Acute Onset of Mood and Psychotic Symptoms After Rapid Discontinuation of a GLP-1 Agonist

Original Source: Journal of Clinical Psychiatry, all rights reserved. —

Glucagon-like peptide-1 (GLP-1) receptor agonists are prescribed for type 2 diabetes and obesity due to their effectiveness in improving glycemic control and promoting weight loss. GLP-1 receptors are distributed in the central nervous system and may influence neural pathways involved in reward and mood regulation. This report describes 2 cases of mood and psychotic symptoms associated with discontinuation of GLP-1 agonists.

Case 1

The first patient was a 61-year-old man with a past medical history of depression, metabolic dysfunction–associated steatohepatitis (MASH) cirrhosis, and stage 3a chronic kidney disease who presented in October 2025 for worsening confusion and erratic behavior. The patient endorsed low mood, paranoia, auditory and visual hallucinations, and Cotard delusion. The patient met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a psychotic disorder based on the presence of hallucinations, delusions, and functional impairment. His depression had worsened over the month prior to admission. Sensorium remained intact. The patient had recently stopped tirzepatide in August 2025 due to nausea.

Medical workup was notable for negative urine drug studies, and cerebrospinal fluid, brain magnetic resonance imaging (MRI), and electroencephalogram results were unremarkable. The patient continued home sertraline and was initiated on aripiprazole, which was transitioned to olanzapine and then to haloperidol. At the time of discharge, psychotic symptoms were resolved, and depression had improved. The patient was readmitted weeks later for depression with catatonic features, requiring inpatient psychiatry admission and a course of electroconvulsive therapy.

Case 2

The second patient was a 52-year-old man with a past medical history of anxiety and gastroesophageal reflux disease who presented in October 2025 for erratic behavior and mood swings. The patient had multiple symptoms of mania, including hyperverbal and disorganized speech, grandiosity, impulsivity, and irritability. He met DSM-5 criteria for a manic episode, with elevated/irritable mood, increased goal-directed activity, and associated symptoms causing functional impairment. The patient had stopped tirzepatide abruptly in September 2025 after significant weight loss (100 lb over 6 months) and had increased marijuana use in the weeks preceding presentation.

No focal neurological deficits were noted. Laboratory studies showed a low vitamin B₁₂ level (160 pg/mL) and otherwise unremarkable metabolic and infectious laboratory studies. A brain MRI revealed chronic lacunar infarcts in the left thalamus and bilateral cerebellum, not explaining the presentation; no evidence of acute findings was noted. The patient was started on risperidone and transferred to an outside psychiatric facility.

Discussion

While the neuropsychiatric effects of GLP-1 agonist treatment are increasingly recognized,¹ including those related to addiction,² the psychiatric implications of discontinuing these medications remain poorly characterized. In particular, the precise mechanism of how GLP-1 agonists impact the central nervous system (CNS) is unclear. GLP-1 receptors are present in the brain, and GLP-1 receptor agonists can penetrate the CNS.³ Emerging data suggest that GLP-1 receptor agonists can modify neuroinflammatory processes and influence dopaminergic cells.^4,5 While likely not the sole factor, it is plausible that discontinuation of a GLP-1 receptor agonist may contribute to acute-onset mood or psychotic symptoms in a select population of at-risk patients (including patients with nutritional deficiencies associated with, or exacerbated by, GLP-1 use, such as the second patient with a low vitamin B₁₂ level). That is, there are likely many more patients who have rapidly discontinued GLP-1 agonists and not developed acute symptoms. However, we suggest that, in the right subset of patients, abrupt cessation may represent one potential precipitant within a multifactorial process. It is also notable that both patients had a previous diagnosis of depression and anxiety, respectively, suggesting that a prior psychiatric history might play a role in the development of the acute symptoms described here. As the use of GLP-1 agonists expands, discontinuation due to cost, medication shortages, or adverse effects may become more common. Prescribers should be aware of potential neuropsychiatric side effects. Providers could also consult the US Food and Drug Administration Adverse Event Monitoring System to be aware of related symptoms associated with GLP-1 discontinuation.

Acute-onset mood or psychotic symptoms following GLP-1 receptor agonist discontinuation may represent an underrecognized clinical phenomenon. Increased awareness of potential psychiatric sequelae associated with GLP-1 withdrawal may be important for consultation-liaison psychiatrists when evaluating patients with acute psychiatric symptoms in the context of recent medication changes.

Article Information

Published Online: October 22, 2026. https://doi.org/10.4088/PCC.26cr04314
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(5):26cr04314
Submitted: June 24, 2026; accepted August 26, 2026.
To Cite: Horien C, Curran J, Sudhakar E, et al. Acute onset of mood and psychotic symptoms after rapid discontinuation of a GLP-1 agonist. Prim Care Companion CNS Disord 2026;28(5):26cr04314.
Author Affiliations: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania (all authors).
Corresponding Author: Corey Horien, MD, PhD, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania ([email protected]).
Financial Disclosure: None.
Funding/Support: This work was supported by a Penn Psychiatry Residency Research Track award R25MH119043-07 (Horien).
Role of the Sponsor: The sponsor had no role in preparation, review, or approval of the manuscript.
Patient Consent: Consent was received from the patients to publish the case reports, and information, including dates, has been de-identified to protect patient anonymity.

Journal of Clinical Psychiatry, all rights reserved.