To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine.
Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment.
At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly.
Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.
"Furthermore, the average weight gains after 10-week treatments with clozapine and olanzapine were 3.99 and 3.51 kg, respectively (Allison et al. 1999). The mechanisms responsible for these side effects are poorly understood and are not prevented by any of the agents that are routinely used to treat type 2 diabetes (Baptista et al. 2006; Dwyer and Donohoe 2003). In addition to promoting weight gain, metabolic syndrome, and diabetes, the side effects of atypical antipsychotics result in poor compliance and interfere with effective treatment of psychiatric disease. "
[Show abstract][Hide abstract] ABSTRACT: Weight gain and dysfunction of glucose and lipid metabolism are well-known side effects of atypical antipsychotic drugs (AAPD). Here, we address the question whether a heat-shock protein (HSP) co-inducer, insulin sensitizer drug candidate, BGP-15, can prevent AAPD-induced glucose, lipid, and weight changes. We also examined how an AAPD alters HSP expression and whether BGP-15 alters that expression. Four different experiments are reported on the AAPD BGP-15 interventions in a human trial of healthy men, a rodent animal model, and an in vitro adipocyte cell culture system. Olanzapine caused rapid insulin resistance in healthy volunteers and was associated with decreased level of HSP72 in peripheral mononuclear blood cells. Both changes were restored by the administration of BGP-15. In Wistar rats, weight gain and insulin resistance induced by clozapine were abolished by BGP-15. In 3T3L1 adipocytes, clozapine increased intracellular fat accumulation, and BGP-15 inhibited this process. Taken together, our results indicate that BGP-15 inhibits multiple metabolic side effects of atypical antipsychotics, and this effect is likely to be related to its HSP co-inducing ability.
"Thus, the total number of study arms (N ¼ 32 + 2 ¼ 34) and patients (n ¼ 1482 + 82 ¼ 1564) in the analyses is higher than the total number of studies (N ¼ 32) and patients (n ¼ 1482). To examine potential moderator variables, four sensitivity analyses were performed: (1) intervention studies (N ¼ 22, n ¼ 947) (Arman et al, 2008; Assuncao et al, 2006; Atmaca et al, 2003, 2004; Baptista et al, 2007, 2008b, 2009; Borovicka et al, 2002; Bustillo et al, 2003; Carrizo et al, 2009; Deberdt et al, 2005; Goodall et al, 1988; Graham et al, 2005; Henderson et al, 2005, 2007, 2009; Joffe et al, 2008; Klein et al, 2006; Ko et al, 2005; Modell and Hussar, 1965; Nickel et al, 2005; Wu et al, 2008b), that is, weight loss agent given after weight gain with antipsychotic treatment, vs prevention studies (N ¼ 10, n ¼ 535) (Baptista et al, 2006; Cavazzoni et al, 2003; Hinze-Selch et al, 2000; Kim et al, 2006; Lu et al, 2004; Poyurovsky et al, 2002, 2003, 2004, 2007; Wu et al, 2008a), that is, weight loss agent was given concomitantly with newly initiated antipsychotic treatment; (2) short-term trials of p8 weeks (N ¼ 10, n ¼ 296) (Atmaca et al, 2003, 2004; Henderson et al, 2009; Hinze-Selch et al, 2000; Modell and Hussar, 1965; Nickel et al, 2005; Poyurovsky et al, 2002, 2003, 2004, 2007) vs medium-term trials of 12–16 weeks (N ¼ 22, n ¼ 1186) (Arman et al, 2008; Assuncao et al, 2006; Baptista et al, 2006, 2007, 2008b, 2009; Borovicka et al, 2002; Bustillo et al, 2003; Carrizo et al, 2009; Antipsychotic-related weight gain and metabolic abnormalities L Maayan et al Cavazzoni et al, 2003; Deberdt et al, 2005; Goodall et al, 1988; Graham et al, 2005; Henderson et al, 2005, 2007; Joffe et al, 2008; Kim et al, 2006; Klein et al, 2006; Ko et al, 2005; Lu et al, 2004; Wu et al, 2008a,b); (3) outpatient status (N ¼ 12, n ¼ 454) (Assuncao et al, 2006; Borovicka et al, 2002; Bustillo et al, 2003; Carrizo et al, 2009; Goodall et al, 1988; Graham et al, 2005; Henderson et al, 2005, 2007, 2009; Kim et al, 2006; Nickel et al, 2005; Wu et al, 2008b) vs inpatient status (N ¼ 14, n ¼ 514) (Arman et al, 2008; Baptista et al, 2006, 2008b, 2009; Hinze-Selch et al, 2000; Klein et al, 2006; Ko et al, 2005; Lu et al, 2004; Modell and Hussar, 1965; Poyurovsky et al, 2002, 2003, 2004, 2007; Wu et al, 2008a) vs mixed status (N ¼ 6, n ¼ 514) (Atmaca et al, 2003, 2004; Baptista et al, 2007; Cavazzoni et al, 2003; Deberdt et al, 2005; Joffe et al, 2008); and (4) adults with chronic antipsychotic treatment (N ¼ 23, n ¼ 1149) (Assuncao et al, 2006; Atmaca et al, 2003, 2004; Baptista et al, 2006, 2007, 2008b, 2009; Borovicka et al, 2002; Carrizo et al, 2009; Cavazzoni et al, 2003; Deberdt et al, 2005; Goodall et al, 1988; Graham et al, 2005; Henderson et al, 2005, 2007, 2009; Hinze-Selch et al, 2000; Joffe et al, 2008; Kim et al, 2006; Ko et al, 2005; Lu et al, 2004; Modell and Hussar, 1965; Nickel et al, 2005) vs first episode or youth samples (N ¼ 9, n ¼ 333) (Arman et al, 2008; Bustillo et al, 2003; Klein et al, 2006; Poyurovsky et al, 2002, 2003, 2004, 2007; Wu et al, 2008a,b). "
[Show abstract][Hide abstract] ABSTRACT: Antipsychotic-related weight gain and metabolic effects are a critical outcome for patients requiring these medications. A literature search using MEDLINE, Web of Science, PsycNET, and EMBASE for randomized, open and double-blind, placebo-controlled trials of medications targeting antipsychotic-induced weight gain was performed. Primary outcome measures were change and endpoint values in body weight and body mass index (BMI). Secondary outcomes included >or=7% weight gain, all-cause discontinuation, change in waist circumference, glucose and lipid metabolism parameters, and psychiatric symptoms. Sensitivity analyses were conducted to explain heterogeneity of the results. Across 32 studies including 1482 subjects, 15 different medications were tested: amantadine, dextroamphetamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin+sibutramine. Compared with placebo, metformin had the greatest weight loss (N=7, n=334, -2.94 kg (confidence interval (CI:-4.89,-0.99)), followed by d-fenfluramine (N=1, n=16, -2.60 kg (CI:-5.14,-0.06)), sibutramine (N=2, n=55, -2.56 kg (CI:-3.91,-1.22)), topiramate (N=2, n=133, -2.52 kg (CI:-4.87,-0.16)), and reboxetine (N=2, n=79, -1.90 kg (CI:-3.07,-0.72)). Weight loss remained significant with metformin initiation after weight gain had occurred, but not when started concomitantly with antipsychotics. Nausea rates were not higher with any treatment compared with placebo. In all, 5 of 15 psychopharmacologic interventions aimed at ameliorating antipsychotic-induced weight gain outperformed placebo. Results were most robust for metformin, although these were modest and heterogeneous. Only one (negative) combination treatment study was available and head-to-head studies are absent. None of the agents were able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage. Antipsychotics with no or minimal cardiometabolic liability, as well as interventions that prevent or normalize adverse antipsychotic cardiometabolic effects are needed.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2010; 35(7):1520-30. DOI:10.1038/npp.2010.21 · 7.05 Impact Factor
"Klein and colleagues, in their randomized, double-blind, placebo-controlled trial of metformin in children and adolescents taking atypical antipsychotics , found arrested weight gain, as well as improved insulin resistance (Klein et al. 2006). Whereas Baptista and associates found that metformin did not prevent olanzapineinduced weight gain in a group of adult patients with schizophrenia (Baptista et al. 2006), Wu and colleagues published two studies indicating that metformin, administered to a group of adult patients with schizophrenia on antipsychotics , including olanzapine, was effective in attenuating "
[Show abstract][Hide abstract] ABSTRACT: Metformin was assessed as an interventional medication for weight gain in children and adolescents taking atypical antipsychotic agents.
A 12-week open-label trial was conducted to evaluate metformin's effectiveness and safety for weight management. Eleven subjects, ages 10-18 years, participated in the study. Each subject received metformin orally up to 2000 mg/day. Primary outcome measures included weight, body mass index (BMI), and waist circumference. Secondary outcome measures included serum glucose, insulin, and fasting lipid profile. Changes in weight, BMI, waist, and metabolic profile were obtained by using repeated measures of covariance.
The mean reduction in weight, waist, BMI, serum glucose, and serum insulin was not statistically significant. However, 5 out of 11 patients lost weight (mean, -2.82 kg +/- 7.25), and overall the sample did not continue to gain weight. There was a significant decrease in triglyceride levels. Metformin was fairly well tolerated.
Preliminary data suggests that metformin may safely and effectively improve the triglyceride profile. However, contrary to study hypotheses, weight, waist, and BMI reduction were not statistically significant. Future double-blind studies with larger sample sizes and of longer duration are warranted to assess more fully the safety and efficacy of this intervention.
Journal of child and adolescent psychopharmacology 07/2009; 19(3):275-9. DOI:10.1089/cap.2008.094 · 2.93 Impact Factor
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