Association of GLP‐1 Receptor Agonists With Risk of Suicidal Ideation and Behaviour: A Systematic Review and Meta‐Analysis

Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are a class of medications primarily used to manage type 2 diabetes mellitus and obesity. These drugs have demonstrated favourable effects on glycaemic control, weight reduction, and cardiovascular outcomes, positioning them as pivotal components of modern diabetes treatment regimens [1, 2, 3]. However, recent post‐marketing surveillance has raised concerns about potential neuropsychiatric side effects, including suicidal ideation and behaviour, among patients using GLP‐1RAs. The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both issued safety communications and called for further investigation into this possible association [4].

While randomised controlled trials (RCTs) and observational studies have primarily focused on the metabolic and cardiovascular safety profiles of GLP‐1RAs, limited evidence exists regarding their effects on mental health outcomes [5]. Emerging data from clinical practice and pharmacovigilance databases have suggested that GLP‐1RAs might influence mood and behaviour, but findings remain inconclusive, and the magnitude of risk is not well‐defined [6]. Given the growing use of these agents and the seriousness of suicidal ideation as a potential adverse event, there is a critical need for a systematic evaluation of the available evidence to inform clinical decision‐making and regulatory guidelines.

This systematic review and meta‐analysis aimed to assess the association between GLP‐1RA use and the risk of suicidal ideation or behaviour by synthesising data from clinical trials and observational studies. By addressing this knowledge gap, we seek to clarify the potential neuropsychiatric risks associated with GLP‐1RAs and provide evidence‐based recommendations for clinicians and policymakers.

This systematic review and meta‐analysis were conducted following the PRISMA guidelines (Table S1) [7]. The study protocol was registered in the PROSPERO database.

The findings from this systematic review and meta‐analysis indicate that there is no statistically significant association between GLP‐1RA use and an increased risk of suicidal ideation or behaviour (RR: 0.568, 95% CI: 0.077–4.205). However, the high heterogeneity observed across studies (I² = 98%) raises concerns about the reliability of this finding and necessitates cautious interpretation. The considerable heterogeneity likely stems from the diverse methodologies, populations, and comparators used in the included studies, which introduce variability in outcomes. Most of the included studies were based on pharmacovigilance databases, which are inherently prone to underreporting and reporting biases. These databases primarily capture spontaneous adverse event reports, which may not accurately reflect the true incidence of neuropsychiatric events such as suicidal ideation. Moreover, the wide prediction interval observed in the meta‐analysis further underscores the uncertainty surrounding the true relationship between GLP‐1RAs and suicidality. Given the seriousness of suicidal ideation as a clinical outcome, it remains imperative that clinicians maintain vigilance when prescribing GLP‐1RAs, especially in patients with pre‐existing psychiatric conditions who may be at elevated risk.

Despite these limitations, the results of this review are consistent with several recent studies that have explored the potential link between GLP‐1RA use and suicidality. For instance, Nguyen (2024) [12] conducted a Mendelian randomisation study that found no causal evidence linking the glycaemic and BMI‐lowering effects of GLP‐1RAs to an increased risk of suicide attempts, either in the general population or in individuals with pre‐existing mental health conditions. Nguyen's findings align with the results of RCTs of GLP‐1RAs, which have not demonstrated an increased risk of suicidality, although it is important to note that these trials typically included populations at lower risk for suicide, such as older adults or individuals without significant psychiatric histories. Additionally, real‐world evidence, particularly from propensity‐matched cohort studies, has suggested that semaglutide use may be associated with reductions in major depression and suicidal ideation. However, Nguyen et al. 2024 cautioned that small sample sizes limited these studies and were not adequately powered to exclude the possibility of suicide attempts.

Arillotta (2024) [22] employed a mixed‐method approach to analyse patient discussions about GLP‐1RAs on social media platforms, including Reddit, YouTube, and TikTok. Arillotta's analysis found mixed reports on mood and mental health changes after initiating GLP‐1RA therapy. While some users reported marked improvements in mood, better control of addictive behaviours, and reductions in anxiety, others reported increases in depressive symptoms, anxiety, and insomnia. These mixed perceptions highlight the complexity of patient experiences with GLP‐1RAs and underscore the difficulty of establishing a clear cause‐and‐effect relationship between these medications and suicidality based solely on patient reports. Nonetheless, the study offers valuable insight into how these drugs are perceived by the public and emphasises the need for further research to understand the full spectrum of neuropsychiatric effects associated with GLP‐1RAs.

Conversely, pharmacovigilance data have raised concerns about potential neuropsychiatric side effects, particularly with semaglutide. Schoretsanitis et al. (2024) [14] conducted a disproportionality analysis using the World Health Organization's (WHO) global adverse drug reaction database, identifying 107 cases of suicidal and self‐injurious behaviours associated with semaglutide and 162 cases with liraglutide. The analysis found a significant signal for semaglutide‐related suicidal ideation, with a reporting odds ratio (ROR) of 1.45 (95% CI: 1.18–1.77). Notably, the risk was substantially higher in patients who were co‐prescribed antidepressants (ROR: 4.45, 95% CI: 2.52–7.86) or benzodiazepines (ROR: 4.07, 95% CI: 1.69–9.82), suggesting that individuals with pre‐existing mental health conditions may be more vulnerable to the neuropsychiatric effects of GLP‐1RAs. This finding is particularly important because it suggests a potential interaction between GLP‐1RAs and psychiatric medications, which may amplify the risk of adverse neuropsychiatric outcomes in certain populations. On the other hand, Guirguis et al. (2024) [15] analysed data from the FDA's FAERS database and found that among 5378 psychiatric adverse drug reactions (ADRs) related to GLP‐1RAs, there were 236 cases of suicidal ideation and 13 completed suicides across various GLP‐1RAs, including semaglutide and liraglutide. Although semaglutide had a relatively high ROR for suicidal ideation (2.03), no definitive causality could be established, and the overall incidence of suicide‐related events remained low.

Taken together, these studies highlight the complexity of assessing the association between GLP‐1RA use and suicidality. On the one hand, the available evidence from clinical trials, observational studies, and real‐world data largely suggests that GLP‐1RAs do not significantly increase the risk of suicidal ideation or behaviour [23]. In fact, some studies have even suggested a potential protective effect of these medications on mood and cognition, possibly due to the presence of GLP‐1 receptors in the central nervous system (CNS) [24]. GLP‐1 receptors are known to play a role in regulating appetite and energy homoeostasis, and their activation may indirectly influence mental health by modulating reward pathways, mood, and stress responses [25]. Furthermore, GLP‐1RAs are capable of crossing the blood‐brain barrier, and their neuroprotective effects may extend beyond metabolic regulation, potentially contributing to improvements in cognitive function and overall mental well‐being [26]. By mitigating metabolic disturbances such as obesity, diabetes, and associated neuroinflammation—conditions that frequently overlap with mental health disorders—GLP‐1RAs may provide secondary benefits for mental health [27].

However, the potential for neuropsychiatric side effects, particularly in vulnerable populations such as individuals with pre‐existing psychiatric conditions, cannot be ignored. The findings from pharmacovigilance databases, which report isolated cases of suicidal ideation and self‐injurious behaviour, particularly in patients co‐administered with psychiatric medications such as antidepressants or benzodiazepines, suggest that clinicians should be cautious when prescribing GLP‐1RAs to these populations. The potential for drug interactions and the heightened sensitivity of certain individuals to neuropsychiatric side effects warrant close monitoring of mental health in patients receiving GLP‐1RA therapy, particularly as these medications are increasingly prescribed for indications beyond diabetes management, including obesity and weight loss.

The strengths of the evidence included in this systematic review and meta‐analysis stem from the diversity of study designs, including observational cohort studies, and pharmacovigilance analyses. This wide range of data sources provides a comprehensive view of the potential neuropsychiatric effects of GLP‐1RAs. Additionally, the inclusion of real‐world data, such as studies utilising large pharmacovigilance databases such as FAERS and the WHO global database, allows for the identification of rare adverse events that may not be captured in clinical trials. Furthermore, the use of rigorous methodologies, such as adherence to PRISMA guidelines and the application of a random‐effects model in the meta‐analysis, enhances the robustness of the findings by accounting for between‐study variability.

There are notable limitations that affect the quality and reliability of the evidence. The substantial heterogeneity reported across the included studies (I² = 98%) highlights the significant variability in study populations, methodologies, and comparators, which might impact the reliability of the pooled effect estimate. While the high level of heterogeneity suggests considerable variation in the study results, a more detailed discussion on the potential sources of this heterogeneity, such as differences in study design, population characteristics, and outcome definitions, would enhance the interpretability of the findings. Additionally, many of the included studies relied on pharmacovigilance data, which are inherently prone to underreporting and reporting biases, particularly for rare adverse events such as suicidal ideation. Furthermore, the exclusion of individuals with a history of mental illness from most clinical trials introduces selection bias, potentially underestimating the true risk of neuropsychiatric events in vulnerable populations. Finally, the relatively small number of studies included in the meta‐analysis, combined with wide prediction intervals, adds to the uncertainty regarding the true relationship between GLP‐1RA use and suicidal ideation or behaviour.

In terms of implications for clinical practice, policy, and future research, these findings underscore the importance of individualised patient care. While no strong evidence links GLP‐1RA use to an increased risk of suicidality, clinicians should exercise caution when prescribing these medications to patients with co‐existing psychiatric conditions. Close monitoring of mental health, particularly in individuals taking concurrent psychiatric medications, is warranted. The potential neuroprotective benefits of GLP‐1RAs, as suggested by some studies, highlight the need for further exploration of these drugs' effects on mood and cognition. For policy, regulatory bodies such as the FDA and EMA should continue to monitor post‐marketing safety data related to GLP‐1RAs, particularly as their use expands to broader populations for obesity and weight loss treatment. Updated clinical guidelines could include recommendations for screening patients with a history of psychiatric disorders before initiating GLP‐1RAs and advice on the importance of monitoring mental health during treatment.

Future research should focus on large‐scale, well‐designed longitudinal studies that include populations with psychiatric comorbidities to better understand the long‐term neuropsychiatric effects of GLP‐1RAs. Mechanistic studies investigating how GLP‐1RAs interact with the central nervous system (CNS) and their potential impact on mood and cognition will be crucial to further clarify their safety profile. Given the complexity of the relationship between metabolic and neuropsychiatric factors, future studies should also consider the potential influence of rapid weight loss, neuroinflammation, and metabolic improvement on mental health outcomes in patients using GLP‐1RAs.

This systematic review and meta‐analysis found no statistically significant association between GLP‐1RA use and increased risk of suicidal ideation or behaviour. However, substantial heterogeneity across studies and limitations inherent to pharmacovigilance data necessitate cautious interpretation. While most evidence suggests GLP‐1RAs do not elevate suicidality risk and may offer mood benefits, isolated reports of neuropsychiatric side effects, particularly in patients with pre‐existing psychiatric conditions, warrant continued monitoring. Clinicians should remain vigilant when prescribing GLP‐1RAs, especially for vulnerable populations, and further research is essential to clarify their long‐term neuropsychiatric safety.

Conceptualisation: S.R., B.S.T., A.M.G.; Data curation: M.G., M.S., H.A.S., S.S.; Formal analysis: A.S.C., A.A., M.G.; Investigation: G.B., A.S.C., K.B., S.R.; Methodology: P.B., S.B.; Project administration: S.R., G.B.; Resources: N.U., M.P.S., M.N.K.; Software: S.S., M.G., A.S.C.; Supervision: S.R., M.S.; Validation: G.B., H.A.S., S.S., M.R.K., A.A.; Visualisation: A.S.C., K.B.; Writing–original draft: S.R., N.U., P.B.; Writing–review & editing: G.B., S.S., S.R., M.G.

The authors have nothing to report.

The authors declare no conflicts of interest.