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

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<br/>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<br/>event by which clozapine could induce a change in mRNA expression of the obesity-related genes?<br/>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.<br/>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.

Name dc:type.qualificationname

Doctor of Philosophy (awarded by OU/Aberdeen)

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Edinburgh

Year dc:date.issued

2016

Author dc:creator

• Mustard, Colette

Language dc:language

eng

Identifier

oai:pure.atira.dk:studenttheses/3e4585b2-4892-4bed-a673-41ab0d83f673

OAI identifier oai:identifier

oai:pure.atira.dk:studenttheses/3e4585b2-4892-4bed-a673-41ab0d83f673