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In recent years, drugs such as semaglutide (Ozempic) and tirzepatide (Mounjaro) have attracted considerable attention not only for their effectiveness in the treatment of diabetes and weight loss, but also for concerns about potential psychiatric side effects. The European Medicines Agency (EMA) launched a review in 2023 to examine whether these drugs can increase the risk of suicide, fueled by reports of about 150 cases of patients who have reported suicidal thoughts or self-injury behavior. These concerns are particularly relevant for those who suffer from obesity, a condition strongly linked to depression and suicidal thoughts. 

OBESITY AND DEPRESSION: A VICIOUS CIRCLE 

Obesity is often associated with a number of psychiatric complications such as depression. Numerous studies have shown that people with obesity are more prone to suffering from depressive disorders than the general population. The relationship between obesity and depression is bidirectional: on the one hand, excess weight can cause problems of self-esteem, discrimination and social isolation, which contribute to the development of depression; on the other hand, depression can lead to a sedentary lifestyle and overeating, aggravating the problem of weight. This vicious circle, which is based on a double inflammatory process in peripheral organs – such as the adipose organ – and in the brain, can increase the risk of suicidal thoughts, creating a particularly fragile psychological situation for these patients (Plackett B., Nature 608: S42-S43, 2022).  

According to several studies, people with obesity have a significantly higher risk of developing depression and anxiety than those with a normal weight (Blasco et al., Psychiatry Investig. 17(8): 715–724, 2020). This risk is particularly high for women and those suffering from severe obesity. It is important to emphasize that depression, especially if left untreated, is one of the main risk factors for suicide. 

THE INTERVENTION OF DRUGS FOR WEIGHT LOSS: RISKS AND BENEFITS 

Weight loss drugs, such as GLP-1 receptor agonists, are seen as a hope for those suffering from obesity and the psychiatric complications associated with it. These drugs can significantly reduce body weight, thereby improving the self-esteem and quality of life of many patients. Reducing obesity could, therefore, have a positive impact on depression and mental well-being. 

However, some experts have raised concerns about the potential negative impact of these drugs on the central nervous system. GLP-1 agonists, such as semaglutide, interact with brain receptors and may, in some cases, alter the neurochemical balance. This effect could theoretically affect mood and behavior, exacerbating some people’s predisposition to depression or suicidal thoughts. Although the evidence to support such a risk is not definitive, the interaction between these drugs and the brain requires further investigation.     

EVIDENCE FROM REAL-WORLD DATA 

One of the main challenges in assessing the risk of suicide related to semaglutide or other drugs of this class is the rarity of events such as suicide in clinical contexts. Randomized studies, however rigorous, are not ideal for detecting significant differences in such rare events. That’s why the scientific community has begun to rely on real-world data, such as those from national medical records in countries such as Sweden and Denmark. 

A recently published study (Ueda et al., JAMA Intern Med. Published online September 3, 2024. doi:10.1001/jamainternmed.2024.4369) analyzed data from 124,517 people who started therapy with semaglutide or liraglutide between 2013 and 2021, comparing them with 174,036 users of SGLT2 inhibitors, another class of diabetes drugs. The results did not show a significant increase in the risk of suicide in patients taking GLP-1 agonists, although the suicide rate was slightly higher (6 out of 10,000 versus 4 out of 10,000 for SGLT2 inhibitors). Interestingly, patients who were prescribed semaglutide tended to have a history of depression or antidepressant use, which may have influenced the results. 

OTHER RESEARCH AND POINT OF VIEW 

A further study published in Nature Medicine (Wang et al., Nat Med. 30: 168–176, 2024) provided a different perspective, suggesting that the use of drugs such as semaglutide could even reduce the suicide rate. In particular, this study involved over a million patients and showed that GLP-1 agonists could have protective effects, probably related to reducing compulsive behaviors and weight loss. In overweight or obese patients (mean age 50.1 years, 72.6% women), semaglutide compared to non-agonist GLP1 receptor anti-obesity drugs was associated with a lower risk of incidental (HR = 0.27, 95% CI = 0.20-0.60) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent with stratification by sex, age and ethnicity. Similar results were replicated in patients with type 2 diabetes mellitus (mean age 57.5 years, 49.2% women). Overall, these results suggest that there is no greater risk of suicidal ideation with semaglutide than with non-agonist GLP1 receptor anti-obesity or diabetes drugs.   

A COMPLEX RISK TO EVALUATE 

The issue of suicide in patients taking semaglutide or similar drugs is complex, since suicide is the product of multiple factors that interact with each other, including the psychological state of the individual, social and cultural conditions and access to psychological support services. Scandinavia, for example, with its high rate of national happiness and, paradoxically, also high suicide rates, may not be directly comparable to other contexts, such as the United States or other European countries. 

What is clear is that obesity itself is an important risk factor for depression and suicide, and that any medical intervention that significantly modifies body weight and eating behaviors must be carefully monitored for psychological effects. 

CONCLUSIONS

In light of current evidence, there is no clear and definitive correlation between the use of semaglutide and other GLP-1 drugs and an increased risk of suicide. However, considering the strong association between obesity and depression, it is crucial that patients treated with these drugs are monitored not only for weight loss, but also for any changes in mood or behavior. Obesity-related depression is a serious condition that can increase the risk of suicide, and the use of drugs that act on the central nervous system requires special attention to these aspects.

In conclusion, the treatment of obesity with these so innovative and effective drugs certainly offers many benefits, but it must be accompanied by a continuous evaluation of the patient’s mental health. Only with a holistic approach will it be possible to guarantee long-term positive results for both the body and the mind. 

In conclusione, il trattamento dell’obesità con questi farmaci così innovativi e efficaci offre sicuramente molteplici benefici, ma deve essere accompagnato da una valutazione continua della salute mentale del paziente. Solo con un approccio olistico sarà possibile garantire risultati positivi a lungo termine sia per il corpo che per la mente.

*Enzo Nisoli is Scientific Coordinator of the Center for the Study and Research on Obesity (CSRO) and Full Professor of Pharmacology – Department of Medical Biotechnology and Translational Medicine at the University of Milan. 

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