Discussion
obesity, WBH, reductions in peripheral inflammation, reduced depression, MDD, depression, hyperthermia
ACUTE INFECTION, OBESITY, CHRONIC INFLAMMATION, CENTRAL NERVOUS SYSTEM INFLAMMATION, HEAT, PATHOGENESIS
This examination of cytokine responses to a single session of mild-intensity WBH versus sham treatment in participants with MDD provided disconfirmatory evidence for the a priori hypothesis that WBH would produce an antidepressant effect in association with reductions in peripheral inflammation. Indeed, within the constraints imposed on our ability to detect smaller effect sizes because of the modest study sample, WBH had no long-term effect on any of the assayed immune biomarkers. On the other hand, WBH produced a large effect size immediate increase in IL-6 that resolved completely within a week of treatment. This acute IL-6 response was shown to moderate the effect of treatment, such that, in the study sample as a whole, larger immediate IL-6 responses to treatment (WBH and sham groups combined) were associated with reduced HDRS depression scores over the 6-week follow-up period, with this effect being numerically maximal at post-treatment week 2 when examined by simple correlations. We suspect that the failure to observe a group x time x post-intervention IL-6 interaction for this effect results from the fact that our sham condition might be better characterized as low-dose WBH. The provision of heat in the sham condition—while useful for blinding—significantly raised core body temperature in many of the subjects, and thereby blurred between-group differences in acute IL-6 response. In fact, two participants in the sham group reached a higher maximum core body temperature than the core body temperature reached by WBH participants who had the smallest increase in core body temperature with treatment.The finding that increased circulating levels of IL-6 were associated with reduced depression seems counter-intuitive given multiple lines of evidence implicating IL-6 in the pathogenesis of MDD. Indeed, increased baseline circulating IL-6 is among the most replicable immune findings in individuals with MDD who are otherwise healthy [These findings must be balanced against an intriguing set of contradictory observations, consistent with the fact that IL-6 is a pleiotropic cytokine with anti-inflammatory and neurotrophic effects, in addition to its proinflammatory effects [Importantly, exercise is not the only antidepressant or mood elevating modality reported to induce acute increases in IL-6. Electroconvulsive therapy (ECT), bright light exposure, sleep deprivation, fasting, and ketamine have also been reported to have this effect [As with ketamine and fasting, it is possible that the association between increased IL-6 and reduced depression in response to WBH might reflect the ability of IL-6 to induce anti-inflammatory cytokines with neurotrophic properties, in particular IL-4, which promotes stress resilience, neurogenesis, and protection against the damaging effects of central nervous system inflammation [Nonetheless, both the sources and therapeutic relevance of IL-6 induction in response to WBH and other antidepressant modalities are poorly understood. Nor is it known whether increases in IL-6 reflect enhanced biological signaling or are a compensatory response to inhibition of IL-6-inducible downstream pathways, such as STAT3 [The current study has a number of strengths [e.g., believability of the sham condition, i.e., 71% of sham-treated patients believed they received active WBH [An additional limitation is the fact that acute post-treatment immune measures were only assessed once, immediately after the WBH session, and not assessed again until a week later. Because of this, it cannot be determined whether the effect of WBH on circulating cytokines was maximal at the time point of our assessment, raising the possibility that other cytokines may have shown an association with WBH at later time points in the acute response. Subsequent studies that more completely characterize the time course of the acute cytokine response (i.e., within the first 24 h) to WBH may therefore uncover additional effects and/or relationships not apparent from our one assessment immediately post-WBH. Finally, a larger sample size might have allowed the detection of smaller effects of WBH on longer-term plasma cytokine concentrations and/or smaller associations between such effects and changes in depression. In future studies, it will also be important to explore other longer-term mechanisms that may have been activated by the acute IL-6 stimulus, including immune effects in targeted tissues (i.e., brain) and/or non-immune pathways.In conclusion, results from this study suggest a hitherto unrecognized relationship between hyperthermia, the immune system, and depression, and may point to WBH as a potential modality for exploring behavioral effects of IL-6 in isolation from the inflammatory mediators (e.g., TNF, IL-1-beta) that activate the cytokine in the context of acute infection or in response to the triggers for chronic inflammation (e.g., obesity, sedentary lifestyle) that are all too common in the modern world. Future research should seek to replicate these findings in a larger participant sample and more thoroughly characterize the complete time course of the acute cytokine response to WBH. Finally, the availability of commercially available IL-6 antagonists, raises the interesting possibility that blocking the acute IL-6 response might attenuate longer-term antidepressant effects of the procedure.