Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

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.

Automated summary

Recent postmortem transcriptomic studies have found many differentially expressed genes in schizophrenia, but the relationship between these gene expression changes and antipsychotic drug exposure is uncertain. Comparing gene expression in the prefrontal cortex of schizophrenic patients who were positive or negative for antipsychotic drugs at the time of death, we found that drug exposure had significant effects on the brain transcriptome, especially with atypical antipsychotic drugs. Macaque brain transcriptome data also showed that antipsychotic drugs affect the expression of functionally relevant genes, some of which were also changed in schizophrenia. Co-expression modules related to synaptic function had similar patterns in schizophrenia and antipsychotic drug effects, while modules associated with inflammation and glucose metabolism showed predominantly different patterns. Cell-type shifts in schizophrenia were largely unaffected by antipsychotic drug use. These findings suggest that antipsychotic drugs may confound gene expression changes related to schizophrenia in postmortem brain tissue, and unraveling these effects can help identify causal genes and improve our understanding of the neurobiology of schizophrenia.