A study looking at whether metformin (a diabetes drug) can prevent weight gain caused by antipsychotics in people experiencing their first episode of psychosis

ISRCTN	ISRCTN47913690
DOI	https://doi.org/10.1186/ISRCTN47913690
Integrated Research Application System (IRAS)	1010474
Central Portfolio Management System (CPMS)	63386
National Institute for Health and Care Research (NIHR)	167171
Sponsor	Pennine Care NHS Foundation Trust
Funder	National Institute for Health and Care Research

Submission date: 06/10/2025
Registration date: 27/01/2026
Last edited: 27/01/2026

Recruitment status: Not yet recruiting
Overall study status: Ongoing
Condition category: Mental and Behavioural Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Many people in the UK with psychosis are started on antipsychotic medication to help with their symptoms. However, these drugs can cause a lot of weight gain, which can cause other problems in the future, such as heart disease or diabetes. It also has an impact on how people feel about themselves. Importantly, it may make people want to stop taking their antipsychotic treatment.
Metformin is a drug that has been used for over 60 years in the treatment of diabetes. Small studies suggest that it might help stop some of the weight gain caused by antipsychotics and prevent diabetes. This study will look at whether metformin can stop, or reduce, weight gain for people taking antipsychotics in their first episode of psychosis.

Who can participate?
The study will involve 340 people who are experiencing psychosis for the first time and have started their antipsychotic medication no longer than a month ago. The study will take place in approximately 15 UK mental health services.

What does the study involve?
Patients will be randomly split into two groups. One group will be asked to take metformin for a year. The other group will be asked to take a placebo. A placebo - also known as a “dummy” or “sham” drug - doesn’t contain any active treatment. METRIC is a blinded trial, meaning that participants and their doctors will not know which drug they are given, until all participants have finished the trial. This is important so we can measure the true effect of metformin by comparing the weight of those taking metformin with those taking placebo.
Participants will be seen by their mental health team every 3 months while taking the drug and for up to 6 months afterwards. We will measure weight, mental health symptoms and how people feel in general about their health. We will also ask if they have been to other services about their psychosis or weight.

What are the possible benefits and risks of participating?
The risks of metformin are low but we will take some blood tests to make sure that taking the drug is not causing any side effects to patients. The study treatment, metformin, may not directly benefit participants as we do not know if the drug will be effective. This is why we are doing this trial. However, participation will help healthcare professionals in the future to manage weight gain for others with first episode psychosis.

Where is the study run from?
Pennine Care NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
June 2025 to May 2029

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).

Who is the main contact?
METRIC_RCT@sheffield.ac.uk

Contact information

Ms Sienna Hamer-Kiwacz
Public, Scientific

Sheffield Clinical Trials Research Unit, ScHARR, University of Sheffield, 387 Glossop Road
Sheffield
S10 2HQ
United Kingdom

Email	METRIC_RCT@sheffield.ac.uk

Dr Paul French
Principal investigator

Pennine Care NHS Foundation Trust, Trust Headquarters, 225 Old Street
OL6 7SR
Ashton-under-Lyne
United Kingdom

Email	Paul.french8@nhs.net

Prof Richard Holt
Principal investigator

University Hospital Southampton NHS Foundation Trust, Tremona Road
Southampton
SO16 6YD
United Kingdom

Email	R.I.G.Holt@soton.ac.uk

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Placebo
Assignment	Parallel
Purpose	Treatment, Safety
Scientific title	Metformin in psychosis for weight gain prevention
Study acronym	METRIC
Study objectives	Primary objective: To determine if metformin plus usual care reduces weight gain by at least 4 kg (equivalent to 5% of the expected baseline body weight) at 1 year compared to placebo plus usual care. Secondary objectives: 1. To conduct an economic evaluation alongside the clinical trial and long-term cost effectiveness modelling from NHS and societal perspectives. 2. To undertake a process evaluation to understand acceptability of adding metformin to usual care alongside considerations for future implementation. 3. To assess the effect of withdrawing metformin and matching placebo on weight, up to 6 months post withdrawal.
Ethics approval(s)	Submitted 15/01/2026, Brighton and Sussex Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0) 2071048202; brightonandsussex.rec@hra.nhs.uk), ref: 26/LO/0126
Health condition(s) or problem(s) studied	Antipsychotic induced weight gain in first episode psychosis
Intervention	Intervention: Modified release (MR) metformin tablets and usual care. Dose titrated to reduce side effects. Tablets will be commenced at 500mg daily orally with food, increasing by 500mg daily every 10-15 days to the maximum of 2g daily, in accordance with BNF and product licence. Participants not tolerating the increased dose will be asked to remain on the highest tolerated dose. Taken orally at home (or if an inpatient, within hospital). Participants will be randomised within 4 weeks of AP initiation, following which treatment will commence. Treatment will be continued for 1 year, after which there will be a 3-6month washout period during which we will observe the effects of treatment cessation. Control: Blinded, matched placebo tablets, and usual care. Placebo tablets will be prescribed in line with the intervention group.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Metformin
Primary outcome measure(s)	Weight (kg) measured using calibrated scales at baseline and 1 year post randomisation.
Key secondary outcome measure(s)	1. Weight is measured using calibrated scales at baseline, 3 months, 6 months, 9 months, and 12 months 2. Body Mass Index (BMI) is calculated from height and weight measurements using calibrated scales at baseline, 3 months, 6 months, 9 months, and 12 months 3. Proportion of participants who have gained more than 5% and 10% of their baseline body weight is assessed using weight measurements at 12 months 4. Proportion of participants with BMI ≥25 kg/m² and BMI ≥30 kg/m² is assessed using BMI calculations at 12 months 5. Change in BMI category is assessed using BMI calculations at baseline and 12 months 6. Waist circumference is measured using a tape measure at baseline, 3, 6 and 9 months 7. Lipid profile (total cholesterol, HDL, LDL, triglycerides), HbA1c, and vitamin B12 are measured using venous blood samples at baseline and 12 months (all), and at 3 and 6 months (lipid profile and HBA1c) 8. Adverse events are recorded by site staff using the METRIC Adverse Event CRF. Site staff will check for adverse events at each study visit (baseline, 3, 6, 9, 12, 15 and 18 months). Events identified outside of study visits at routine care appointments will also be recorded. 9. Mental health status is measured using the Clinical Global Impressions Scale (CGI) at 3, 6 and 12 months. 10. Medication adherence is measured using pill counts for metformin/placebo and clinician survey for antipsychotic medication at 3, 6, 9 and 12 months. 11. Quality of life is measured using the Recovering Quality of Life questionnaire (ReQoL-10) at baseline, 3, 6 and 12 months. 12. Health-related quality of life is measured using the EQ-5D-5L questionnaire at baseline, 3, 6 and 12 months. 13. Health resource use is measured using the METRIC healthcare resource use form at baseline, 3, 6 and 12 months. 14. Cost effectiveness is assessed using via an embedded health economic analysis. 15. Weight is measured using calibrated scales at 12 months and 18 months to assess the effect of withdrawing metformin or placebo 16. Acceptability and factors influencing adherence are evaluated via an embedded process evaluation, incorporating qualitative interviews with participants and site staff.
Completion date	31/05/2029

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	16 Years
Upper age limit	65 Years
Sex	All
Target sample size at registration	340
Key inclusion criteria	1. Adults with FEP (age ≥18 yrs <65 yrs) 2. Within 4 weeks of starting any APs 3. Intention to continue AP drugs for ≥1 year
Key exclusion criteria	1. Body Mass Index (BMI) < 18.5 kg/m² 2. Current prescription of metformin 3. Contraindication to the use of metformin (as advised by the SmPC and British National Formulary (BNF)): chronic stable heart failure, concomitant use of drugs that can acutely impair renal function, renal dysfunction (eGFR <30mL/minute/1.73m2.), significant liver disease with increased likelihood of tissue hypoxia, hypersensitivity or previous intolerance to metformin 4. Any diabetes mellitus 5. Other condition that would independently affect body weight, e.g. Cushing’s syndrome, untreated thyroid dysfunction 6. Current engagement in any systematic weight management programme (or within the past 3 months). Including the use of GLP-1 receptor agonists and GLP-1 receptor GIP dual agonists 7. Any concomitant physical or mental condition that according to the investigator’s assessment makes the participant unsuitable for trial participation 8. Lack of capacity
Date of first enrolment	01/06/2026
Date of final enrolment	31/08/2027

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Sites currently being identified

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-
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England

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan

Editorial Notes

06/10/2025: Trial's existence confirmed by the National Institute for Health and Care Research (NIHR) (UK).