Translation of a-t 2026; 57: 14

Exacerbation of depression in a patient receiving treatment with tirzepatide (MOUNJARO)

A 53-year-old woman with stable depression and obesity was taking the antidepressant escitalopram (CIPRALEX, generics) and the sedative antihistamine promethazine (ATOSIL, generics). When she was prescribed the GLP-1 and GIP receptor agonist tirzepatide (MOUNJARO; 2.5 mg subcutaneously once weekly) for weight loss, she noticed nausea and a drastic aversion to and distaste for food four days after the first administration, which reminded her of symptoms of previous depressive episodes. Severe internal unrest, anxiety, sleep disorders and pronounced suicidal thoughts occurred after the second injection. However, she was not taking a tricyclic antidepressant she was subsequently prescribed as she suspected tirzepatide as the trigger of the symptoms and discontinued it. Two weeks later her previously stable mental status had been restored (NETWORK report 18.544). It remains unclear which pathomechanism could have triggered the exacerbation. In a report about a man with newly developed depression and a woman with a recurrence and suicidal thoughts taking the pure GLP-1 agonist semaglutide (OZEMPIC, WEGOVY), a decrease in the free dopamine in certain regions of the brain as a result of the stimulation of cerebral GLP-1 receptors was discussed.¹ However, a safety review conducted by the European Medicines Agency (EMA) completed in 2024 and limited to pure GLP-1 agonists did not confirm a risk signal for suicidal tendencies (a-t 2024; 55:40). The FDA in the US also saw no evidence of this in its recently completed review that included the "twincretin" tirzepatide. Among other things, the FDA justified this with a meta-analysis of 91 placebo-controlled studies and a retrospective cohort study initiated by the authority on the basis of electronic health data. For patients with type 2 diabetes using a GLP-1 agonist including tirzepatide for the first time (n = 1,161,983), no increased risk of suicidal actions was calculated compared to first users of SGLT2 inhibitors matched using a propensity score (n = 1,081,155) (adjusted Hazard Ratio [aHR] 1.03; 95% confidence interval 0.51-2.07), also in the sub-group with obesity (aHR 0.99).^2,3 The FDA therefore called for the warnings of suicidal tendencies to be removed from the US product information for the preparations of the GLP-1 agonists tirzepatide, semaglutide and liraglutide (SAXENDA, VICTOZA, biosimilars).^2,4 In the patient mentioned above, tirzepatide may also have impaired the absorption of escitalopram and/or promethazine as a result of delayed gastric emptying. However, according to the summary of product characteristics, dose adjustments for medicinal products administered perorally at the same time should mostly not be necessary.⁵ Psychological effects are also conceivable, in particular the association of aversion to food with previous depressive episodes. The loss of the positive emotions linked to food could also have worsened the depression.⁶ The safety of tirzepatide in users with a corresponding history that may be predisposed to negative effects of this type⁷ appears to us, however, to have been insufficiently investigated. Patients with previous instances of attempted suicide and "significant active or unstable depression" or other severe psychiatric disorders in the two years before the start of the study were excluded from the studies relevant to the approval for obesity,⁶ as they were for those studies on pure GLP-1 agonists (a-t 2023; 54: 57-61).⁸ We believe that users of GLP-1 agonists including tirzepatide should continue to be monitored for depression and suicidal tendencies, particularly if they have a corresponding history, –Ed.

©  arznei-telegramm (Berlin/Germany), Februar 2026, protected by copyright laws.