Abstract: Some antipsychotics probably increase the risk of metabolic syndrome. Antipsychotics may differentially influence some elements of metabolic syndrome (obesity, hyperlipidemia, hyperglycemia or hypertension) through various pharmacological mechanisms. In a published study of all first psychotic episodes in a Spanish hospital's catchment area population in Cantabria (Spain), patients were randomly assigned to receive haloperidol (3?9 mg/day), olanzapine (5?20 mg/day) or risperidone (3?6 mg/day). In this article, a structural-equation modeling approach tested the mechanistic hypothesis that olanzapine directly (without the mediation of weight gain) increases triglyceride levels, whereas risperidone and haloperidol do not have these effects. A structural equation model was built using the 110 patients whose assigned antipsychotic was not changed during the first 3 months of treatment, and who provided both triglyceride and body mass index (BMI) measurements at baseline and at the end of the 3rd month of treatment. A second structural equation included 72 patients whose antipsychotic was not changed during the first year. After 3 months and controlling for confounders, olanzapine patients had triglyceride levels that were 29.2 mg/dL higher [95% confidence interval, (10.9, 47.5)] than those of risperidone patients with comparable baseline triglyceride levels. After 12 months, they were 63.1 mg/dL higher (18.6, 107.6) than those of patients with a comparable history of triglyceride values during the first 3 months. Haloperidol effects on triglyceride levels and BMI were no different from those of risperidone. In conclusion, olanzapine increased triglyceride levels without the mediation of weight gain during a one-year study in naïve patients.

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