Real-world data suggest that new obesity drugs may have a different mental health profile, with warning signs for anxiety and insomnia shown for tirzepatide compared to semaglutide in people without diabetes, although rates of some psychiatric diagnoses are lower.
Study: Neuropsychiatric associations of tirzepatide and semaglutide in obesity with and without type 2 diabetes. Image credit: Love Employee / Shutterstock
In a recent study published in the journal communication medicineA group of researchers examined the association between initiation of tirzepatide or semaglutide and incident neuropsychiatric diagnoses compared with other weight loss treatments in adults with obesity, analyzing individuals with and without type 2 diabetes separately.
background
Currently, more than 650 million adults worldwide suffer from obesity, which affects their physical and mental health. People with obesity are more likely to suffer from mental illnesses such as anxiety and depression than people who are not obese. Additionally, mental illness can increase the likelihood of developing obesity. New incretin-based drugs such as semaglutide and tirzepatide have revolutionized obesity treatment by producing significant weight loss, but their impact on neuropsychiatric health remains uncertain in daily clinical practice.
About research
Researchers conducted a retrospective cohort study from January 2020 to November 2025 using deidentified electronic medical records from the TriNetX United States Collaborative Network. Adults who met the study’s obesity criteria and newly started tirzepatide or semaglutide were identified and compared with matched individuals who started naltrexone-bupropion, phentermine, or phentermine-topiramate. The study included two separate analyzes based on whether participants had type 2 diabetes, and patients who underwent bariatric surgery and a non-pharmacological weight loss cohort were also evaluated as situational comparison groups.
To increase comparability between treatment groups, propensity score matching was performed using demographic characteristics, body mass index (BMI), glycated hemoglobin (HbA1c), medical history, concomitant treatments, healthcare utilization, and laboratory test results. Patients with type 1 diabetes, history of bariatric surgery, history of organ transplantation, human immunodeficiency virus (HIV) infection, or end-stage renal disease were not included. Patients were monitored for up to 24 months from the start of treatment until the first diagnosis of neuropsychiatric outcome, death, loss to follow-up, or study termination.
The primary outcome was a new diagnosis of an anxiety disorder. Secondary outcomes included diagnoses of depression, mood disorders, insomnia, broad cognitive impairment, neuropathy, peripheral neuropathy, and substance-related disorders. Cox proportional hazards models were used to obtain hazard ratios with 95% confidence intervals (CIs), adjusting for possible confounders, and various sensitivity analyzes were also performed.
Research results
Before matching, individuals initiating incretin-based treatment differed significantly from the comparison group, particularly with regard to psychiatric disorders and psychotropic medication use. After propensity score matching, each group had very similar baseline demographic characteristics, cardiometabolic health problems, laboratory values, and health care utilization, allowing for more reliable comparisons between treatment groups.
People receiving semaglutide and tirzepatide generally had a lower risk of several documented neuropsychiatric diagnoses than people who had bariatric surgery.
In individuals with obesity and type 2 diabetes, both drugs were associated with lower risks of anxiety disorders, broad cognitive impairment, mood disorders, and depression. Similar results were seen in individuals without type 2 diabetes, but neurological outcomes were less consistent between groups.
Semaglutide was associated with a higher risk of neuropathy in participants without diabetes, whereas tirzepatide showed a lower risk of substance-related disorders and peripheral neuropathy compared with bariatric surgery. Negative control analyzes found no clinically meaningful differences, providing some reassurance about the analytical approach.
Compared with naltrexone-bupropion, semaglutide was associated with a lower risk of anxiety disorders, depression, cognitive impairment, and insomnia in adults with type 2 diabetes. Tirzepatide also showed a lower risk of anxiety disorders, depression, mood disorders, and cognitive impairment within this group.
Similar reductions were observed in adults without diabetes, indicating that both drugs were consistently associated with lower rates of several recorded psychiatric diagnoses than this comparator.
A direct comparison of tirzepatide and semaglutide in adults without type 2 diabetes showed that tirzepatide was associated with a higher risk of anxiety and insomnia than semaglutide, but no consistent differences were observed for most neurological outcomes after statistical adjustment. However, the authors noted that this direct comparison resulted in different absolute and relative estimates of anxiety and insomnia, so these small differences should be interpreted with caution.
Absolute risk differences showed that patients with type 2 diabetes had a greater reduction in anxiety disorders than patients without diabetes when tirzepatide or semaglutide were compared with naltrexone-bupropion.
Sensitivity analyzes generally confirmed the main findings. Per-protocol and post-treatment analyzes showed a similar direction of the association between anxiety and depression, although the strength of some associations varied depending on treatment continuation. We also observed less use of psychiatric medications, particularly selective serotonin reuptake inhibitors (SSRIs), in patients receiving incretin-based therapy compared with a matched comparison group.
Subgroup analyzes suggested that this association was generally consistent across age, BMI, and clinical characteristics, with stronger associations observed among older adults and those with severe obesity.
Exploratory analyzes generally showed greater reductions in body weight and HbA1c over 24 months in the incretin-based treatment group than in the traditional anti-obesity drug group, although some comparisons varied by diabetes status and outcome measures.
Additional sensitivity analyzes using more stringent outcome definitions and alternative cohort criteria yielded directionally similar results, although smaller sample sizes reduced the precision of some estimates. Importantly, cognitive findings are sensitive to outcome definitions, and broad cognitive endpoints include codes that may reflect acute or transient changes in mental status rather than dementia or progressive cognitive decline.
conclusion
This finding suggests that initiation of tirzepatide and semaglutide is associated with different patterns of neuropsychiatric outcomes depending on the comparator treatment and the presence of type 2 diabetes. Compared to naltrexone-bupropion, both drugs were found to have a generally lower risk of anxiety and depression. In contrast, tirzepatide showed a higher risk of anxiety and insomnia than semaglutide in adults without type 2 diabetes.
These findings provide clinicians and patients with important real-world evidence to inform treatment decisions, while highlighting the need for continuous patient monitoring. However, this study relied on diagnostic codes, which remain susceptible to residual confounding and misclassification, so the results should not be interpreted as evidence that these drugs prevent dementia, progressive cognitive decline, or psychiatric illness.
Furthermore, as this study is observational, prospective studies with standardized neuropsychiatric assessments are needed to confirm these associations. Further research is needed to understand how these drugs affect mental health outcomes in different patient populations.
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Reference magazines:
- Huang, Y.-N., Liu, K.-W., Li, P.-H., Chen, J.-C., Meyerowitz-Katz, G., Su, P.-H., Huang, C.-C. (2026). Neuropsychiatric associations of tirzepatide and semaglutide in obesity with and without type 2 diabetes. Communication medicine. Doi: 10.1038/s43856-026-01750-z. https://www.nature.com/articles/s43856-026-01750-z
