Comparing the effects of high-dose vitamin E with those of placebo on insulin resistance in patients with schizophrenia treated with olanzapine.

To the Editors: I t has been reported that atypical antipsychotics may cause metabolic adverse disturbances, such as weight gain, elevated fasting plasma glucose levels, and insulin resistance. There is increasing evidence on free radicalYmediated oxidative stress involvement in the development of such side effects including insulin resistance. Vitamin E is reported to improve oxidative stress and therefore might be beneficial in decreasing insulin resistance. We present an 8-week study that assessed the effect of high-dose >-tocopherol on fasting blood glucose (FBG), glycated hemoglobin (HbA1C), and fasting insulin in patients with schizophrenia treated with olanzapine. Thirty-six adults with schizophrenia who had been on olanzapine treatment for a minimum of 30 days were eligible for this 8-week, double-blind, placebo-controlled study.Exclusioncriteria includeddiagnosed diabetes mellitus, cardiovascular disorders, hematologic problems, pregnancy, breastfeeding, a history of electroconvulsive therapy within the past 6 months and the use of any medication known to affect glycemic control measures within 2 months before the initiation of the study. All subjects (or parents/guardians) gave their written consent to participate in the study after all procedures and possible adverse drug effects were explained to them. Patients were randomized by blocked randomization to receive >-tocopherol 400 IU or placebo capsules twice a day for 2 weeks, then 3 times a day for 6 more weeks. The FBG, HbA1C, and fasting insulin levels were assessed at baseline and at 4 and 8 weeks. Data were analyzed performing 1-way analysis of variance (ANOVA) and independent samples t test via SPSS (Ver.11.5). In addition, a 2-way repeated-measures ANOVA (time-treatment interaction) was used. The 2 groups as a between-subjects factor (group) and the 3 measurements during treatment as the within-subject factor (time) were considered. Thirty-two patients aged between 18 and 49 years (15 in the vitamin E group and 17 in the placebo group) completed this study. One-way ANOVA showed that in the vitamin E group, the mean FBG level decreased from 91.6 T 10.0 mg/dL at baseline to 83.6 T 9.3 mg/dL at week 8 (P = 0.09). However, in the placebo group, FBG level was increased from 87.8 T 12.8 mg/dL at baseline to 91.3 T 5.7mg/dL at week 8 (P = 0.4). The changes were not statistically significant in both groups. Independent samples t test revealed a significant difference of j7.50 mg/dL in FBG levels between vitamin E and placebo at week 8 (P = 0.01). The mean fasting insulin level of patients in the vitamin E group dropped from the baseline value of 6.9T 2.2KIU/mL to5.5T 1.9KIU/mLonweek 8 (P=0.3). On the other hand, in the placebo group, the mean fasting insulin level increased from the baseline value of 6.7 T 2.6 KIU/mL to 7.4 T 1.9 KIU/mL on week 8 (P = 0.06). In addition, the mean HbA1C percentage decreased from 5.2% T 0.2% to 5.1% T 0.3% in the vitamin E group (P = 0.7) and stayed the same 5.5% T 0.5% at baseline and after 8 weeks in the placebo group. Independent samples t test showed significant differences of j1.90 KIU/mL in fasting insulin (P = 0.017) and j0.41% in HbA1C (P = 0.016) between the 2 groups at the end of the study. The homeostasis model assessment of insulin resistance (HOMA-IR) index for insulin resistance was calculated based on a formula by Matthews et al. The formula is as follows: [FBG (mg/dL) RIA Insulin (KIU/mL)]/405. The mean value of HOMA-IR index for insulin resistance of patients under vitamin E treatment decreased from 1.6 T 0.4 at baseline to 1.1 T 0.4 at week 8 (P = 0.10) and increased from 1.5 T 0.7 to 1.6 T 0.4 (P = 0.3) during the same time in the placebo group. Independent samples t test noted a significant difference of j0.48 in HOMA-IR between vitamin E and placebo group after 8 weeks (P = 0.006). In addition, the differences between the 2 protocols were not significant as indicated by the effect of group, the between-subjects factor. Table 1 shows the difference between the 2 protocols as indicated by the effect of group, the between-subjects factor. DISCUSSION Olanzapine has been reported to increase FBG levels, increase insulin resistance, and increase the risk of type 2 diabetes. Jain et al noted that Vitamin E 100 IU/d for 3 months decreased HbA1C in patients with type 1 diabetes. The present study was designed to assess the effects of an 8-week treatment with a relatively high dose of vitamin E on insulin resistance of patients who had been receiving olanzapine for at least 1 month. We calculated the insulin resistance based on the formula mentioned earlier. In this study, by using 1-way ANOVA, although there were no significant changes in the insulin resistance of patients on high-dose vitamin E, there was a trend in decreasing this factor (P = 0.09). However, mixed-model ANOVA did not show any significant effects or trend of vitamin E on insulin resistance. In addition, no significant changes were observed in the levels of FBG or HbA1C by using both statistical models. It may be argued that glycemic control measures may change mostly during the first month of treatment with olanzapine and that vitamin E may not have a significant effect on these factors after receiving olanzapine for a longer period. Therefore, considering the results of this study, it may not be wise to add relatively high-dose vitamin E to improve insulin resistance in patients who are already on olanzapine. Further studies are needed to confirm the results of this study and to assess the preventive effects of high-dose vitamin E on developing insulin resistance in patients who are going to be started on olanzapine.