The impact of antipsychotic drugs on the expression of genes associated with obesity

Abstract

Schizophrenia is a severe and debilitating disorder, primarily treated with antipsychotic medication. Weight gain is a serious side-effect associated with most second generation antipsychotic drugs such as clozapine. The mechanism behind clozapine-induced weight gain remains poorly understood, but changes in eating behaviour and energy homeostasis may be involved. Recently, genome-wide association studies have identified a number of genetic
variants associated with obesity risk; however the effects of these risk variants on clozapineinduced weight gain have not been investigated. This doctoral thesis focused on the following research questions: (1) Does schizophrenia share a genetic link with obesity? (2) Can various antipsychotics alter the expression of obesity-related genes? (3) What is the initial signalling
event by which clozapine could induce a change in mRNA expression of the obesity-related genes?
The major findings from this work included that there was no demonstrable association between obesity-related variants and schizophrenia, and that low and intermediate doses of clozapine (0.125 μg/ml and 0.25 μg/ml) induced changes in mRNA expression of a panel of obesity-related genes in U937 cells. This effect was not observed in cells treated with haloperidol. However, the mRNA expression was also altered by treatment with olanzapine in most obesity-related genes tested but only in one gene when treated with risperidone. Treatment with 5-HT promoted an increase in mRNA expression of some obesity-related genes, which was similar to the treatment with 0.25 μg/ml clozapine although this effect was not apparent with a combination of clozapine and 5-HT. Changes in mRNA expression in clozapine-treated cells were likely mediated by the IP3 signalling pathway.
In conclusion, the mechanism behind weight gain in patients treated with either clozapine or olanzapine is multi-factorial: this study suggests that there may be an additional risk factor that could facilitate antipsychotic-induced weight gain: the altered the mRNA expression of obesityrelated genes.

Date of Award	31 Jul 2016
Original language	English
Awarding Institution	University of Edinburgh
Sponsors	SAGB
Supervisor	Jun Wei (Supervisor), Ian Megson (Supervisor), Phillip D Whitfield (Supervisor) & Giovanna Bermano (Supervisor)