Large meta-analysis finds GLP-1 drugs don’t raise depression or suicidality and modestly boost quality of life and eating control in diabetes/obesity.
TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A monthly column dedicated to reviewing the literature and sharing clinical implications.
Diabetes and obesity have a bidirectional relationship with psychiatric symptoms. It has been found that individuals with type 2 diabetes are twice as likely to have depression, and having depression significantly increases the odds of developing obesity.
Pierret ACS, Mizuno Y, Saunders P, et al.
Medical Research Council-UK, Maudsley Charity, Wellcome Trust, National Institute for Health Research, King’s College London, UK Research and Innovation Hub for Metabolic Psychiatry, UK Academy of Medical Sciences, and the Brain and Behavior Research Foundation.
To evaluate the relationship between GLP-1 receptor agonist (GLP-1 RA) use in obese or diabetic individuals and changes in psychiatric symptoms, mental health-related QOL measures, and cognitive outcomes.
A systematic search of several databases (MEDLINE, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials) was conducted for studies published in any language from inception to June 2024. Key terms were related to GLP-1 RAs, mental health and psychiatric measures, QOL measures, and cognition outcomes. Included studies were double-blind randomized controlled trials comparing GLP-1 RA treatment with placebo in adults with either diabetes or obesity. Studies examining patients with known psychiatric or neurological conditions were excluded. Two reviewers independently performed article review for inclusion. Studies were also assessed for risk of bias using the revised Cochrane risk-of-bias tool.
A random-effects model was used during data analysis to handle heterogeneity among the studies. Effect sizes were calculated for diabetic, obese, and combined populations. Separate meta-analyses were conducted for subdomains of mental health symptoms (
Random-effects meta-regression was conducted to determine whether any of the following impacted outcome: baseline/demographic characteristics, treatment duration, and change in weight or hemoglobin A1C.
A total of 80 randomized, double-blind, placebo-controlled trials (totaling 107,860
1. This is a well-powered, comprehensive meta-analysis with study selection criteria that limited the risk of bias.
2. This study addresses an important question regarding safety and possible adverse psychiatric symptoms in a population that has grown rapidly in recent years (those with diabetes and/or obesity who are prescribed GLP-1 RAs).
3. This study examined a broad range of psychiatric, cognitive, and QOL measures using standardized and validated instruments.
1. Excluding participants with preexisting psychiatric or neurological disorders limits external validity and likely contributed to low baseline depressive scores in this analysis.
2. Data on anxiety, suicidality, and cognition were limited to qualitative measures.
3. Different GLP-1 RA doses were used across studies (a potential source of heterogeneity), although differential GLP-1 RA dosing meta-analyses did not yield appreciably different outcomes.
participants; mean age, 60.1 years; 59.9% male; average treatment duration, 28 weeks) were included for meta-analysis. Most studies evaluated liraglutide and/or semaglutide. The meta-analysis demonstrated no increase in either serious or nonserious psychiatric adverse events among individuals treated with GLP-1 RAs compared with placebo. The nonserious psychiatric symptoms included anxiety or insomnia (log[RR]=−0.03; 95% CI, −0.21 to 0.16; P=0.76) and the serious adverse events included suicidality, major depression, or psychosis (log[RR]=−0.02; 95% CI, −0.20 to 0.17; P=.87). There was also no significant change in depressive symptom scores between groups (g= 0.02; 95% CI, −0.51 to 0.55; P=.94). When compared with placebo, the use of GLP-1 RAs was associated with statistically significant improvements in restrained eating (g= 0.35; 95% CI, 0.13-0.57; P=.002), emotional eating behavior (g= 0.32; 95% CI, 0.11-0.54; P=.003), mental health–related QOL (g=0.15; 95% CI, 0.07-0.22; P<.001), physical health–related QOL (g=0.20; 95% CI, 0.14-0.26; P<.001), diabetes-related QOL (g=0.23; 95% CI, 0.15-0.32; P<.001), and weight-related QOL (g=0.27; 95% CI, 0.18-0.35; P<.001). The improvements in mental health–related QOL did not correlate directly with the amount of weight lost, suggesting that benefits may involve central psychological mechanisms, not weight loss alone. The findings were unchanged by excluding studies of participants with type 1 diabetes, and baseline variables or magnitude of weight/HbA1C change did not affect mental health–related QOL outcomes. Lastly, the cognitive outcomes data were limited to 4 studies. The investigators did not find any improvements in cognitive functioning (g=0.01; 95% CI, −0.02 to 0.04; P=.17) with the use of GLP-1 RAs when compared with placebo.
This meta-analysis demonstrated no increase in depressive symptoms, suicidality, or serious psychiatric adverse events in individuals with obesity or diabetes who were treated with GLP-1 RAs when compared with placebo. GLP-1 RA use in this population was associated with improved QOL across physical health-, mental health-, diabetes-, and weight-related domains, as well as improvements in eating restraint and emotional eating. There was no clear association between GLP-1 RA use and improvement in cognitive outcomes.
This study provides encouraging evidence regarding relative psychiatric safety and mental QOL benefits with GLP-1 RA use. However, generalizability to psychiatric patient populations is potentially limited by this study’s exclusion criteria. As weight gain and other metabolic adverse effects are common with many psychotropics, further consideration should be given to the role of GLP-1 RAs in patients with comorbid metabolic disturbances (diabetes, obesity, or significant risk factors for developing these) and psychiatric diagnoses.
This systematic review and meta-analysis of randomized controlled trials shows that GLP-1 RA use is relatively safe from a psychiatric standpoint in those with diabetes and/or obesity, and is also associated with modest improvements in mental well-being.
Dr Impallaria is a third-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Leconte is a second-year psychiatry resident at Creighton University. Dr Matsneva is a first-year psychiatry resident at Creighton University. Dr Dickan is a fourth-year psychiatry resident at Creighton University. Dr Schuster is an assistant professor of psychiatry at Creighton University School of Medicine. Dr Mullen is an assistant professor of psychiatry at Saint Louis University School of Medicine in Missouri. Dr Tampi is professor and chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.
Reference
Pierret ACS, Mizuno Y, Saunders P, et al.
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