The MEtformin-LIfestyle in Antipsychotic users trial

SUMMARY

Rationale: Antipsychotics are the mainstay treatment modality for schizophrenia. Of the insidious adverse drug reactions (ADRs) to antipsychotics, Antipsychotic-induced Weight Gain (AiWG) is the most debilitating and prevalent ADR. AiWG negatively impacts life expectancy, quality of life, treatment adherence, chances of developing type-2 diabetes and likelihood of readmission. Treatment of AiWG is currently very challenging and few interventions have been investigated in well powered trials of sufficient quality.

Objective: We aim to optimize the application of an existing drug, metformin, for a new indication, AiWG, by showing that metformin in combination with lifestyle interventions reduces AiWG compared to placebo in combination with lifestyle interventions. Furthermore, we aim to investigate the difference in reduction of AiWG between two subgroups; clozapine use versus other antipsychotic use. At last, we aim to assess whether metformin compared to placebo improves metabolic traits, quality of life, general physical and psychological health, cost effectiveness and whether genetic liability to BMI and metabolic syndrome may help estimate weight reduction following initiation of metformin treatment.

Study design: A randomized, double blind, multicenter, placebo-controlled, pragmatic trial.

Study population: Two groups of schizophrenia patients who undergo lifestyle interventions: 1) general patients suffering from psychosis and overweight who use a range of antipsychotics; and 2) those considered (relatively) treatment resistant, therefore are treated with clozapine and suffer from overweight. Patients must have a diagnosis of schizophrenia spectrum disorders according to DSM-IV-TR or DSM-5 criteria. They must have been using the same antipsychotic for at least 3 months. Patients are at least 16 years of age and are overweight (BMI>25).

Intervention (if applicable): Metformin or placebo started at 2dd500mg and then increased to 2dd1000mg after two weeks.

Main study parameters/endpoints: The primary outcome measure is difference in weight (from treatment inception until 26 weeks of treatment) as a continuous trait. Secondary and tertiary outcome measures include subgroup analysis for clozapine versus antipsychotic use only and differences between treatment inception and 26 weeks of treatment in: 1) All other elements of metabolic syndrome; 2) A measure of response, defined as ≥5% body weight loss at 26 weeks relative to treatment inception; 3) Quality of life; 4) General psychological and physical health; and 5) Cost-effectiveness. Safety outcomes include adverse drug reactions. At last, we aim to assess whether genetic liability to BMI and metabolic syndrome may help estimate weight reduction following initiation of metformin treatment as tertiary outcome.
 
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risks associated with participation are minimal considering the wide experience, well known safety profile and generally mild side effect profile of metformin. The burden for participants consists of taking medication daily (either placebo or metformin), one short telephone visit of five minutes, three face-to-face visits of approximately 20-120 minutes during which questionnaires are filled out, three blood tubes are drawn, physical examination and a physical endurance test are done, and one face-to-face visit of 20 minutes one year after completing the first study visit.Their weight and waist circumference will be assessed during all live visits. Except for the blood draw and time investment, also including travelling to the institute, we expect no physical or physiological discomfort associated with participation. We do not include incapacitated persons in our study.

We expect that metformin in combination with lifestyle interventions reduces Antipsychotic induced Weight Gain compared to placebo in combination with lifestyle interventions.

Week 0- Visit 1 - Face to face visit, screening & randomisation. Start dose 500mg B.I.D.
Week 2 - Visit 2 - Phone call visit, dose and side effects verification and evaluation. Dose 1000 mg B.I.D.
Week 13 - Visit 3 Face to face visit.
Week 26 - Visit 4 Face to face visit.
Week 52 - Visit 5 Face to face visit.

One year after the last study visit (visit 4), body weight, waist circumference, blood pressure and physical endurance are measured and medication use is assessed during a 20 minute follow-up visit.

Metformin or placebo started at 2dd500mg and then increased to 2dd1000mg after two weeks.