Off Target Effects of the Atypical Antipsychotic Clozapine Associated with Increased Infection Risk

Antipsychotic (AP) medications are increasingly recognised for their association with a heightened risk of infections. Clozapine, an atypical AP reserved for treatment-resistant schizophrenia (TRS), has been particularly linked to an elevated risk of respiratory infections. AP that exert antimicrobial properties are known to cause microbiome imbalances, fostering an environment for pathobiont colonisation. In a dysbiotic oral microbiome, colonisation with opportunistic pathogens could heighten respiratory infection risks. An increased respiratory infection trend is observed amongst patients prescribed clozapine “on” and "off-label". Our work aims to characterise the transient oral pathobiont colonisation rate linked to clozapine usage.

Saliva samples were collected from patients diagnosed with TRS prescribed clozapine and a control group not on AP or diagnosed with schizophrenia or schizoeffective disorder. Participants' background medical history and oral health were also surveyed. Identified transient pathobiont isolates underwent phenotypic and genomic analysis, including antimicrobial susceptibility testing (AST), genome sequencing, and typing of virulence factors (VFs) and antimicrobial resistance genes (ARGs).

Transient pathobionts were found in the saliva of 74% of clozapine users, with 43% showing multi-colonisation. The control group had a less than 10% colonisation rate. Sixteen species of Enterobacteriaceae and three species of Moraxellaceae were identified. All isolate genomes had genotypes of increased virulence potential, averaging 77 VF genes per genome. Notably virulent Escherichia coli and Kalamiella piersonii have been was identified encoding VF facilitating blood-brain barrier penetration. Possible patient-to-patient transmission of Enterobacter hormaechei was also noted.

Clozapine use is linked to oral transient pathobiont colonization, which may contribute to the increased risk of respiratory infections observed in antipsychotic users.