Metabolic syndrome (MetS) is prevalent in patients with schizophrenia (SCZ); highest amongst those on antipsychotics, driving cardiovascular risk and premature mortality. While previous studies have investigated the nuanced connections between SCZ and MetS, gaps remain in understanding pathways driving long-term metabolic outcomes. This narrative review addresses these gaps by comparing drugtargeted mechanisms of metabolic risk in SCZ and aims to inform personalized treatment regimens. Review of randomized controlled trials (RCTs), meta-analyses and longitudinal studies from 2006-2025 was conducted, focusing on effects of antipsychotics on metabolism in those with SCZ. OpenEvidence, PubMed, Embase, Cochrane Review, and ClinicalTrials.gov were used and scanned with the following MeSH terms: SCZ, metabolism, antipsychotics, cardiovascular, diabetes. Through literature analysis, trends in receptor modulation, downstream intracellular pathways, and organ system-specific effects were used to compare the mechanisms behind metabolic outcomes shared amongst many antipsychotics. 18 total antipsychotics were investigated, including haloperidol, chlorpromazine, clozapine, olanzapine, aripiprazole, risperidone, xanomeline-trospium chloride (KarXT). Through potent central and peripheral receptor binding, alterations to appetite, inflammation, and glucose/lipid-related processes occur via activation of ER stress, MAPK, AMPK, TLR4, and NF-kB signaling pathways. Findings demonstrate that olanzapine and clozapine induce dyslipidemia, polyphagia, and insulin desensitization. In comparison, xanomeline likely enhances insulin secretion via M3 receptor agonism. Thus, patients with SCZ and type 2 diabetes (T2D) may benefit from therapies like KarXT. Nonetheless, there were limitations in data interpretation, population access, and study duration. Future directions should involve long-term RCTs that evaluate metabolic outcomes of novel vs. conservative antipsychotic regimens in patients with SCZ.
