The Influence of Vitamin D on Atypical Antipsychotic-induced Weight Gain
Condition: Schizophrenia; Metabolic Syndrome; Vitamin D Deficiency
MeSH terms: Metabolic Syndrome; Vitamin D Deficiency; Weight Gain; Schizophrenia
Study type: Observational

Summary: 
      Schizophrenia and bipolar disorders are major public health problems. The second generation
      anti-psychotic drugs have efficacy for both positive and negative symptoms and a favorable
      risk profile as far as movement disorders. However, these drugs are associated with
      clinically significant weight gain and metabolic effects. The underlying mechanisms of these
      side effects are unclear, however in our preliminary studies with schizophrenic patients on
      atypical anti-psychotic drugs, we found that weight gain and vitamin D deficiency was present
      in about 50% of this population. Given the considerable heterogeneity among the patients on
      atypical anti-psychotics and potential for weight gain in vitamin D-deficient states, we
      propose that patients with schizophrenia who gain weight on atypical antipsychotic
      medications are vitamin D-deficient. This hypothesis will be tested in patients with
      schizophrenia receiving second-generation anti-psychotic drugs for a minimum duration of 4
      months. 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.
    

Detailed description: 
      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.

      Age-matched subjects of both sex and all ethnicities will participate in this study.
      Potential subjects will be approached by treating clinicians (inpatient or outpatient) for
      possible participation; or potential study participants may respond to advertisements in the
      form of IRB approved flyers that will be distributed at area hospitals and medical clinics.
      Patients who indicate interest in the study will be asked to sign an informed consent to
      allow research personnel to review clinical records and speak with the PI or other treating
      physician about appropriateness for protocol participation. In the Alegent-Creighton clinics
      we have sufficient number of minority patients, including African-Americans, Hispanics and
      women. No children will be recruited in this study.

      Experimental Protocol: Upon the recruitment of the subjects in this study, the following
      information will be collected for each of the 40 patients: (i) Demographic data, including
      age, sex, ethnicity, duration of the illness and the medication regimen and (ii)
      Anthropometry data, including height, weight, BMI, blood pressure, pulse rate. The following
      psychiatric rating scale will be used as a diagnostic measure.

      The MINI International Neuropsychiatric Interview (M.I.N.I.), a well known psychiatric
      diagnostic interview protocol, will be administered at baseline before collecting the blood
      sample. The M.I.N.I. includes items that assess the hallmark symptoms of the exclusionary
      psychotic depression, other psychotic disorders, bipolar disorder, eating disorder and
      substance dependence. We will use these modules only to help exclude patients with the
      prescribed diagnoses.

      Following the MINI protocol, 40 ml venous blood, in a fasting state, will be collected in
      three separate vacutainer EDTA tubes. One tube of 10 ml will be sent to the Clinical
      Pathology Laboratories for the measurement of complete blood count, complete metabolic panel,
      fasting lipid profile for the measurement of triglycerides, high density lipoproteins, low
      density lipoproteins, very low-density lipoproteins. The complete blood count and complete
      metabolic panel will be done to rule out infection or any other co-morbidity. Another 10 ml
      tube will be sent to Clinical Pathology lab for the measurement of serum 25-hydroxy D levels.
      The third tube with 20 ml blood will be used for isolating buffy coat to measure protein and
      mRNA expression of vitamin D receptor (VDR), CYP24A1 and CYP27B1, and for separating serum to
      measure leptin and adiponectin levels. This latter part will be done in the research
      laboratory of the PI using the following procedures.
    

Intervention name(s): Blood Draw
Intervention type(s): Other
Intervention description(s): Blood Draw
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        approximately 40 subjects with schizophrenia, bipolar disorder, and schizoaffective
        disorder, both male and female, 21-65 years, of all ethnicities will be recruited.
      
Biospecimen description: 
      40 ml venous blood will be collected in three separate tubes. One tube of 10 ml will be sent
      to the Clinical Pathology Labs for the measurement of complete blood count, complete
      metabolic panel, fasting lipid profile for the measurement of triglycerides, high density
      lipoproteins, low density lipoproteins, very low-density lipoproteins. The complete blood
      count and complete metabolic panel will be done to rule out infection or any other
      co-morbidity. Another 10 ml tube will be sent to Clinical Pathology lab for the measurement
      of serum 25-hydroxy D levels. The third tube with 20 ml blood will be used to measure protein
      and mRNA expression of vitamin D receptor (VDR), CYP24A1 and CYP27B1, and to measure leptin
      and adiponectin levels.