Hepatic Safety of Atypical Antipsychotics: Current Evidence and Future Directions

The newer atypical antipsychotic agents (AAPs) represent an attractive therapeutic option for a wide range of psychotic disorders, including schizophrenia and bipolar mania, because of the reduced risk of disabling extrapyramidal symptoms. However, their growing use has raised questions about their tolerability over the endocrine, metabolic, and cardiovascular axes. Indeed, atypical antipsychotic drugs are associated, to differing extents, with mild elevation of aminotransferases related to weight gain, AAP-induced metabolic syndrome, and nonalcoholic fatty liver disease. Although the hepatic safety of new AAPs seems improved over that of chlorpromazine, they can occasionally cause idiosyncratic liver injury with varying phenotypes and, rarely, lead to acute liver failure. However, AAPs are a group of heterogeneous, chemically unrelated compounds with distinct pharmacological and pharmacokinetic properties and substantially different safety profiles, which precludes the notion of a class effect for hepatotoxicity risk and highlights the need for an individualized therapeutic approach. We discuss the current evidence on the hepatotoxicity potential of AAPs, the emerging underlying mechanisms, and the limitations inherent to this group of drugs for both establishing a proper causality assessment and developing strategies for risk management.