Being overweight is common in people with a serious mental illness, the cause of which may be attributable to lifestyle factors such as poor diet and physical inactivity, and also due to medication side effects. Weight gain is a well-documented side effect of many antipsychotic medications, particularly the newer second-generation medications. This could in part be a result of the wide mode of action of antipsychotic drugs, including disruption of metabolic pathways.

Excessive weight gain is a serious health concern, it is associated not only with reduced quality of life and social stigma, but can affect treatment adherence and increase morbidity (both physical and psychological) and mortality. Obesity is reported to double the risk of all-cause mortality, as well as related diseases such as coronary heart disease, stroke and type-2 diabetes.

Pharmacological strategies are at best only moderately effective for weight management, thus the ideal non-pharmacological strategies for weight management should combine diet, exercise and psychological/behavioural components. Weight management is important to ensure that the benefits of medications are not outweighed by the increased risk of physical disease.

What is the evidence for treatments for weight gain?

Moderate to high quality evidence suggests lifestyle interventions are effective for weight reduction in people with any severe mental illness. Moderate to low quality evidence suggests lifestyle interventions also reduces body mass and improves depressed mood.

November 2021

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Many antipsychotic medications are associated with weight gain, and various pharmacological approaches have been investigated for this problem. Effective adjunctive pharmaceutical treatments for side effects such as weight gain increase adherence to antipsychotic medications and reduces the risk of psychotic relapse.

What is the evidence for adjunctive medications for weight reduction?

Moderate quality evidence finds a benefit of adjunctive metformin for reducing weight in adults and children with schizophrenia. Moderate to low quality evidence finds more weight reduction with metformin plus lifestyle intervention than placebo (less 5.05kg), metaformin alone (less 1.5kg) or lifestyle intervention alone (less 3.30kg). Triglycerides, glucose, insulin and cholesterol levels may also be improved with metformin.

There were large effects of reduced weight and BMI with topiramate. There were also medium to large effects of improved triglycerides and low-density lipoproteins with topiramate. Lower quality evidence finds improvements with topiramate in fasting blood insulin, insulin resistance and systolic blood pressure. There were no improvements over placebo in total cholesterol, high density lipoproteins, leptin, fasting blood glucose and diastolic blood pressure.

Moderate quality evidence finds more weight reduction with adjunctive reboxetine or sibutramine than placebo. Glucagon-like peptide-1 receptor agonists also reduce weight, waist circumference and BMI, and improve haemoglobin A1c, glucose and visceral adiposity. Moderate to low quality evidence also finds benefits of adjunctive amantadine for weight reduction. Moderate to low quality evidence finds reduced BMI, but not weight with adjunctive ranitidine.

Moderate quality evidence suggests switching antipsychotic medications from olanzapine to aripiprazole or quetiapine may reduce weight and blood glucose levels.

There were no benefits for weight of adjunctive fluoxetine, rosiglitazone famotidine, nizatidine, norepinephrine, orlistat, or metformin + sibutramine, and no benefits for metabolic disturbances of adjunctive melatonin.

October 2020

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