Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can lead to significant weight loss and improve blood sugar control in adults with severe mental illness, as well as having positive effects on mood, well-being, and quality of life in those both with and without mental illness, according to a systematic review of the available evidence being presented at this year's European Congress on Obesity (ECO) in Malaga, Spain (11-14 May).
"Our findings suggest that GLP-1RAs might be just as safe and effective in adults with mental illness as they are in mentally healthy individuals, significantly reducing psychotropic drug-induced weight gain and improving glucose control, while protecting cardiometabolic health," said lead author Dr Sigrid Breit from the University of Bern, Switzerland. "These results are particularly important for people with severe mental disorders who are three times more likely to be living with obesity than the general population."
Mental illnesses are associated with an increased risk of weight gain and metabolic disorders like obesity and type 2 diabetes. Estimates suggest that around 60% of people with severe mental disorders are living with overweight or obesity [1].
Substantial weight gain is also a common side effect of many mood-altering drugs (psychotropics), which include antidepressants and antipsychotics, especially for individuals with severe mental illnesses like schizophrenia and major depressive disorder who must take their medications indefinitely to reduce the risk of symptom relapse.
Originally developed to treat diabetes, GLP-1RAs like liraglutide and semaglutide mimic the action of a hormone called glucagon-like peptide 1 (GLP-1), which stimulates insulin production and lowers blood sugar levels. More recently, they have emerged as effective treatments for obesity—slowing digestion, increasing feelings of fullness, and reducing hunger.
However, evidence for the impact of GLP-1RAs in individuals with obesity and mental illness is limited. There have also been concerns that these medications may increase the risk of suicide and self-harm.
To find out more, Swiss researchers systematically reviewed the evidence from clinical trials and case series examining the safety and the impact of GLP-1RAs on psychotropic drug-induced metabolic disorders such as obesity and type 2 diabetes as well as mental illness outcomes from January 1st, 2010 to August 31st, 2024.
Data were analysed for 36 studies involving a total of 25,677 adults (aged 18 or older) from 19 countries. Eighteen studies examined the effect of GLP-1RAs on weight loss, glucose control and mental illness outcomes in adults with a severe mental disorder, such as major depressive disorder, bipolar effective disorder, schizophrenia spectrum disorders, and alcohol use disorder.
The other 18 studies examined emotional well-being and quality of life in adults with overweight or obesity but with no history of severe mental illness following GLP-1RAs treatment.
Overall, four different GLP-1RAs were investigated in the trials—liraglutide (also known as Victoza), semaglutide (Ozempic or Wegovy), exenatide (Byetta or Bydureon), and dulaglutide (Trulicity).
The analysis found that treatment with GLP-1RAs led to significant weight loss and improved glycaemic control in adults with mental illness taking psychotropics.
The greatest weight loss was reported in a randomised trial of liraglutide (up to 3 mg daily). Participants with schizophrenia or schizoaffective disorder using this medication lost up to 5.3kg more of their starting weight and lowered their glucose levels (HbA1c) by 3.6 mmol/mol more after 6 months compared with participants taking placebo [2]. Semaglutide (2.4 mg once weekly) produced weight loss of up to 15.7% after 68 weeks in patients taking antidepressants compared with placebo [3].
No link with suicide thoughts or behaviour
Importantly, the results showed that GLP-1RAs were not associated with a worsening of mental state, suicidal behaviour, new mental illness diagnoses, or increased psychiatric admissions.
For example, analysis of four studies on suicidality in adults with bipolar disorder, major or bipolar depressive disorder or no mental illness found that liraglutide was not linked to significantly increased rates of suicidal ideation (having thoughts of suicide).Two further studies of exenatide in patients with alcohol use disorder and liraglutide in bipolar disorder found no significant difference in suicidal behaviour compared with placebo.
Dr Breit cautions. "Until we have better evidence, people taking GLP-1RAs should be carefully monitored, especially those with mental illness."
Beneficial impact on mental health
The analysis also found that GLP-1RAs had a beneficial effect on mental health in adults with and without mental disorders. Five studies found that they were safe and improved mental illness outcome and quality of life in people with schizophrenia spectrum disorders, major depressive disorder, and bipolar effective disorder.
In adults without mental illness, GLP-1RAs demonstrated a superior effect on mood, emotional well-being, and quality of life compared with insulin and other antidiabetic drugs. For example, a randomised trial in patients with type 2 diabetes found that liraglutide (1.2 or 1.8 mg) significantly improved emotional well-being and general perceived health compared to glimepiride (8 mg daily) [4].
As Dr Breit explained, "GLP-1 RAs may have antidepressant and anti-anxiety effects, potentially due to their anti-inflammatory and anti-oxidative properties, which can also help reduce neuroinflammation."
She adds: "This research provides much-needed evidence in support of GLP-1RAs to help safely address the burden of obesity in people with mental illness. However, more data from large-scale randomised trials and longer treatment and follow-up periods are needed to establish the long-term efficacy of GLP-1 RAs, as well as future studies exploring whether these medications might be useful for the direct treatment of mental health disorders."
