Metformin can be used to prevent or treat antipsychotic-induced weight gain

People with severe mental illnesses such as schizophrenia and bipolar affective disorder have higher rates of premature mortality than the rest of the population. Much of this increased risk is attributable to cardiometabolic risk factors, such as overweight and obesity, which are highly prevalent in people with severe mental illness. Weight gain is one of the most commonly reported and distressing side effects of antipsychotic treatment. Patient with low or normal body mass index (BMI) are at higher risk of clinically significant increases in weight. Interventions that reduce this side effect could improve physical health, quality of life and antipsychotic medication adherence.Antipsychotic-induced weight gain can be rapid and severe in the first weeks of treatment. Pharmacologic interventions may be required to help prevent rapid weight gain. Metformin has been used off-label for preventing and treating antipsychotic-induced weight gain and improving cardiometabolic outcomes. It is the most effective pharmacologic intervention studied for the prevention of antipsychotic-induced weight gain, but clinical guidelines for its use are lacking. To assist clinicians, an international group of experts has developed the first published evidence-based clinical practice guideline (using the AGREE II framework and GRADE methods) for the use of metformin to prevent antipsychotic-induced weight gain. The group included experts from Ireland, Denmark, Israel, Germany, the UK, Australia and Canada. The expert group found that metformin is the only pharmacologic agent that has demonstrated efficacy for preventing antipsychotic-induced weight gain. Starting metformin with an antipsychotic medication can reduce the extent of weight gain by about 4 kg compared to controls. There is some evidence that longer durations of metformin therapy can achieve larger effect sizes for high-risk antipsychotic medications. The expert group recommends that all people with first episode psychosis be offered an antipsychotic with low-risk of cardiometabolic side effects where possible at the lowest effective dose. However, if high- or medium-risk antipsychotic medications are necessary, weight gain prevention strategies, such as the early use of metformin, should be offered to these groups. All antipsychotics can cause weight gain, with clozapine and olanzapine having the highest risk. Quetiapine, risperidone and paliperidone generally rank lower than clozapine and olanzapine for cardiometabolic side effects, but still have significant potential to cause clinically significant weight gain and are considered medium-risk antipsychotics. All other antipsychotics are classified as lower risk in terms of causing weight gain.Younger people are particularly susceptible to the metabolic side effects of antipsychotic medications, with rates of antipsychotic-induced weight gain in children and adolescents up to twice that seen in adults. Since severe mental illness often starts early adulthood, it is essential to intervene early to prevent harm from weight gain.The expert group developed a guideline algorithm (see Figure 1 in the guideline), which makes specific recommendations for co-commencement of metformin when starting specific antipsychotics (or when switching antipsychotics), or for starting metformin during antipsychotic therapy if certain criteria are present. For example, metformin should be co-started with antipsychotics that have a high risk of weight gain (i.e., olanzapine or clozapine, which are not first-line agents). Metformin should also be co-started with a medium-risk antipsychotic (i.e., quetiapine, risperidone or paliperidone) if the patient also has one or more risk factors (e.g., hypertension, diabetes, age 10–25, see algorithm for other risk factors). Metformin should be started during therapy with a medium-risk antipsychotic (i.e., quetiapine, risperidone or paliperidone) or a lower-risk antipsychotic (i.e., all other antipsychotics) if more than 3% weight is gained anytime during the first year of antipsychotic therapy. The algorithm also includes criteria for starting a glucagon-like peptide-1 (GLP-1) agonist (e.g., semaglutide): BMI ≥ 30, or BMI 27 to 30 and another risk factor (e.g., hypertension, diabetes, obstructive sleep apnea, see algorithm for others). When metformin is used, a dose escalation regimen is recommended: 500 mg in the morning (week 1); 500 mg morning and evening (week 2), then check for efficacy; 1 g in the morning and 500 mg in the evening (starting week 4), then check for efficacy; then 1 g morning and evening starting in week 6. Metformin should be taken with or after food to minimize gastrointestinal side effects. A slow-release once-daily tablet could be considered if gastrointestinal side effects persist or patients are unable to adhere to twice-daily dosing. Dose reductions are required in renal impairment and this criterion is included in the algorithm. The algorithm also provides information on ongoing patient monitoring and situations in which metformin should be stopped. For all patients taking antipsychotics, the expert group recommends offering behavioural change interventions, including lifestyle and dietary interventions, given their well-documented benefits. These interventions should be continued whenever metformin is started.Reference:Carolan A, Hynes-Ryan C, Agarwal SM, et al. Metformin for the prevention of antipsychotic-induced weight gain: guideline development and consensus validation. Schizophr Bull 2024; published online December 9, 2024. (accessed January 2, 2025).

Metformin can be used to prevent or treat antipsychotic-induced weight gain

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