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bioRxiv · 10.64898/2026.06.24.734301

A Meta-Analysis of the Converging Effects of Different Classes of Antipsychotics on the Frontal Cortex Transcriptome in Laboratory Rodents and Non-Human Primates

Bhuiyan, M. R.·Hagenauer, M. H.·Geoghegan, E. M.·Flandreau, E. I.·Watson, S. J.·Akil, H.
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Abstract

BackgroundPsychotic illnesses are among the most debilitating classes of psychiatric disorders, requiring targeted and effective treatment strategies. Although antipsychotics are the primary pharmacological therapy for psychosis, their full range of effects remain unclear, including effects within the frontal cortex, a brain region linked structurally and functionally to psychotic disorders. MethodsTo examine the effects of antipsychotic treatment on the frontal cortex, we conducted a meta-analysis of publicly available rodent (rat, mice) transcriptional profiling datasets (microarray, RNA-Seq). Five datasets (GSE45229, GSE93918, GSE2547, GSE4031.1, GSE66275) were identified within the Gemma database using pre-specified search terms and inclusion/exclusion criteria (date: 7/7/2024), yielding differential expression results for eight drug vs. control comparisons (collective n=68). A random-effects meta-analysis model was fit to the log2 fold changes for each gene, and p-values adjusted for false discovery rate (FDR), with follow-up analyses exploring robustness, heterogeneity, and publication bias. To increase the power and generalizability of our findings, an exploratory meta-analysis was also run incorporating antipsychotic effects from both rodents and nonhuman primates (collective n=101), and compared to findings from individuals with schizophrenia. ResultsOur meta-analysis yielded stable estimates for 12,190 genes, identifying 63 genes that were differentially expressed following antipsychotic treatment ("DEGs", FDR<0.05). Differential expression included genes important for serotonergic and cholinergic signalling, and was enriched within pathways linked to oligodendrocyte development and myelination, physiological and cellular stress responses, and cardiovascular function. An exploratory meta-analysis combining rodent and nonhuman primate results confirmed these observations and yielded additional findings (117 DEGs total). Comparisons with human post-mortem findings suggested that some schizophrenia-related gene expression may instead reflect antipsychotic treatment. ConclusionFurther validation is necessary, but our findings suggest that antipsychotics may assist in the regulation of specific structural and functional changes within the frontal cortex linked to psychotic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/734301v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1aaa2ecorg.highwire.dtl.DTLVardef@1ae6819org.highwire.dtl.DTLVardef@13454a2org.highwire.dtl.DTLVardef@a0877c_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIPsychosis is treated using two broad types of antipsychotic medication: first-generation (typical) and second-generation (atypical). C_LIO_LIUnderstanding the congruent effects of different types of antipsychotics on regions important for psychosis, such as the frontal cortex, can highlight essential mechanisms. C_LIO_LIA meta-analysis of public transcriptional profiling datasets identified genes and functional gene sets that are differentially expressed across antipsychotic categories. C_LI

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Bhuiyan, M. R., Hagenauer, M. H., Geoghegan, E. M., Flandreau, E. I., Watson, S. J., Akil, H.. 2026-06-29. A Meta-Analysis of the Converging Effects of Different Classes of Antipsychotics on the Frontal Cortex Transcriptome in Laboratory Rodents and Non-Human Primates. https://doi.org/10.64898/2026.06.24.734301

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