MON-632 Ziprasidone-associated Diabetic Ketoacidosis

Abstract Disclosure: A. Gonell: None. E. Jalal: None. S.R. Saul: None. P.D. Greenberg: None. Introduction: Despite awareness of second-generation antipsychotics' (SGAs) metabolic side effects, diabetic ketoacidosis (DKA) linked to ziprasidone is rare. This case highlights potential DKA risk with long-term ziprasidone use and underscores the need for regular diabetes monitoring. Case: A 58-year-old male with a history of hypertension, cerebrovascular accident, and schizophrenia managed with long-term ziprasidone presented with progressive altered mental status, polydipsia, polyuria, and weight loss over several months. He was lethargic, weak, and had nausea/vomiting. Labs revealed glucose 1418 mg/dL, pH 7.11 (n = 7.35 - 7.45), anion gap 45.4 mEq/L (n = 4 - 12 mEq/L), and +serum acetone, consistent with severe DKA. HbA1c was >15.5% (n < 5.7%, 6.2% one year prior). He was admitted to the Intensive Care Unit and treated per DKA protocol with an insulin drip, hydration, electrolyte repletion, transitioned to a basal-bolus insulin regimen, and saw a full recovery. Islet cell (ICA), zinc transporter (ZnT8), glutamic acid decarboxylase (GAD-65), and insulin antibodies (IAA) were negative. Two months later, C-Peptide was 4.1 ng/mL (n = 0.5 - 2 ng/mL). Review of medications revealed over 10 years of intermittent ziprasidone use. His psychiatrist confirmed ziprasidone was prescribed but taken as-needed for auditory hallucinations without regular refills. The patient’s partner was not aware of recent use. Conclusion: SGAs are linked to weight gain, glucose intolerance, dyslipidemia, and hypertension, most commonly associated with olanzapine and clozapine (Pillinger et al., 2020; Guenette et al., 2013). Proposed long-term mechanisms for development of DKA include metabolism dysregulation, insulin signaling impairment, intrinsic pancreatic β-cell dysfunction, immune modulation, and increased counter-regulatory hormones (Bae et al., 2024). Ziprasidone’s receptor antagonism of 5-HT2A, 5-HT1D, D2, and agonism of 5-HT1a may contribute to development of metabolic syndrome (Goodnick, 2001). In the absence of metabolic syndrome, SGAs may still induce acute hyperglycemia, especially within 6 months of initiation (Bae et al., 2024). Animal studies suggest olanzapine induces PERK-mediated β-cell apoptosis (Ozasa et al., 2013). Our case suggests a possible dose/time-dependent relationship between ziprasidone and DKA. A previous case documented DKA after >10 years of ziprasidone use with profound hyperglycemia at 1114 mg/dL, similar to our patient (Thanikonda et al., 2020). Alternatively, our patient’s intermittent use of ziprasidone may have served as an acute trigger for his presentation. The life-threatening nature of DKA necessitates regular glycemic monitoring and control. Most SGA-associated DKA cases occur shortly after initiation, but ziprasidone-associated DKA long after initiation underscores the need for both early and long-term monitoring. Presentation: Monday, July 14, 2025