The first patient was a 52-year-old woman with a 22-year history of recurrent depressive disorder. She had experienced three depressive episodes, the most recent nine years before presentation, and had been stable on a fixed dose of the antidepressant venlafaxine for years. She had no cardiac, pulmonary, or metabolic disease and took no other medication. Seeking cosmetic weight loss with a body mass index of 27 kilograms per square meter, she requested tirzepatide off-label. She was naive to weight-loss medications, and no other injections were given at the time. Around noon she received her first 2.5-milligram dose from a Mounjaro Kwikpen. By late morning the next day she was in the grip of a full panic attack, with anxiety, feelings of oppression, trepidation, shortness of breath, a cold shiver down the spine, nausea, and a globus sensation, the persistent feeling of a lump in the throat.

Notably, the nausea did not improve after she ate; it worsened. This detail matters clinically, because nausea that persists despite food intake argues against hypoglycemia as the driver of the symptoms. The panic symptoms slowly faded toward the evening, but the following morning she woke with severe depression, reporting depressed mood, hopelessness, despair, and lack of impetus until noon. Tirzepatide was discontinued after that single injection, and the panic attacks subsided entirely, with no further episodes. The depressive symptoms, however, persisted for days. Her venlafaxine dose was increased, melatonin was added for sleep disturbances, and two weeks after the injection she was hospitalized without suicidal ideation. On admission her Beck Depression Inventory score was 26, indicating moderate-to-severe depression. Electrocardiography was normal, and laboratory tests of blood count, blood glucose, liver and pancreatic enzymes, kidney function, and thyroid hormones revealed no medical explanation for the panic attacks. After four weeks of inpatient psychotherapy her depression remitted, with a BDI score of 8 at discharge.

The second patient was a 49-year-old woman with recurrent depressive disorder of several years’ standing, previously hospitalized twice for depression and anxiety, most recently three years before. She had been stable on extended-release quetiapine 250 milligrams daily, prescribed for insomnia, with no bipolar, psychotic, or suicidal features. Two months before her first tirzepatide injection her mood had begun to destabilize, treated as needed with promethazine, and she reported rare feelings of panic but no distinct panic attacks. She had obesity with a body mass index of 44, hypertension treated with amlodipine, valsartan, and hydrochlorothiazide, and she began tirzepatide 2.5 milligrams alongside a low-calorie diet at her own request. Two days later, panic attacks began in the morning, and she skipped breakfast because of nausea that again failed to resolve with food.

Over the following days she suffered continuous feelings of panic, oppression, and tremor without remission, peaking on the fourth day and then gradually diminishing. A second injection was given one week after the first, and she was hospitalized the same day for moderate-to-severe depression, with a BDI score of 27 on admission. Two days after that second injection she experienced another severe panic attack, followed by continuous anxiety and panic, with sporadic attacks persisting until six days after the second dose. Tirzepatide was then discontinued. Diagnostics again found no medical cause: the electrocardiogram was normal, and blood glucose, liver and pancreatic enzymes, kidney parameters, and thyroid hormones were unremarkable, although total cholesterol was elevated and a microcytic erythrocytosis was noted. She was treated with sertraline titrated to 200 milligrams daily while quetiapine and antihypertensives were continued. After 17 weeks of intensive inpatient psychotherapy her depression improved to a BDI score of 10, with only one brief panic episode in the final weeks.

A striking qualitative detail emerged from the second patient’s account. She reported that the panic attacks associated with tirzepatide differed from her previous anxiety experiences: whereas her prior anxiety built gradually and remained manageable, the episodes during tirzepatide treatment were sudden in onset, paroxysmal, and overwhelming. This distinction between sustained anxious apprehension and abrupt, overwhelming panic is central to the authors’ argument that the drug may have provoked a distinct phenomenon rather than merely amplifying an existing condition.

The authors are careful about causality. Applying the Naranjo Scale, a standard instrument for assessing adverse drug reactions, Case 1 scored 2 points and Case 2 scored 4 points, both corresponding to a possible adverse drug reaction, and the WHO-UMC causality assessment rated both cases as possible. The rechallenge pattern in Case 2, in which a second injection reproduced panic attacks of similar intensity and course, is the more suggestive finding, hinting at a specific mechanism rather than a purely psychological trigger. Yet the attribution is weakened by overlapping psychiatric symptoms, the absence of validated anxiety questionnaires, and confounders in Case 2, including pre-existing worsening of mood, the simultaneous start of a low-calorie diet that could itself provoke nausea and shakiness, and the stress of hospitalization on the day of the second injection.

Several biological hypotheses could explain how an incretin drug might reach the brain’s panic circuitry. One proposal builds on the GABAergic deficit hypothesis of depression and anxiety, in which impaired inhibitory signaling from the prefrontal cortex fails to restrain the amygdala. In rodent models, glucose-dependent insulinotropic polypeptide appears to activate the inhibitory role of GABAergic neurons and to reduce nausea. If a structural or functional deficit in GABAergic neurons impairs GIP signaling, the nausea provoked by GLP-1 receptor agonists could be intensified, and this physiological distress might then manifest as, or trigger, overwhelming panic. A second pathway involves the nucleus of the solitary tract and the area postrema, brainstem regions closely tied to the autonomic nervous system that are activated by GLP-1 receptor agonists. Overstimulation of these areas can mimic the physical sensations of a panic attack, including rapid heart rate and shortness of breath. A third possibility is direct activation of the hypothalamus-pituitary-adrenal axis, which GLP-1 receptor agonists can stimulate, raising adrenocorticotropic hormone and cortisol. A sudden spike in these stress hormones could produce a physiological state of high alert that the brain interprets as panic, although no cortisol or ACTH measurements were taken during the attacks, leaving this hypothesis untested.

Pharmacokinetics offer a further, more mundane explanation. GLP-1 receptor agonists delay gastric emptying, a well-documented effect that slows the absorption of concurrently administered oral drugs. Delayed absorption of venlafaxine, quetiapine, or promethazine could alter their bioavailability and plausibly contribute to fluctuations in mood and anxiety symptoms independent of any direct central nervous system effect of tirzepatide itself. The authors also note that concomitant medication and, in the second case, the onset of a low-calorie diet could have influenced the occurrence of panic attacks. Disentangling these possibilities will require larger studies with systematic monitoring of anxiety symptoms, drug levels, and stress hormones.

The broader context complicates any simple warning. Post-marketing pharmacovigilance data for tirzepatide show a range of medical and hormonal side effects, but psychiatric adverse events appear restricted to sleep disturbances and anorexia nervosa. A recent post hoc analysis of the SURMOUNT trial program found no elevated risk of depressive symptoms or suicidal ideation or behavior compared with placebo, though those participants had no history of psychiatric illness. An analysis of EudraVigilance data suggested a low level of psychiatric adverse events for tirzepatide relative to other GLP-1 receptor agonists, with anxiety the most prominent rare event, followed by depression and suicidal ideation. Real-world cohort data associate tirzepatide with a lower rate of suicidal ideation or attempts than other anti-obesity medications such as bupropion-naltrexone or orlistat. A PubMed search for tirzepatide and panic attacks from January 2020 to May 2026 returned no scientific literature, although anecdotal reports circulate on social media platforms. Meanwhile, other case reports describe patients with depression and anxiety whose symptoms improved on tirzepatide, with psychiatric benefits emerging gradually during dose titration independent of weight loss. The contrast underscores the authors’ central point: although these drugs are deemed safe in the general population, patients with preexisting psychiatric disorders, who are disproportionately affected by obesity, may need distinct risk assessment before starting incretin therapy, and further reports of this uncommon phenomenon may ultimately clarify the mechanisms involved.

Subject of Research: Panic attacks as a possible adverse effect of the dual GLP-1 and GIP receptor agonist tirzepatide in patients with recurrent depressive disorder

Article Title: Case Report: Panic attacks after tirzepatide injection in two female patients with recurrent depressive disorder

Article References: Case Report: Panic attacks after tirzepatide injection in two female patients with recurrent depressive disorder. (n.d.). https://doi.org/10.3389/fdsfr.2026.1880796

Image Credits: AI Generated

DOI: 10.3389/fdsfr.2026.1880796

Keywords: tirzepatide, GLP-1 receptor agonists, panic attacks, depression, obesity, drug safety, case report, GABAergic signaling, nucleus of the solitary tract, HPA axis, delayed gastric emptying, pharmacovigilance