Association of semaglutide use with depressive symptoms and suicidal behavior in a patient with type 2 diabetes: A case report

Abstract

Semaglutide is a glucagon-like peptide-1 receptor agonist used in the treatment of type 2 diabetes mellitus and management of obesity. Associations of glucagon-like peptide-1 receptor agonist use with psychiatric adverse events and suicidal behavior have been reported. A man in his late 70s with type 2 diabetes and no history of psychiatric illness or cognitive deficits was admitted to our clinic after his first suicide attempt involving the impulsive ingestion of brush cleaner liquid. A month before his presentation, he reported restlessness and depressive mood without any apparent trigger. This period was consistent with the time of semaglutide introduction. His psychiatric symptoms improved after semaglutide discontinuation. This case report highlights the importance of regular monitoring of depression and anxiety symptoms and the possibility of suicidal ideation in individuals with type 2 diabetes treated with semaglutide. This may enable early detection and prevention of serious psychiatric adverse events.

Background

Semaglutide is one of the recently discovered glucagon-like peptide-1 receptor agonists (GLP-1 RAs) used to improve glycemic control, promote weight loss, and reduce cardiovascular risk.^1–4 Several studies have reported serious psychiatric adverse events (e.g. suicide, suicide ideation, and self-injury) associated with GLP-1 RAs, including semaglutide. These events have been reported in the Food and Drug Administration Adverse Event Reporting System, with mixed results regarding the association of semaglutide use with psychiatric symptoms.^1,5–8 The most commonly reported event was depression (50.3%), followed by anxiety (38.7%) and suicidal ideation (19.6%). ⁷ In the literature, only two case reports have been published describing possible depressive symptoms associated with semaglutide.^9,10 We report the case of an older diabetic patient with no psychiatric history who developed depressive symptoms and made a serious suicide attempt after semaglutide introduction. Written informed consent for article publication was obtained from the patient. No ethical approval was sought, as the informed consent was obtained after the symptoms resolved, and the patient had no other symptoms that would affect his judgment. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹¹

Case presentation

A Caucasian man in his late 70 s attempted suicide by ingesting 200 mL of brush cleaner liquid containing ethylene glycol in April 2024. The patient was comatose with marked drowsiness; however, there was no other focal neurological abnormality. He was initially admitted to the Neurological Emergency Department. Laboratory results indicated a high blood alcohol level of 0.22%. Subsequent analysis of blood and urine samples revealed the presence of ethylene glycol. No other abnormalities were detected in the blood or urine laboratory tests. Head computed tomography revealed only mild chronic ischemic leukopathy in the periventricular region. After 48 h, he regained consciousness and agreed to be transferred to the acute inpatient unit of the University Psychiatric Clinic Ljubljana. Upon admission, he was alert, well-oriented, calm, and cooperative. He displayed depressed facial expressions and posture; moreover, he expressed regret over the suicide attempt. He signed an informed consent for admission and treatment at the acute inpatient unit. The day after the admission, a thorough clinical interview was conducted. He reported exacerbation of distress, anxiety, depressive mood, and insomnia that had started 3 weeks ago with no identifiable stress trigger. He described the attempt as impulsive and denied having any previous or current suicidal ideations or plans. A thorough diagnostic process was planned. The patient’s Geriatric Depression Scale (GDS) score was 21/30, his Modified SAD PERSONS Scale score was 4, and the Columbian Suicide Severity Rating Scale (C-SSRS) showed high risk for suicidal behavior.^12–14 The Mini-Mental State Examination score was 28/30. ¹⁵ A week later, he underwent neuropsychological testing, which revealed the presence of depressive and anxiety symptoms; however, no cognitive deficits were identified. Brain magnetic resonance imaging showed mild global cortical atrophy and mild chronic microangiopathy, which are typical findings for this age group.

The patient had a known medical history of hyperlipidemia, arterial hypertension, benign prostatic hypertrophy, and type 2 diabetes. He was living with his wife and had retired 15 years ago. He denied having experienced any recent stressful event. There was no prior record of mental health issues, and there was no family history of cognitive or mental disorders. He also denied regular alcohol or tobacco use. His family members corroborated his statements.

The patient’s medications are listed in Figure 1 (rosuvastatin (10 mg), losartan (50 mg), doxazosin (4 mg), metformin (500 mg BID), gliclazide (60 mg), and semaglutide (3 mg)). Semaglutide (3 mg) was introduced 4 weeks before the suicide attempt for managing his type 2 diabetes.

Figure 1.

Timeline of patient’s symptoms and medications.

Sertraline was introduced to control his depressive symptoms, and quetiapine was temporarily used for the treatment of insomnia. Four days after admission, the patient’s sleep was restored, and he reported reduced anxiety levels. Additionally, a repeat C-SSRS assessment revealed a low risk of suicidal ideations. Following this, the patient was transferred to an open ward, where he participated in group and individual therapies. He was discharged 2 weeks later. Nine days after the suicide attempt and throughout the rest of the hospitalization, the patient exhibited no symptoms of depression or anxiety, indicated by a GDS score of 6/30.

The introduction of semaglutide for the treatment of type 2 diabetes appeared to be the sole apparent trigger for the onset of anxiety and depressive symptoms, which ultimately led to the suicide attempt. Consequently, the medication was discontinued. The patient was discharged with a prescription of sertraline (50 mg). He is currently in a state of stable remission.

Discussion

Several recent reports have published mixed results regarding the association of semaglutide use with suicidal behavior.^6–8 According to recent data, semaglutide has been associated with twice the number of suicidal events compared with exenatide and dulaglutide. Moreover, 50% of all suicidal events occurred during the period of semaglutide prescription, representing 24.3% of all semaglutide-related psychiatric adverse event reports.^6,7 A large community-based cohort study on patients with obesity demonstrated a significant correlation between GLP-1 RA treatment (semaglutide and liraglutide) and an augmented risk of psychiatric disorders, with a 98% increased risk observed. The risk was found to be pronounced for major depressive disorder (195% higher risk), anxiety (108% higher risk), and suicidal behavior (106% higher risk). ¹⁶ However, a retrospective study by Wang et al. concluded that the use of semaglutide resulted in a lower risk of new and recurrent suicidal ideation than that of non-GLP-1 RA anti-obesity and type 2 diabetes medications. The lower risk association with semaglutide use remained consistent despite observed differences in patient characteristics between the overweight/obesity and type 2 diabetes groups. ⁸ Furthermore, patients with type 2 diabetes who were treated with GLP-1 RA exhibited a lower risk of suicide attempts than those treated with dipeptidyl peptidase-4 inhibitors. ¹⁷ In the real-world setting, only a limited number of cases regarding mood symptoms and the use of semaglutide have been reported. Li et al. reported two cases of depression; the first case involved a 54-year-old man with no history of mood disorders who was prescribed semaglutide for weight management, and the second case involved a 40-year-old woman with a history of depression who was prescribed semaglutide for diabetes management. ⁹ In these cases, depressive symptoms emerged 1 and 2 months after semaglutide initiation, respectively, and improved within 2 weeks of medication discontinuation. Manoharan and Madan reported the case of a 54-year-old woman with a history of depression. Her depressive symptoms reemerged after starting semaglutide for diabetes management and improved after discontinuing the medication. ¹⁰ Semaglutide stimulates insulin release, suppresses glucagon secretion, slows gastric emptying, and promotes satiety. ¹⁸ This medication can modulate the activity of different neural pathways, including the reward system. By stimulating the GLP-1 receptor, semaglutide increases the expression of dopamine transporter and reduces free dopamine in the synapses of the lateral septum and striatal brain. ⁹ Furthermore, the reduction of dopamine in the reward system can cause depressive symptoms. ⁹ Semaglutide has a half-life of 7 days. ⁴ After reviewing our patient’s medical records, the only common denominator for depressive symptoms and the subsequent suicide attempt was the introduction of semaglutide. Semaglutide was discontinued after the suicide attempt, and depressive symptoms resolved 9 days later. We speculated that within these 9 days, the concentration of semaglutide in the body decreased to the level that it no longer affected his mood. This finding is in line with that of previous case reports, which have reported symptom improvement within 2 weeks of semaglutide discontinuation.^9,10 According to the Naranjo adverse drug reaction probability scale score of 6, a probable causality between semaglutide use and depressive symptoms with suicidal behavior has been indicated. ¹⁹ A rechallenge was deemed unethical due to the seriousness of the adverse events.

Late-life depression (LLD) is a prevalent mental disorder among the older population, with an estimated prevalence of up to 32%.^20,21 It is associated with factors including cardiovascular and neurodegenerative diseases as well as immune, genetic, psychosocial, and other factors. ²² The diagnosis of LLD is made as per the diagnostic criteria for major depressive disorder. ²³ However, some clinical entities of LLD differ from adult depression, such as LLD secondary to concomitant substance or medication use and depressive symptoms with co-existing cognitive impairments.^20,22 The patient’s medical history included cardiovascular factors linked to LLD, such as hypercholesterolemia, hypertension, and type 2 diabetes. Additionally, the patient exhibited symptoms of major depressive disorder that lasted for more than 2 weeks (including depressed mood, increased distress, restlessness, insomnia, and a suicide attempt), resulting in clinically significant distress.^22,23 A diagnostic process excluded a history of episodes of mood disorders and treatable medical disorders that could mimic depression. The levels of C-reactive protein, vitamin B12, vitamin D3, and folate were normal. A neuropsychological test ruled out cognitive impairment, and there were no moderate or severe white matter hyperintensities on brain imaging, which could be indicative of cerebral small vessel disease, a typical feature of vascular depression.^21,22 Nevertheless, depressive symptoms were observed in the patient; thus, sertraline was initiated. The added effect of sertraline (50 mg) and quetiapine (25 mg) per day may have contributed to the improvement in mood symptoms. However, the effect of sertraline may not have manifested within such a brief period. Considering all the data, especially the consistent timeframe of depressive symptoms and semaglutide introduction, the possible effect of semaglutide discontinuation cannot be neglected.

Older age is a risk factor for suicidal behavior, and the prevalence of suicide increases progressively with aging. ²⁴ Slovenia has an average suicide rate of 19 per 100,000 inhabitants, with the highest rate observed among older adults aged 80–84 years. In men, the suicide risk is up to 5 times higher than that in women; moreover, men tend to use more dangerous suicide methods (e.g. poisoning and violent means).^25,26 In addition to sex, depressive episode severity and psychiatric comorbidity (e.g. anxiety and substance use disorders) represent the most important risk factors for late-life suicidal behavior.^26,27 Other risk factors for suicide in older individuals include dependency on others, living alone, bereavement, and pain.^26,28 In the present case, the patient had no known risk factors for suicide before the introduction of semaglutide, except for sex and age. Thus, following a serious suicide attempt and the onset of depressive symptoms, a series of regular outpatient visits were scheduled to reduce the risk of recurrence of depressive symptoms and suicidal behavior.

Conclusions

Considering current evidence, it is not possible to draw definitive conclusions regarding the causality between semaglutide and depressive symptoms. However, we emphasize the importance of regular monitoring of potential mood symptoms and suicidal ideation in patients with type 2 diabetes initiated on semaglutide. This could prevent the development of severe mood symptoms and suicidal behavior.

Author contributions

A.S. wrote the manuscript. P.R.P. reviewed and edited the manuscript and assisted with case identification. A.K.P. reviewed the manuscript and assisted with manuscript and figure production.

Consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data in this report.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

Not applicable.

Funding

None.