Dose Effect of Extended-Release Metformin on Metabolic Parameters and Neurocognitive Function Treated by Clozapine or Olanzapine in Patients with Schizophrenia---A Randomized, Double-Blinded, Placebo-Controlled Trial

Background: In psychiatric field, some double-blind, placebo-controlled studies (metformin 750-1700 mg/d) showed that metformin could safely decreased body weight and waist circumference, and have beneficial effects on lipid profiles. Metabolic disturbance also has impact on the neurocognitive function in patients with schizophrenia. Until now, no study compares the dose effect of 750 mg/day and 1500 mg/day of extended-release metformin on metabolic features and neurocognitive function. We design a trial using extended-release metformin to minimize side effects, large sample size and long intervention period to improve scientific power, and incorporating neurocognitive assessment, hormonal parameters, and genotyping to achieve multidimensional approach. We hypothesize that metformin 750 mg/d and 1500 mg/day can effectively improve metabolic traits, and the effect would disappear after stopping metformin. Aims: Our study aims are: 1. To compare the effectiveness of 750 mg/day, 1500mg/day of extended-release metformin, and placebo on metabolic features in clozapine- or olanzapine-treated schizophrenia patients with metabolic abnormalities. 2. To monitor the metabolic profile changes after stopping. 3. To investigate the potential biomarkers for metformin response and weight regain Methods: This will be a three-phase study. The first phase is to screen clozapine- or olanzapine-treated patients with schizophrenia. The second phase is a 24-week randomized, double-blind, placebo-controlled study of adjunctive extended-release metformin (750 or 1500 mg/d) or placebo for clozapine- or olanzapine-treated patients with metabolic abnormalities. One hundred and fifty subjects will be recruited into the second phase in 3 years. The third phase is to follow patients’ metabolic features after they stop taking metformin. Intervention procedure: The antipsychotic dosages will be maintained unchanged during the study period. Eligible patients will be randomized to 750, 1500 mg/day extended-release metformin orplacebo group. Phase 2 follow-up assessments: Physical examination, psychiatric assessment, neurocognitive function assessment, and laboratory assay will be repeated at week 4, 8, 12, 16, 20, and 24. Phase 3 follow-up assessments: Metabolic features will be assessed at 8, 16, and 24 weeks after stopping intervention. Anticipated results and future applications We anticipate that metformin will be beneficial and have dose effect on schizophrenic patients with metabolic abnormalities and the beneficial effects would disappear after stopping intervention. Potential biomarkers (SNPs and hormonal parameters) can predict the metformin response and weight regain.