The Effect of Metformin on Anthropometrics and Insulin Resistance in Patients Receiving Atypical Antipsychotic Agents: A Meta-Analysis
ABSTRACT In the Clinical Antipsychotic Trials of Intervention Effectiveness, atypical antipsychotics (AAPs) were found to be associated with weight gain and impairment of glucose metabolism. While metformin has been shown to attenuate weight gain and insulin resistance, not all studies have shown a benefit in the reduction of antipsychotic-induced weight gain and insulin resistance.
To characterize metformin's impact on anthropometrics and insulin resistance in patients taking AAPs.
A systematic literature search of MEDLINE, EMBASE, and Cochrane CENTRAL was conducted from the earliest possible date through December 31, 2008. The search was performed using the following Medical Subject Headings and text keywords: metformin, biguanide(s), in combination with neuroleptic(s), neuroleptic drug(s), antipsychotic(s), dopamine antagonist(s), atypical antipsychotic(s), psychotropic(s), risperidone, olanzapine, quetiapine, ziprasidone, sulpiride, clozapine, iloperidone, aripiprazole, paliperidone, melperone, bifeprunox, amisulpride, zotepine, and sertindole.
Six of 62 identified studies (N = 336 participants) met our inclusion criteria: randomized, placebo-controlled trials of metformin in patients taking AAPs with data on weight, body mass index (BMI), waist circumference, insulin resistance (determined using the homeostasis model assessment of insulin resistance [HOMA-IR]), and/or a diagnosis of diabetes.
Data were independently abstracted by 2 investigators; disagreements were resolved through discussion or by a third investigator using a standardized data abstraction tool. For continuous endpoints, the weighted mean difference (WMD) of the change from baseline with 95% CI was calculated as the difference between the mean in the metformin and placebo groups. For categorical endpoints, the pooled relative risk (RR) with 95% CI was calculated. A random-effects model was used for all analyses.
Compared to placebo, the metformin group had significantly reduced weight (WMD, 3.16 kg; P = .0002), BMI (WMD, 1.21 kg/m²; P = .0001), waist circumference (WMD, 1.99 cm; P = .005), and HOMA-IR (WMD, 1.71; P = .004). The reduction in risk of diabetes was not statistically significant (RR, 0.30; P = .13).
This analysis suggests that using metformin in patients treated with AAPs may reduce metabolic risks. Additional randomized controlled trials are needed, but available data support consideration of this intervention in clinical practice.
- SourceAvailable from: Robin Schmidt
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- "Previous studies have indicated that activating AMPK with metformin (a classic approach to treat the metabolic syndrome) confers a disappointingly small beneficial effect against some of the metabolic effects of OLZ (Ehret et al., 2010 "
ABSTRACT: Olanzapine (OLZ) is an effective treatment for schizophrenia and other disorders, but causes weight gain and metabolic syndrome. Most studies to date have focused on potential effects of OLZ on CNS mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in systemic effects of OLZ. The purpose of this study was to therefore investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg/d) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for GCxGC-TOF MS metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a 'pseudo-fasted' state, which depleted hepatic glycogen reserves; OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMPK signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mTOR) pathways, and yield new insight into the metabolic side effects of this drug.Journal of Pharmacology and Experimental Therapeutics 08/2013; 347(1). DOI:10.1124/jpet.113.207621 · 3.86 Impact Factor
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- "For example, in 2007, Wu and colleagues reported that metformin can effectively mitigate antipsychotics-induced weight gain and abnormal glucose metabolism and several other studies in China report similar findings.– A meta-analysis reported in 2010 found that metformin can reduce weight, body mass index (BMI), waist circumference and insulin resistance, but did not reduce the incidence of diabetes in patients using antipsychotics. "
ABSTRACT: Antipsychotic medications can cause an increase in blood glucose and the development of type II diabetes. Metformin may ameliorate these side effects.06/2013; 25(3):149-56. DOI:10.3969/j.issn.1002-0829.2013.03.004
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- "Current therapy for OL-associated BWG along with the glucose and lipid dysregulation has focused on dietary caloric restriction (which has limited efficacy even in patients without the psychopathology of schizophrenia), weight loss medications (many of which are contraindicated because of CNS side effects) e.g. sibutramine (Henderson et al., 2005) and the frequent use of metformin (Ehret et al., 2010; Praharaj et al., 2011) that may be superior to the other agents particularly when impaired glucose tolerance or type 2 diabetes develops (Bushe et al., 2009). Also, reboxetine (Poyurovsky et al., 2003) and topiramate (Narula et al., 2010) additions to ongoing OL treatment resulted in significant attenuation of BWG, whereas fluoxetine (Poyurovsky et al., 2002) or famotidine (Poyurovsky et al., 2004) proved to be ineffective. "
ABSTRACT: Blockade of opioidergic neurotransmission contributes to reduction in body weight. However, how such blockade affects body weight gain (BWG) attributed to second generation antipsychotic agents (SGAs) has not yet been established. Here we examined the effects of an opioid receptor antagonist, naltrexone (NTX), on food intake and BWG associated with an SGA, olanzapine (OL). Four groups of Wistar Han IGS rats were treated for 28 days with either OL (2 mg/kg twice daily, intraperitoneal (IP)), a combination of OL (2 mg/kg twice daily, IP) + extended-release NTX (50 mg/kg, one-time, intramuscular (IM)), extended-release NTX (50 mg/kg, one-time, IM) or vehicle and their food intake and body weight were measured daily for the first nine days and every other day thereafter. Food intake and BWG that were increased by OL were decreased by the added NTX while NTX alone had no significant effects on food intake or on BWG. Plasma leptin concentrations were significantly elevated in the three groups receiving pharmacological agents, but did not differ among each other, suggesting that changes in leptin secretion and/or clearance alone would not explain the food intake and the body weight findings. Our results extend prior reports on anorexigenic effects of opioid antagonists by demonstrating that such effects may generalize to food intake increases and BWG arising in the context of OL pharmacotherapy.Journal of Psychopharmacology 06/2012; 26(9):1244-51. DOI:10.1177/0269881112450783 · 2.81 Impact Factor