Pharmacy Knowledge

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as liraglutide, semaglutide, and dulaglutide have transformed the management of type 2 diabetes mellitus (T2DM) and obesity. While their efficacy in glycemic control and weight reduction is well established, emerging post-marketing reports and regulatory investigations have raised concerns about potential neuropsychiatric adverse effects, particularly suicidal ideation, in susceptible populations.

Pharmacists, as accessible healthcare providers, are uniquely positioned to monitor for early warning signs of neuropsychiatric side effects, especially in patients with a known history of mental illness.

The Neuropsychiatric Safety Signal

In 2023, the European Medicines Agency (EMA) initiated a review of GLP-1 RAs following reports of suicidal thoughts and self-injury in patients using semaglutide and liraglutide, particularly for weight loss indications1. The U.S. FDA also began evaluating similar safety data. While a causal relationship has not been definitively established, the reports prompted heightened scrutiny due to the seriousness of the potential outcome.

Psychiatric History: A Risk Amplifier?

The precise mechanism by which GLP-1 RAs could influence mood or behavior remains unclear. However, the concern is amplified in individuals with pre-existing psychiatric diagnoses, such as depression, bipolar disorder, or anxiety disorders, who may already have a heightened baseline risk of suicidal ideation.

GLP-1 receptors are expressed not only in the pancreas but also in the brain, including areas involved in mood regulation such as the hypothalamus and brainstem2. Preclinical studies suggest that GLP-1 may modulate neurotransmitter systems linked to mood, including dopamine and serotonin pathways3.

Clinical Evidence: Limited but Noteworthy

Although large clinical trials like the STEP and SUSTAIN programs have not demonstrated a significant increase in suicidal ideation, these trials often exclude individuals with major psychiatric comorbidities, limiting the generalizability of their findings to real-world settings.

A 2022 retrospective cohort study using data from a pharmacovigilance database identified an association between GLP-1 RA use and increased reports of depression and suicidal thoughts, particularly when used for obesity rather than T2DM4. However, the data is observational and prone to confounding factors such as weight loss–related psychological changes or underlying mental illness.

Considerations for Pharmacists

Given the potential link, pharmacists should take the following precautions:

1. Screen for Psychiatric History: Before dispensing GLP-1 RAs, inquire (where appropriate) about a history of mood disorders or suicidal ideation.

2. Counsel Patients and Caregivers: Educate patients and their families on the signs of worsening depression or suicidal thoughts, especially within the first few weeks of therapy.

3. Monitor Behavioral Changes: Encourage patients to report any new or worsening mood symptoms. Document and communicate concerns to the prescriber.

4. Coordinate with the Healthcare Team: Work closely with prescribers, especially psychiatrists, to assess whether GLP-1 RA therapy is appropriate for individuals with significant psychiatric history.

Conclusion

While the current evidence does not definitively confirm a causal relationship between GLP-1 RA therapy and suicidal ideation, especially in patients with psychiatric diagnoses, the potential risk warrants caution and proactive monitoring. Pharmacists can play a pivotal role in early detection and intervention, contributing to safer and more personalized patient care.

References

Footnotes

1. European Medicines Agency. EMA investigating reports of suicidal thoughts and self-injury with GLP-1 receptor agonists. 2023. https://www.ema.europa.eu ↩

2. Cork SC, Richards JE, Holt MK, et al. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718-731. doi:10.1016/j.molmet.2015.07.008 ↩

3. Anderberg RH, Richard JE, Hansson C, et al. GLP-1 is both anxiogenic and antidepressant: differential effects of central and peripheral administration. Neuropsychopharmacology. 2016;41(6):1450–1459. doi:10.1038/npp.2015.294 ↩

4. Hensel RL, Brown JD, Goetzinger C, et al. Reports of depressive symptoms and suicidal ideation with GLP-1 receptor agonists: A retrospective analysis of FDA Adverse Event Reporting System (FAERS). Obesity Pillars. 2022;3:100034. doi:10.1016/j.obpill.2022.100034 ↩