Case reports have shown a potential association with adverse psychological effects.
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Monique Hook, PharmD, is a PGY1 ambulatory care resident at AdventHealth Celebration in Orlando, Florida.
Raechel Lozano, PharmD, BCACP, is the PGY2 ambulatory care residency program director and clinical pharmacy specialist at AdventHealth Celebration in Orlando, Florida.
The popularity of glucagon-like peptide-1 (GLP-1) receptor agonists has skyrocketed in recent years, despite their having been on the market for nearly 2 decades for the treatment of type 2 diabetes. As GLP-1 receptor agonists continue to rise in demand, adverse psychological effects, including suicidality and depression, have been reported among patients, prompting increased awareness and monitoring from several agencies, including the FDA.1
Medications that target the GLP-1 receptor have demonstrated impressive weight-loss effects comparable to those of gastric bypass surgery, with reductions in body weight of up to 20% with tirzepatide and 15% with semaglutide.2,3 The mechanism of action of a GLP-1 receptor agonist involves mimicking the incretin hormone naturally produced in the small intestine, which stimulates the GLP-1 receptors, leading to an increase in insulin secretion in response to glucose. The effects of exogenous GLP-1 observed in patients with diabetes include decreased glucagon concentrations, improved insulin sensitivity, decreased hemoglobin A1c level, slowed gastric emptying, increased satiety, decreased free fatty acid concentrations, and decreased body weight.4 Despite these benefits, which have contributed to improved cardiovascular and glycemic outcomes in patients with diabetes, case reports have emerged potentially associating the use of GLP-1 receptor agonists with depression and suicidality, thereby requiring further investigation.5
In July 2023, the European Medicines Agency (EMA) released a statement regarding the ongoing review of 150 instances of possible self-injury and suicidal thoughts among patients using GLP-1 receptor agonists. The review was initially launched in response to 2 reports from the Icelandic Medicines Agency, based on 2 cases involving liraglutide and 1 case for semaglutide. EudraVigilance, an adverse drug reaction reporting agency, added at least 170 case reports for the EMA to review. It has been reported that the FDA had received 265 reports of suicidal thoughts or behavior in patients taking GLP-1 receptor agonists between 2010 and 2023.6 The EMA released a statement in December 2023 stating that the investigation will continue and the topic will be revisited during the April 2024 meeting, as it was declared that at this point no conclusion can be drawn on a causal association, but several issues still need clarification.7
Currently, the FDA-approved label of semaglutide (Wegovy; Novo Nordisk) for chronic weight management states, “Suicidal behavior and ideation have been reported in clinical trials with other weight management products.” Liraglutide (Saxenda; Novo Nordisk) carries a similar FDA warning, as Novo Nordisk observed suicidal thoughts or behaviors in some of its patients during clinical trials. Semaglutide (Ozempic; Novo Nordisk) lacks this type of language; however, the label on the most recent FDA-approved weight loss drug, tirzepatide (Zepbound; Eli Lilly and Company), carries adverse effect (AE) warnings of depression or thoughts of suicide.8 Both Wegovy and Saxenda clinical trials excluded participants with a history of depression or suicidal behavior. According to Saxenda’s label, 9 of 3384 participants (0.3%) who received the drug in clinical trials reported suicidal ideation compared with 2 of 1941 participants (0.1%) who received the placebo.1,9 Both Saxenda and Wegovy drug labels advise health care providers to monitor for signs and symptoms of depression and suicidal thoughts and to discontinue the medication if those symptoms occur.9,10
Data exist describing a possible link between weight change and suicide in the context of bariatric surgery. Among those who undergo bariatric surgery, rates of suicide are significantly higher than those in the general population, and GLP-1 receptor agonists demonstrate comparable amounts of weight loss to those of bariatric surgery.11 There are several hypotheses proposed as to the possible association between weight loss and suicide, including hormonal changes due to ghrelin and lower triglyceride levels.12,13
Furthermore, weight loss that is lower than anticipated, or even weight gain, could trigger depressive symptoms in patients using GLP-1 receptor agonists. In the phase 3 SURMOUNT-4 trial (NCT04660643) evaluating tirzepatide, patients were provided with open-label tirzepatide for 36 weeks and then randomly assigned to either continue tirzepatide or switch to placebo. Those who remained on tirzepatide lost a mean of 26% body weight, and those who switched to placebo regained weight but still lost 9.5% below starting weight.13,14 Jackson et al sought to examine associations between changes in weight and changes in wellbeing in overweight and obese adults free from depression and serious illness at baseline. In this study of 1979 overweight and obese adults in the UK, individuals who lost 5% or more of their initial or baseline body weight over 4 years were more likely to report depressed mood than those who stayed within 5% of their original weight. Furthermore, after controlling for confounding caused by serious health issues and major life events (ie, bereavement), the increased odds of depressed mood remained statistically significant at 52%. The researchers of this study proposed that depressed mood following weight loss could be due to the inability to maintain their new weight in the long term or the unrealistic expectation that weight loss could improve other aspects of life.15 Individuals may realize that weight loss is likely not the sole source of happiness as weight loss alone may not automatically improve their lives. The psychological impact of patient variability in terms of net weight loss and/or weight gain is a gray area that highlights the need for further research as patients continue taking GLP-1 receptor agonists chronically for weight management.
Additional data are expected in April 2024 after further analysis by regulatory agencies, such as the EMA. Health care providers are encouraged to continue monitoring for symptoms of depression and suicidality in patients receiving GLP-1 receptor agonist therapy. More information on reporting AEs is available within the package inserts and online through the FDA Adverse Event Reporting System.
