Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities
Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities
Metformin has been used for alleviating metabolic abnormalities in patients with
 schizophrenia. Until now, the lowest dose of metformin to treat metabolic abnormalities in
 clozapine-treated patients is 1000 mg/d. The aim of this study was to determine whether a
 lower dosage of metformin, such as 500 mg/d, is effective for improving metabolic profiles in
 clozapine-treated patients with pre-existing metabolic abnormalities.

 Methods:

 In this 12-week, randomized, double-blind, placebo-controlled trial, metformin 500 mg/d or
 1000 mg/d or a placebo was prescribed to clozapine-treated patients with schizophrenia having
 pre-existing metabolic abnormalities. The recruited patients underwent physical and
 laboratory evaluations at week-4, week-8, and week-12.
Methods In this 12-week, randomized, double-blind, placebo-controlled trial, metformin 500
 mg/d or 1000 mg/d or placebo was prescribed to clozapine-treated patients with schizophrenia
 having pre-existing metabolic abnormalities. The study was approved by an institutional
 review board and was conducted at Taipei Medical University-Wan Fang Hospital and Taipei City
 Psychiatric Center from May 2013 to January 2015. All clinical investigation had been
 conducted according to the principles expressed in the Declaration of Helsinki. The
 investigators screened clozapine-treated patients in the first phase and enrolled eligible
 patients in this clinical trial. Written informed consent was obtained from all patients
 before the screening.

 Patients in the first-phase screening Patients diagnosed with schizophrenia or
 schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental
 Disorders, Fourth Edition; aged 20-65 years; and who had taken clozapine for at least 3
 months were invited to the first-phase screening. Clinical interviews were conducted, and
 medical records were evaluated for collecting patient demographics and clinical information,
 namely diagnosis, age of onset, and dosage of clozapine use.

 Measurements The height, BW, waist circumference (WC), and blood pressure (BP) of all
 patients were measured. The body mass index (BMI) was calculated as the BW in kilograms
 divided by the square of the height in meters. After overnight fasting, blood was collected
 for analyzing the fasting plasma glucose (FPG), TG, and high-density lipoprotein cholesterol
 (HDL-C) levels. Under manufacture's guide, fasting TG, FPG, and HDL-C levels were measured
 using an automated system (Roche Cobas C501).

 Patients in the metformin trial Patients in the first-phase screening were enrolled in the
 present trial if they had at least one of the following metabolic abnormalities: BMI ≥ 24; WC
 > 90 cm (men) or 80 cm (women); fasting serum TG level ≥ 150 mg/dL; fasting serum HDL-C level
 ≤ 40 mg/dL (men) or 50 mg/dL (women); systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg; current
 use of antihypertensive agents; and FPG level = 100-126 mg/dL. The exclusion criteria were
 the following: history of diabetes mellitus (DM); current use of hypoglycemic or
 hypolipidemic agents; pregnancy; allergy to metformin; a creatinine level > 1.4 ng/dL; an
 abnormal liver function test result; and chronic cardiopulmonary insufficiency.

 Trial procedures Patients recruited in the trial were randomized to three groups, metformin
 500 mg/d, metformin 1000 mg/d, or placebo. The randomization was conducted by a research
 assistant, who was blinded to the patient's status. To ensure the concealment of the
 randomization, the metformin and placebo were provided in coded containers. The appearance of
 the placebo was identical to that of metformin tablets. All patients, caregivers, and
 investigators were masked to the randomization.

 In the first week, 500 mg of metformin was administered in the morning to the groups of
 metformin 500 mg/d and 1000 mg/d, and placebo was administered to the placebo group. In the
 second week, the dosage was revised to 500 mg of metformin in the morning and the placebo in
 the evening for the group of metformin 500 mg/d, 500 mg of metformin twice a day for the
 group of metformin 1000 mg/d, and placebo twice daily for the placebo group. For all
 patients, the clozapine dosage remained unchanged throughout the intervention. The recruited
 patients underwent physical and laboratory evaluations at week-4, week-8, and week-12.

 Statistical analyses The investigators used descriptive statistics for summarizing the
 baseline clinical characteristics of patients and analysis of variance for examining the
 differences in these characteristics among all groups. Patients who continued the
 intervention for at least 4 weeks were included in the analyses. The investigators adopted
 the last observation carried forward (LOCF) approach for replacing missing data, assuming no
 change in the missing values of metabolic indices after an event of dropout. Furthermore, for
 investigating whether repeated measures collected in a longitudinal manner change over time,
 the investigators first used the paired t test for examining differences between the baseline
 and follow-up measures. Repeated measure analyses were conducted using 2-way within-subjects
 analysis of variance for examining group (df = 2, between groups), time (df = 3, within
 subjects), and interaction (df = 6, interaction between time and groups) effects on the
 changes in metabolic profiles over time. The analyses were conducted using SPSS Version 20.0
 (IBM, Armonk, NY). P < 0.05 was considered to indicate statistical significance.
Inclusion Criteria:

 1. patients diagnosed with schizophrenia or schizoaffective disorder according to the
 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

 2. aged 20-65 years

 3. had taken clozapine for at least 3 months

 4. had at least one of the following metabolic abnormalities: BMI ≥ 24; WC > 90 cm (men)
 or 80 cm (women); fasting serum TG level ≥ 150 mg/dL; fasting serum HDL-C level ≤ 40
 mg/dL (men) or 50 mg/dL (women); systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg; current
 use of antihypertensive agents; and FPG level = 100-126 mg/dL.

 Exclusion Criteria:

 1. history of diabetes mellitus

 2. current use of hypoglycemic or hypolipidemic agents

 3. pregnancy

 4. allergy to metformin

 5. a creatinine level > 1.4 ng/dL

 6. an abnormal liver function test result

 7. chronic cardiopulmonary insufficiency.