For centuries, different cultures around the world have embraced traditions that utilize hyperthermia as a means of promoting health and well-being. These practices, including Finnish saunas, Russian banyas, and Japanese onsen (hot spring baths), use different techniques for raising the core body temperature; however, we are only now being to understand the health benefits of hyperthermia.
New research indicates that whole-body hyperthermia (WBH) may be a promising new treatment for major depressive disorder (MDD). WBH involves raising the body’s core temperature, typically to about 38.5°C to 38.9°C (101.3°F to 102°F), for 60 to 120 minutes. Previous studies have demonstrated that a single session of WBH can produce rapid and sustained antidepressant effects that last up to six weeks post-treatment.
Exactly how hyperthermia elicits these antidepressant effects is not fully understood. Researchers have hypothesized that WBH activates warm-sensitive thermosensory pathways in the skin that project to specific subcortical and cortical regions of the brain and may thus affect neural activity and behavior. Another hypothesis is that the antidepressant effects of WBH may reflect modulation of the immune system; because inflammation is associated with depressive disorders, researchers speculate that anti-inflammatory pathways triggered by hyperthermia may be responsible for its antidepressant effects.
Whole-Body Hyperthermia and Interleukin-6 Signaling Pathways
To better understand the effects of hyperthermia on the immune system, Naoise Mac Giollabhui, PhD and colleagues from the Mass General Depression Clinical and Research Program examined changes in interleukin-6 (IL-6) signaling in a group of patients treated with WBH or a sham intervention. This research builds on the findings of an earlier study (Flux et al, 2023) demonstrating that WBH resulted in increased plasma levels of IL-6 (but not other cytokines) immediately post-treatment and that this acute increase in IL-6 levels seen immediately after treatment was associated with reduced depressive symptoms over the course of the six weeks of follow-up.
These findings are somewhat paradoxical, given that elevated levels of IL-6 and other cytokines are typically associated with inflammation and worsening or persistent depressive symptoms. Mac Giollabhui notes that IL-6 has both anti- and pro-inflammatory activities, and he hypothesized that WBH may preferentially activate the anti-inflammatory classical signaling pathway of IL-6 rather than the pro-inflammatory trans signaling pathway and that activation of the anti-inflammatory IL-6 signaling pathway is responsible for the antidepressant effects of WBH.
In order to test this hypothesis, data from a 6-week, randomized, double-blind study comparing whole-body hyperthermia with a sham intervention was analyzed. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized to receive whole-body hyperthermia or a sham intervention. Participants were free of psychotropic medications at study entrance and for the duration of the study. In this study, 26 individuals were randomized to receive whole-body hyperthermia (n = 12; 75 % female) or sham (n = 14; 57.1 % female).
The research team observed an acute, time-limited increase in the ratio of interleukin-6 (IL-6) to soluble IL-6 receptors that was indicative of activation of the anti-inflammatory classical signaling pathway This was not observed in those receiving the sham intervention. And most importantly , this increase in the ratio between IL-6 and soluble IL-6 receptors was associated with the antidepressant effects of whole-body hyperthermia over the subsequent weeks of the study.
Targeting the Classical IL-6 Signaling Pathway
The current study suggests that preferential activation of the classical (anti-inflammatory) IL-6 signaling pathway rather than the pro-inflammatory trans signaling pathway may mediate—at least in part—the antidepressant effects of WBH. Interestingly, a number of other interventions with antidepressant effects, including electroconvulsive therapy, ketamine, physical exercise, and sleep deprivation, have been observed to trigger transient increases in IL-6 levels. This is the first study to examine whether a specific antidepressant treatment is associated with a biomarker of classical IL-6 signaling.
There is considerable data indicating that inflammation, and specifically dysregulation of IL-6 signaling, may play a role in the etiology and maintenance of psychiatric disorders, at least in some individuals, and there has been a push to develop antidepressant interventions with anti-inflammatory properties. While further research is needed to explore the optimal parameters for WBH, such as the intensity and frequency of treatments, in order to maximize its therapeutic potential, this information will help to better understand and to develop novel antidepressant treatments. Mac Giollabhui notes that activation of the classical IL-6 signaling pathway may represent a previously unrecognized mechanism for antidepressants that could be harnessed to expand our antidepressant armamentarium.
Read More
Mac Giollabhui N, Lowry CA, Nyer M, Foster SL, Liu RT, Smith DG, Cole SP, Mason AE, Mischoulon D, Raison CL. The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway. Brain Behav Immun. 2024 Jul; 119:801-806.
Mac Giollabhui N, Foster S, Lowry CA, Mischoulon D, Raison CL, Nyer M. Interleukin-6 receptor antagonists in immunopsychiatry: Can they lead to increased interleukin-6 in the central nervous system (CNS) and worsening psychiatric symptoms? Brain Behav Immun. 2022 Jul; 103:202-204.
