Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach

Background: Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In vitro cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function. Methods: We identified published scientific literature in the PubMed database using the following search strategy: (“antipsychotic” OR “olanzapine” OR “clozapine” OR “risperidone” OR “quetiapine” OR “haloperidol”) AND (“metabolic syndrome” OR “insulin action” OR “insulin resistance” OR “up-regulation” OR “down-regulation” OR “dyslipidemia”) AND (cell models). Results: Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS. Conclusions: Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level. In the final section of the manuscript, we highlight the potential of individual-specific stem-cell–based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.