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23/169 Metformin to prevent antipsychotic-induced weight gain


Published: 30 November 2023

Version: 1.0 November 2023

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The aim of the HTA Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research Question

What is the clinical and cost-effectiveness of metformin to prevent antipsychotic-induced weight gain in people with first episode psychosis? 

  • Intervention: Metformin plus usual care.  Applicants to define and justify i) dose and regimen and ii) usual care.
  • Patient group: People with first episode psychosis at commencement of antipsychotic treatment. Applicants to define and justify exact criteria.
    Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field.
  • Setting: Early Intervention Services.
  • Control: Placebo plus usual care.  
  • Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial. 
  • Important outcomes: Change in weight.
    Other outcomes: Adherence (to both metformin and the prescribed antipsychotic), psychotic symptoms, side effects, quality of life, other physical and biochemical measures e.g. cholesterol (applicants to justify which ones are relevant to the patient group), mental wellbeing, patient acceptability, cost-effectiveness, occupational/education outcomes.
    Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise. Applicants are encouraged to report recruitment and findings disaggregated by sex (and other demographic factors where relevant).  
  • Minimum duration of follow-up: 1 year.
    Longer-term follow up: If appropriate, researchers should consider obtaining consent to allow potential future follow up through efficient means (such as routine data) as part of a separately funded study.


Psychotic disorders are serious mental illnesses where people typically experience distressing delusions, hallucinations or disordered thoughts. The first-line pharmacological treatment for people experiencing their first episode of psychosis is antipsychotics. While they can be effective for reducing the symptoms of psychosis, one of the most common debilitating side effects reported by patients is weight gain.

The fastest weight gain occurs in the first six months after commencing an antipsychotic and early weight gain appears to be a predictor of longer-term weight gain. It is a serious problem as being overweight has a significant impact on physical health, for example, an increased risk of developing high blood pressure and type 2 diabetes and of having a heart attack or stroke. Life expectancy is reduced by 20 years in people with schizophrenia, with physical illness and cardiovascular disease being the main contributors. Weight gain can have a negative impact on a person’s mental wellbeing and can disrupt their adherence to medication. Consequently, having effective interventions for addressing weight gain is very important for both a person’s current and future wellbeing.

NICE recommends lifestyle interventions to address weight gain; however, a meta-analysis concluded that the improvements from these interventions while statistically significant were not clinically significant. The British Association of Psychopharmacology recommend considering switching antipsychotics or adding adjunctive medications but only when weight has already been gained.

An alternative approach that has been investigated is to prevent antipsychotic-induced weight gain rather than to treat it. Focus has been on metformin, a medication already offered in the NHS to support lifestyle change for people who are at risk of type 2 diabetes. There is already evidence to suggest that metformin can help people to lose antipsychotic-induced weight.

A recent Cochrane review looking at pharmacological interventions for prevention of weight gain in people with schizophrenia, highlighted the possibility of using adjunctive metformin for this purpose and concluded that further research is needed. Two small trials have demonstrated its efficacy when compared to placebo.

Investigating the effectiveness of metformin to prevent weight gain does not mean reducing the emphasis on lifestyle interventions, and applicants should give consideration to these. Instead, it is about considering, that given individual differences and the complexity of obesity, a range of approaches that can be discussed and offered to patients would be helpful, and that early intervention is likely to be an advantage.

The impact of antipsychotic-induced weight gain and its medical consequences can be severe, reducing both quality and duration of life. Addressing this problem is an important clinical need for both patients and clinicians and the HTA Programme is interested in commissioning research to meet this need.

To support the ambitions of NIHR’s Best Research for Best Health: the next chapter, we strongly encourage the inclusion of nurses, midwives and allied health professionals within well-developed research teams responding to this call, to increase the building of research activity, capacity and capability across these professions.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email

Making an application

If you would like to apply for this call, you can begin your application via the funding opportunity page.

Your application must be submitted online no later than 1pm on 28 March 2024. Applications will be considered by the HTA Funding Committee at its meeting in May 2024.

Guidance notes and supporting information for HTA Programme applications are available.

Shortlisted Stage 1 applicants will be given 8 weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in September 2024.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team, other than in unusual circumstances (for example, a lead from a named charity or a unique national expert in a condition).

For such exceptions, each application needs to state the case as to why the same person is included. The shared co-applicant should not divulge application details between teams, and both teams should acknowledge in their application that they are aware of the situation, and that study details have not been shared.

Should you have any queries please contact