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CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

ABSTRACT: INTRODUCTION:Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation. METHODS AND ANALYSIS:A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2?g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5%?body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants. ETHICS AND DISSEMINATION:Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER:ACTRN12617001547336; Pre-results.

SUBMITTER: Siskind D

PROVIDER: S-EPMC5855211 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

Siskind Dan D Friend Nadia N Russell Anthony A Russell Anthony A McGrath John J JJ Lim Carmen C Patterson Sue S Flaws Dylan D Stedman Terry T Moudgil Vikas V Sardinha Savio S Suetani Shuichi S Kisely Steve S Winckel Karl K Baker Andrea A

BMJ open 20180302 3

<h4>Introduction</h4>Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation.<h4>Methods and analysis</h4>A 24-week ...[more]

PMID: 29500217

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Project description:Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes.Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23).Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo.Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Project description:BackgroundPeople with schizophrenia have a 15-20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap.MethodsWe retrospectively analysed digital health records of patients with TRS aged 18-65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio.ResultsAmong 90 patients initiated on clozapine, metformin use (n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight.ConclusionIn this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

Project description:BACKGROUND:Weight gain is common for people with schizophrenia and this has serious implications for health and well being. OBJECTIVES:To determine the effects of both pharmacological (excluding medication switching) and non pharmacological strategies for reducing or preventing weight gain in people with schizophrenia. SEARCH STRATEGY:We searched key databases and the Cochrane Schizophrenia Group's trials register (April 2006), reference sections within relevant papers, hand searched key journals, and contacted the first author of each relevant study and other experts to collect further information. SELECTION CRITERIA:We included all clinical randomised controlled trials comparing any pharmacological or non pharmacological intervention for weight gain (diet and exercise counselling) with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS:We reliably selected, quality assessed and extracted data from studies. As weight is a continuous outcome measurement, weighted mean differences (WMD) of the change from baseline were calculated. The primary outcome measure was weight loss. MAIN RESULTS:Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. AUTHORS' CONCLUSIONS:Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia.

Dataset Information

CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

Publications

CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

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