Adjunctive Low-dose Metformin in Patients With Schizophrenia and Metabolic Abnormalities

Treatment of Metabolic Abnormalities in Patients With Schizophrenia: 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.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Drug: metformin 500 mg; Drug: clozapine 100 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: metformin 500 mg/d; clozapine 100 mg; In the first week, 500 mg of metformin was administered in the morning. In the second week, the dosage was revised to 500 mg of metformin in the morning and the placebo in the evening. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.	Drug: metformin 500 mg; metformin 500 mg QAM for metformin 500 mg/d group; metformin 500 mg 1 BID for metformin 1000 mg/d; Other Names: Loditon; Drug: clozapine 100 mg; Clozapine dose remained unchanged during metformin intervention period in recruited patients.; Other Names: Clozaril
Active Comparator: metformin 1000 mg/d; clozapine 100 mg; In the first week, 500 mg of metformin was administered in the morning. In the second week, 500 mg of metformin twice a day was administered. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.	Drug: metformin 500 mg; metformin 500 mg QAM for metformin 500 mg/d group; metformin 500 mg 1 BID for metformin 1000 mg/d; Other Names: Loditon; Drug: clozapine 100 mg; Clozapine dose remained unchanged during metformin intervention period in recruited patients.; Other Names: Clozaril
Placebo Comparator: placebo; clozapine 100 mg; In the first week, one pill of placebo was given and in the second week, placebo BID was given. During metformin intervention period, the clozapine dose remained unchanged in these recruited clozapine-treated patients.	Drug: metformin 500 mg; metformin 500 mg QAM for metformin 500 mg/d group; metformin 500 mg 1 BID for metformin 1000 mg/d; Other Names: Loditon; Drug: clozapine 100 mg; Clozapine dose remained unchanged during metformin intervention period in recruited patients.; Other Names: Clozaril

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in body weight	baseline; week-4; week-8; week-12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in waist circumference		baseline; week-4; week-8; week-12
Changes in blood pressure		baseline; week-4; week-8; week-12
Changes in fasting triglyceride level		baseline; week-4; week-8; week-12
Changes in fasting high-density lipoprotein cholesterol level		baseline; week-4; week-8; week-12
Changes in fasting glucose level		baseline; week-4; week-8; week-12
Changes in scores of positive and negative syndrome scale (PANSS)	Recruited patients were interviewed by research assistants to get PANSS scores.	baseline; week-4; week-8; week-12

Collaborators and Investigators

• Sponsor: Taipei Medical University WanFang Hospital
• Collaborators: Taipei City Hospital
• Investigators: Principal Investigator: Chun-Hsin Chen, MD, Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Publications and helpful links

General Publications

• Chiu CC, Lu ML, Huang MC, Chen PY, Lin YK, Lin SK, Chen CH. Effects of Low Dose Metformin on Metabolic Traits in Clozapine-Treated Schizophrenia Patients: An Exploratory Twelve-Week Randomized, Double-Blind, Placebo-Controlled Study. PLoS One. 2016 Dec 14;11(12):e0168347. doi: 10.1371/journal.pone.0168347. eCollection 2016. Erratum In: PLoS One. 2018 Feb 16;13(2):e0193315.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: April 25, 2016
• First Posted (Estimate): April 26, 2016

Study Record Updates

• Last Update Posted (Estimate): April 28, 2016
• Last Update Submitted That Met QC Criteria: April 26, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: schizophrenia; metformin; clozapine; metabolic traits
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Insulin Resistance; Hyperinsulinism; Schizophrenia; Metabolic Syndrome; Congenital Abnormalities; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; GABA Agents; GABA Antagonists; Metformin; Clozapine
• Other Study ID Numbers: TMU-JIRB 201303005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided