Whole-blood transcriptomic response to whole-body hyperthermia in participants with major depressive disorder

Depression is the leading cause of global disability according to the World Health Organization, and Major Depressive Disorder (MDD) makes up a majority of these cases. Current pharmacological interventions suffer from significant limitations and side effects, highlighting a need for novel therapeutic approaches. Whole-body hyperthermia (WBH) has been identified as a promising avenue of treatment; however, a comprehensive understanding of the mechanisms responsible for the antidepressant effects of WBH remains elusive. In this study we utilized high-throughput RNA sequencing (RNA-seq) to compare the whole-blood transcriptomic response, 30 minutes post intervention, of participants with MDD exposed to WBH or sham WBH. Briefly, 34 individuals with moderate to severe MDD (HDRS score > 16) were randomized to a WBH (n = 17) or sham WBH (n = 17) condition. Of 34 participants who were randomized, 22 participants provided blood samples (13 WBH and 9 sham WBH) that were available for sequencing, and 18 participants provided blood samples (9 WBH [33% female] and 9 sham WBH [44% female]) that were included in final RNA-seq analysis. Through differentially expressed gene (DEG) analysis with a false discovery rate (FDR) adjusted p-value (q-value) < 0.01 we identified 17 upregulated DEGs including multiple genes encoding heat-shock proteins (e.g., HSP70 [HSPA1A, HSPA1B, HSPA4], HSP90 [HSP90AB1, HSP90AA1], and HSP110 families [HSPH1]). Resulting log-fold changes and unadjusted p-values for all genes were used in Gene Set Enrichment Analysis (GSEA), which identified enriched (family-wise error rate-adjusted p-value < 0.05) biological processes (BPs) including “chaperone mediated protein folding”, “chaperone cofactor dependent protein refolding”, “cellular response to heat”, “positive regulation of response to cytokine stimulus”, “B cell receptor signaling pathway”, “peptide antigen assembly with MHC protein complex”, “positive regulation of type I interferon production”, and “positive regulation of interferon beta production”. These data identify novel genes and BPs that warrant further investigation as potential mediators of the antidepressant effects of WBH.