TIRZEPATIDE PRECIPITATING ACUTE LITHIUM TOXICITY IN STABLE BIPOLAR I DISORDER

Background

Lithium is the most efficacious treatment for bipolar disorder, yet remains underprescribed due to concerns regarding its narrow therapeutic window and primary dependence on renal elimination. Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucosedependent insulinotropic polypeptide (GIP) receptor agonists are frequently prescribed for weight loss but have been identified as potential causes of acute kidney injury (AKI), particularly in association with severe gastrointestinal symptoms. Data suggest lithium toxicity can occur following initiation of semaglutide, and the prescribing information for tirzepatide explicitly warns against concurrent administration with narrow-therapeutic-index medications, including lithium. We describe a case of lithium toxicity developed following tirzepatide initiation in a patient on stable lithium therapy for a decade. Case Presentation: We present a 55-year-old male with bipolar I disorder, multiple psychiatric hospitalizations, and suicide attempts. Comorbidities include obesity and essential tremor. After trials of multiple psychotropics including lamotrigine, valproate, and antipsychotics, he was treated with lithium for almost a decade (600-1,200 mg/day), remaining stable. Over eight years, lithium levels were within, or slightly below, the therapeutic range (0.3–1.2 mEq/L), and serum creatinine remained between 1.0–1.3 mg/dL, with no evidence of kidney disease. Tirzepatide 2.5 mg weekly was started three months before presentation and increased to 5 mg weekly three weeks prior. After this dose increase, he developed hyporexia, nausea, and vomiting, leading to poor oral intake. He maintained lithium adherence; levels were not monitored. As the intensity of his gastrointestinal symptoms escalated, he developed new and progressively worsening cognitive deficits, odd behaviors, and worsening tremor, prompting emergency department evaluation. At an outside hospital, he was dehydrated with AKI (creatinine 2.51 mg/dL, eGFR 29) and lithium 4.1 mEq/L. After IV hydration, he transferred to our center with lithium 2.4 mEq/L and creatinine 1.5 mg/dL at admission. He was confused with impairments in attention, short-term memory, and orientation. He underwent three hemodialysis sessions over 48 hours. Lithium concentrations decreased progressively, falling to 0.3 mEq/L after the third session, and creatinine normalized. His confusion gradually diminished and overall cognitive function showed ongoing improvement. EEG showed nonspecific diffuse slowing; neuroimaging was unremarkable. Lithium was held during hospitalization.

Conclusion

This case highlights the risk of acute severe AKI and lithium toxicity associated with GLP-1/GIP receptor agonists. The unmonitored use of GLP-1 and GLP-1/GIP agonists in patients with bipolar disorder and other mental health conditions underscores the urgent need to educate prescribers of these agents and to develop clear guidance on lithium dose reduction, adjustment, and monitoring when these medications, especially long-acting formulations such as semaglutide and tirzepatide, are initiated. Such guidance is essential to prevent toxicity while preserving appropriate use of lithium as an effective mood stabilizer. As proposed by our group, several mechanisms may contribute to lithium toxicity in this context: delayed gastric emptying with altered lithium absorption, potential direct effects on renal function, and, most plausibly in this case, gastrointestinal adverse effects leading to poor oral intake, volume depletion, AKI, and reduced lithium clearance.