Many atypical antipsychotic drugs, in particular olanzapine, induce significant weight gain, which can have serious implications for drug compliance and the health of the patient. Previous studies in our laboratory have shown that olanzapine enhances feeding behaviour in the runway to food-goal paradigm suggestive of an inhibition of the natural progression of satiety (Thornton-Jones et al., 2002). However, the novel antipsychotic agent, ziprasidone, induces minimal weight gain in humans (Allison et al., 1999). Whether this is due to ziprasidone having a weaker effect at receptors implicated in weight gain, such as 5-HT_2C or histamine H1, or whether ziprasidone has an intrinsic protective mechanism, remains unclear. The present study aimed to determine whether ziprasidone could prevent the acute effect of olanzapine on feeding behaviour.

Subjects were 32 adult male hooded-Lister rats weighing 350g ± 35g (Harlan, UK) maintained at 85% free-feeding weight, group housed under standard laboratory conditions with free access to water. Animals were trained to run for Noyes pellets in a runway to food goal paradigm and tested as described previously (Neill et al., 1990; Thornton-Jones et al., 2002). Data are expressed as mean ± s.e.m. of behaviour in 5 trial blocks each consisting of 3 trials (n=8 subjects per group). Statistical comparisons were made using 2 way and 1 way ANOVA with post-hoc Dunnett's t-test. Olanzapine (0.5 mg/kg, i.p.), administered 30 minutes prior to testing, induced a significant increase in food intake compared to the vehicle control group in trial block 1 (2.54g ± 0.56g vs 1.48g ± 0.26g, p<0.05) and the increase observed in trial block 2 closely approached significance (1.96g ± 0.32g, vs 1.21g ± 0.26g, p=0.052). Total food intake was also significantly increased following olanzapine treatment (17.70g ± 0.30g vs 11.99g ± 0.21g, p<0.05). Ziprasidone (1 mg/kg, administered i.p. 30 minutes prior to testing) did not affect total food intake or food intake in any trial block. Ziprasidone (1 mg/kg) co-administered with olanzapine (0.5 mg/kg) significantly reduced the increase in total food intake produced by olanzapine alone (11.34g ± 0.21g vs 17.70g ± 0.30g, p<0.05). Assessment of locomotor activity under similar conditions indicated that sedation was not a confounding factor (olanzapine 985 ± 213, ziprasidone 1237 ± 254, ziprasidone with olanzapine 949 ± 119 vs vehicle 1271 ± 156 beam breaks/hr).

These results confirm our previous findings showing that acute olanzapine increases ingestive behaviour in the runway to food-goal paradigm (Thornton-Jones et al., 2002). The results demonstrate a lack of effect of ziprasidone to enhance ingestive behaviour and that it prevents the hyperphagic effect of olanzapine in this test. The differences in the receptor pharmacology of these drugs suggest that the partial agonism of ziprasidone at 5-HT_1A receptors could provide a possible mechanism of action.

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Thornton-Jones, Z. et al., 2002, J Psychopharmacol, 16:35-37.