Whole-body hyperthermia shows promising antidepressant effects via anti-inflammatory pathways

New research provides preliminary evidence that whole-body hyperthermia may have antidepressant effects that operate through activation of an anti-inflammatory immune signaling pathway. The results were published in the journal Brain, behavior and immunity.

Depression is a leading cause of disability worldwide and is expected to become the leading cause of the global burden of disease by 2030. Despite the availability of various antidepressant treatments, their effectiveness remains limited for many people. This has pushed researchers to explore alternative treatments and better understand their mechanisms.

Previous research has indicated that whole-body hyperthermia reaching fever can produce rapid and sustained antidepressant effects, but the underlying biological mechanisms remain unclear. Whole-body hyperthermia involves raising the body’s core temperature to therapeutic levels, usually 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 Giolabhui, a clinician 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 idea of ​​heated therapies is new to psychiatry and also has an ancient lineage. Cultures around the world have used heat for thousands of years to promote health. I was led to understand why this happens and the likely underlying neuroimmune mechanisms that explain it.

The new study aimed to delve deeper into these mechanisms, focusing on the role of inflammatory responses, particularly interleukin-6 (IL-6), a type of cytokine, which is a protein involved in the immune response of the ‘body. IL-6 is known to play complex roles in inflammation and has been associated with depression, but its specific pathways and effects in the context of whole-body hyperthermia required further exploration.

A previous study found that whole-body hyperthermia led to a short-term increase in IL-6 levels, linked to its antidepressant effects. But high IL-6 is usually associated with depression in medical conditions. So what could explain the link between increased IL-6 and reduced depression after whole body hyperthermia? :

The researchers noted the dual signaling pathways of IL-6. IL-6 binds either to a membrane IL-6 receptor (IL-6R), triggering classical anti-inflammatory signaling, or to a soluble IL-6 receptor (sIL-6R), triggering pro-inflammatory trans-signalling. They hypothesized that the antidepressant effects of whole-body hyperthermia are due to preferential activation of the classical anti-inflammatory signaling pathway.

To examine this hypothesis, researchers conducted a double-blind, randomized, sham-controlled trial in 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 consisted of increasing the participant’s body temperature to 38.5°C using infrared lights and heating coils, followed by a cooling phase. The simulated treatment mimicked the procedure but without the active heating elements.

Participants’ depressive symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) before treatment and at several time points over the following six weeks. Blood samples were collected to measure levels of IL-6 and its soluble receptor before treatment, immediately after, and at subsequent follow-ups. The key measurement used in the study was the ratio of IL-6 to sIL-6R in the blood, which served as an indicator 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 greater reduction in depressive symptoms over the following weeks, suggesting that the antidepressant effects of whole body hyperthermia may be mediated by an anti-inflammatory mechanism involving the ‘IL-6.

Despite the promising results, the study has several limitations. First, the sample size was relatively small. This limits the generalizability of the results and highlights the need to replicate them in larger trials. Additionally, the study used the IL-6/sIL-6R ratio as an indirect measure of classical anti-inflammatory signaling. Direct assessment of where IL-6 binds in the body, whether membrane receptors or soluble receptors, is necessary to confirm the proposed mechanism.

“We do not directly measure the anti-inflammatory immune signaling pathway and use a very imprecise proxy to estimate it,” explained Mac Giolabhui. “As such, these results should be considered preliminary and suggestive rather than conclusive.”

However, if the results are confirmed in future studies, “acute activation of classical IL-6 signaling may emerge as a new, previously unrecognized mechanism that could be exploited to expand the armamentarium of antidepressants.” , 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 Giolabhui, 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.