Analysis of Psychiatric Adverse Events for Semaglutide, Liraglutide, and Tirzepatide Reported to the EudraVigilance Database

doi:10.21203/rs.3.rs-3419258/v1

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Research Article

Analysis of Psychiatric Adverse Events for Semaglutide, Liraglutide, and Tirzepatide Reported to the EudraVigilance Database

https://doi.org/10.21203/rs.3.rs-3419258/v1

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Journal Publication

published 24 Jan, 2024

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Background

Weight reduction is essential for improving health in people with obesity and type 2 diabetes mellitus. Semaglutide, liraglutide, and tirzepatide are glucagon-like peptide-1 receptor agonists that are effective for weight management in conjunction with behavioral changes.

Aim

To identify and analyse the occurrence and the outcome of psychiatric adverse events associated with semaglutide, liraglutide, and tirzepatide.

Methods

All individual case safety reports (ICSR) for semaglutide, liraglutide, and tirzepatide reported to the EudraVigilance database from 01/01/2021 to 5/30/2023 were analysed. Descriptive statistics were used to describe the study population characteristics. Differences in proportions between the groups were compared using the chi-square test.

Results

During the study period, 31,444 adverse events reports were identified: semaglutide (n = 13,956, 44.4%), liraglutide (n = 16,748, 53.2%), and tirzepatide (n = 740, 2.3%). There were 372 reports with psychiatric adverse events reports (n = 372, 1.18%) with a total of 481 adverse events. Women accounted for 65% (n = 242) of these reports. Depression was the most commonly reported adverse event (n = 187, 50.3%), followed by anxiety (n = 144, 38.7%) and suicide ideation (n = 73, 19.6%). Nine deaths (8 with liraglutide and 1 with semaglutide), and 11 life-threatening outcomes (4 associated with liraglutide and 7 with semaglutide) were reported. The fatal outcomes occurred primarily among men (8 out of 9), resulting from completed suicidal attempts and depression.

Conclusion

Psychiatric adverse events comprised only 1.2% of the total reports for semaglutide, liraglutide, and tirzepatide; however, the severity and fatal outcomes of some of these reports warrant further study.

suicide

anxiety

depression

semaglutide

liraglutide

tirzepatide

Psychiatric adverse events appear to be a potential concern with semaglutide, liraglutide, and tirzepatide, but their true risk is unknown. Therefore, endocrinologists and psychiatrists should monitor and assess the emotional and mental status of patients before and after using these anti-obesity medications.
The decision to start drug therapy for obesity should be made on a case-by-case basis after weighing the risks and benefits. It is essential to set clear treatment goals and consider the patient's preferences and tolerability, as these can significantly impact patients' adherence.
Practicing vigilance and proper clinical management for the three GLP-1 anti-diabetic and anti-obesity medications and continuing to report adverse events is essential.
Neuropsychiatric safety should be a key consideration in any randomized clinical trial and clinical risk-benefit assessment associated with GLP1 anti-obesity medications, and the data provided here contribute to thoughtful and objective decision-making and dialogue between patients and clinicians.

Obesity is a global health challenge, with few pharmacologic available options for treatment. Weight reduction is undoubtedly essential for improving the outcome for people with obesity and type 2 diabetes mellitus (T2DM) [1]. The Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medicines that mimic the effects of GLP-1 to regulate blood sugar levels, including stimulating insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. They bind to the GLP-1 receptor on cells in the pancreas and gut and are used to treat type 2 diabetes and obesity [2–5].

Semaglutide, liraglutide, and tirzepatide are injectable GLP-1RA drugs that act as GLP-1 receptor agonists [6–9]; however, tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist that combines the actions of both incretin hormones into a single molecule [7]. All three drugs exhibit significant weight loss effects in patients with obesity or who are overweight with comorbidities in various clinical trials; however, tirzepatide has superior weight loss potential compared with semaglutide or liraglutide [6–9].

The FDA first approved liraglutide in 2010 for the treatment of type 2 diabetes. In 2014, it was also approved for the treatment of obesity, whereas tirzepatide was first approved by the FDA in 2022 for the treatment of type 2 diabetes. It is currently being studied for the treatment of obesity [10]. Semaglutide at 2.4 mg once weekly plus lifestyle intervention was associated with clinically meaningful weight loss in adults with obesity [11].

A systematic review was conducted for subcutaneous semaglutide, which involved six placebo-controlled and seven active-controlled trials. Semaglutide significantly decreased glycated hemoglobin (A1C) levels compared with sitagliptin, liraglutide, exenatide ER, and dulaglutide; however, adverse reactions (nausea, vomiting) were more likely to occur with semaglutide [12].

Clinical trials of GLP-1 anti-diabetic and anti-obesity medications have reported varied adverse drug reactions (ADRs). According to Marso et al. (2016), the most common ADRs associated with liraglutide were mild or moderate nausea and diarrhea. Serious adverse events occurred in 6.2% of patients in the liraglutide group and 5.0% in the placebo group. Thirteen patients had pancreatic cancer in the liraglutide group and 5 in the placebo group, but the finding was not significant. Gastrointestinal (GIT) adverse events were the most common, leading to the discontinuation of liraglutide [13]. However, no psychiatric ADRs associated with liraglutide were reported in the trial [13].

In a trial involving tirzepatide and semaglutide (Frias JP et al., 2021), GIT adverse events such as nausea, vomiting, and diarrhea were the most commonly reported. The incidence ranged between 6–22%. However, no psychiatric adverse events were reported in this trial [14]. A similar safety profile was observed in the SURMOUNT-2 randomized trial of tirzepatide in adults with obesity and type 2 diabetes, where GIT adverse events were the most frequently reported and no data on neuro or psychiatry adverse events were available [15].

Common adverse effects of GLP-1 receptor agonists include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, headache, and nasopharyngitis [16]. Although there is a concern for the development of rare pancreatitis, pancreatic cancer, or thyroid cancer, a Meta-analysis of several databases did not suggest any increased risk of acute pancreatitis or pancreatic cancer with GLP-1RA treatment in T2DM patients [17].

Neuropsychiatric safety issues have become an area of interest, given that many approved anti-obesity medications are centrally acting appetite suppressants [18, 19]. Rimonabant, the first selective central cannabinoid (CB1) receptor antagonist, was never approved by the FDA because of concerns regarding psychiatric adverse events, including depression, anxiety, and suicidal ideation [20]. Rimonabant was authorized in Europe in 2006 as an anti-obesity medication and then withdrawn by the European Medicines Agency (EMA) in 2009, leading to the termination of the development of other cannabinoid receptor 1 (CB1) blockers for obesity [21, 22].

Depression is a prevalent mood disorder and a significant health concern that often co-occurs with other diseases, including metabolic disorders like type 2 diabetes and obesity [23]. Studies have shown that people living with obesity and T2D are more likely to experience mental health issues [23]. Treatment with GLP-1RAs may be helpful for the treatment of depressive disorders [24]. Some studies have indicated that administering GLP-1RAs may directly exert an antidepressant effect on experimental animals [24].

Although semaglutide and liraglutide show antidepressant and anxiolytic effects in animal models of depression and anxiety, in July 2023, the European Medicine Agency (EMA)’s safety committee, PRAC, is reviewing data on the risk of thoughts of suicide and self-harm associated with GLP-1 receptor agonists, including semaglutide (Ozempic) and liraglutide (Saxenda) [25]. Therefore, these medications should be used cautiously and closely monitored in patients with a history or risk of psychiatric disorders [25]. Furthermore, as previously mentioned, there is a lack of data on psychiatric adverse events associated with GLP-1 receptor agonists reported in clinical trials [13, 14, 15].

Aim

The aim of this study was to identify and analyse the reported occurrence of psychiatric adverse events and clinical outcomes for three anti-diabetic and anti-obesity medications, namely semaglutide, liraglutide, and tirzepatide, based on reports from the EudraVigilance database

Ethics approval

Data derived from the EV database are anonymous and in compliance with the ethical standard; therefore, no access authorization was requested. The access policy of EMA states that "No authorization for accessing the ICSR (Level 1) data set by means of the adrreports.eu portal is required; i.e., all academic researchers can access adverse reaction data of interest”.

The Eudravigilance database was searched; a centralized EU system, maintained by the European Medicines Agency (EMA) and supports monitoring the safe and effective use of medicines that have been authorized or studied in clinical trials in the EU. A medication safety database was previously used to report adverse effects with pharmaceuticals [26, 27]. All individual case safety reports (ICSR) for semaglutide, liraglutide, and tirzepatide reported to the EudraVigilance database from 01/01/2021 to 5/30/2023 were analysed for psychiatric adverse events.

Liraglutide Saxenda® was the first anti-obesity drug approved by the US FDA in December 2014, followed by semaglutide Wegovy® in June 2021. Tirzepatide Mounjaro®, a new dual-Targeted Treatment for Type 2 diabetes, was approved in May 2022, but not for weight management. The analysis will cover the period of approval of these drugs and compare the occurrence of adverse events in comparable time interval.

Line listing search was conducted for data collection; The search included all spontaneous reports of psychiatric adverse drug reactions, regardless of the dose, frequency, or route of administration of the selected medication. The following information were recorded for each ICSR; a unique identifier number, age group (age groups: ≥85 years old, 65–84, 18–64 and 12–17 years, non-specified age), sex, date of reporting, origin of the report (EU or non-EU), reporter’s profession (healthcare professional or non-healthcare professional), concomitant conditions and psychotic ADRs outcome and seriousness. Each ICSR may include more than one suspected ADR.

The results of the line listing search were then exported to Microsoft excel files and data were cleaned by removing irrelevant columns and fields, tabulated and presented according to the type of psychiatric ADR and clinical outcome, by gender and age. The clinical outcomes were categorised into four sections: (i) recovered/resolved, (ii) recovering/resolving, (iii) not recovered/not resolved, (iv) fatal/life-threatening, and (v) unknown outcome.

Descriptive statistics were used to describe the study population characteristics. Variables were reported as absolute numbers and percentages. All analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA). Differences in proportions between the groups were compared using the chi-square test. A p-value of less than 0.05 was considered statistically significant. The chi-square test was used to compare life-threatening and fatal outcomes and the frequency of suicidal adverse events between the studied medications. Due to the relatively new marketing date of Tirzepatide and the small number of ICRS reports, it was excluded from this comparison.

During the study period, 31,444 ADR reports were identified: semaglutide (n = 13,956, 44.4%), liraglutide (n = 16,748, 53.2%), and tirzepatide (n = 740, 2.3%). There were 372 reports with psychiatric adverse events submitted to the EV database during the study period (372/31,444, 1.18%) and 480 adverse events in total, as each report may contain more than one ADR. Women accounted for 65% (n = 242) of the reports, whereas men accounted for 29% (n = 108). The sex in the remaining 6% was not specified. Figure 1 illustrates the age and sex distribution of the patients with reported psychiatric adverse events.

Depression was the most commonly reported adverse event (n = 187, 50.3%), followed by anxiety (n = 144, 38.7%) and suicide ideation (n = 73, 19.6%) [Table 1]. Nine deaths were reported (8 for liraglutide and 1 for semaglutide), and 11 life-threatening outcomes (4 for liraglutide and 7 for semaglutide) were reported during the study period. The fatal outcomes occurred mainly among men (8 out of 9) due to completed suicidal attempts and depression [Tables 2–3]. There was no significant association between the type of medication (liraglutide and semaglutide) and the life-threatening/fatal outcome (P value = 0.07).

Table 1

General characteristic of patients with psychiatric adverse events.
Total	LIRAGLUTIDE		SEMAGLUTIDE		TIRZEPATIDE		Total
	147		210		15		372
	No	%	No	%	No	%	No	%
Report Year 2021 2022 2023	43 70 34	29.3% 47.6% 23.1%	63 81 66	30.0% 38.6% 31.4%	0 5 10	0.0% 33.3% 66.7%	106 156 110	28.5% 41.9% 29.6%
Age group in years 12–17 18–64 65–85 More than 85 Not specified	4 74 7 0 62	2.7% 50.3% 4.8% 0.0% 42.2%	0 103 30 1 76	0.0% 49.0% 14.3% 0.5% 36.2%	0 11 1 0 3	0.0% 73.3% 6.7% 0.0% 20.0%	4 188 38 1 141	1.1% 50.5% 10.2% 0.3% 37.9%
Sex Male Females Not Specified	113 33 1	76.9% 22.4% 0.7%	121 72 17	57.6% 34.3% 8.1%	8 3 4	53.3% 20.0% 26.7%	108 242 22	29.0% 65.1% 5.9%
Country of report European Economic Area Non-European Economic Area	50 97	34.0% 66.0%	72 138	34.3% 65.7%	0 15	0 100%	122 250	32.8% 67.2%
The reporter Healthcare Professional Non-Healthcare Professional	78 69	53.1% 46.9%	108 102	51.4% 48.6%	7 8	46.7% 53.3%	193 179	51.9% 48.1%
Psychiatric adverse events Anxiety Depression Suicide attempt Suicide Ideation Completed suicide Depression with suicidal Suspected suicide Other*	60 66 7 29 4 4 2 11	40.8% 44.9% 6.1% 19.4% 0.0% 4.1% 1.4% 7.5%	71 117 5 40 0 6 0 34	33.8% 55.7% 2.4% 19.0% 1.9% 1.9% 0.0% 16.2%	13 4 0 4 0 0 0 0	86.7% 26.7% 0.0% 26.7% 0.0% 0.0% 0.0% 0.0%	144 187 12 73 4 10 2 45	38.7% 50.3% 4.6% 19.6% 1.1% 2.7% 0.5% 12.1%
*Includes Affective disorders, Hallucinations, Mania, Mood swings and one case of suicidal behaviour with liraglutide.

Table 2

Outcome and severity of psychiatric adverse events reported in the EV database by age group and sex
Sex	Age	Not Recovering/ Not Resolving		Recovered/ Resolved		Recovering/ Resolving		Life-threatening/ Fatal		Unknown
Sex	Age	No	%	No	%	No	%	No	%	No	%
Male	12–17	0	16.7%	0	11.4%	0	17.6%	1	40.0%	2	12.2%
	18–64	11	6.1%	10	6.8%	6	5.9%	8	0.0%	20	4.3%
	65–85	4	0.0%	6	0.0%	2	0.0%	0	0.0%	7	0.0%
	Moe than 85	0	4.5%	0	8.0%	0	11.8%	0	15.0%	0	8.5%
	Not specified	3	27.3%	7	26.1%	4	35.3%	3	60.0%	14	26.2%
	Total	18	0.0%	23	0.0%	12	0.0%	12	0.0%	43	0.6%
Female	12–17	0	34.8%	0	35.2%	0	44.1%	0	15.0%	1	35.4%
	18–64	23	7.6%	31	5.7%	15	2.9%	3	0.0%	58	4.3%
	65–85	5	0.0%	5	0.0%	1	0.0%	0	5.0%	7	0.0%
	More than 85	0	24.2%	0	27.3%	0	17.6%	1	20.0%	0	25.6%
	Not specified	16	66.7%	24	68.2%	6	64.7%	4	40.0%	42	65.9%
	Total	44	0.0%	60	0.0%	22	0.0%	8	0.0%	108	0.0%
Not specified	12–17	0	0.0%	0	1.1%	0	0.0%	0	0.0%	0	1.2%
	18–64	0	0.0%	1	0.0%	0	0.0%	0	0.0%	2	0.6%
	65–85	0	0.0%	0	0.0%	0	0.0%	0	0.0%	1	0.0%
	Moe than 85	0	6.1%	0	4.5%	0	0.0%	0	0.0%	0	6.1%
	Not specified	4	6.1%	4	5.7%	0	0.0%	0	0.0%	10	7.9%
	Total	4	16.7%	5	11.4%	0	17.6%	0	40.0%	13	12.2%
Grand Total		66		88		34		20		164
*Percentage of the total number of reports in the respective outcome group.

Table 3

Details of the fatal and life-threatening outcome.
No	Outcome	Age in years	Sex	Adverse Event-Outcome	Medication List
1	Death	18–64	Male	Completed suicide-Death	Liraglutide + Metformin + Perindopril
2		18–64	Male	Completed suicide-Death	Liraglutide + Metformin + Perindopril
3		18–64	Male	Completed suicide-Death	Liraglutide + Rosuvastatin
4		18–64	Male	Completed suicide-Death	Liraglutide + Metformin + Perindopril
5		18–64	Male	Suspected suicide-Death	Liraglutide + Insulin Glargine + Paracetamol + Lisinopril
6		18–64	Male	Suspected suicide-Death	Liraglutide + Insulin Glargine + Paracetamol + Lisinopril
7		Not specified	Male	Depression*-Death	Liraglutide + Sitagliptin
8		Not specified	Male	Depression**-Death	Liraglutide + Sitagliptin + Metformin
9		More than 85	Female	Depression-Death	Semaglutide
10	Life-threatening condition	12–17	Male	Suicide attempt-Recovering	Liraglutide
11		18–64	Male	Depression, suicidal-Unknown	Liraglutide
12		18–64	Male	Delerium^-Unknown	Semaglutide + Ramipril + Chlorhexidine + Metformin
13		Not Specified	Male	Anxiety- Not Recovered	Semaglutide
14		18–64	Female	Suicide ideation-Recovering	Liraglutide
15		18–64	Female	Suicidal ideation-Recovered	Semaglutide
16		18–64	Female	Depression-Recovering	Semaglutide
17		Not Specified	Female	Suicide ideation, aggravated depression-Unknown	Liraglutide + Fluoxetine Hydrochloride
18		Not Specified	Female	Suicide ideation-Recovering	Semaglutide
19		Not Specified	Female	Suicide ideation-Not Recovered	Semaglutide
20		Not Specified	Female	Suicide attempt-Unknown	Semaglutide
The patient had cancer pancreas. * The patient had cancer prostate. ^ The patient had Cerebral haemorrhage and acute Kidney injury.

Suicidal Adverse Events

During the study period, the database recorded one hundred and two adverse events related to suicide. The events included suicidal ideations (n = 73), suicidal attempts (n = 12), depression with suicidal ideations (n = 10), completed suicides (death) (n = 4), suspected suicides (n = 2), and suicidal behavior (n = 1). Overall, in terms of total reported suicidal events, 50.0% occurred with semaglutide (51/102, 50%) and constituted 24.3% of the total semaglutide psychiatric adverse events reports (51/210, 24.3%), followed by liraglutide (48/147, 32.7%) of the total liraglutide psychiatric adverse events reports. Four suicidal reports 3.9% were associated with tirzepatide (4/15, 26.7%). Sixty-two percent of suicidal events occurred in females, and almost half of the reports (44.6%) occurred in the 18–64 age group. Table 4 illustrates the age and sex distribution and the outcome of the suicide-related adverse events.

Table 4: Suicidal events associated with Liraglutide, Semaglutide, and Tirzepatide and their outcome

A: Liraglutide

Receipt Date	The reporter	Source Country	Age group in years	Sex	Adverse Event (Outcome)
11/01/2021	Non Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Not Recovered/Not Resolved)
26/03/2021	Healthcare Professional	Non-EU	65-85	Female	Suicidal ideation (Unknown)
20/05/2021	Healthcare Professional	Non-EU	N/S	Male	Suicidal ideation, Depression (Unknown ),
27/05/2021	Healthcare Professional	Non-EU	18-64	Male	Completed suicide (Fatal - Results in Death)
02/06/2021	Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
03/06/2021	Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation, Depression (Recovered/Resolved)
11/06/2021	Healthcare Professional	Non-EU	N/S	Female	Suicide attempt (Unknown)
02/08/2021	Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
02/09/2021	Non Healthcare Professional	Non-EU	65-85	Female	Suicidal ideation (Recovering/Resolving)
21/10/2021	Healthcare Professional	Non-EU	18-64	Male	Completed suicide (Fatal - Results in Death)
03/11/2021	Healthcare Professional	Non-EU	18-64	Male	Completed suicide (Fatal - Results in Death)
24/01/2022	Non Healthcare Professional	Non-EU	N/S	Female	Depression suicidal (Not Recovered/Not Resolved)
24/01/2022	Non Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Not Recovered/Not Resolved)
11/04/2022	Healthcare Professional	Non-EU	18-64	Male	Suicidal ideation (Unknown)
11/05/2022	Non Healthcare Professional	Non-EU	N/S	Female	Depression suicidal (Unknown)
20/05/2022	Healthcare Professional	Non-EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
10/06/2022	Healthcare Professional	Non-EU	18-64	Male	Completed suicide (Fatal - Results in Death)
27/06/2022	Healthcare Professional	EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
26/07/2022	Healthcare Professional	Non-EU	18-64	Male	Depression suicidal (Life Threatening)
28/07/2022	Healthcare Professional	Non-EU	N/S	Female	Suicidal behaviour (Recovered/Resolved)
17/08/2022	Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Unknown)
08/09/2022	Non Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Unknown)
09/09/2022	Healthcare Professional	Non-EU	18-64	Male	Suicidal ideation (Unknown)
22/09/2022	Non Healthcare Professional	Non-EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
13/10/2022	Non Healthcare Professional	EU	18-64	Female	Suicidal ideation (Not Recovered/Not Resolved)
28/10/2022	Non Healthcare Professional	EU	N/S	Female	Suicidal ideation (Unknown)
03/11/2022	Healthcare Professional	EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
16/11/2022	Non Healthcare Professional	Non-EU	12-17	Male	Suicide attempt (Recovering/Resolving - Life Threatening)
12/12/2022	Healthcare Professional	Non-EU	N/S	Female	Depression (Recovered/Resolved), Suicidal ideation (Unknown)
28/12/2022	Healthcare Professional	Non-EU	18-64	Male	Suicide attempt (Unknown - Prolonged Hospitalisation)
09/01/2023	Healthcare Professional	Non-EU	N/S	Male	Suicidal ideation (Recovering/Resolving)
16/01/2023	Healthcare Professional	Non-EU	18-64	Male	Suspected suicide (Fatal - Results in Death)
16/01/2023	Healthcare Professional	Non-EU	18-64	Male	Suspected suicide (Fatal - Results in Death)
31/01/2023	Non Healthcare Professional	EU	18-64	Female	Suicidal ideation (Unknown)
10/02/2023	Healthcare Professional	Non-EU	65-85	Female	Suicide attempt (Recovered/Resolved - Prolonged Hospitalisation)
01/03/2023	Non Healthcare Professional	Non-EU	18-64	Female	Suicidal ideation (Not Recovered/Not Resolved - Disabling)
14/03/2023	Non Healthcare Professional	Non-EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
29/03/2023	Non Healthcare Professional	Non-EU	18-64	Male	Suicide attempt (Unknown)
31/03/2023	Healthcare Professional	Non-EU	12-17	Male	Depression suicidal (Unknown - Prolonged Hospitalisation)
07/04/2023	Non Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Unknown - Life Threatening)
10/04/2023	Non Healthcare Professional	Non-EU	18-64	Female	Suicidal ideation (Recovering/Resolving)
17/04/2023	Non Healthcare Professional	Non-EU	12-17	Female	Suicidal ideation (Recovered/Resolved)
05/05/2023	Healthcare Professional	Non-EU	N/S	Male	Suicide attempt (Unknown)
08/05/2023	Healthcare Professional	Non-EU	N/S	Female	Suicidal ideation (Unknown)
16/05/2023	Healthcare Professional	Non-EU	12-17	Male	Suicidal ideation (Not Recovered/Not Resolved)
24/05/2023	Healthcare Professional	Non-EU	65-85	Female	Suicide attempt (Recovered/Resolved - Prolonged Hospitalisation),
26/05/2023	Healthcare Professional	EU	18-64	Female	Suicidal ideation (Recovered/Resolved)

N/S; Not Specified

B: Semaglutide

Receipt Date	The reporter	Source Country	Age group in years	Sex	Adverse event (Outcome)
16/12/2021	Non Healthcare Professional	EU	18-64	Female	Suicidal ideation (6.5d - Recovered/Resolved)
03/12/2021	Healthcare Professional	EU	N/S	Female	Suicide attempt (Unknown - Prolonged Hospitalisation)
21/10/2021	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
14/10/2021	Non Healthcare Professional	Non EU	N/S	Male	Depression suicidal (Unknown)
28/09/2021	Healthcare Professional	Non EU	65-85	Male	Suicidal ideation (Recovered/Resolved with Sequelae - Disabling)
14/09/2021	Non Healthcare Professional	Non EU	18-64	Female	Depression suicidal (Recovering/Resolving)
21/07/2021	Non Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
14/05/2021	Non Healthcare Professional	Non EU	65-85	Male	Suicidal ideation (Unknown)
29/03/2021	Non Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
19/02/2021	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Unknown)
29/12/2022	Healthcare Professional	EU	18-64	Female	Suicidal ideation (Recovering/Resolving - Prolonged Hospitalisation)
22/11/2022	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Unknown)
18/11/2022	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Unknown)
03/11/2022	Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Not Recovered/Not Resolved)
21/10/2022	Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
06/09/2022	Non Healthcare Professional	Non EU	N/S	Female	Depression (Unknown), Suicidal ideation (Unknown)
22/06/2022	Non Healthcare Professional	Non EU	18-64	Female	Depression suicidal (Not Recovered/Not Resolved)
26/04/2022	Non Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Unknown)
01/03/2022	Healthcare Professional	Non EU	N/S	Female	Depression suicidal (Recovered/Resolved)
17/05/2023	Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Recovered/Resolved - Prolonged Hospitalisation)
12/05/2023	Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovering/Resolving)
13/04/2023	Healthcare Professional	EU	18-64	Female	Depression suicidal (Recovered/Resolved)
31/03/2023	Healthcare Professional	Non EU	N/S	Female	Suicide attempt (Unknown - Prolonged Hospitalisation)
07/03/2023	Healthcare Professional	EU	18-64	Female	Suicidal ideation (Not Recovered/Not Resolved)
20/02/2023	Non Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
20/02/2023	Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Unknown)
10/02/2023	Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (2d - Recovered/Resolved)
10/02/2023	Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Recovering/Resolving)
03/02/2023	Healthcare Professional	Non EU	18-64	Female	Depression suicidal (32d - Recovered/Resolved)
28/09/2021	Non Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
23/07/2021	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Not Recovered/Not Resolved)
14/12/2022	Non Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Unknown)
24/08/2022	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
18/08/2022	Non Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Recovered/Resolved)
18/08/2022	Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovered/Resolved)
01/08/2022	Healthcare Professional	Non EU	N/S	Female	Suicide attempt (Unknown)
24/06/2022	Non Healthcare Professional	EU	18-64	Female	Suicidal ideation (Recovered/Resolved - Life Threatening)
27/04/2022	Non Healthcare Professional	Non EU	N/S	Female	Suicide attempt (Unknown - Life Threatening)
18/04/2022	Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Not Recovered/Not Resolved
24/05/2023	Non Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Recovering/Resolving - Life Threatening)
22/05/2023	Non Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Unknown)
17/05/2023	Healthcare Professional	Non EU	18-64	Male	Suicide attempt (Recovered/Resolved -Prolonged Hospitalisation)
16/05/2023	Non Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Not Recovered/Not Resolved)
16/05/2023	Healthcare Professional	Non EU	N/S	Female	Suicidal ideation (Not Recovered/Not Resolved - Life Threatening)
27/04/2023	Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Recovered/Resolved)
05/04/2023	Non Healthcare Professional	Non EU	N/S	Male	Suicidal ideation (Recovered/Resolved)
17/03/2023	Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Not Recovered/Not Resolved)
17/03/2023	Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Recovered/Resolved)
17/03/2023	Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Recovered/Resolved)
16/03/2023	Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Not Recovered/Not Resolved)
07/02/2023	Non Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Unknown)

N/S; Not Specified

C: Tirzepatide

Receipt Date	The reporter	Source Country	Age group in years	Sex	Adverse Event (Outcome)
03/05/2023	Non Healthcare Professional	Non EU	18-64	Male	Suicidal ideation (Not Recovered/Not Resolved)
11/04/2023	Non Healthcare Professional	Non EU	N/S	N/S	Suicidal ideation (Unknown)
09/12/2022	Non Healthcare Professional	Non EU	18-64	Female	Suicidal ideation (Not Recovered/Not Resolved)
25/10/2022	Healthcare Professional	Non EU	65-85	Male	Suicidal ideation (Not Recovered/Not Resolved)

N/S; Not Specified

No significant relationship was found between the frequency of reported adverse events related to suicide and the type of medication (semaglutide and liraglutide), P value = 0.13.

Key Findings

Between January 2021 and May 2023, there were 372 adverse event reports with 481 psychiatric events associated with three GLP-1 agonists (semaglutide, liraglutide, and tirzepatide) reported to the European Eudravigilance database. Some of the events resulted in severe consequences, including suicidal attempts and completed suicides (deaths). The number of reported events for these medicines has increased over the study years, which may be due to their increased use. There are a lower number of reports for tirzepetide, likely because it was recently approved by the FDA in 2022 for the treatment of type 2 diabetes and not yet for obesity.

Approximately 50% of the reports occurred in the 18–64-year age group, and 65% of the reports were from females. This may be due to the higher use of these medications in adult women. A previous database study conducted using the Clinical Practice Research Datalink in the UK found that among 589 patients prescribed a GLP-1 receptor agonist, 56.4% were female, and the median age was 54 years.

A comparison between the three studied medications revealed more fatal adverse events associated with liraglutide (8 patients had a fatal outcome out of 147 ICSR) compared with semaglutide (one death out of 210 ICSR), and none with tirzepatide (out of 15 ICSR). Fatal outcomes were primarily the result of completed suicide and were more common in males in the 18–64 age group [28].

In this study, half (50.0%) of the reported suicidal events occurred with semaglutide followed by liraglutide, whereas only four occurred with tirzepatide.

A pooled post-hoc analysis of neuropsychiatric safety data across weight management trials with liraglutide revealed a “small numerical imbalance” in suicidal ideation with liraglutide compared with placebo. Nine (0.3%) patients in the liraglutide group vs 2 (0.1%) individuals in the placebo group reported suicidal ideation or behavioral adverse events [29]. Suicidal ideation events were detected for 8 of 11 individuals using the Columbia-Suicide Severity Rating Scale (C-SSRS), all of which occurred in the liraglutide group [29].

In a study of 201 adolescents with obesity, it was found that a smaller percentage of participants in the semaglutide group reported psychiatric adverse events compared to the placebo group (7% vs. 15%). However, the study did not provide any details on the type of symptoms or severity experienced by the participants [30].

Of note, there is evidence to suggest a link between obesity, being overweight, and psychiatric events, such as depression, anxiety, and suicidal ideation [31–33]. The relationship between obesity and psychiatric events is complex and can be bidirectional. Although obesity may increase the risk of psychiatric disorders, mental health conditions also contribute to the development or worsening of obesity through various mechanisms, such as emotional eating and decreased motivation for physical activity [33, 34].

The relationship between obesity and depression has been extensively studied in scientific literature, with some studies showing significant associations while others yielding contradictory results, with a large proportion of cross-sectional studies that are very heterogeneous in their design, has made it difficult to draw clear conclusions [34, 35].

In the US FDA’s Adverse Event Reporting System (FAERS), 1200 reports of adverse reactions had been reported for semaglutide since 2018, including 60 cases of suicidal ideation and 7 suicide attempts (5%, 0.5%) respectively. For liraglutide, of > 35,000 reports of adverse reactions, there have been 71 cases of suicidal ideation, 28 suicide attempts, and 25 completed suicides (2%, 0.8%, 0.7%), respectively [36].

Strengths and weaknesses

To the authors' best knowledge, this is the first study that evaluated in a real-world setting the psychiatric adverse events associated with three anti-diabetic and anti-obesity GLP1 receptor agonist medications. Although a low number of psychiatric adverse events were reported in this study, 20 patients had a fatal or life-threatening outcome among the severe clinical outcomes associated with the three drugs. However, this finding should be interpreted with caution because of the nature of the data and the passive reporting system used. Other limitations include the use of pharmacovigilance databases. Data from the EudraVigilance and other drug safety databases relies on spontaneous reporting, which may introduce reporting bias, underreporting adverse events, and missing information. Furthermore, the observational design of the study contributes to the lack of detailed information on underlying patient conditions and hinders the establishment of a causal relationship between GLP-1 receptor agonists and adverse psychiatric effects. The lack of a denominator for the total population taking the medications, where reports came from European and non-European countries, makes it difficult to determine if there is a significant risk.

Psychiatric adverse events appear to be a potential concern with semaglutide, liraglutide, and tirzepatide, but their true risk is unknown. Therefore, endocrinologists and psychiatrists should monitor and assess the emotional and mental status of patients before and after using these anti-obesity medications [37].

There are a variety of interventions to assess a patient's risk of suicide, depending on their individual situation. Screening tools, such as the Patient Health Questionnaire-9 (PHQ-9) and the Columbia Suicide Severity Rating Scale (C-SSRS), can be used to identify individuals at risk of suicide. These tools are easy to administer and can be incorporated into electronic medical records [38, 39].

The decision to start drug therapy for obesity should be made on a case-by-case basis, after weighing the risks and benefits. It is important to set clear treatment goals and to consider the patient's preferences and tolerability, as these can have a big impact on patients’ adherence [37].

In the future, it is recommended to include a more significant number of follow-up studies based on unified criteria to understand better the relationship between obesity and psychiatric disorders, including suicide, anxiety and depression [35, 36]. Furthermore, further research is needed to identify the psychiatric adverse events associated with new anti-obesity medications. Additional well-conducted and well-reported studies are needed, accompanied by the use of accepted definitions and causality assessment tools to address the lack of published literature regarding this issue.

Although adverse psychiatric events account for only 1.2% of the total reports associated with semaglutide, liraglutide, and tirzepatide, 20 patients had a fatal or life-threatening outcome. The seriousness of these adverse events warrants additional research to explore the causal relationship. Neuropsychiatric safety should be a key consideration in any clinical risk-benefit assessment associated with GLP1 anti-obesity medications and the data provided here contribute to thoughtful and objective decision-making and dialogue between patients and clinicians.

Authors’ contributions

MT conceived the study and the research question. HE performed the database search and analyses of data. Both authors were involved in writing the paper and the final approval of the submitted and published versions

Funding

None.

Competing Interests

The authors have none to declare.

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Analysis of Psychiatric Adverse Events for Semaglutide, Liraglutide, and Tirzepatide Reported to the EudraVigilance Database

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