allocation concealment, and 3 RCTs specifically described randomization methods. CONCLUSION: Combining metformin and lifestyle intervention shows significant effect in reducing AP-related weight gain. Higher quality and larger RCTs are needed to confirm these findings. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: meta-analysis of randomised controlled trials

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Authors Goh KK , Chen CH , Lu ML
Journal International journal of psychiatry in clinical practice
Year 2019
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Objective: Weight gain is one of the most challenging issues in patients with schizophrenia treated with antipsychotics. Several meta-analyses have been conducted to review the efficacy of topiramate in reducing weight, however, several issues regarding the methodology had arisen of which make the results remain ambiguous. Methods: We conducted a meta-analysis of randomised controlled trials about the use of topiramate in patients with schizophrenia for weight reduction. Ten double-blinded randomised placebo-controlled trials and seven open-label randomised controlled trials included 905 patients. Results: Patients treated with topiramate experienced a greater reduction in body weight and BMI. Patients in countries of the lower overweight population showed more significant BMI reduction. Besides, studies from the Middle East and South Asia showed the greatest effect in body weight change, followed by East Asia, then Europe/America. Topiramate group was outperformed control group with significant psychopathology improvement. No difference between two groups regarding the overall side effects. Conclusions: Topiramate was significantly superior to control group in mitigating weight gain and psychopathology in antipsychotic-treated patients with schizophrenia. The effects of topiramate augmentation need further investigations in larger definitive studies using methodological rigor and thorough assessments. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Systematic review

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Effect of adjunctive ranitidine for antipsychotic-induced weight gain: A systematic review of randomized placebo-controlled trials

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Journal The Journal of international medical research
Year 2018
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This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. © The Author(s) 2017.

Systematic review

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Antipsychotic augmentation vs. monotherapy in schizophrenia: Systematic review, meta‐analysis and meta‐regression analysis.

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Journal World psychiatry : official journal of the World Psychiatric Association (WPA)
Year 2017
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Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta‐analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co‐primary outcomes were total symptom reduction and study‐defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N = 694, standardized mean difference, SMD = –0.53, 95% CI: −0.87 to −0.19, p = 0.002). However, superiority was only apparent in open‐label and low‐quality trials (both p &lt; 0.001), but not in double‐blind and high‐quality ones (p = 0.120 and 0.226, respectively). Study‐defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N = 938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p = 0.061), being clearly non‐significant in double‐blind and high‐quality studies (both p = 0.990). Findings were replicated in clozapine and non‐clozapine augmentation studies. No differences emerged regarding all‐cause/specific‐cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N = 931, SMD = –0.38, 95% CI: −0.63 to −0.13, p &lt; 0.003), but only in studies augmenting with aripiprazole (8 studies, N = 532, SMD = –0.41, 95% CI: −0.79 to −0.03, p = 0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p = 0.028), but more prolactin elevation (p = 0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p &lt; 0.001) and body weight (p = 0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double‐blind/high‐quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

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Solving a weighty problem: systematic review and meta-analysis of nutrition interventions in severe mental illness.

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Journal The British journal of psychiatry : the journal of mental science
Year 2017
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BACKGROUND: Nutrition interventions would appear fundamental for weight management and cardiometabolic risk reduction in people experiencing severe mental illness (SMI). Comprehensive evaluation of nutrition interventions is lacking. AIMS: To subject randomised controlled trials of nutrition interventions in people with SMI to systematic review and meta-analysis, and to measure anthropometric and biochemical parameters and nutritional intake. METHOD: An electronic database search identified trials with nutrition intervention components. Trials were pooled for meta-analysis. Meta-regression analyses were performed on anthropometric moderators. RESULTS: Interventions led to significant weight loss (19 studies), reduced body mass index (17 studies), decreased waist circumference (10 studies) and lower blood glucose levels (5 studies). Dietitian-led interventions (6 studies) and studies delivered at antipsychotic initiation (4 studies) had larger effect sizes. CONCLUSIONS: Evidence supports nutrition interventions as standard care in preventing and treating weight gain among people experiencing SMI.

Systematic review

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Amantadine for antipsychotic-related weight gain: Meta-analysis of randomized placebo-controlled trials.

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Journal Journal of Clinical Psychopharmacology
Year 2017
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PURPOSE: Weight gain associated with antipsychotics in schizophrenia has been an ongoing concern. This meta-analysis examined the efficacy and safety of amantadine as an adjunctive treatment of weight gain in schizophrenia by systematically searching and analyzing randomized controlled trials (RCTs). RCTs comparing adjunctive amantadine with placebo in adult patients with schizophrenia were included in the meta-analysis. METHODS: Two independent investigators searched the literature and extracted data.Weighted and standardized mean differences (WMDs/SMDs) and risk ratio ± 95% confidence intervals were calculated. RESULTS: Five RCTs (n = 265) with double-blinded design lasting 8.2 ± 5.9 weeks were included in the analysis. Amantadine outperformed placebo regarding weight reduction with moderate effect size (trials, 3; n = 205; WMD −2.22 kg; <i>P</i> = 0.001, <i>I</i>² = 45%). Amantadine also outperformed placebo at endpoint in the negative symptom (the Positive and Negative Syndrome Scale [PANSS] [1 trial] and the Scale for the Assessment of Negative Symptoms [1 trial]) scores (trials, 2; n = 84; SMD, −0.56; <i>P</i> = 0.01, <i>I</i>² = 12%), but not in the PANSS total scores (trials, 2) (SMD, −0.31; <i>P</i> = 0.16, <i>I</i>² = 0%) and the positive symptom (PANSS [1 trial] and the Scale for the Assessment of Positive Symptoms [1 trial]) scores (SMD, 0.13; <i>P</i> = 0.54, <i>I</i>² = 0%). Except for insomnia (<i>P</i> = 0.007; number needed to harm, 6; 95% confidence interval, 4–16), all-cause discontinuation (risk ratio, 1.12; <i>P</i> = 0.54, <i>I</i>² = 0%) and other adverse events were similar between the amantadine and placebo groups. CONCLUSIONS: According to this meta-analysis of 5 RCTs, adjunctive amantadine seems to be an effective option for attenuating antipsychotic-related weight gain in patients with schizophrenia. More RCTs are needed to inform clinical recommendations. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome.

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Journal European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Year 2016
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Metabolic complications are commonly found in people treated with clozapine. Reviews on the management of this problem have generally drawn conclusions by grouping different types of studies involving patients treated with various different antipsychotics. We carried out a systematic review and meta-analysis of pharmacological and non-pharmacological treatments for clozapine-induced obesity or metabolic syndrome. Two researchers independently searched PubMed and Embase for randomised controlled trials (RCTs) of treatments for clozapine-induced obesity or metabolic syndrome. All other types of studies were excluded. We only included RCTs where more than 50% of participants were taking clozapine. We identified 15 RCTs. Effective pharmacological treatments for clozapine-induced obesity and metabolic syndrome include metformin, aripiprazole, and Orlistat (in men only). Meta-analysis of three studies showed a robust effect of metformin in reducing body mass index and waist circumference but no effects on blood glucose, triglyceride levels, or HDL levels. In addition, there is limited evidence for combined calorie restriction and exercise as a non-pharmacological alternative for the treatment of clozapine-induced obesity, but only in an in-patient setting. Rosiglitazone, topiramate, sibutramine, phenylpropanolamine, modafinil, and atomoxetine have not shown to be beneficial, despite reports of efficacy in other populations treated with different antipsychotics. We conclude that randomised-controlled trial data support the use of metformin, aripiprazole, and Orlistat (in men only) for treating clozapine-induced obesity. Calorie restriction in combination with an exercise programme may be effective as a non-pharmacological alternative. Findings from trials in different populations should not be extrapolated to people being treated with clozapine. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

Systematic review

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Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis.

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Journal PloS one
Year 2016
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BACKGROUND: Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine. METHODS: We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers. RESULTS: Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results. CONCLUSIONS: Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered. TRIAL REGISTRATION: PROSPERO registration number: CRD42015029723.

Systematic review

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Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized Controlled Trials

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Journal Journal of Clinical Psychopharmacology
Year 2016
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This meta-analysis of randomized controlled trials (RCTs) evaluated the efficacy and safety of adding aripiprazole to other antipsychotics in schizophrenia. A systematic computer search identified 55 RCTs including 4457 patients who were randomized to aripiprazole (14.0 ± 7.0 mg/d) versus placebo (18 RCTs) or open antipsychotic treatment (37 RCTs). Aripiprazole significantly outperformed the comparison interventions based on psychiatric scales: (1) total score in 43 RCTs (N = 3351) with a standardized mean difference (SMD) of -0.48 (95% confidence interval [CI], -0.68 to -0.28; P < 0.00001; I2 = 88%), (2) negative symptom score in 30 RCTs (N = 2294) with an SMD of -0.61(95% CI, -0.91 to -0.31; P < 0.00001; I2 = 91%), and (3) general psychopathology score in 13 RCTs (N = 1138) with a weighted mean difference (WMD) of -4.02 (95% CI, -7.23 to -0.81; P = 0.01; I2 = 99%), but not in positive symptoms in 29 RCTs (N = 2223) with a SMD of -0.01 (95% CI, 0.26 to 0.25; P = 0.95; I2 = 88%). Differences in total score based on psychiatric scales may be explained by the use of an antipsychotic for comparison rather than placebo in 31 RCTs with a nonblind design. Aripiprazole outperformed the comparison interventions for body weight in 9 RCTs (N = 505) with a WMD of -5.08 kg (95% CI, -7.14 to -3.02; P < 0.00001; I2 = 35%) and for body mass index (BMI) in 14 RCTs (N = 809) with a WMD of -1.78 (CI: -2.25 to -1.31; P < 0.00001; I2 = 54%). The BMI meta-regression analysis indicated aripiprazole's association with lower BMI was stronger in females. Adjunctive aripiprazole appears safe but better RCTs are needed to demonstrate efficacy. Chinese journals and scientific societies should encourage the publication of high-quality RCTs and require registration in a centralized Chinese database. © 2016 Wolters Kluwer Health, Inc. All rights reserved.