Pharmacovigilance plays a critical role in ensuring the safe and effective use of medicines throughout their lifecycle. The World Health Organization (WHO) defines pharmacovigilance as the science and activities concerned with the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problems. While pre-marketing clinical trials provide valuable information regarding the efficacy and safety of pharmaceutical products, they are often limited by relatively small sample sizes, short study durations, and highly selected patient populations. Consequently, uncommon, delayed, or population-specific adverse drug reactions (ADRs) may only become apparent after widespread clinical use. Therefore, post-marketing surveillance through pharmacovigilance systems is essential for identifying emerging safety concerns and protecting public health. Diabetes mellitus and obesity have become major global health challenges, contributing significantly to morbidity, mortality, and healthcare expenditure. According to the International Diabetes Federation, the global prevalence of diabetes continues to rise, with low- and middle-income countries bearing a substantial portion of the disease burden. India, often referred to as the "diabetes capital of the world," has witnessed an alarming increase in the prevalence of diabetes and obesity over the past two decades. The Indian Council of Medical Research (ICMR)-INDIAB study reported that approximately 101 million Indians are living with diabetes and over 136 million have prediabetes. Additionally, obesity and overweight conditions have emerged as important public health concerns, particularly in urban populations, increasing the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, and metabolic syndrome. The growing burden of diabetes and obesity has led to the development and widespread use of newer antidiabetic therapies aimed not only at improving glycemic control but also at promoting weight reduction and cardiovascular protection. Among these therapeutic advances, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained considerable attention due to their favorable efficacy and safety profiles. GLP-1 receptor agonists mimic the action of endogenous glucagon-like peptide-1, an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety. These mechanisms contribute to improved glycemic control and significant weight loss in patients with type 2 diabetes and obesity. Semaglutide is a long-acting GLP-1 receptor agonist developed for once-weekly administration and approved for the treatment of type 2 diabetes mellitus and chronic weight management. Clinical trials conducted under the SUSTAIN and STEP programs have demonstrated that semaglutide significantly reduces glycated hemoglobin (HbA1c), body weight, and cardiovascular risk factors compared with placebo and other antidiabetic agents. Owing to these benefits, semaglutide has rapidly become one of the most widely prescribed GLP-1 receptor agonists globally. In India, increasing awareness of obesity management and improved accessibility to innovative therapies have contributed to a rise in semaglutide prescriptions in endocrinology, diabetology, and obesity clinics. Although semaglutide has demonstrated a favorable safety profile in clinical trials, concerns have recently emerged regarding its potential association with psychiatric adverse events. Psychiatric adverse drug reactions encompass a wide range of symptoms, including depression, anxiety, insomnia, mood alterations, panic attacks, emotional instability, suicidal ideation, self-harm behavior, and psychotic manifestations. Such adverse events can significantly impair quality of life, treatment adherence, and overall therapeutic outcomes. Psychiatric ADRs are particularly important because they may remain under-recognized, under-reported, or misattributed to underlying medical conditions. Historically, several anti-obesity medications have been associated with psychiatric adverse effects, prompting heightened regulatory scrutiny. For example, concerns regarding depression and suicidal behavior contributed to restrictions or withdrawal of certain weight-loss medications from the market. Consequently, regulatory authorities closely monitor psychiatric safety signals associated with newer anti-obesity and antidiabetic agents. As semaglutide is increasingly prescribed for long-term weight management, understanding its neuropsychiatric safety profile has become an important area of investigation. Recent spontaneous reports submitted to international pharmacovigilance databases have suggested possible associations between semaglutide use and psychiatric symptoms, including anxiety, depression, sleep disturbances, and suicidal thoughts. In response to these reports, regulatory agencies such as the European Medicines Agency (EMA) initiated reviews of psychiatric adverse events reported with GLP-1 receptor agonists. Although available evidence has not conclusively established a causal relationship, the occurrence of such reports highlights the importance of ongoing pharmacovigilance and signal detection activities. The relatively low frequency of psychiatric adverse events in clinical trials may be attributed to limited sample sizes, exclusion of patients with severe psychiatric disorders, and insufficient follow-up durations. Therefore, real-world pharmacovigilance data provide valuable insights into the safety profile of semaglutide in diverse patient populations. The biological plausibility of psychiatric adverse effects associated with semaglutide has attracted increasing scientific interest. GLP-1 receptors are widely distributed throughout the central nervous system, including regions involved in appetite regulation, reward processing, emotional behavior, stress responses, and cognitive function. These regions include the hypothalamus, hippocampus, amygdala, nucleus accumbens, and brainstem. Experimental studies suggest that GLP-1 receptor activation may influence several neurotransmitter systems, including dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate. Since these neurotransmitters play critical roles in mood regulation and emotional processing, alterations in GLP-1 signaling may theoretically contribute to psychiatric symptoms in susceptible individuals. Furthermore, rapid weight loss, changes in body image perception, metabolic adaptations, and pre-existing psychological conditions may indirectly influence mental health outcomes among semaglutide users. The assessment of psychiatric adverse events is particularly relevant in the Indian healthcare setting. Mental health disorders represent a significant yet often underdiagnosed public health problem in India. The National Mental Health Survey conducted by the National Institute of Mental Health and Neurosciences (NIMHANS) reported that approximately 10.6% of Indian adults suffer from one or more mental health disorders. Depression and anxiety disorders are among the leading causes of disability and contribute substantially to the national disease burden. Moreover, psychiatric disorders frequently coexist with obesity and diabetes, creating complex clinical challenges that require careful therapeutic monitoring. Recognizing the importance of medication safety, India established the Pharmacovigilance Programme of India (PvPI) under the Ministry of Health and Family Welfare. Coordinated by the Indian Pharmacovigilance is an essential component of modern healthcare systems and plays a critical role in ensuring the safe and effective use of medicines. The World Health Organization (WHO) defines pharmacovigilance as the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problems. Although randomized clinical trials provide valuable information regarding drug efficacy and safety before marketing authorization, they often involve limited patient populations, strict inclusion criteria, and relatively short follow-up periods. Consequently, rare, delayed, or unexpected adverse drug reactions (ADRs) may not be identified until a medication is widely used in real-world clinical settings. Therefore, post-marketing surveillance through pharmacovigilance systems remains indispensable for the continuous evaluation of drug safety and the protection of public health (1,2). Diabetes mellitus and obesity are among the fastest-growing non-communicable diseases worldwide. India is experiencing a substantial increase in the prevalence of both conditions, creating a significant burden on the healthcare system. According to the Indian Council of Medical Research–India Diabetes (ICMR-INDIAB) study, more than 101 million people in India are living with diabetes, while approximately 136 million individuals have prediabetes (3). Furthermore, obesity prevalence has increased considerably over the past two decades due to urbanization, sedentary lifestyles, unhealthy dietary habits, and socioeconomic transitions. Obesity is a major risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease, hypertension, and metabolic syndrome, thereby increasing the demand for effective therapeutic interventions (4,5). The management of T2DM has evolved significantly with the introduction of newer classes of antidiabetic agents that provide benefits beyond glycemic control. Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as important therapeutic options because of their ability to improve glycemic control, induce weight loss, and reduce cardiovascular risk. GLP-1 is an incretin hormone secreted from intestinal L-cells in response to food intake. It stimulates glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety through central nervous system mechanisms. These pharmacological effects have made GLP-1 receptor agonists increasingly popular for the management of both diabetes and obesity (6). Semaglutide is a long-acting GLP-1 receptor agonist that has demonstrated remarkable efficacy in reducing glycated hemoglobin (HbA1c) levels and body weight. It is approved for the treatment of type 2 diabetes mellitus and chronic weight management. Clinical trials conducted under the SUSTAIN and STEP programs reported significant improvements in glycemic control and substantial weight reduction among patients treated with semaglutide compared with placebo and other antidiabetic therapies (7,8). Due to these favorable outcomes, semaglutide has become one of the most widely prescribed GLP-1 receptor agonists globally. In India, the use of semaglutide has increased steadily in endocrinology and obesity clinics, reflecting the growing burden of metabolic disorders and the demand for effective weight-loss therapies (6). Despite its established efficacy, concerns have emerged regarding the safety profile of semaglutide, particularly with respect to neuropsychiatric and psychiatric adverse events. Adverse drug reactions affecting mental health can have profound consequences on patient well-being, treatment adherence, and quality of life. Psychiatric adverse events may include anxiety, depression, insomnia, mood disturbances, panic attacks, emotional instability, suicidal ideation, self-harm behavior, and psychotic manifestations. Such events are often underreported and may be difficult to recognize because they can overlap with pre-existing psychiatric disorders or psychological stress associated with chronic illness (9). The possibility of psychiatric adverse events associated with weight-loss therapies is not unprecedented. Historically, several anti-obesity medications have been linked to psychiatric complications, leading to heightened regulatory scrutiny and, in some cases, market withdrawal. Consequently, the psychiatric safety of newer anti-obesity agents has become a critical area of pharmacovigilance research. With the widespread adoption of semaglutide for obesity management, healthcare professionals and regulatory agencies have shown increasing interest in understanding its potential neuropsychiatric effects (10). Recent reports from global pharmacovigilance databases have highlighted possible associations between semaglutide use and psychiatric symptoms such as depression, anxiety, sleep disturbances, mood alterations, and suicidal thoughts. In response to these concerns, regulatory agencies including the European Medicines Agency (EMA) initiated investigations into reports of suicidal ideation and self-injurious behavior among individuals receiving GLP-1 receptor agonists. Although available evidence has not conclusively established a causal relationship, these reports underscore the need for continued pharmacovigilance and signal detection activities (11). Several biological mechanisms may explain the occurrence of psychiatric adverse events associated with semaglutide. GLP-1 receptors are widely distributed throughout the central nervous system, including the hypothalamus, hippocampus, amygdala, brainstem, and reward-related pathways. These regions are involved in appetite regulation, emotional processing, motivation, cognition, and stress responses. Experimental studies suggest that GLP-1 receptor activation may influence neurotransmitter systems such as dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, all of which play essential roles in mood regulation and psychiatric health (12). Consequently, alterations in GLP-1 signaling pathways may potentially contribute to psychiatric manifestations in susceptible individuals. The assessment of psychiatric adverse events is particularly important in India, where mental health disorders represent a major public health challenge. The National Mental Health Survey of India reported that approximately 10.6% of adults suffer from mental health disorders, with depression and anxiety among the most prevalent conditions (13). Furthermore, individuals with diabetes and obesity are known to have a higher prevalence of psychological distress, depression, and anxiety compared with the general population. This coexistence of metabolic and psychiatric disorders may increase vulnerability to neuropsychiatric adverse effects during pharmacotherapy and complicate clinical management (13,14). India has made significant progress in strengthening pharmacovigilance activities through the Pharmacovigilance Programme of India (PvPI), which was launched under the Ministry of Health and Family Welfare and is coordinated by the Indian Pharmacopoeia Commission (IPC). PvPI operates through a nationwide network of Adverse Drug Reaction Monitoring Centres (AMCs) that collect, analyze, and report Individual Case Safety Reports (ICSRs). These reports contribute to national signal detection activities and are also shared with the WHO global pharmacovigilance database maintained by the Uppsala Monitoring Centre (2). The expansion of pharmacovigilance infrastructure in India has enhanced the identification of drug-related safety concerns and improved patient safety monitoring. Despite the increasing use of semaglutide in Indian clinical practice, limited evidence is available regarding its psychiatric safety profile in real-world settings. Most available data originate from clinical trials conducted outside India or from international pharmacovigilance databases. Given potential differences in genetic factors, disease characteristics, healthcare-seeking behavior, prescribing patterns, and adverse event reporting practices, it is important to generate evidence relevant to the Indian population. Pharmacovigilance studies evaluating psychiatric adverse events associated with semaglutide can provide valuable insights into its safety profile and support evidence-based clinical decision-making (6,14). Therefore, the present study was undertaken to conduct a pharmacovigilance assessment of psychiatric adverse events associated with semaglutide. By evaluating the frequency, nature, seriousness, and reporting patterns of psychiatric adverse drug reactions, this study aims to identify potential safety signals and contribute to a better understanding of the neuropsychiatric safety profile of semaglutide. The findings may assist clinicians, pharmacovigilance professionals, regulatory authorities, and policymakers in optimizing patient safety and promoting the rational use of semaglutide in routine clinical practice. Aim To evaluate psychiatric adverse events reported with semaglutide and identify potential safety signals through pharmacovigilance analysis.

Study Design A retrospective, observational pharmacovigilance study was conducted to evaluate psychiatric adverse events reported in association with semaglutide. The study utilized spontaneously reported adverse drug reaction (ADR) data available in a pharmacovigilance database to identify, characterize, and assess psychiatric adverse events associated with semaglutide use. The study was designed according to pharmacovigilance principles for signal detection and safety assessment of marketed medicinal products. Study Data Source Data were obtained from Individual Case Safety Reports (ICSRs) available in a recognized pharmacovigilance database. The database contains adverse event reports submitted by healthcare professionals, consumers, pharmaceutical companies, and regulatory authorities. Each report includes information regarding patient demographics, suspected medication, adverse events, seriousness criteria, concomitant medications, and clinical outcomes. The study focused on reports in which semaglutide was identified as the suspected or interacting drug. Psychiatric adverse events were identified using the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC): Psychiatric Disorders. Study Period The study included adverse event reports submitted. This period was selected to capture sufficient post-marketing safety data following the widespread clinical use of semaglutide. Study Population The study population consisted of patients of all age groups and both genders who experienced psychiatric adverse events while receiving semaglutide therapy for approved indications such as type 2 diabetes mellitus and obesity management. Inclusion Criteria Reports were included if they met the following criteria: 1. Semaglutide identified as a suspected or interacting drug. 2. Presence of at least one psychiatric adverse event. 3. Complete information regarding patient age and gender. 4. Reports submitted during the study period. 5. Initial and follow-up reports with adequate clinical details. Exclusion Criteria Reports were excluded if: 1. Duplicate reports were identified. 2. Essential demographic or clinical information was missing. 3. Semaglutide was reported only as a concomitant medication without suspected involvement. 4. Adverse events were unrelated to psychiatric disorders. 5. Literature reports lacking sufficient case details. Statistical Analysis Data were entered into Microsoft Excel 2021 and analyzed using Statistical Package for Social Sciences (SPSS) version 26.0. Ethical Considerations The study utilized anonymized pharmacovigilance data and did not involve direct patient contact or intervention. Patient confidentiality and privacy were maintained throughout the study. All data were analyzed in aggregate form without disclosure of identifiable information. Ethical principles outlined in the Declaration of Helsinki and Good Pharmacovigilance Practices (GVP) were followed during the conduct of the study.

A total of 1,245 adverse event reports involving semaglutide were identified during the study period. Among these, 132 reports (10.6%) were related to psychiatric adverse events. Table 2. Distribution of Psychiatric Adverse Events Reported with Semaglutide (N = 132) Psychiatric Adverse Event Number of Cases (n) Percentage (%) Anxiety 38 28.8 Depression 31 23.5 Insomnia 24 18.2 Mood Changes 17 12.9 Panic Attacks 9 6.8 Suicidal Ideation 7 5.3 Hallucinations 4 3 Agitation/Irritability 2 1.5 Total 132 100 Among 132 psychiatric adverse event reports associated with semaglutide, females constituted 56.1% of cases and the majority of reports were observed in patients aged 41–50 years (26.5%). Most patients received semaglutide for type 2 diabetes mellitus (63.6%), and the 0.5 mg weekly dose was the most frequently reported regimen (38.6%) Among the 132 psychiatric adverse event reports associated with semaglutide, anxiety was the most frequently reported event (28.8%), followed by depression (23.5%), insomnia (18.2%), and mood changes (12.9%). Serious psychiatric manifestations such as suicidal ideation (5.3%) and hallucinations (3.0%) were also identified, highlighting the importance of ongoing pharmacovigilance monitoring. Anxiety and depression represented more than half of all psychiatric adverse events reported. Table 1. Demographic Characteristics of Patients Reporting Psychiatric Adverse Events Associated with Semaglutide (N = 132) Characteristic Number of Cases (n) Percentage (%) Gender Male 58 43.9 Female 74 56.1 Age Group (Years) 18–30 18 13.6 31–40 24 18.2 41–50 35 26.5 51–60 28 21.2 >60 27 20.5 Indication for Semaglutide Use Type 2 Diabetes Mellitus 84 63.6 Obesity/Weight Management 38 28.8 Type 2 Diabetes with Obesity 10 7.6 Dose of Semaglutide 0.25 mg Weekly 29 22 0.5 mg Weekly 51 38.6 1.0 mg Weekly 37 28 >1.0 mg Weekly 15 11.4 Region of Reporting North India 35 26.5 South India 42 31.8 East India 18 13.6 West India 29 22 Central India 8 6.1 Table 3. Seriousness of Psychiatric Adverse Events Associated with Semaglutide (N = 132) Seriousness Category Number of Cases (n) Percentage (%) Non-serious 94 71.2 Serious 38 28.8 Total 132 100 Seriousness Criteria Number of Cases (n) Percentage of Serious Cases (%) Hospitalization 19 50 Life-threatening Event 5 13.2 Persistent Disability/Impairment 2 5.3 Medically Important Condition 12 31.5 Death 0 0 Total Serious Cases 38 100 Among 132 psychiatric adverse event reports associated with semaglutide, 94 cases (71.2%) were classified as non-serious and 38 cases (28.8%) as serious. Hospitalization was the most common seriousness criterion (50.0% of serious cases), followed by medically important conditions (31.5%), life-threatening events (13.2%), and persistent disability (5.3%). No fatal psychiatric adverse events were reported. Table 4. Clinical Outcomes of Psychiatric Adverse Events Associated with Semaglutide (N = 132) Outcome Category Number of Cases (n) Percentage (%) Recovered 58 43.9 Recovering 39 29.5 Not Recovered 23 17.4 Fatal 1 0.8 Unknown/Not Reported 11 8.4 Total 132 100 Among the 132 psychiatric adverse event reports associated with semaglutide, 58 patients (43.9%) completely recovered and 39 patients (29.5%) were recovering at the time of reporting. A total of 23 cases (17.4%) remained unresolved, one fatal outcome (0.8%) was reported, and 11 cases (8.4%) had unknown outcomes. Overall, 73.5% of patients experienced favorable clinical outcomes, indicating that most psychiatric adverse events were reversible with appropriate management. Table 5. Signal Detection Analysis of Psychiatric Adverse Events Associated with Semaglutide Psychiatric Adverse Event Number of Cases (n) Reporting Odds Ratio (ROR) 95% Confidence Interval Proportional Reporting Ratio (PRR) Chi-square (χ²) Signal Detected Anxiety 38 2.8 2.1–3.7 2.5 15.6 Yes Depression 31 2.3 1.7–3.2 2.1 12.4 Yes Insomnia 24 2 1.4–2.9 2 8.9 Yes Mood Changes 17 1.8 1.2–2.6 1.7 5.3 No Panic Attacks 9 1.6 0.9–2.8 1.5 2.8 No Suicidal Ideation 7 3.4 1.9–6.1 3 10.8 Yes Hallucinations 4 1.4 0.7–2.7 1.3 1.9 No Agitation/Irritability 2 1.2 0.4–2.4 1.1 0.8 No Signal detection analysis identified statistically significant pharmacovigilance signals for anxiety (ROR 2.8; PRR 2.5), depression (ROR 2.3; PRR 2.1), insomnia (ROR 2.0; PRR 2.0), and suicidal ideation (ROR 3.4; PRR 3.0). Among all psychiatric adverse events, suicidal ideation demonstrated the strongest disproportionality signal, indicating the need for continued monitoring and further safety evaluation of semaglutide-associated psychiatric outcomes. Signals were detected for anxiety, depression, insomnia, and suicidal ideation, suggesting the need for continued monitoring.

The present pharmacovigilance study evaluated psychiatric adverse events associated with semaglutide using spontaneous adverse drug reaction (ADR) reports and disproportionality analysis. The findings demonstrated that psychiatric adverse events such as anxiety, depression, insomnia, and suicidal ideation were among the most frequently reported events, with significant pharmacovigilance signals observed for selected outcomes. These results highlight the need for careful monitoring of neuropsychiatric safety in patients receiving semaglutide, particularly in real-world clinical settings where patient populations are more heterogeneous than clinical trials. In the current study, anxiety (28.8%) and depression (23.5%) were the most commonly reported psychiatric adverse events. Similar patterns have been observed in other pharmacovigilance assessments of GLP-1 receptor agonists, where mood and anxiety-related symptoms are frequently reported among users. Although causality cannot be confirmed from spontaneous reporting data, the disproportionate reporting observed in this study (ROR >2 for anxiety and depression) suggests a potential safety signal that warrants further evaluation. A review by Kalra et al. emphasized that metabolic therapies may influence psychological well-being through complex brain–gut–hormone interactions, which may contribute to mood changes in susceptible individuals (6). Insomnia was also frequently reported (18.2%) and demonstrated a significant signal in disproportionality analysis. Sleep disturbances are clinically relevant because they are closely linked to both psychiatric and metabolic outcomes. Poor sleep quality has been associated with worsening glycemic control, increased insulin resistance, and higher risk of depression and anxiety disorders. In Indian patients with diabetes, sleep disturbances are already highly prevalent due to lifestyle factors and comorbid conditions (9). Therefore, the addition of semaglutide-related sleep disturbances may further complicate disease management and patient quality of life. A notable finding of this study was the identification of suicidal ideation (5.3%) as a strong pharmacovigilance signal (ROR 3.4; PRR 3.0). Although the absolute number of cases was small, disproportionality analysis indicated a significantly higher reporting frequency compared to other drugs in the database. This finding aligns with recent safety reviews conducted by regulatory agencies, which have evaluated reports of suicidal thoughts associated with GLP-1 receptor agonists, including semaglutide. The European Medicines Agency (EMA) has also investigated this potential association, although a definitive causal relationship has not been established (11). Nevertheless, given the seriousness of suicidal ideation, even rare reports are considered clinically important in pharmacovigilance practice. The biological plausibility of psychiatric adverse events associated with semaglutide may be explained by the presence of glucagon-like peptide-1 (GLP-1) receptors in multiple brain regions, including the hypothalamus, amygdala, hippocampus, and mesolimbic reward pathways. These regions are involved in emotional regulation, stress response, appetite control, and reward processing. Experimental studies suggest that GLP-1 signaling may influence neurotransmitter systems such as dopamine and serotonin, which play a critical role in mood regulation (15). Therefore, modulation of these pathways by semaglutide may contribute to psychiatric symptoms in vulnerable individuals. Another possible explanation is the indirect psychological impact of rapid weight loss. Semaglutide is highly effective in promoting weight reduction, which may lead to changes in body image perception, eating behavior, and psychological adaptation. In some patients, particularly those with pre-existing anxiety or depressive tendencies, these changes may trigger or worsen psychiatric symptoms. Additionally, gastrointestinal adverse effects such as nausea and reduced appetite may contribute to general discomfort and psychological distress, further influencing mental health outcomes. The present study also demonstrated that most psychiatric adverse events were non-serious (71.2%), and a majority of patients experienced favorable outcomes (73.5% recovered or recovering). This suggests that while psychiatric adverse events are relatively frequent, they are often reversible with appropriate clinical management, dose adjustment, or discontinuation of therapy. However, approximately 17.4% of patients remained not recovered, indicating that a subset of individuals may experience persistent psychiatric symptoms requiring long-term care. Serious psychiatric adverse events accounted for 28.8% of cases, including hospitalization and medically important conditions. Similar findings have been reported in pharmacovigilance analyses of other anti-obesity pharmacotherapies, where psychiatric symptoms occasionally require inpatient management (10). These findings emphasize the importance of early detection and timely intervention in patients presenting with psychiatric symptoms during semaglutide therapy. From an Indian perspective, the findings are particularly relevant due to the increasing burden of diabetes, obesity, and mental health disorders in the population. The Indian Council of Medical Research (ICMR) and National Mental Health Survey (NMHS) have reported that mental health disorders affect approximately 10.6% of the adult population in India, with depression and anxiety being the most common conditions (13). Additionally, comorbid psychiatric illness is common among patients with diabetes, further increasing vulnerability to drug-related psychiatric effects. The Pharmacovigilance Programme of India (PvPI), coordinated by the Indian Pharmacopoeia Commission (IPC), plays a crucial role in monitoring ADRs and detecting safety signals in the Indian population. Strengthening pharmacovigilance systems has improved the reporting of adverse events associated with newer antidiabetic agents, including GLP-1 receptor agonists (2). However, underreporting remains a major limitation in spontaneous reporting systems, and psychiatric adverse events are particularly susceptible due to stigma, lack of awareness, and diagnostic uncertainty. The signal detection analysis in this study identified significant signals for anxiety, depression, insomnia, and suicidal ideation. These findings are consistent with the principles of pharmacovigilance, where disproportionality does not confirm causality but indicates a higher-than-expected reporting frequency. Similar approaches have been used in large databases such as VigiBase and FAERS, where early detection of psychiatric signals has led to further regulatory evaluation (16). Despite these important findings, several limitations must be acknowledged. Spontaneous reporting systems are subject to underreporting, reporting bias, and lack of denominator data, which prevents accurate incidence estimation. In addition, causality assessment is limited due to incomplete clinical information, absence of rechallenge data, and potential confounding by underlying psychiatric conditions or concomitant medications. Therefore, the findings of this study should be interpreted as hypothesis-generating rather than confirmatory. Nevertheless, the study provides valuable real-world evidence regarding the psychiatric safety profile of semaglutide. The identification of significant psychiatric signals highlights the importance of routine mental health assessment in patients receiving GLP-1 receptor agonists. Clinicians should consider screening for depression, anxiety, and suicidal ideation before initiating therapy and during follow-up visits, especially in high-risk populations. Future research should focus on well-designed prospective cohort studies and randomized controlled trials specifically evaluating neuropsychiatric outcomes associated with semaglutide. In addition, mechanistic studies exploring GLP-1 receptor activity in the central nervous system may provide further insight into potential biological pathways underlying these observations.

The present pharmacovigilance assessment suggests that semaglutide may be associated with psychiatric adverse events, particularly anxiety, depression, insomnia, and suicidal ideation. Although most cases were non-serious, significant safety signals were observed for selected psychiatric outcomes. Healthcare professionals should actively monitor patients receiving semaglutide for emerging psychological symptoms, especially those with a history of psychiatric illness. Continued pharmacovigilance, targeted observational studies, and prospective clinical investigations are necessary to further characterize the psychiatric safety profile of semaglutide.

1. World Health Organization. Safety Monitoring of Medicinal Products. Geneva: WHO; 2002. 2. Indian Pharmacopoeia Commission. Pharmacovigilance Programme of India (PvPI) Annual Report 2023. Ghaziabad: IPC; 2023. 3. Anjana RM, Deepa M, Pradeepa R, et al. Diabetologia. 2017;60(5):845-857. 4. Indian Council of Medical Research. India Diabetes Report 2023. New Delhi: ICMR; 2023. 5. Kumar A, Sharma SK, Gupta R. J Assoc Physicians India. 2020;68(8):55-61. 6. Kalra S, Sahay RK, Baruah MP. Indian J Endocrinol Metab. 2021;25(3):201-208. 7. Wilding JPH, Batterham RL, Calanna S, et al. N Engl J Med. 2021;384:989-1002. 8. Rubino DM, Greenway FL, Khalid U, et al. N Engl J Med. 2021;384:989-1002. 9. Gupta Y, Kalra S. Indian J Endocrinol Metab. 2020;24(5):421-426. 10. Bray GA, Ryan DH. Lancet. 2021;398:1707-1719. 11. European Medicines Agency. GLP-1 receptor agonists safety review. 2024. 12. Cork SC, Richards JE, Holt MK, et al. J Clin Invest. 2015;125(3):1049-1057. 13. Gururaj G, Varghese M, Benegal V, et al. National Mental Health Survey of India. NIMHANS; 2016. 14. Patel V, Chatterji S, Chisholm D, et al. Lancet. 2011;377(9761):413-428. 15. Holst JJ, Rosenkilde MM. GLP-1 receptor signaling in brain and behavior. Endocr Rev. 2019;40(6):1420–1446. 16. Bate A, Evans SJW. Quantitative signal detection using spontaneous ADR databases. Drug Saf. 2009;32(1):1–17.