Olanzapine (LY170053, 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] Benzodiazepine), but Not the Novel Atypical Antipsychotic ST2472 (9-Piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine), Chronic Administration Induces Weight Gain, Hyperphagia, and Metabolic Dysregulation in Mice (original) (raw)
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No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs
International journal of obesity (2005), 2007
Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet. Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA. AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). A...
Psychopharmacology, 2006
Most of atypical antipsychotics (AAPs) are highly related to a major risk of metabolic drawbacks leading to dyslipidemia and obesity. To set up a mouse model of the AAP-associated weight gain in mice under the influence of chronic olanzapine regimen. Female mice were housed in pairs and habituated to spontaneous feeding with a high-palatable diet (10% sucrose wet mash). Firstly, we orally administered olanzapine (0.75, 1.5 and 3 mg/kg), evaluating body weight and periuterine fat mass, as well as insulin, non-esterified fatty acids, triglycerides, and glucose levels. In a second experiment, we assessed the effect of olanzapine on energy expenditure through indirect calorimetry (IC). A third experiment was conducted to investigate the effects of olanzapine on a high fat-high sweet palatable diet (10% sucrose + 30% fat, HF-HS) in mice implanted with subcutaneous osmotic mini-pumps. Locomotor activity was also assessed. In experiment 1, the highest dose of chronically administered olanz...
…, 2006
Although it is generally accepted that atypical antipsychotics differ in their risk for diabetic side effects, the underlying pharmacological mechanisms are unknown. Studies on the mechanisms of antipsychotic-induced hyperglycemia or insulin resistance are often confounded by the concomitant weight gain and dyslipidemia, known diabetic risk factors. To investigate whether antipsychotics can acutely cause metabolic effects before any change in body composition, we studied the effects of four atypical antipsychotics on whole-body insulin resistance. Using the hyperinsulinemic, euglycemic clamp technique in conscious rats, insulin and somatostatin were infused at a constant rate to provide constant hyperinsulinemia and to suppress pancreatic insulin secretion. Glucose was infused at a variable rate, adjusted to maintain euglycemia. At steady state, animals were administered vehicle (V) or antipsychotic and the glucose infusion rate was monitored as an index of insulin sensitivity. Clamp experiments using radiotracers and studies on glucose uptake into isolated skeletal muscle were conducted to differentiate between effects on hepatic glucose production (HGP) and on peripheral glucose uptake. Olanzapine (OLAN) and clozapine (CLOZ) acutely impaired whole-body insulin sensitivity in a dose-dependent manner (Po0.001 vs V), whereas ziprasidone and risperidone had no effect. CLOZ also induced profound insulin resistance after dosing 10 mg/kg/day for 5 days (Po0.05 vs V). Tracer studies indicated that acute changes mainly reflect increased HGP, consistent with the lack of effect on glucose uptake. OLAN and CLOZ can thus rapidly induce marked insulin resistance, which could contribute to the hyperglycemia and ketoacidosis reported for patients receiving those therapies.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2014
Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic treatment, as well as the influence of a preceding chronic treatment on the acute effects of olanzapine on glucose metabolism. The effect of chronic olanzapine treatment (±6.5 mg/kg/day, administered via drinking water) on body weight, locomotor activity, body temperature, fat distribution and energy expenditure was investigated in male rats. After 5 weeks, the animals received an acute olanzapine challenge (intragastric, IG) at 3 mg/kg/h during 160 min to investigate the acute effects of olanzapine on glucose metabolism. Chronic olanzapine-treated animals showed a slight decrease in nocturnal body temperature, and increased perirenal fat pad weights as well as plasma leptin. In addition, chronic olanzapine-treated animals showed hyperinsulinaemia with unchanged blood glucose concentrations. The acute challenge with IG olanzapine elevated blood glucose levels and endogenous glucose production in control animals, but not in chronic olanzapine-pre-treated rats. Chronic olanzapinetreated animals also showed reduced locomotor activity and a higher respiratory exchange ratio. Thus, chronic treatment with olanzapine in rats causes desensitization to its acute effects on glucose metabolism but promotes adiposity probably due to a shift from lipids to carbohydrates as an energy source. Chronic exposure to olanzapine changes body fat distribution and insulin sensitivity in an unfavourable direction, but it is still unclear what the primary mechanism is.
Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men
Obesity, 2010
Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 ± 2.2 kg/m 2 , respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-α (TNF-α) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2004
Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm 3 /kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake ( p=0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model. D 2004 Elsevier Inc. All rights reserved.
2013
Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO 2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10 mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO 2 , and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO 2 , in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO 2 , or physical activity. The VO 2 and RER effects appear independent of sedation/ physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO 2 by itself caused precipitous drops in VO 2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO 2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.
Diabetes, 2005
Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S I), and pancreatic -cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n ؍ 10), RIS (5 mg/day; n ؍ 10), or gelatin capsules (n ؍ 6) for 4-6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (؉91 ؎ 20%; P ؍ 0.000001) reflecting marked increases in subcutaneous (؉106 ؎ 24%; P ؍ 0.0001) and visceral (؉84 ؎ 22%; P ؍ 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S I [pre-versus postdrug]: 6.05 ؎ 0.98 vs. 1.53 ؎ 0.93 dl ⅐ min ؊1 ⅐ kg ؊1 /[U/ml], respectively; P ؍ 0.009). -Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 ؎ 0.15, postdrug: 1.07 ؎ 0.25 U ⅐ ml ؊1 /[mg/dl]; P ؍ 0.6). OLZinduced -cell dysfunction was further demonstrated when -cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (؉8% of calories from fat; n ؍ 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that -cell compensation is under neural control.