Biomarkers that are clinically useful for the diagnosis and treatment of schizophrenia are lacking. Biomarkers are critical tools that reduce the incidence of misdiagnosis, identify subgroups of patients, assist in the proper characterization of patient phenotypes, predict response to treatment or the development of side effects, and can serve as targets for novel therapeutic interventions. In this study, we evaluated small (< 200 nucleotide) and long (> 200 nucleotide) RNAs found in extracellular vesicles (EVs) isolated from the cerebrospinal fluid (CSF) and plasma of individuals with schizophrenia spectrum disorders (SSD) and healthy volunteers (HV). As EVs carry cargo from all tissues in the body, they act as a potential proxy for the tissue of origin, including cells from the brain. We compared the transcriptomic features of EVs from these two biofluids and examined their ability to discriminate between SSD and HV participants, identifying a total of 141 differentially expressed genes, some of which have been previously associated with SSD. Next, we evaluated the potential cell-types that give rise to the SSD-associated CSF RNA cargo, and found the majority were predominantly expressed in excitatory neurons. Our results highlight the potential of EVs as both a source of schizophrenia relevant biomarkers, and molecular insight into disease mechanisms.

JAG has participated as site PI in multi-site, industry sponsored studies by Neurocrine and Click Therapeutics. AKM is a consultant for the Dedham Group, Iqvia, and MEDAcorp. All other authors have nothing to disclose.

This study was funded in parts by a NARSAD Young Investigator Grant (PI: JAG) from the Brain & Behavior Research Foundation and a K23MH100264 from the National Institute of Mental Health (PI: JAG).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of the Northwell Health System and The Institutional Review Board of NewYork-Presbyterian Hospital gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.