A new study provides initial evidence that whole-body hyperthermia may have an anti-inflammatory effect that works by activating an anti-inflammatory signaling pathway. The findings were published in the journal Brain, behavior and immunity.
Depression is the leading cause of disability worldwide and is expected to account for the largest share of the global burden of disease by 2030. Despite the availability of various antidepressant treatments, their effectiveness is limited for many individuals. This has led researchers to investigate alternative therapies and better understand their mechanisms.
Previous studies have indicated that fever-range whole-body hyperthermia can produce a rapid and sustained antidepressant effect, but the underlying biological mechanisms are not clear. Whole-body hyperthermia involves raising the body’s core temperature to therapeutic levels, typically through methods such as infrared heat. This process produces a fever-like state, which can activate various physiological responses.
“I was drawn to this subject for a number of reasons,” said study author Naoise McGiolabhui, a clinical fellow at Massachusetts General Hospital. “There is an urgent clinical need for new antidepressant treatments, and whole-body hyperthermia is a treatment with great potential to alleviate human suffering.”
“Interestingly, the concept of heat therapy is novel in psychology, and has an ancient lineage. Cultures around the world have used heat to promote health for thousands of years. I became interested in understanding why this is and the neuroprotective mechanisms that might explain it.
The new study aims to delve deeper into these mechanisms, focusing specifically on a protein called interleukin-6 (IL-6), a type of cytokine involved in the body’s immune response. IL-6 is known to play complex roles in inflammation and is associated with depression, but its specific pathways and effects in the context of whole-body hyperthermia need further exploration.
A Preliminary study Whole-body hyperthermia induced a short-term increase in IL-6 levels, which was associated with an antidepressant effect. But elevated IL-6 is commonly associated with depression in medical conditions. So what might explain the association between elevated IL-6 and reduced depression after total body temperature?
The researchers looked at IL-6’s dual signaling pathways. IL-6 binds to the membrane-bound IL-6 receptor (IL-6R), initiating classical anti-inflammatory signaling, or to the soluble IL-6 receptor (sIL-6R), triggering pro-inflammatory trans-signaling. They hypothesized that the antidepressant effects of whole-body hyperthermia are mediated by preferential activation of the classical anti-inflammatory signaling pathway.
To test this hypothesis, the researchers conducted a double-blind, randomized, sham-controlled trial with 26 adults with major depressive disorder.
Participants were randomly assigned to either an active whole-body hyperthermia group or a sham (placebo) group. Active therapy involves raising the participant’s core body temperature to 38.5°C using infrared lights and heating batteries, followed by a cooling phase. The sham treatment mimicked the process but without the active heating elements.
Participants’ depressive symptoms were assessed at multiple points on the Hamilton Depression Rating Scale (HDRS) before treatment and over the following six weeks. Blood samples were taken to measure IL-6 levels and its soluble receptor before, immediately and after treatment. A key parameter used in the study was the ratio of IL-6 to sIL-6R in the blood, which served as a proxy for 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 after treatment. This increase was not observed in the sham group. Importantly, this increased ratio was associated with a significant reduction in depressive symptoms in the following 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 findings and emphasizes the need for replication in larger trials. In addition, 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 it is a membrane-bound receptor or a soluble receptor, is essential to validate the proposed mechanism.
“We’re not directly measuring the anti-inflammatory immune signal and we’re using a very imprecise proxy to estimate it,” Mac Giolabhui explained. “Thus, these results should be considered preliminary and encouraging rather than conclusive.”
However, if the findings are confirmed in future studies, “immediate activation of classical IL-6 signaling may emerge as a previously unrecognized novel mechanism that could be used 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.Authored by Naois Mc Jolabhui, Christopher A.