Background

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.

Study design
We will conduct a pragmatic, randomised, double blind, placebo-controlled multicenter trial of metformin in schizophrenia patients suffering from AiWG and undergoing lifestyle interventions. 256 participants will be randomised in a 1:1 fashion to: 1) placebo; or 2) metformin for 26 weeks. Metformin will be started at 500mg 2dd1 (oral) and escalated to 2dd1000mg (2x2 tablets) two weeks thereafter.

The estimated length of the study will be four years (including a participants’ enrolment phase of three years) and participants will be followed-up for one year. This design was chosen to investigate the possible added value of metformin over lifestyle interventions and to align the design as much as possible with clinical practice where lifestyle interventions are offered in most institutes across the country for patients on antipsychotics who suffer from relatively high weight. Lifestyle interventions are a combination of an exercise program and dietary interventions, which are standardised across sites. 

The dietary intervention consists of five consultations with a dietician (referral by G.P.) to ensure both healthy food and appropriate caloric intake and measurement of weight, BMI and waist circumference. The exercise program consists of at least 60 minutes per week of unsupervised exercise by choice, i.e. walking, dancing or jogging, either privately, group endurance workouts or strength training. Furthermore, participants gather in weekly lifestyle group sessions under supervision of a lifestyle coach, including weekly weight measurements and assessment of physical activity using the Physical Activity Vital Sign questionnaire (PAVS). During those sessions participants perform a low- intensity exercise, such as strolling, reflect how their exercise program and dietary interventions are getting along, report whether they exercised 60 minutes that week, and provide tips to one another about how to overcome certain barriers. Participants may wish to discontinue lifestyle interventions at any moment and still continue with the current trial. Similarly, patients may continue with the trial after switching or stopping antipsychotic use.

Time schedule participants
Participants will undergo 4 main, face-to-face visits of 20 - 120 minutes, as well as one short telephone visit. During every face-to-face visit multiple questionnaires are done, 3 blood tubes are drawn and physical examination is done including weight, waist circumference, blood pressure and a physical endurance test. One year after the first study visit, body weight, waist circumference, blood pressure and physical endurance are measured and medication use is assessed during a 20-minute follow-up visit.

Recruitment
We are looking for men and women of at least 16 years old meeting the following criteria:

• A diagnosis of schizophrenia spectrum disorder according to DSM-IV-TR or DSM-5 criteria
• Antipsychotic use for at least 3 months
• Willing to undergo lifestyle therapy
• Mentally competent
• Dutch speaking and reading
• Overweight (BMI>25)

Presence of one of the following criteria leads to exclusion:

• Suffer from neurodegenerative extrapyramidal disease
• Carry metformin-related contra-indications, i.e.: conditions predisposing to tissue 
hypoxia, metabolic acidosis, precoma diabeticum, kidney failure (GFR<30ml/min) and conditions predisposing to kidney failure (e.g. dehydration, infections and hypovolemic shock),disorders in the use of alcohol defined as > 2 reported consumptions daily and/or a gGT of over 60U/L, and liver failure

• Use of one or more of the following medication(s): NSAIDs , ACE-inhibitors
, ARBs (angiotensin receptor blockers), diuretics
, OCT (organic cation transporters) 1 and 2 inhibitors (e.g. cimetidine, dolutegravir, isavuconazol, trimethoprim, vandetanib, crizotinibib, vandetanib, and verapamil) and inductors (e.g.rifampicin)
• Suffer from vitamin B12 deficiency 

• Suffer from diabetes mellitus 
• Are pregnant or breast feed or women of child bearing age using no 
contraceptives

If you have any questions or if you are interested in participating, please contact us.

Research Team
Prof. dr. Wiepke Cahn, psychiatrist UMC Utrecht
Dr. Jurjen Luykx, psychiatrist UMC Utrecht
Dr. Sinan Gülöksüz, psychiatrist Maastricht University
Dr. Nini de Boer, PhD student and coordinating investigator UMC Utrecht

Participating centers

• UMC Utrecht, PI dr. Jurjen Luykx
• GGNet, PI drs. Mike Veereschild
• Mondriaan Maastricht, PI dr. Maarten Bak
• Amsterdam UMC, referral center
• GGz Centraal, referral center
• GGZ inGeest, referral center
• Altrecht GGZ, referral center
• Psychiatrie Rivierenland, referral center
• GGZ Rivierduinen, referral center

If you are interested to participate with your hospital or institution, please contact us.

Publications
No publications available yet.

Funding
This study has been financed by ZonMw (Goed Gebruik Geneesmiddelen).