Reference
Flux MC, Smith DG, Allen JJB, et al. Association of plasma cytokines and antidepressant response following mild-intensity whole-body hyperthermia in major depressive disorder. Transl Psychiatry. 2023;13(1):132.
Study Objective
To determine the effects of whole-body hyperthermia (WBHT) on immune parameters and depressive symptoms in patients with major depressive disorder (MDD)
Key Takeaway
The antidepressant effects of fever range WBHT are correlated with the induction of interleukin 6 (IL-6) in patients with MDD, indicating a more complex role for IL-6 in mood disorders.
Design
Randomized, single-blind, sham-controlled trial
Participants
The trial involved 30 participants aged 18 to 65 years who were medically healthy, met the criteria for major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]), and scored 16 or greater on the Hamilton Depression Rating Scale (HDRS) for at least 4 weeks prior to study enrollment. Participants needed to be off psychotropic medications prior to and during the study.
Intervention
Participants were randomized to receive either a single WBHT treatment or sham treatment. Participants in the study group were heated using a Heckel HT3000 whole-body hyperthermia device until their internal core body temperature reached 38.5 0C; they were then allowed a 1-hour cooldown. Participants in the sham group used the same device, but the session consisted of a mild-heating coil, fan noise, and colored lights to simulate a WBHT treatment.
Study Parameters Assessed
Investigators administered the 17-item HDRS to participants at pretreatment baseline and at 1, 2, 4, and 6 weeks after WBHT/sham treatment.
Investigators measured cytokines, including interferon (IFN)-gamma, interleukin (IL) 1-alpha, IL-1-beta, IL-4, IL- 6, IL-8, IL-10, IL-12p70 (heterodimer), and tumor necrosis factor (TNF; active trimer), in plasma at 8:30 am on the treatment morning, 30 minutes at study intervention, and 1 and 4 weeks post interventions.
Primary Outcome
The study was designed to assess whether changes in body temperature during WBHT treatment correlated with changes in MDD symptoms and cytokine levels.
Key Findings
In this study, WBHT-induced increases in body temperature directly correlated with increased production of IL-6 post treatment (P<0.001). Increased IL-6 production was directly correlated with reductions in HDRS scores (P<0.01).
Transparency
The authors provided their full funding sources and affiliations in the initial publication of the clinical trial.1
Funding for this study was provided by the Brain & Behavior Research Foundation (Independent Investigator Award), the Depressive and Bipolar Disorder Alternative Treatment Foundation, the Institute for Mental Health Research, the Braun Foundation, and from Barry and Janet Lang and Arch and Laura Brown. The authors’ disclosures did not involve a relationship with the device being used in the study.
Practice Implications
This study by Michael Flux and team was the first to attempt to assess the effects of WBHT on immune function relative to symptoms of MDD. The study’s design was unique in that it attempted to deliver a sham/placebo treatment to minimize participant bias. Early studies in WBHT and depression showed encouraging results in reducing symptoms of MDD but were criticized for small sample size and lack of controls.2
Other research in the fields of aging and chronic/degenerative disease has shown that disruption in immune rhythms is key to dysregulation.
Research into the role of immune function and inflammation in MDD has led to the finding that MDD is associated with chronic inflammation. In metanalysis reviews, patients suffering from depression were found to have increased levels of TNF-α, IL-6, IL-13, IL-18, IL-12, IL-1 receptor antagonist, and serum-soluble TNF receptor 2 (sTNFR2), along with decreased levels of the proinflammatory cytokine IFN-γ.3 Immune-targeted therapies such as anti-IL-6 and anti-TNF agents have been shown to improve symptoms of depression and fatigue in patients.4 Research into the effects of pharmacological agents, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), on inflammatory cytokines has had mixed results. In a metanalysis review of human studies, researchers found that antidepressant medications reduce IL-1β, IL-4, IL-6, and IL-10, although the effects are not uniform across medication classes.5
In this study, most inflammatory cytokines were not affected by WBHT. Only IL-6 showed a significant increase immediately post WBHT treatment, but normalized in future measurements. Even more interesting was that these observed changes in IL-6 concentrations directly correlated with improvements in participants’ HDRS score. The improvement in symptoms was maximal 2 weeks after WBHT treatment. This was not what researchers were expecting, and the findings led them to posit that acute changes in IL-6 may have a yet-to-be understood impact on mood. A plausible explanation is that the transient rise in IL-6 is more akin to exercise-induced increases in IL-6, which are known to have unique cellular effects when compared to chronically high IL-6 actions. Researchers acknowledge that some changes in inflammatory cytokines relative to the control group may have been missed since patients in the control received a sham treatment consisting of mild heating. This mild heating served as a low-temperature WBHT and, ultimately, was not true null-treatment control.
This study shows us that we need to think differently about inflammation and chronic diseases like MDD, which have long been associated with low-grade, chronic, nonproductive inflammation.6 Clinically, we often approach these cases with anti-inflammatory therapies to reduce the impact of inflammation on degenerative trends. In this study, Flux and his team showed that MDD symptoms were positively affected by WBHT through transient increases in IL-6, while there were no reductions in other inflammatory mediators.
Other research in the fields of aging and chronic/degenerative disease has shown that disruption in immune rhythms is key to dysregulation. A recent review on the topic by Keyu Su et al summarized the evidence that loss of circadian immune rhythm is caused by a variety of genetic, epigenetic, and metabolic mechanisms and is associated with depression and altered inflammatory cytokine patterns.7 Future research in this field should focus on methods to restore productive immune/inflammatory pathways. WBHT and other transient fever-inducing therapies may provide useful clinical tools in the treatment not only of depression, but other chronic inflammatory diseases by helping to restore this important biological function.
