Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus

• Published in: Molecular psychiatry 2022-04, Vol.27 (4), p.2061-2067
• Main Authors: Perzel Mandell, Kira A., Eagles, Nicholas J., Deep-Soboslay, Amy, Tao, Ran, Han, Shizhong, Wilton, Richard, Szalay, Alexander S., Hyde, Thomas M., Kleinman, Joel E., Jaffe, Andrew E., Weinberger, Daniel R.
• Format: Article
• Language: English
• Subjects: 38/23; 45; 45/91; 631/208; 631/378; 692/699/476/1799; Antipsychotics; Behavioral Sciences; Biological Psychology; Brain; Caudate nucleus; DNA methylation; Epigenetics; Gene expression; Genomes; Medicine; Medicine & Public Health; Mental disorders; Neurosciences; Pharmacotherapy; Phenotypes; Psychiatry; Psychotropic drugs; Schizophrenia; Toxicology
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01453-6

Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.