The Role of Vitamin D and Quetiapine-induced Weight Gain

Specific Aim: We predict that the patients with schizophrenia, who gain weight with antipsychotic treatment, are vitamin D-deficient compared to the patients who do not gain weight. We will examine circulating levels of serum 25(OH)D, mRNA transcripts and protein expression of vitamin D receptor (VDR) and the enzymes, CYP24A and CYP27B, in the white blood cells of the subjects and correlate with BMI and the blood levels of leptin and adiponectin.

Experimental Approach:

Recruitment of Patients: Subjects will be recruited from the psychiatry clinics of Alegent-Creighton Clinics where the PI is working on a full-time basis. Dr. Selvaraj, the PI of this project, provides psychiatric care annually to an average of 300 patients with schizophrenia and bipolar disorder. In addition, other psychiatrists in the same clinic also see patients with schizophrenia. Thus, there is an ample population available for this study. The patients will be recruited based on the inclusion and exclusion criteria, as shown in Figure 1. Patients with schizophrenia who are on the atypical antipsychotic, quetiapine, will be recruited. The underlying major mechanism of action of this anti-psychotic medication is to block both dopamine (D2 and D4) and serotonin (5-HT2A and 5-HT2c) receptors (24). Also, this antipsychotic medication has been shown to increase weight in the patients. According to the data, mean increase in weight after 8-10 weeks on anti-psychotics is about 12.2 lbs with quetiapine (24). In most cases, increase in weight reaches to a plateau within 8-10 weeks (24). Therefore, we will recruit age-matched patients who have been taking quetiapine 100mg or more for at least 12 weeks. There is no relationship in weight gain and the severity of psychosis or the dose of the anti-psychotic drug. During the first episode, most of these patients are in their 20s and 30s. The patients will be divided into two experimental groups: (i) "Weight gain" and (ii) "No weight gain". In the weight gain group, we will recruit those patients who have gained 10% increase from the baseline weight. In the no weight group, we will recruit patients who have lost weight, did not gain weight or have gained weight <5% over the baseline weight. The baseline weight data and other information will be obtained from the electronic health record through the EPICS system, upon recruitment in the study.

The human research protocol with the Informed Consent and HIPPA forms has been approved by the Institutional Review Board of Creighton University.

Statistical Analysis: The association between weight gain and vitamin D deficiency will be analyzed using 2x2 contingency tables and tests for independence. The three most common tests for independence are the likelihood ratio test (LRT), the Pearson's chi-square statistic, and Fisher's exact test. Both Pearson's chi-square and Fisher's exact test will be used to analyze the data. If the expected number of counts in any one cell is less than five (5), only Fisher's exact test will be reported. The purpose of this pilot is to estimate/confirm a reasonable confidence interval for the true odds ratio and reference proportion to design a larger scale study. We believe we can reasonably recruit between 30 and 40 patients. Should we recruit a total of 40 patients, we believe we can achieve a minimum detectable odds ratio of 9 (with desired power of 0.80 and significance level of 0.05) with reference proportion of 0.35. This initial analysis was based on a preliminary study where 35% of schizophrenic patients gained weight on atypical antipsychotic drugs. Since there is no follow up of these patients, but the collection of the blood and clinical data only at one time point, the question of potential drop-outs or the follow-ups does not arise.