Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men

Pfizer Global Research and Development, New London, Connecticut, USA.
Obesity (Impact Factor: 3.73). 08/2010; 18(8):1646-51. DOI: 10.1038/oby.2010.6
Source: PubMed


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-alpha (TNF-alpha) 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.

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Available from: James P Mancuso, Oct 21, 2014
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    • "Several clinical studies suggest that altered eating behaviour is a major component of olanzapine-induced weight gain, as patients treated with olanzapine frequently reported an increase in appetite and food intake (Basson et al., 2001; Costa e Silva et al., 2001; Eder et al., 2001). Unfortunately, most of these findings are based on self-reported questionnaires, and only a few studies have objectively investigated the effects of antipsychotics on ingestive behaviour in humans: increased total caloric intake was reported in two studies (Gothelf et al., 2002; Fountaine et al., 2010), but no effect on food intake was observed in a different study (Blouin et al., 2008). The amount of quantitative data from clinical studies is, therefore, limited. "
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    ABSTRACT: The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms.
    Full-text · Article · Oct 2013 · The International Journal of Neuropsychopharmacology
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    • "Although we did not directly measure the caloric intake of these patients, we assessed their subjective appetite, which was expected to be associated with caloric intake. Previous studies have consistently reported that increased appetite is a common adverse effect of olanzapine treatment [26,28,29], but not of ziprasidone treatment [12,13,15,17]. Although we found that neither agent increased appetite significantly, ziprasidone-treated patients showed a greater decrease in appetite than olanzapine-treated patients, suggesting that this difference in change in appetite may have contributed, at least in part, to the lower propensity toward weight gain with ziprasidone than with olanzapine. "
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    ABSTRACT: In contrast to olanzapine, ziprasidone has been reported to cause minimal or no weight gain. This study aimed to compare the effects of ziprasidone and olanzapine on weight, body composition, appetite, resting energy expenditure, substrate oxidation, and metabolic parameters in adults with schizophrenia or other psychotic disorders. Twenty adults with schizophrenia or other psychotic disorders were randomized 1:1 to ziprasidone 20--160 mg/day or olanzapine 5--20 mg/day for 12 weeks. The mean doses during the 12-week study period were 109(range: 65--140) mg/day for ziprasidone and 11.6(range: 8.2--15.5) mg/day for olanzapine. Body weight, appetite, body composition, resting energy expenditure, and metabolic parameters were measured before and after drug treatment. Outcome measurements before and after medication were compared, and ziprasidone- and olanzapine-treated patients were compared. After 12 weeks, olanzapine-treated patients showed significant weight gain, particularly fat gain, with increased low density lipoprotein-cholesterol and decreased high density lipoprotein-cholesterol concentrations. In contrast, ziprasidone-treated patients showed no significant weight gain with increased high density lipoprotein-cholesterol concentration. Ziprasidone was associated with a lower propensity for weight gain and central fat deposition than olanzapine. Studies in larger patient samples are required to confirm these results.
    Full-text · Article · Jul 2013 · Behavioral and Brain Functions
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    • "By administering the drugs to healthy volunteers, one can determine whether metabolic effects are independent of disease. A handful of studies have used this approach, reporting either no effect (19–21) or decreases in insulin sensitivity in the presence of modest weight gain after short-term administration (10–15 days) of olanzapine compared with other AAPs or placebo (22). Weight-independent effects in control subjects have only been reported in two studies, with olanzapine decreasing insulin sensitivity (23) and increasing fasting glucose and leptin after an oral glucose tolerance test (24). "
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    ABSTRACT: Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
    Full-text · Article · Jul 2013 · Diabetes
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