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This meta-analysis examined gene expression changes in the frontal cortex of laboratory animals treated with antipsychotic medications, analyzing five public datasets comprising 68 rodent subjects and expanding to 101 subjects when including non-human primates. The study identified 63 genes significantly altered by antipsychotic treatment, primarily affecting pathways related to brain myelination, serotonergic and cholinergic signaling, stress responses, and cardiovascular function. Comparison with human postmortem data suggests some gene expression changes previously attributed to schizophrenia itself may actually result from antipsychotic treatment rather than the disease.
Why it matters
These findings help distinguish between molecular changes caused by psychotic disorders versus those induced by their treatment, which is crucial for developing more targeted therapies with fewer side effects. The identification of specific biological pathways affected by antipsychotics may also guide the development of new medications and help clinicians better understand the full range of effects these drugs have on brain structure and function.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Psychotic 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. Methods: To 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. Results: Our 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. Conclusion: Further 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.