Pharmacogenetic Profiling of Antipsychotics-Induced X-Syndrome and Diabetes (PAXD)

Diabetes is prevalent in schizophrenics and may be induced by antipsychotic treatments. Several retrospective studies have suggested that psychiatric patients exposed to atypical antipsychotics may be at a higher risk for developing diabetes and ketoacidosis. The association between these atypical antipsychotics and the onset of diabetes is further strengthened by observations of:

1. the time sequence between the initiation of antipsychotic treatment and the onset of diabetes;
2. remission after the discontinuation of medications; and
3. re-emergence of diabetes following the re-introduction of atypical antipsychotics.

The treatment emergent diabetes, along with other metabolic disturbances, represents a serious issue in the use of atypical antipsychotics. Major current debates and unresolved research issues which are also the focus of this proposal, are:

1. schizophrenia per se, versus the use of antipsychotics, in triggering diabetes;
2. whether there are differences between "typicals" and "atypicals" in such an effect;
3. whether there are differences among different "atypicals";
4. whether, and to what extent, treatment emergent diabetes may be associated with, or independent of, weight gain, which also often is associated with the use of antipsychotics; and
5. genetic and environmental risks in association with treatment emergent diabetes.

The policy of some hospitals in Taiwan that discourages the use of atypical antipsychotics for new onset schizophrenia directs the investigators to a study design looking at the associated diabetes of both types of antipsychotics. Such a design may provide some hints to the unresolved research issues mentioned above.

Meanwhile, a broader defined term, X-syndrome, or metabolic syndrome, is being used to describe the diabetic condition associated with antipsychotics. X-syndrome is a risky condition leading to cardiovascular diseases and diabetes, with insulin resistance as the major outcome, associated with two of the following conditions: truncal obesity (deposited in the thorax and abdomen, instead of the hips and thighs), high triglycerides, high low-density lipoprotein (LDL) cholesterol or hypertension. The proposed study will combine the phenotypes of diabetes and X-syndrome to explore the abnormal metabolism caused by antipsychotics, bridge important information gaps, and provide data contributing towards a better understanding of the risk and management of diabetes and X-syndrome associated with the use of antipsychotics. Three assessment tools, namely the Clinical Global Severity (Clinical Global Impressions - Severity) or the Positive and Negative Symptom Scale (PANNS), the Diabetes Risk Assessment (ADA) and the Life Style Survey, together with physical measurements, collect additional information for this study. Diabetes related biochemistry, including glucose, insulin, leptin, lipids and glycohemoglobin, will be measured to form a composite phenotype for further pharmacogenetic studies. Candidate genes involved in pancreatic beta cell insulin secretion will be examined in priority to see if they play a role in the development of the antipsychotics-induced diabetes.