Antipsychotic Drugs and the Risk of Diabetic Complications: A Systematic Review of Observational Studies

Background: In recent years, case reports and case series have suggested an association between the use of second- (SGAs), but not first-generation antipsychotics (FGAs), also known as atypical and typical APDs, respectively, and hyperglycemic complications, notably diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS). Although this evidence is informative, there is a need for more observational studies to strengthen this body of knowledge. Objective: To conduct a systematic review of evidence established in observational studies on adverse drug events, specifically DKA and HHS, associated with the use of FGAs and SGAs. Methods: Pertinent bibliographic databases (MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL)) were searched using appropriate index phrases and keywords through October 17, 2025. Exposure included at least one United States Food and Drugs Administration (US FDA)-approved antipsychotic drug (APD); outcomes were limited to DKA and HHS. Results: A total of 15 observational studies were included in this review, including seven analytical and eight descriptive studies. These studies varied in scope and used different case definitions, study populations, exposures, and outcomes. The observational studies support existing evidence of an association between atypical APDs and DKA, mainly. As a class, typical APDs were associated with an increased risk of DKA, when compared to non-antipsychotic drug use. Although some studies evaluated this association in relation to HHS, there is insufficient information to draw conclusions for this outcome at this time. Conclusions: This analysis provides additional evidence of an association between use of atypical APDs and DKA. Additional analytical studies using administrative health databases are needed to clarify this association.