Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts various physiological functions throughout the body, most notably in regulating blood glucose levels and controlling appetite [1]. Glucagon-like peptide-1 receptor agonist (GLP1RA) helps to regulate blood glucose levels by mimicking endogenous GLP-1 [2]. Semaglutide, originally developed for the treatment of diabetes, was approved by the FDA on 4 June 2021 as a weight-loss medication due to its ability to activate glucagon-like peptide-1 receptor (GLP1R) in the central nervous system [3], reducing food intake and promoting weight loss [4]. With advancements in research, GLP-1 has demonstrated promising potential in areas like cardioprotection and neuroprotection [5], generating significant interest in its effects beyond lowering of glucose and weight reduction.

Mental illnesses refer to a group of severe disorders that lead to brain dysfunction, causing significant public health concerns worldwide [6]. Affecting approximately 18% of the global population [7], they contribute to substantial mortality and economic burden [7,8]. Affected individuals experience disturbances in mood, cognition, or behavior. Mood improvement was initially observed in diabetic patients treated with GLP1RA. A large-scale cohort study of 10,690 diabetes patients over 6 to 7 years found that GLP1RA users had a lower incidence of depressive and anxiety disorders compared to non-users [9]. This observation sparked interest in the potential use of GLP1RAs for managing mental illnesses. GLP1Rs are widely distributed in the brain and play a role in regulating neuronal function [5,10,11], synaptic plasticity [12], and neurotransmitter release [13]. Although evidence from preclinical studies and clinical trials remains limited, liraglutide has been shown to improve executive function and memory in patients with major depressive disorder and bipolar disorder [14] as well as memory in individuals with prediabetes or early-stage type 2 diabetes and obesity [15]. In animal models, GLP1RAs have been found to enhance neurogenesis and regulate stress response circuits associated with mood disorders [16]. In addition, GLP1RAs have also demonstrated anti-inflammatory and antioxidant properties [13], which may offer potential benefits for a variety of mental illnesses. Overall, emerging evidence suggests that GLP1RA may have neuropsychiatric benefits. However, there is currently no direct evidence confirming the neuropsychiatric effects of GLP1RA in humans, and high-quality randomized controlled trials (RCTs) are still lacking. Most existing findings come from observational studies, and further research is still in its early stages. Recently, an observational study with a cohort of up to 2.4 million participants systematically examined the association between GLP1RAs and 175 health outcomes [17]. This study stands as the most extensive investigation of GLP1RAs to date. We took particular interest in the section on mental illnesses and found that the study reported that GLP1RA may reduce the risk of alcohol use disorder (AUD), cannabis use disorder (CUD), schizophrenia (SZ), and other mental health outcomes. Establishing a causal link between GLP1RAs and mental illness management could pave the way for new clinical indications. Equally important is the need to assess the potential psychiatric risks associated with long-term GLP1RA use. Therefore, further exploration of the causal relationships and underlying mechanisms between GLP1RAs and psychiatric disorders is warranted.

Mendelian randomization (MR) is a genetic study that assesses causal relationships between exposure and outcome [18]. Observational studies are often subject to biases such as confounding and reverse causation. In contrast, MR prevents these biases by utilizing the random allocation of genetic variants from parents to offspring during conception, thereby offering robust causal inference capabilities [19]. Based on rigorous instrumental variable selection procedure, drug target MR uses genetic variants to simulate the agonistic effects of drug targets, helping to evaluate their long-term exposure impact on diseases [20,21]. By selecting outcomes of interest, it can be used to study the potential efficacy and safety of new drug targets [22,23] as well as to explore the repurposing potential and adverse effects of existing drugs [20]. When RCTs are unavailable, drug target MR can provide high-level human genetic evidence to support drug repositioning and the identification of adverse effects [24]. We have observed that several MR studies have explored the associations between GLP1RA and conditions such as stroke, Alzheimer's disease, osteoarthritis, and cancer [25,26,27,28], contributing to a comprehensive evaluation of GLP1RA. Drug target MR can provide valuable insights into the clinical management of GLP1RA in relation to mental illnesses.

Overall, accumulating evidence suggests an association between GLP1RA and the risk of various mental illnesses, though the exact causal relationship remains unknown. In this context, we hypothesize that GLP1RA use may influence the risk of mental illness. This study aims to investigate the causal relationships between GLP1RA and 10 common mental illnesses: AUD, CUD, SZ, attention deficit and hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Specifically, we first perform drug-target MR analyses to examine the causal relationship between GLP1RA use and the aforementioned disorders. Additionally, for the identified causal relationships, we adopt MR mediation analysis to explore the potential mediating roles of glycemic control and weight management, which aids in understanding the underlying biological mechanisms of GLP1RA. This is the first systematic MR study investigating GLP1RA and the risk of mental illnesses. This research not only contributes to exploring the potential indications of GLP1RA but also provides valuable insights for assessing the risks of mental illnesses with their use.

The intriguing link between neuroscience and endocrinology holds the potential to lead to groundbreaking therapies for mental illnesses. In recent years, there has been an increasing interest in the effects of GLP1RA beyond their role in regulating blood glucose. Although observed improvements in mood among diabetic patients receiving GLP1RA therapy have offered valuable insights, the ultimate effects and underlying mechanisms remain unclear. In this study, we performed a robust Mendelian randomization analysis and systematically investigated for the first time the causal relationship between GLP1RA and the risk of 10 mental illnesses. We found that genetically proxied GLP1R activation was associated with a reduced risk of schizophrenia and further mediation analysis suggests that this effect might not be related to glucose control but mediated by BMI.

Cognitive impairment is a core feature of schizophrenia [29], with current antipsychotic therapies primarily addressing positive symptoms, while cognitive deficits remain largely unaddressed [30]. Currently, the clinical application of GLP1RAs in schizophrenia management has primarily focused on their role in weight regulation. When co-administered with antipsychotic medications such as lithium, clozapine, and olanzapine, GLP1RAs have demonstrated the ability to mitigate metabolic disturbances and prevent cognitive deterioration [31]. However, research exploring the cognitive-enhancing effects of GLP1RA remains scarce and is predominantly confined to preclinical studies. Preclinical evidence has shown that GLP1RA can substantially improve spatial learning and memory [32,33,34,35,36,37,38]. In murine models, liraglutide has been observed to prevent MK-801-induced schizophrenia-like behaviors [39]. These findings support the potential benefits of GLP1RA for schizophrenia. Notably, GLP1RA has also been shown to enhance cognitive function in models of diabetes and neurodegenerative diseases, such as Alzheimer's disease [40]. This suggests that GLP1RA may have a direct effect on cognitive function independent of glucose normalization. In summary, these results provide compelling evidence that targeting GLP1R may have a positive impact on the clinical management of schizophrenia. This finding is consistent with the conclusions of large-scale observational studies [17]. This MR study suggests that the use of GLP1RA is associated with a reduced risk of schizophrenia, and the evidence from the animal models supports the potential of GLP1R as a therapeutic target for schizophrenia. Despite the genetic evidence, further studies are needed to ultimately confirm these findings and investigate the underlying molecular mechanisms.

Mediation analysis suggests that the mechanism by which GLP1RA reduces the risk of schizophrenia is related to weight management. Some genome-wide cross-trait analysis uncovers a shared genetic architecture between schizophrenia and BMI, indicating a complex biological connection between them [41,42,43]. While the molecular pathways of GLP1RA signaling have been identified, the direct mechanisms by which they enhance cognitive processes remain unclear. Current research suggests that these mechanisms may involve biological processes such as promoting neurogenesis and synaptic plasticity, reducing neuroinflammation, enhancing insulin signaling, preventing neuronal apoptosis, and minimizing oxidative stress [44]. The mechanisms by which GLP1RA exerts potential benefits on schizophrenia through weight management remain unclear, but clues can be found in the pathophysiology of schizophrenia. Weight loss is commonly associated with reduced systemic inflammation, and neuroinflammation is considered a key factor in the pathogenesis of schizophrenia. One possible mechanism is that GLP1RA may reduce inflammation through weight loss, thereby offering protective effects on the nervous system. This hypothesis is plausible. In current clinical practice, obesity has been associated with adverse psychiatric outcomes in individuals with SZ [45,46]. It is important to note that current studies on the cognitive-improving effects of GLP1RA are mainly based on diabetes and Alzheimer's disease models. Future explorations of the mechanisms should focus more on schizophrenia models to better understand the potential therapeutic effects of GLP1RA.

Another contribution of this study is the lack of evidence for a causal relationship between GLP1RA and the risk of other mental disorders. GLP1RAs are demonstrating significant development potential, and clinical evidence reporting the long-term usage risks for mental disorders remains relatively scarce. It is important to evaluate them as comprehensively as possible. In our study, there was insufficient evidence to support a causal relationship between GLP1RA use and other mental illnesses. Although in the analysis with outcomes from PGC, GLP1RA use was associated with an increased risk of AN, and in the analysis with outcomes from FinnGen, GLP1RA use was associated with a reduced risk of ADHD, ASD, and PTSD, the meta-analysis failed to reach statistical significance. These findings will be regarded as "suggestive evidence" and may provide promising directions for future in-depth studies. We noted that larger research interests are primarily focused on anxiety, depression, eating disorders, and addictive disorders. Improvement in anxiety and depression is of particular interest. Preclinical studies have provided preliminary evidence for the antidepressant and anxiolytic properties of GLP1RA [47], and several clinical studies have reported improvements in depressive symptoms following GLP1RA treatment [48,49]. However, there is also evidence reporting the emergence of anxiety and depressive symptoms associated with the use of semaglutide [50,51]. There is even evidence from the FDA Adverse Event Reporting System (FAERS) suggesting that the use of semaglutide may be associated with an increased risk of suicidal ideation [52]. This makes the relationship between GLP1RA use and anxiety and depression unclear. Additionally, our study found suggestive evidence indicating an increased risk of anorexia nervosa. In contrast, liraglutide is considered a safe and effective treatment for bulimia nervosa and binge eating disorder [53]. These findings suggest the need for continued attention to the effects of GLP1RA use in the management of eating disorders. Another promising research direction for GLP1RA is their potential in controlling the risk of addiction disorders. An observational study involving 2.4 million people supports this [17], but as they pointed out in their discussion, "observational studies cannot establish causality". Currently, there is not enough investigation to determine the exact effects of long-term use. In fact, the conclusions of the vast majority of current studies on the above diseases come from observational research, which cannot establish causality. Research on the psychiatric benefits of GLP1RAs is still in its early stages. Therefore, as a result of a MR study, we recommend conducting more large-scale, long-term follow-up, multi-center randomized controlled trials in the future to validate all of our conclusions. This will contribute to drug repositioning of GLP1RAs and the prediction of adverse reactions, ultimately translating into clinical practice. After confirming the causal relationship, further investigation into the mechanisms is needed to distinguish whether the neuropsychiatric effects of GLP1RAs are direct or mediated through the improvement of the original indications (T2D and obesity). This distinction may be important, as it may reveal a unique therapeutic mechanism of GLP1RAs for mental illnesses.

Our study has several strengths. First, to our knowledge, this is the first study to apply drug target MR to systematically investigate the effects of GLP1RA on mental illnesses, offering stronger causal inference compared to traditional observational studies. Second, due to the differences in GLP1R expression between mice and humans, it is challenging to extend preclinical research findings to clinical trials [54]. Our analysis, based on large-scale human GWAS summary-level data, can provide more valuable insights beneficial to clinical practice. Finally, triangulation across multiple databases and the design of positive controls further improved the design of drug target MR. And meta-analysis helps to avoid potential biases.

However, it must be noted that, like other MR studies on drug targets, our conclusions are subject to several limitations. First, unlike drug administration in clinical practice, which typically occurs over a shorter timeframe, genetic variants used as proxies for drug effects represent lifelong cumulative effects of small-scale perturbations to the drug target [55]. This means that the odds ratios presented in this study cannot be directly used to guide clinical practice. In fact, estimates from genetic proxy analyses are generally smaller than those observed in clinical practice [56]. Furthermore, when larger scale tissue-specific eQTL data become available, it will be important to explore the relationship between GLP1RA and the risk of mental illness across more tissues for a more in-depth evaluation. The study population was limited to individuals of European ancestry, so caution is needed when generalizing the findings to other populations.

This MR study suggests that GLP1RAs are causally associated with a reduced risk of schizophrenia, providing genetic evidence for their use in the clinical management of schizophrenia. This neuropsychiatric benefit may be associated with weight management effects. Our findings may also provide valuable guidance for selecting weight-loss medications for overweight individuals at high risk of schizophrenia.