The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature

Abstract

Objective: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. Methods and results: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. Conclusion: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

“…However, one short-term study suggested that eight days of olanzapine treatment can lead to small but significant increase in pre-and postprandial total ghrelin levels (Vidarsdottir et al, 2010), indicating an acute upregulatory effect of SGAs on ghrelin production. This view is supported by two pharmacological animal studies which showed that acute olanzapine or clozapine treatments can increase both preand postprandial total ghrelin levels in rodents (van der Zwaal et al, 2012). Furthermore, our preliminary data also showed that one week of oral olanzapine treatment can increase plasma total ghrelin levels in rats (Zhang et al, unpublished data).…”

“…Clinical data has indicated ghrelin production and signalling is upregulated, at least in a subpopulation of patients under SGA treatments (Esen-Danaci et al, 2008;Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005;Perez-Iglesias et al, 2008), which was supported by the majority of acute and chronic animal studies (Murashita et al, 2007b;van der Zwaal et al, 2012;Weston-Green et al, 2011). Although ghrelin signalling is only indirectly related to SGAs, and therefore other mechanisms (for example, antagonism of H1, H3, 5-HT2a, M3 receptors) cannot be excluded, the majority of data as discussed above indicate that the altered ghrelin signalling under SGA treatments can at least partly explain the weight gain sideeffects induced by SGAs.…”

Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

“…Consistent with this, there is significant incidence of somnolence in people treated with many second-generation APDs (Gao et al, 2008 ). Furthermore, thermogenesis is another measure of body energy consumption and olanzapine administration was shown to cause reductions in body core temperature in animal model (van der Zwaal et al, 2012 , 2014 ). Therefore, these drug-induced decreases in body core temperature suggest overall decreases in energy expenditure.…”

Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

“…Although a recent study found an increased heat production in mice treated with olanzapine (Lord et al, 2017 ), a previous study reported a decrease of metabolic rate in mice with olanzapine infusion (8 mg/kg/day) but not in mice with a lower dose (4 mg/kg/day) (Coccurello et al, 2009 ). Furthermore, a number of studies in rats reported that olanzapine reduced core body temperature or thermogenesis of brown adipose tissue (BAT) accompanied with decreased expression of functional thermogenic proteins, uncoupling protein1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) of BAT (Stefanidis et al, 2009 ; van der Zwaal et al, 2012 ; Zhang et al, 2014b ). Therefore, further studies are necessary to clarify the effects of APDs on thermogenesis.…”