New Data on GLP-1 RAs and Psychiatric Side Effects

Medscape

21-05-2025

Treatment with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for weight loss or diabetes management doesn 't raise the risk for adverse psychiatric events and improves quality of life (QOL) in people with no history of mental illness, a large new review has found.
The results, gleaned from placebo-controlled trials involving over 100,000 participants, are important given recent concerns about an increased risk for suicidality, self-injury, and psychiatric adverse events in people prescribed GLP-1 RAs.
Toby Pillinger, PhD
'Our analysis of data from a large number of clinical trials shows that GLP-1 RAs are not only safe from a psychiatric perspective but may improve mental health outcomes. As the use of these medications continues to grow, our findings provide important reassurance to patients and clinicians alike that these treatments can support both body and mind,' investigator Toby Pillinger, PhD, clinical lecturer, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, England, told Medscape Medical News .
However, patients with serous psychiatric diagnoses were excluded from reviewed studies, so the findings may not completely settle the question of whether GLP-1 RAs impact mental illness in all individuals, Pillinger added.
The findings were published online on May 14 in JAMA Psychiatry .
'Reassuring' Findings
GLP-1 RAs are highly effective in treating obesity and type 2 diabetes, and there's some evidence they're also beneficial for patients with type 1 diabetes. However, a few meta-analyses of randomized clinical trials have examined their psychiatric effects.
The analysis included 107,860 adults (mean age, 60 years; 40% women) enrolled in 80 randomized double-blind controlled trials that compared mental health outcomes between those treated with a GLP-1 RA and those treated with a placebo.
About 62% of the studies included patients with type 2 diabetes, while 29% of those had patients with overweight or obese, and 9% enrolled those with type 1 diabetes. The most studied drug was liraglutide (30% of studies), followed by semaglutide (24.7%).
Studies that included participants with preexisting psychiatric or neurologic disorders such as Alzheimer's disease were excluded.
The analysis found no significant difference in rates of serious psychiatric adverse events (log risk ratio [logRR], −0.02; 95% CI, −0.20 to 0.17; P = .90, with moderate certainty) or of nonserious psychiatric adverse events (logRR, −0.03; 95% CI, −0.21 to 0.16; P = .76, with low certainty) between GLP-1 RAs and placebo.
GLP-1 RA treatment was associated with significantly improved restrained eating and reduced emotional eating. This finding, said the authors, was expected given the medications have known satiety-inducing effects leading to reduced food intake.
'Overall, our results provide reassurance regarding the psychiatric safety profile of GLP-1 RAs and suggest that GLP-1 RA treatment is associated with improved mental well-being, in addition to the known physical health improvements,' investigators wrote.
Improved QOL
The analysis also found GLP-1 RA treatment positively affected several aspects of QOL relative to placebo, including improved mental health ( P < .001), physical health ( P < .001), diabetes-related QOL ( P < .001), weight-related QOL ( P < .001), and overall QOL ( P = .01), all with moderate certainty.
There were greater improvements in physical health–related QOL in women and younger patients.
'The reason for this is unclear, and these results should be interpreted cautiously,' said Pillinger, adding the analysis wasn't based on individual patient data, which limited the ability to explore the full range of contributing factors.
Interestingly, the analysis didn't uncover a relationship between QOL and the amount of weight loss or degree of improved blood sugar control. Pillinger speculated that in addition to the impact losing weight or optimizing diabetes control can have on self-esteem and well-being, a neurobiological mechanism may also be at play.
'One possibility is that GLP-1 RAs exert direct effects on the brain, particularly within regions involved in mood and reward processing,' said Pillinger. 'These central pathways may influence emotional well-being independently of physical health improvements.'
There was no clear evidence of an association between GLP-1 RA treatment and cognitive outcomes, likely owing to the small number of studies.
Sensitivity analyses looking at different GLP-1 RA doses relative to placebo yielded results similar to the main analysis. This was also the case for an analysis excluding studies of patients with type 1 diabetes, although due to the limited number of related trials, it's impossible to draw firm conclusions concerning type 1 diabetes, said Pillinger.
'More research specifically in people with type 1 diabetes is needed to determine whether the psychiatric and quality-of-life effects of GLP-1 receptor agonists are consistent across diabetes subtypes,' he said.
As researchers didn't perform separate meta-analyses for individual drugs, more head-to-head studies are needed to determine whether some GLP-1 RA agents are more beneficial than others.
'For now, the evidence supports a broadly reassuring psychiatric safety profile across commonly used GLP-1 RAs,' Pillinger said.
While this new analysis found no relationship between GLP-1 RAs and adverse psychiatric outcomes, previous studies have. Pillinger explained that people living with obesity and diabetes already have a higher baseline risk for psychiatric symptoms, including depression and suicidal ideation.
'Previously observed signals of suicidality may reflect this underlying vulnerability in the patient population rather than an effect of the drug itself,' he said.
Included studies didn't collect data on a broader range of psychiatric symptoms, such as changes in energy or activity levels, sleep, and obsessional symptoms. Another limitation was that mental health effects were secondary rather than primary outcomes of included studies.
Questions Remain
Reached for comment, Mahavir Agarwal, MD, PhD, associate professor, Department of Psychiatry, University of Toronto, and medical head of Clinical Research, Schizophrenia Division, Center for Addiction and Mental Health, both in Toronto, Ontario, Canada, said the review shows 'fairly well' that psychiatric issues 'are unlikely to be a common side effect' of GLP-1 RAs.
However, Agarwal reiterated that studies that enroll people with diabetes or obesity, like those included in the review, typically exclude anyone with a severe mental illness, so the study cohorts are generally a relatively 'mentally healthy' population.
Agarwal and his colleagues are conducting a study of these drugs in people with schizophrenia who have gained weight while taking antipsychotics. It is one of several such projects underway to investigate the effects of GLP-1 RAs in people with psychiatric illnesses and addiction.
Importantly, said Agarwal, side effects and responses to these relatively new drugs may vary from patient to patient. 'What happens at an individual level is still unpredictable, and therefore, clinicians should still be on guard.'
Indeed, there is some reported evidence of people with depression or anxiety actually experiencing worsening symptoms while on these weight-loss drugs, noted Paul Keedwell, MBChB, PhD, consultant psychiatrist and fellow of the Royal College of Psychiatrists, London, England, said in a statement from the nonprofit Science Media Centre.
'(F)or most people, these drugs seem mentally safe, and may even help mood, but for those with a history of mental illness, there may be a risk,' Keedwell said. 'More research is needed, and anyone with past mental health issues should speak with a doctor before starting them.'