GLP-1 Receptor Agonists Show Potential to Reduce Mental Health Risks in People with Diabetes and Obesity
Key Takeaways:
- GLP-1 receptor agonists were associated with a reduced risk of worsening mental illness in people living with diabetes and co-existing anxiety or depression
- Semaglutide and liraglutide showed the most notable effects, including reductions in depression, anxiety, and self-harm risk
- Findings from a large Swedish cohort study highlight potential dual benefits, though randomised trials are still needed
Growing interest in the mental health effects of GLP-1 therapies
A large national cohort study from Sweden, published in The Lancet Psychiatry, suggests that glucagon-like peptide-1 receptor agonists may offer benefits beyond metabolic control. The findings indicate that medications such as semaglutide and liraglutide could help reduce the risk of worsening mental illness in people living with diabetes and co-existing obesity, anxiety, or depression.
GLP-1 receptor agonists are widely used in the management of type 2 diabetes and obesity. However, their impact on mental health outcomes has remained uncertain, with previous research producing mixed results. This study contributes new large-scale evidence suggesting a potentially protective effect.
Mental illness and diabetes – a high-risk overlap
People living with diabetes are known to have a higher risk of mental health conditions, including depression, anxiety, and suicide. This overlap creates a complex clinical picture, where both metabolic and psychological factors influence outcomes.
The researchers emphasised that understanding how commonly prescribed antidiabetic medications affect mental health is essential, particularly in populations already at elevated psychiatric risk.
Study design and population
The study analysed data from Swedish national electronic health registers, covering the period from 2009 to 2022. Researchers identified individuals with diagnosed depression or anxiety who were also receiving antidiabetic treatment.
Participants who used GLP-1 receptor agonists were compared with those who did not use these medications, as well as with individuals taking other second-line antidiabetic therapies.
In total, nearly 95,500 people were included in the analysis. Approximately 60% of participants were female and 40% male, with a mean age of around 50 years. Data on ethnicity were not available.
During the follow-up period, almost 22,500 individuals used GLP-1 receptor agonists.
Outcomes measured
The study assessed several primary and secondary outcomes related to mental health.
Primary outcomes included:
- Psychiatric hospitalisation
- Sick leave exceeding 14 days due to psychiatric reasons
- Hospitalisation due to self-harm
- Death by suicide
Secondary outcomes included:
- Worsening symptoms of depression or anxiety
- Substance use disorder
- Self-harm
Reduced risk of worsening mental illness
The findings indicated that some GLP-1 receptor agonists were associated with a lower risk of worsening mental health outcomes.
Semaglutide and liraglutide were linked to a 42% and 18% lower risk of worsening mental illness, respectively, compared with people who did not use GLP-1 therapies.
When examining specific outcomes:
- Semaglutide was associated with a 44% lower risk of worsening depression
- A 38% reduced risk of worsening anxiety
- A 47% lower likelihood of worsening substance use disorder
Liraglutide showed a more limited effect, with a 26% reduction in the risk of worsening depression, but no significant impact on other mental health outcomes.
Other GLP-1 receptor agonists, including exenatide and dulaglutide, did not demonstrate meaningful changes in risk.
Impact on self-harm risk
One of the most notable findings was the association between GLP-1 receptor agonist use and a reduced risk of self-harm.
Overall, these medications were linked to a 44% lower risk of self-harm compared with non-use, suggesting a potentially important role in mitigating severe psychiatric outcomes in this population.
Implications for clinical practice
The results suggest that certain GLP-1 receptor agonists may provide dual therapeutic benefits for people living with diabetes and obesity, addressing both metabolic and mental health outcomes.
However, the authors cautioned that observational findings cannot establish causality. They highlighted the need for randomised controlled trials to confirm these associations and better understand the mechanisms involved.
Conclusion
This large Swedish cohort study provides evidence that some GLP-1 receptor agonists, particularly semaglutide and liraglutide, may be associated with reduced risks of worsening mental illness and self-harm in people living with diabetes and co-existing psychiatric conditions.
While further research is required, the findings point towards a potentially valuable role for these medications in addressing the interconnected challenges of metabolic and mental health.
CCH insight:
Yet more positive news about GLP-1 medications. This is very encouraging, particularly as there are so many drugs that have negative side-effects regarding mental health. However, this study only shows an association, and not causation, and did not adjust for the possible effects of losing weight – those on GLP-1 therapy may have experienced improved mood and mental health due to the fact they were losing weight, rather than as a direct effect of the drug. More research is needed to elucidate the complex interactions of obesity and mental health and the effects of GLP-1 medications.
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Tirzepatide Not Linked to Increased Depression or Suicidal Ideation in Obesity Trials
Key Takeaways:
- A post hoc analysis of three SURMOUNT trials found no evidence that tirzepatide increases the risk of depression compared with placebo over 72 weeks.
- Rates of suicidal ideation and behaviour were low and similar between tirzepatide and placebo groups, with most reports assessed as low risk.
- Experts emphasise the need for routine mental health assessment in people living with obesity, alongside further research in populations with established psychiatric conditions.
Overview of the analysis
Once-weekly subcutaneous tirzepatide was not associated with an increased risk of depression compared with placebo, according to a post hoc analysis of the SURMOUNT clinical trial programme. The findings were published in Obesity and add to the growing body of evidence examining the psychiatric safety of incretin-based therapies used for weight management.
As previously reported by Healio, in January the Food and Drug Administration requested the removal of warnings related to suicidal ideation and behaviours from the labels of several obesity medications, including liraglutide 3 mg (Saxenda), semaglutide 2.4 mg (Wegovy) and tirzepatide (Zepbound).
In the newly published analysis, researchers reported that adults receiving tirzepatide across three SURMOUNT trials did not experience worsening of depression over the course of the studies.
“The low occurrence of these events with tirzepatide is similar to that observed in pooled analyses of semaglutide 2.4 mg and liraglutide 3 mg, both GLP-1 receptor agonists approved for weight management,” said Thomas A. Wadden, PhD, professor of psychology in psychiatry at the Perelman School of Medicine, University of Pennsylvania, in comments to Healio. “The present report provides the first detailed analysis of the risk of these psychiatric events with tirzepatide.”
Study design and assessment methods
The analysis included data from the SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3 studies. Across all three trials, adults living with obesity or with overweight and at least one weight-related comorbidity were randomly assigned to receive once-weekly subcutaneous tirzepatide or placebo for 72 weeks.
Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). Suicidal ideation and behaviour were assessed using the Columbia-Suicide Severity Rating Scale. In addition, investigators recorded neuropsychiatric adverse events during scheduled study visits.
Depression symptoms over time
A total of 4,056 adults were included in the pooled analysis, of whom 63 percent were women and 74 percent were White. Overall, 2,806 participants received tirzepatide and 1,250 received placebo. At baseline, mean PHQ-9 scores were 2.7 in the tirzepatide group and 2.6 in the placebo group, indicating minimal or no depressive symptoms.
By week 72, participants receiving tirzepatide experienced a 0.6-point greater reduction in PHQ-9 score compared with those receiving placebo.
Among participants who had no or minimal depression symptoms at baseline and received tirzepatide, 79.4 percent remained in that category through the end of safety follow-up. During follow-up, 17 percent reported mild symptoms, 2.9 percent reported moderate symptoms, 0.7 percent reported moderately severe symptoms and 0.1 percent reported severe symptoms.
A smaller proportion of participants in the tirzepatide group moved to a more severe depression category compared with the placebo group, 18.2 percent versus 24.3 percent respectively, with this difference reaching statistical significance (P < .001). Conversely, a higher proportion of those receiving tirzepatide moved to a less severe depression category compared with placebo, 52.4 percent versus 41.8 percent (P < .001).
Suicidal ideation and behaviour
At baseline, a history of suicidal ideation or behaviour was reported by 70 participants receiving tirzepatide and 38 participants receiving placebo. Through the end of safety follow-up, 0.6 percent of participants in both the tirzepatide and placebo groups reported suicidal ideation. Most of these events were classified as low risk.
Moderate-risk suicidal ideation was reported by 0.3 percent of participants receiving tirzepatide and 0.1 percent of those receiving placebo. High-risk suicidal ideation occurred in three participants receiving tirzepatide and one participant receiving placebo.
Suicidal behaviour was reported by two participants in the tirzepatide group and by none in the placebo group.
Treatment-emergent nervous system disorder adverse events occurred in 15.8 percent of participants receiving tirzepatide and 13 percent of those receiving placebo. The investigators reported no difference between groups in the occurrence of treatment-emergent psychiatric disorders overall.
Implications for mental health care in obesity
Wadden noted that he and his colleagues supported the FDA decision to remove warnings related to suicidal ideation and behaviour from the labels of incretin-based obesity medications. However, he stressed that mental health assessment remains essential in the care of people living with obesity.
“Persons with obesity, particularly with a BMI of more than 40 kg/m2, are at substantially increased risk of major depression and anxiety disorders,” Wadden said. “It’s critical that they receive the same mental health care that persons of average weight would when presenting with these conditions.”
He also highlighted the need for further research to better understand the effects of incretin-based therapies in people with established psychiatric conditions.
“Randomized trials of the GLP-1 obesity medications largely excluded persons who, in the past 2 years, had experienced major depression, schizophrenia or bipolar disorder, or who had a lifetime history of suicide attempt,” Wadden said. “GLP-1 medications potentially could be beneficial to individuals who suffer from these conditions. Small, carefully controlled studies would appear warranted, as would a close examination of the FDA’s recent retrospective cohort study of more than 2 million individuals. The FDA’s dataset likely included a far greater range of psychiatric status than found in the randomized controlled trials that evaluated tirzepatide and semaglutide for chronic weight management.”
Disclosures
Wadden reports advising for Novo Nordisk and WW and receiving grants on behalf of the University of Pennsylvania from Eli Lilly, Epitomee Medical and Novo Nordisk. All other relevant financial disclosures are reported in the study.
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Dietary Melatonin Intake Linked to Lower Rates of Obesity and Depression
Key Takeaways:
- Higher intake of melatonin from foods was associated with lower prevalence of obesity and depression in a large cohort of Brazilian university graduates.
- No significant associations were found between dietary melatonin intake and most cardiometabolic outcomes, including hypertension, metabolic syndrome or type 2 diabetes.
- The strongest associations were observed at moderate rather than very high levels of dietary melatonin intake, highlighting the complexity of diet–health relationships.
Background and study context
In a study published in the Journal of Human Nutrition and Dietetics, researchers examined the melatonin content of commonly consumed foods and explored how dietary melatonin intake was associated with a range of health outcomes. The analysis used cross-sectional data from a large cohort of Brazilian university graduates.
Melatonin is a hormone best known for regulating circadian rhythms and sleep–wake cycles. Beyond its endogenous production, melatonin is also present in both animal-based and plant-based foods. Experimental, observational and supplementation studies have linked melatonin to sleep regulation, mood, and metabolic health. Although the concentration of melatonin in foods is considerably lower than in supplements, diets rich in melatonin-containing foods have been shown to increase circulating melatonin levels within physiological ranges.
Previous evidence suggests that increasing melatonin intake through food may deliver doses that align more closely with natural circadian rhythms than pharmacological supplementation, potentially avoiding suprapharmacological exposure. On this basis, dietary melatonin has attracted interest as a marker of broader dietary patterns rather than as a direct therapeutic intervention.
Rationale for examining dietary melatonin
Obesity, depression and sleep disorders represent a substantial and growing public health burden. Prior observational and experimental studies have suggested that melatonin may have protective effects against inflammatory, metabolic and neurobehavioural outcomes. In addition, observational research has reported inverse associations between melatonin exposure and outcomes such as liver cancer incidence and all-cause mortality.
Despite this, relatively few studies have investigated habitual dietary melatonin intake or its associations with chronic conditions in adult populations. The present study aimed to address this gap by estimating melatonin intake from the diet and examining its relationship with multiple health outcomes in a large cohort.
Study design and population
The analysis drew on data from the Cohort of Universities of Minas Gerais (CUME+) study. CUME+ is an open, prospective cohort designed to assess the impact of dietary patterns and nutrition transition on noncommunicable diseases.
At baseline, participants completed a questionnaire administered in two parts. The first part collected information on sociodemographic characteristics, clinical history, lifestyle factors, anthropometric measures and self-reported morbidity.
Dietary assessment and estimation of melatonin intake
The second part of the baseline assessment included a food frequency questionnaire (FFQ), alongside questions on dietary habits, supplement use and cooking practices. Nutrient intake was estimated using established food composition tables.
Dietary melatonin content was estimated based on values reported in the scientific literature for individual food items. These estimates were then adjusted for total energy intake to account for differences in overall food consumption between participants.
Health outcomes and definitions
The health outcomes assessed in the study included obesity, obstructive sleep apnoea (OSA), hypertension, metabolic syndrome (MetS), type 2 diabetes (T2D), sleep duration, dyslipidaemia and depression.
Obesity was defined as a body mass index of 30 kg/m² or higher. Depression and OSA were identified based on self-reported medical diagnoses.
Dyslipidaemia was defined as the presence of at least one abnormal lipid parameter, including total cholesterol of 200 mg/dL or higher, triglycerides of 150 mg/dL or higher, high-density lipoprotein cholesterol below 40 mg/dL for males or below 50 mg/dL for females, or low-density lipoprotein cholesterol of 130 mg/dL or higher.
Cardiometabolic criteria
Metabolic syndrome was defined as central obesity plus any two of the following criteria: elevated triglycerides or treatment for hypertriglyceridaemia, reduced high-density lipoprotein cholesterol or treatment, elevated blood pressure or treatment for hypertension, and elevated fasting plasma glucose or a diagnosis of type 2 diabetes.
Hypertension was defined by the use of antihypertensive medication, a physician diagnosis, systolic blood pressure of 140 mmHg or higher, or diastolic blood pressure of 90 mmHg or higher. Type 2 diabetes was defined as a self-reported or physician diagnosis, use of antidiabetic medication, or fasting plasma glucose of 126 mg/dL or higher.
Sleep duration was categorised as short if participants reported sleeping less than seven hours per day, and normal if they reported seven hours or more per day.
Statistical analysis
Associations between dietary melatonin intake and health outcomes were estimated using logistic and Poisson regression models. Analyses were adjusted for a wide range of potential confounders, including age, sex, family income, binge drinking, smoking status, screen time, physical activity, medication use and sleep duration.
Participant characteristics
The final analysis included 8,320 participants with a mean age of 35.9 years. Most participants were female and reported that they did not smoke. Around one third of the cohort reported short sleep duration.
Dyslipidaemia, depression, obesity and hypertension were the most commonly reported health conditions within the study population.
Melatonin content of foods and dietary sources
Melatonin content was estimated for 119 of the 144 food items included in the FFQ. Reported concentrations ranged from 0 to 169.9 ng per gram of food. Mean daily melatonin intake was estimated at 25,554.7 ng and was significantly higher in males than in females.
The main dietary sources of melatonin in this population were coffee, lentils and beans, and rice. Higher melatonin intake was associated with lower intake of protein, cholesterol, and saturated and monounsaturated fats, alongside higher intake of fibre and carbohydrates. These patterns suggest that dietary melatonin intake may reflect broader differences in dietary composition.
Associations with health outcomes
After full adjustment, no significant associations were observed between dietary melatonin intake and obstructive sleep apnoea, hypertension, metabolic syndrome or type 2 diabetes. Initial associations with sleep duration and dyslipidaemia were attenuated after adjustment for age and sex and did not remain statistically significant.
In contrast, dietary melatonin intake showed an inverse association with both obesity and depression. Participants with daily melatonin intakes between approximately 14,900 and 34,400 ng were less likely to have obesity, while intakes between approximately 14,900 and 25,000 ng were associated with a lower likelihood of depression.
Notably, the strongest associations were observed in intermediate intake quintiles rather than among those with the highest melatonin intake, suggesting a non-linear relationship.
Conclusions and implications
In this cohort of Brazilian university graduates, higher dietary melatonin intake was associated with lower prevalence of obesity and depression, while no significant associations were identified for most other cardiometabolic outcomes or sleep duration.
The findings support existing hypotheses that dietary melatonin may play a role in metabolic and neurobehavioural regulation, potentially through anti-inflammatory pathways. However, the cross-sectional design of the study means that causal relationships cannot be established.
Further longitudinal and experimental research is needed to confirm these associations, determine whether dietary melatonin has an independent effect beyond overall dietary patterns, and clarify the biological mechanisms that may underlie the observed relationships.
CCH insights:
This is an interesting study, but it is difficult to see where this research leads to. If a person is suspected of having obesity, depression or some other condition due to a lack of melatonin, the solution is surely likely to be supplementation of melatonin, not an increase in melatonin-rich foods – because dietary changes are notoriously difficult to adhere to and when we are looking at just one nutrient, supplementation is a much easier option.
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