Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities
Condition: Metabolic Syndrome
MeSH terms: Congenital Abnormalities; Metabolic Syndrome; Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): metformin 500 mg; clozapine 100 mg
Intervention type(s): Drug; Drug
Intervention description(s): metformin 500 mg QAM for metformin 500 mg/d group; metformin 500 mg 1 BID for metformin 1000 mg/d; Clozapine dose remained unchanged during metformin intervention period in recruited patients.
Other intervention name(s): Loditon; Clozaril
Intervention MeSH terms: Metformin; Clozapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: metformin; clozapine; schizophrenia; metabolic traits