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A parametric analysis of olanzapine-induced weight gain in female rats

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Abstract

Rationale

Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear.

Objective

The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings.

Methods

Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration.

Results

Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose–response curve, with the maximal effect at the highest dose (4 mg/kg).

Conclusions

These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

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Notes

  1. Daniels et al. (2003) reported, in an Abstract, that in female rats olanzapine (5 mg/kg, p.o., b.i.d., 14 days) induced a small (12%), but significant (p<0.05), reduction in glucose. These preliminary data contrast with ours for reasons that are at present unclear.

  2. The prolactin data might appear to contrast with the typical characterisation of olanzapine as an APD that is “prolactin-sparing” in humans. The reported increases in prolactin probably reflect the use of high doses given b.i.d. with a dosing regime which allowed drug levels to accumulate. Thus we do not consider these data to be incompatible with the notion that in humans olanzapine is a “prolactin-sparing” drug.

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Acknowledgements

We are greatly indebted to Eli Lilly for the generous supplies of olanzapine. G.D. Cooper was supported by a University of Liverpool Research Studentship. We thank Miss Juliet McAdams for invaluable technical support and Dr. J. Harrold for comments on the paper.

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Authors and Affiliations

  1. School of Psychology, Liverpool University, Eleanor Rathbone Building, Bedford Street, Liverpool, L69 7ZA, UK

    G. D. Cooper, J. C. G. Halford & A. J. Goudie

  2. Department of Veterinary Preclinical Science, Liverpool University, Liverpool, UK

    L. C. Pickavance

  3. Department of Diabetes and Endocrinology, Liverpool University, Liverpool, UK

    J. P. H. Wilding

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  1. G. D. Cooper
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  2. L. C. Pickavance
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  3. J. P. H. Wilding
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  4. J. C. G. Halford
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  5. A. J. Goudie
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Correspondence to A. J. Goudie.

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Cooper, G.D., Pickavance, L.C., Wilding, J.P.H. et al. A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology 181, 80–89 (2005). https://doi.org/10.1007/s00213-005-2224-4

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