“These side effects are well recognised but affect people variably, with some people experiencing severe side effects and other people none at all,” says psychiatrist Dr Wayne Miles, Clinical Associate Professor at The University of Auckland. “There is evidence that interventions aimed at diet control and exercise can control weight gain, but unwell people are less likely to be able to use such approaches. Understanding the biochemical reasons that these side effects occur may eventually help to make treatment more tolerable”
The latest study, focusing on the popular antipsychotic olanzapine, has been published in the Archives of Physiology and Biochemistry. It is part of a wider programme of research, led by Professor Peter Shepherd and Dr Greg Smith from The University of Auckland and the Maurice Wilkins Centre for Molecular Biodiscovery, examining the effects of novel antipsychotics including olanzapine and clozapine.
“Olanzapine and clozapine are recognised as the most effective medications for treating many people with schizophrenia and are very widely used, but they are often associated with significant weight gain and defects in glucose metabolism,” says Dr Shepherd. “People with schizophrenia are at increased risk of metabolic syndrome and type-2 diabetes, which can have serious implications for long-term health. While there is some evidence for a genetic link between the conditions, it is also clear that antipsychotic medications can directly affect metabolism and we want to understand how this happens.”
“Our research showed that treatment with olanzapine caused changes in food preference, body composition, glucose metabolism and insulin secretion in rats. In the short-term it induced large increases in blood glucose and insulin secretion. Treatment with olanzapine induced a strong preference for a high fat, high-sugar diet and, in animals given access to this diet, resulting in a greater-than normal increase in both weight and fat mass.”
The research also pointed to a possible mechanism for at least some of these changes. Reductions in GLP-1, a hormone that acts to lower blood levels of glucose and the glucose-regulator glucagon, were observed. The researchers concluded that olanzapine was likely to cause a reduction in GLP-1, resulting in a short-term spike in blood glucose levels. Olanzapine-induced reductions in GLP-1 may also explain the changes in food preference observed, with evidence from other studies demonstrating a link between GLP-1 levels and body weight, taste response, and food selection. The research has shown that treatments that restore GLP-1 signalling can reverse these effects. Studies are now beginning to see whether the olanzapine and clozapine work in the same way in humans.
The study was undertaken by scientists at The University of Auckland’s Faculty of Medical and Health Sciences, the Maurice Wilkins Centre for Molecular Biodiscovery, the Liggins Institute, and the National Research Centre for Growth and Development. It was supported by funding from the Lottery Health Research Fund (NZ), the Oakley Mental Health Research Fund and Eli Lilly Australia.