@article{18f949b17ca5430fa6c3c063c566c673,
title = "Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia",
abstract = "Recent postmortem transcriptomic studies of schizophrenia (SCZ) have shown hundreds of differentially expressed genes. However, the extent to which these gene expression changes reflect antipsychotic drug (APD) exposure remains uncertain. We compared differential gene expression in the prefrontal cortex of SCZ patients who tested positive for APDs at the time of death with SCZ patients who did not. APD exposure was associated with numerous changes in the brain transcriptome, especially among SCZ patients on atypical APDs. Brain transcriptome data from macaques chronically treated with APDs showed that APDs affect the expression of many functionally relevant genes, some of which show expression changes in the same directions as those observed in SCZ. Co-expression modules enriched for synaptic function showed convergent patterns between SCZ and some of the APD effects, while those associated with inflammation and glucose metabolism exhibited predominantly divergent patterns between SCZ and APD effects. In contrast, major cell-type shifts inferred in SCZ were primarily unaffected by APD use. These results show that APDs may confound SCZ-associated gene expression changes in postmortem brain tissue. Disentangling these effects will help identify causal genes and improve our neurobiological understanding of SCZ.",
keywords = "Humans, Schizophrenia/drug therapy, Antipsychotic Agents/pharmacology, Brain/metabolism, Prefrontal Cortex/metabolism, Transcriptome",
author = "Anton Schulmann and Stefano Marenco and Vawter, {Marquis P.} and Nirmala Akula and Agenor Limon and Ajeet Mandal and Auluck, {Pavan K.} and Yash Patel and Lipska, {Barbara K.} and McMahon, {Francis J.}",
note = "Funding Information: We thank the families who donated the brain of their loved ones for research, and the Offices of the Medical Examiner of the District of Columbia, Central and Northern Virginia for referrals and brain extraction. Data were analyzed on the high-performance Biowulf cluster at NIH. Brain tissue for the study was obtained from the following brain bank collections: The Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer{\textquoteright}s Disease Core Center, the University of Pittsburgh Brain Tissue Donation Program, and the NIMH Human Brain Collection Core. CMC Leadership: Panos Roussos, Joseph Buxbaum, Andrew Chess, Schahram Akbarian, Vahram Haroutunian (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur (University of Pennsylvania), Chang-Gyu Hahn (Thomas Jefferson University), Enrico Domenici (University of Trento), Mette A. Peters, Solveig Sieberts (Sage Bionetworks), Stefano Marenco, Barbara K. Lipska, Francis J. McMahon (NIMH). This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Funding Information: This research was supported by the Intramural Research Program of the NIMH (ZIA MH002810 and ZIC MH002903) and the following extramural grants: R01 MH085801 (MPV), R21 MH113177 (AL and MPV), and K22 MH126015 (AS). Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, U01MH116442, project ZIC MH002903, and contract HHSN271201300031C through IRP NIMH. Rhesus macaque tissue was provided by Scott Hemby through the Stanley Medical Research Institute for Funding for Non-Human Primate Research and funded by NIMH grant R01MH074313. Open Access funding provided by the National Institutes of Health (NIH). Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2023",
month = mar,
day = "17",
doi = "10.1038/s41398-023-02392-8",
language = "English (US)",
volume = "13",
pages = "93",
journal = "Translational psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "1",
}