Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.685271
Title: The impact of antipsychotic drugs on the expression of genes associated with obesity
Author: Mustard, Colette J.
ISNI:       0000 0004 5924 4077
Awarding Body: University of Aberdeen and University of the Highlands and Islands
Current Institution: University of Aberdeen
Date of Award: 2016
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Abstract:
Schizophrenia is a severe and debilitating disorder, primarily treated with antipsychotic medications. 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 clozapine-induced 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 of most obesity-related genes tested 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 obesity-related genes.
Supervisor: Not available Sponsor: Schizophrenia Association of Great Britain
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.685271  DOI: Not available
Keywords: Schizophrenia ; Antipsychotic drugs ; Obesity
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