Can Tirzepatide (Zepbound) Cause Anxiety?
Anxiety has been reported as an adverse event with tirzepatide, though it occurs infrequently and represents a small fraction of total adverse events reported with GLP-1/GIP receptor agonists.
Psychiatric Adverse Event Profile
Anxiety was reported in 38.7% of psychiatric adverse event cases associated with GLP-1 receptor agonists (including tirzepatide, semaglutide, and liraglutide) in the EudraVigilance database, making it the second most common psychiatric adverse event after depression 1
However, psychiatric adverse events comprised only 1.2% of total adverse event reports for these medications, indicating that anxiety and other psychiatric symptoms are relatively uncommon overall 1
In the specific breakdown, depression was the most commonly reported psychiatric adverse event (50.3%), followed by anxiety (38.7%) and suicidal ideation (19.6%) 1
Clinical Context and Mechanism
GLP-1 receptors are expressed in multiple brain regions, including the hypothalamus, brainstem, hippocampus, neocortex, spinal cord, and cerebellum, which may explain neuropsychiatric effects beyond simple appetite suppression 2, 3
The distribution of these receptors in the central nervous system could theoretically contribute to mood and anxiety-related side effects, though the exact mechanism remains unclear 3
Gastrointestinal Side Effects as Primary Concern
The most commonly reported adverse events with tirzepatide are gastrointestinal, including nausea (17-22%), diarrhea (13-16%), vomiting (6-10%), and constipation, which are dose-dependent and typically mild-to-moderate 4, 5
These GI symptoms are far more prevalent than psychiatric adverse events and should be the primary counseling focus when initiating therapy 6, 4
Practical Clinical Approach
Screen for pre-existing psychiatric conditions before initiating tirzepatide, as patients with depression or anxiety disorders may warrant closer monitoring 1
Counsel patients that anxiety is a rare but reported adverse event, occurring in less than 0.5% of all patients based on the overall psychiatric adverse event rate 1
Monitor for new or worsening anxiety symptoms during dose titration, particularly in the first 3 months of therapy when GI side effects are most prominent 6
If anxiety develops, consider whether it may be secondary to other factors such as gastrointestinal distress, dietary changes, or weight loss-related body image concerns rather than a direct drug effect 1
When to Discontinue or Modify Treatment
Discontinue tirzepatide if severe psychiatric symptoms emerge, including significant anxiety that impairs daily functioning, new-onset depression, or suicidal ideation 1
The severity and fatal outcomes of some psychiatric adverse event reports, though rare, warrant serious consideration and prompt intervention 1
Consider dose reduction or slower titration if mild anxiety symptoms develop, as psychiatric effects may be dose-related similar to GI adverse events 4