Early perturbation in feeding behaviour and energy homeostasy in olanzapine-treated rats

UMR914 Physiologie de la Nutrition et du Comportement Alimentaire, INRA, 16 rue Claude Bernard, 75005, Paris, France.
Psychopharmacology (Impact Factor: 3.88). 08/2009; 206(1):167-76. DOI: 10.1007/s00213-009-1593-5
Source: PubMed


The antipsychotic drug, olanzapine, often induces weight gain and glucose metabolism disturbances, which may result from feeding pattern abnormalities.
The objectives of the study were to examine the effects of a chronic olanzapine treatment on feeding patterns in the rat and to investigate a potential time-related association between feeding patterns and the appearance of glucose metabolism abnormalities and adiposity.
Male rats were treated with olanzapine (2 mg/kg/day), haloperidol (1 mg/kg/day) or a control solution (drugs mixed with the food). In experiment 1, treatments lasted 26 days and feeding patterns were measured on day 21. In experiment 2, treatments lasted for 46 days, and an oral glucose tolerance test (OGTT) was realised on day 31. At the end of both experiments, plasma parameters and body composition were analysed.
In experiment 1, olanzapine-treated animals showed increased meal number, decreased ingestion rate, meal size and inter-meal interval, and no change in total food intake. Plasma glucose, OGTT and body composition were not altered. In experiment 2, after 31 days of treatment, fasting blood glucose was increased and OGTT indicated an insulin resistance. After 46 days of treatment, hyperglycaemia was aggravated (compared to 31 days), and adiposity was increased in olanzapine-treated animals. In both experiments, the haloperidol-treated rats did not differ from the control ones.
Chronic olanzapine treatment produces changes in feeding patterns, in a way consistent with an increased incentive drive to eat. As a whole, the results raise the hypothesis that long-term alteration of feeding pattern by olanzapine may predispose to disturbances in the regulation of energy metabolism.

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    • "Modelling olanzapine-induced weight gain in rats 179 (Davoodi et al., 2009; van der Zwaal et al., 2010). Conversely, one chronic study observed decreased meal size and increased meal frequency (Victoriano et al., 2009). In this study olanzapine was first mixed with a powdered diet in the home-cage for 21 d, followed by administration in a mash of powdered diet and water during 2 d of meal patterning. "
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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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    • "Furthermore, the male rats treated with olanzapine (4 mg/kg) did not show increases in body weight gain but did however show increased adiposity. This finding supports clinical and pre-clinical studies which found increased adiposity following olanzapine treatment with (Ader et al. 2008; Raskind et al. 2007; Victoriano et al. 2009) and without weight gain (Victoriano et al. 2009). Increased visceral mass is considered a key factor in the development of the metabolic syndrome and in particular the development of insulin resistance (Bjorntorp 1991; Demerath et al. 2008). "
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    ABSTRACT: Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats. Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL-1β)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed. Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1β, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders. This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment.
    Full-text · Article · Jan 2012 · Psychopharmacology
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    • "Experimental studies in animals on the mechanisms underlying Olanzapine's metabolic effects also provide confusing data. Female rats appear to increase body weight more profoundly than male rats (Cooper et al., 2005, 2007) and this increase in body weight, predominantly adipose tissue, may be related to a decreased level of physical activity (the sedative effect of Olanzapine), or by an increase in food intake, although again contradictory results have been found (Lee and Clifton, 2002; Victoriano et al., 2009; Davoodi et al., 2009). Furthermore, Olanzapine has also been shown to induce hypothermia (Oerther and Ahlenius, 2000) and to block orexin-A induced hyperthermia (Monda et al., 2008), but these effects have not been investigated in the face of Olanzapine's effect on body weight gain. "
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    ABSTRACT: Olanzapine is an a-typical antipsychotic drug antagonizing predominantly 5-HT and dopamine, but also histamine, muscarin, and α-adrenergic receptors. In humans, Olanzapine induces weight gain and increases the risk of type 2 diabetes. The underlying mechanisms of Olanzapine-induced weight gain are unclear. To study this we administered Olanzapine (5mg/kg) in female Wistar rats on a medium fat diet for 14 days via a permanent gastric catheter twice a day, just prior to the onset and at the middle of dark phase. Food and water intake, locomotor activity and body temperature were measured. Olanzapine acutely induced hypothermia, markedly decreased locomotor activity and increased body weight during 14 days of treatment. Olanzapine treatment did not result in an alteration of 24h food intake, but diurnal patterns of feeding behavior and body temperature were dramatically changed. We conclude that in female Wistar rats Olanzapine has an acute hypothermic effect, that the effect of Olanzapine on feeding behavior is secondary to the effect on activity, and that Olanzapine-induced weight gain is primarily the result of reduction in locomotor activity.
    Full-text · Article · Nov 2010 · Pharmacology Biochemistry and Behavior
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