The regulatory effects of second-generation antipsychotics on lipid metabolism: Potential mechanisms mediated by the gut microbiota and therapeutic implications

Abstract

Second-generation antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and other neuropsychiatric diseases but cause a high risk of disruption to lipid metabolism, which is an intractable therapeutic challenge worldwide. Although the exact mechanisms underlying this lipid disturbance are complex, an increasing body of evidence has suggested the involvement of the gut microbiota in SGA-induced lipid dysregulation since SGA treatment may alter the abundance and composition of the intestinal microflora. The subsequent effects involve the generation of different categories of signaling molecules by gut microbes such as endogenous cannabinoids, cholesterol, short-chain fatty acids (SCFAs), bile acids (BAs), and gut hormones that regulate lipid metabolism. On the one hand, these signaling molecules can directly activate the vagus nerve or be transported into the brain to influence appetite via the gut–brain axis. On the other hand, these molecules can also regulate related lipid metabolism via peripheral signaling pathways. Interestingly, therapeutic strategies directly targeting the gut microbiota and related metabolites seem to have promising efficacy in the treatment of SGA-induced lipid disturbances. Thus, this review provides a comprehensive understanding of how SGAs can induce disturbances in lipid metabolism by altering the gut microbiota.

Impact of clozapine monotherapy on gut microbiota and metabolism in people with schizophrenia

“…Previous studies have confirmed that antipsychotics can induce changes in the diversity and composition of the gut microbiota ( Chen et al, 2023 ). The present study also found that the α-diversity index was significantly lower in the MA group of SCM than that in the MN group of SCM, and there was also a significant difference in the β-diversity of the gut microbiota between the MA and MN groups of SCM.…”

“…This difference may be because the participants in that study were taking a wider variety of antipsychotics, unlike the present study, which included schizophrenia patients treated with clozapine monotherapy. Studies have found that taking different antipsychotic medications can have different effects on the composition and abundance of gut microbiota ( Chen et al, 2023 ). We speculate that it is this reason that accounts for this discrepancy.…”

“…Study participants met the diagnostic criteria for schizophrenia in the International Classification of Diseases, Tenth Revision (ICD-10), were Han Chinese, aged >18 years, currently on single-agent oral clozapine therapy for more than six consecutive months, and volunteered to participate. Participants in the MA group met the diagnostic criteria for metabolic syndrome of the Chinese Diabetes Association (2021) and Chen et al (2023) . In contrast, participants in MN did not meet the diagnostic criteria for metabolic syndrome.…”

“…Although certain second-generation antipsychotics alter the abundance and composition of the gut microbiota and induce metabolic disturbances in people with schizophrenia ( Chen et al, 2023 ), it is unclear whether gut microbiota is also involved in the mechanism of metabolic abnormalities caused by clozapine. Therefore, We analyzed the characterization of gut microbiota in people with schizophrenia with and without metabolic syndrome (MetS) after monotherapy with clozapine and the relationship between gut microbiota and Glycemic or lipids.…”

The footprint of gut microbiota in gallbladder cancer: a mechanistic review

“…Intestinal bacteria carry out complex metabolic activities in the gut, providing not only energy and nutrients for host growth but also active metabolites that affect human physiology ( Rossi et al., 2020 ). Microbial metabolism is responsible for producing or modifying approximately 36% of the small molecules found in the human bloodstream ( Chen et al, 2023 ). The vast range of metabolic substrates and metabolites associated with bacteria in GBC is of great significance.…”