New research provides preliminary evidence that whole-body hyperthermia may have antidepressant effects that operate through the activation of an anti-inflammatory immune signaling pathway. The findings have been published in the journal Brain, Behavior, and Immunity.
Depression is a leading cause of disability worldwide and is expected to become the largest contributor to global disease burden by 2030. Despite the availability of various antidepressant treatments, their effectiveness remains limited for many individuals. This has driven researchers to explore alternative treatments and better understand their mechanisms.
Previous research indicated that fever-range whole-body hyperthermia could produce rapid and sustained antidepressant effects, but the underlying biological mechanisms remained unclear. Whole-body hyperthermia involves raising the body’s core temperature to therapeutic levels, typically through methods such as infrared heat. This process induces a fever-like state, which can activate various physiological responses.
“I was drawn to this topic for a number of reasons,” said study author Naoise Mac Giollabhui, a clinical fellow at Massachusetts General Hospital. “There is an urgent clinical need for novel antidepressant treatments and whole-body hyperthermia is a treatment with great potential to alleviate human suffering.”
“Interestingly, the idea of heated therapies is novel in psychiatry and also has an ancient lineage. Cultures all over the world have used heat for thousands of years to promote health. I was drawn to understanding why this is and the likely underlying neuroimmune mechanisms explaining it.”
The new study aimed to delve deeper into these mechanisms, focusing on the role of inflammatory responses, specifically interleukin-6 (IL-6), a type of cytokine, which is a protein involved in the body’s immune response. IL-6 is known to play complex roles in inflammation and has been linked to depression, but its specific pathways and effects in the context of whole-body hyperthermia needed further exploration.
A prior study had found that whole-body hyperthermia led to a short-term increase in IL-6 levels, which was linked to its antidepressant effects. But elevated IL-6 is typically associated with depression in medical conditions. So what could explain the link between elevated IL-6 and reduced depression after whole-body hyperthermia?:
The researchers noted IL-6’s dual signaling pathways. IL-6 binds to either a membrane-bound IL-6 receptor (IL-6R), initiating anti-inflammatory classical signaling, or to a soluble IL-6 receptor (sIL-6R), triggering pro-inflammatory trans-signaling. They hypothesized that whole-body hyperthermia’s antidepressant effects are due to the preferential activation of the anti-inflammatory classical signaling pathway.
To examine this hypothesis, the researchers conducted a double-blind, randomized, sham-controlled trial with 26 adults diagnosed with major depressive disorder.
Participants were randomly assigned to either an active whole-body hyperthermia group or a sham (placebo) group. The active treatment involved raising the participant’s core body temperature to 38.5°C using infrared lights and heating coils, followed by a cool-down phase. The sham treatment mimicked the procedure but without the active heating elements.
Participants’ depressive symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) before the treatment and at several points over the following six weeks. Blood samples were taken to measure levels of IL-6 and its soluble receptor before the treatment, immediately after, and at subsequent follow-ups. The key measure used in the study was the ratio of IL-6 to sIL-6R in the blood, which served as a proxy for the activation of the classical anti-inflammatory signaling pathway.
The study found that participants who received whole-body hyperthermia experienced a significant increase in the ratio of IL-6 to sIL-6R immediately following the treatment. This increase was not observed in the sham group. Importantly, this heightened ratio was associated with a greater reduction in depressive symptoms over the subsequent weeks, suggesting that the antidepressant effects of whole-body hyperthermia may be mediated by an anti-inflammatory mechanism involving IL-6.
Despite the promising results, the study has several limitations. First, the sample size was relatively small. This limits the generalizability of the findings and underscores the need for replication in larger trials. Additionally, the study used the ratio of IL-6 to sIL-6R as an indirect measure of classical anti-inflammatory signaling. Direct assessment of where IL-6 binds in the body, whether to membrane-bound receptors or soluble receptors, is necessary to confirm the proposed mechanism.
“We are not measuring the anti-inflammatory immune signaling pathway directly and are using a very imprecise proxy to estimate it,” Mac Giollabhui explained. “As such, these results should be considered preliminary and suggestive, rather than conclusive.”
However, if the findings are confirmed in future studies, “the acute activation of classical IL-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium,” the researchers concluded.
The study, “The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway,” was authored by Naoise Mac Giollabhui, Christopher A. Lowry, Maren Nyer, Simmie L. Foster, Richard T. Liu, David G. Smith, Steven P. Cole, Ashley E. Mason, David Mischoulon, and Charles L. Raison.
