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. Current pharmacologic 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 of major depressive disorder (MDD); however, the mechanisms responsible for the antidepressant effects of WBH are not completely understood. In a previously published trial, we randomized adults with moderate to severe MDD (Hamilton Depression Rating Scale (HDRS) score >16) to one of two interventions (WBH or sham WBH). We collected whole blood 30 min post-intervention and followed participants for 6 weeks. In these analyses, we used a high-throughput RNA sequencing (RNA-seq) approach to compare the whole-blood transcriptomic response 30 min post-intervention. Differentially expressed gene (DEG) analysis with a Benjamini-Hochberg false discovery rate (FDR)-adjusted p-value (q-value) < 0.01 identified 17 upregulated DEGs including, as expected, multiple genes encoding heat-shock proteins belonging to the heat-shock protein (HSP) 70, HSP90, and HSP110 families, but also identified upregulated DEGs associated with immune response. Resulting log-fold changes and unadjusted p-values for all genes were used in Gene Set Enrichment Analysis (GSEA), which identified 88 enriched gene sets using a Benjamini-Hochberg FDR-adjusted p-value (q-value) of <0.05) representing biological processes (BPs) including those related to heat-shock responses and immune responses, including "interleukin 6 production", which has been identified as a potential mediator of the antidepressant effects of WBH. These results are consistent with previous analyses identifying effects of WBH on heat shock response and interleukin (IL) 6 and, furthermore, identify novel genes and BPs that warrant further investigation as potential mediators of the antidepressant effects of WBH.