GLP1 agonists linked to depression risk in new genetic study

A groundbreaking study published in the journal Current Neuropharmacology highlights a concerning potential link between Glucagon-like Peptide-1 (GLP1) receptor agonists-widely used in blockbuster drugs like Ozempic-and the risk of depression and suicidal ideation (SI). Using advanced pharmacogenomic computational analyses, the international team of 24 researchers revealed genetic pathways that may induce depressive phenotypes in users of GLP1 agonists, raising significant concerns about the safety of these medications for certain individuals.

The study, led by researchers across the United States, Brazil, Iran, and Israel, demonstrates that while GLP1 agonists benefit individuals with hyperdopaminergia (excess dopamine activity), they may have harmful effects on individuals with hypodopaminergia (low dopamine function). The authors found genetic associations between GLP1 receptor agonists and genes such as DRD3, BDNF, and CREB1, which are implicated in mood regulation and reward pathways. Their findings suggest that chronic use of these drugs could dysregulate dopamine signaling, potentially leading to depressive symptoms, mood disturbances, and SI.

Cautionary voices from experts

While the idea of GLP1 agonism induction of depression and SI is controversial with both negative and positive reporting, based on the evidence presented in this article by Alireza Sharafshah, a PhD candidate from Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran, the authors caution against promoting chronic stimulation via GLP-1 agonists.

This study should not be ignored, despite the hype surrounding the positive clinical outcomes of GLP1 receptor agonists. We urge the clinical prescribing community to proceed with caution to avoid another tragic wave of 'people dying to lose weight.'" Dr. Kenneth Blum, Senior Author, Research Professor at Western University Health Sciences and Ariel University

Dr. Mark S. Gold, an addiction psychiatry pioneer and co-author, emphasized, "The paper provides critical evidence for re-evaluating the widespread use of GLP1 receptor agonists. The FDA and other regulatory agencies should carefully consider our findings when it comes to labeling and monitoring these drugs."

Rising global concerns

Professor Albert Pinhasov, Provost of Ariel University, echoed these sentiments, stating, "While there are encouraging short-term benefits of GLP1 receptor agonists, we must acknowledge the potential risks highlighted in this study. These findings should encourage regulatory agencies and clinicians to investigate further, given the heterogeneity of the human population."

The European Medicines Agency (EMA) has already initiated a review of GLP1 agonists following reports of suicidal thoughts and other psychiatric adverse events. Co-author Dr. Kai Uwe Lewandowski, Professor of Surgery at the University of Arizona School of Medicine, noted, "Depression was the most commonly reported adverse event associated with these drugs, followed by anxiety and suicidal ideation. Our findings strongly support a need for further investigation to safeguard public health."

The role of genetic testing

The study advocates for personalized medicine approaches, including genetic testing for hypodopaminergia, to identify individuals at risk before prescribing GLP1 receptor agonists. Professor Panayotis K. Thanos of Buffalo University commented, "Before prescribing GLP1 receptor agonists, it would be prudent to use genetic testing tools to assess a patient's dopamine function and addiction risk profile."

Balancing hope with vigilance

Professor Igor Elman of Harvard University warned, "While GLP1 receptor agonists hold promise for treating addictive and behavioral disorders, we must remain vigilant about their potential harm. This study is not intended to break the bubble of hope but to add a layer of precaution in their over-prescription."

About the study

The article, titled "In Silico Pharmacogenomic Assessment of Glucagon-like Peptide-1 (GLP1) Agonists and Genetic Addiction Risk Score (GARS) Related Pathways: Implications for Suicide Ideation and Substance Use Disorder," provides a detailed map of the genetic pathways involved in these risks. The study serves as a critical reminder that while these medications can provide significant health benefits, their potential risks warrant careful scrutiny and further research.

Conclusion

This cross-cultural research study provides essential insights that could save lives. It urges regulatory agencies such as the FDA and EMA to monitor these drugs closely and calls on clinicians to balance their benefits with caution.

Sharafshah, A., et al. (2025). In Silico Pharmacogenomic Assessment of Glucagon-like Peptide-1 (GLP1) Agonists and the Genetic Addiction Risk Score (GARS) Related Pathways: Implications for Suicide Ideation and Substance Use Disorder. Current Neuropharmacology. doi.org/10.2174/011570159x349579241231080602.