Suche
Mein Konto
reference
Flux MC, Smith DG, Allen JJB, et al. Association between plasma cytokines and antidepressant response after mild whole-body hyperthermia in major depressive disorder.Transl. psychiatry. 2023;13(1):132.
Study objective
Determining the Effects of Whole Body Hyperthermia (WBHT) on Immune Parameters and Depressive Symptoms in Patients With Major Depressive Disorder (MDD)
Key to take away
The antidepressant effects of WBHT in the fever range correlate with the induction of interleukin 6 (IL-6) in patients with MDD, suggesting a more complex role of IL-6 in mood disorders.
design
Randomized, single-blind, sham-controlled trial
Participant
The study included 30 participants aged 18 to 65 who were medically healthy and met criteria for major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, 4ThEdition, Text Revision (DSM-IV-TR)) and achieved a score of 16 or greater on the Hamilton Depression Rating Scale (HDRS) for at least 4 weeks prior to enrollment in the study. Participants were not required to take any psychotropic medications before or during the study.
intervention
Participants were randomized to receive either a single WBHT treatment or a sham treatment. The participants in the study group were heated with a Heckel HT3000 whole-body hyperthermia device until their internal core body temperature reached 38.50C; They were then granted a one-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 WBHT treatment.
Evaluated study parameters
Researchers administered the 17-item HDRS to participants at baseline pretreatment and 1, 2, 4, and 6 weeks after WBHT/sham treatment.
Researchers 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 a.m. on the morning of treatment, 30 minutes at study intervention and 1 and 4 weeks after the interventions.
Primary outcome
The study aimed to investigate whether changes in body temperature during WBHT treatment correlate 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 after treatment (P<0.001). Increased IL-6 production was directly correlated with a reduction in HDRS values (P<0.01).
transparency
The authors disclosed 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 Barry and Janet Lang and Arch and Laura Brown. The authors' information contained no connection to the device used in the study.
Effects on practice
This study by Michael Flux and his team was the first to attempt to evaluate the effects of WBHT on immune function in relation to the symptoms of MDD. The design of the study was unique in that it attempted to use a sham/placebo treatment to minimize participant bias. Early studies of WBHT and depression showed encouraging results in reducing symptoms of MDD, but were criticized for small sample sizes and lack of controls.2
The researchers of this study had already published the results of the key results of the clinical trial, showing that WBHT significantly reduced the symptoms of MDD.1This paper investigated the relationship between changes in MDD symptoms and changes in immunological parameters. Specifically, the researchers wanted to find out whether WBHT could reduce inflammatory cytokine markers and, if so, whether these reductions correlated with symptomatic improvement.
Other research in the areas of aging and chronic/degenerative diseases has shown that disruption of immune rhythms is the key to dysregulation.
Studies on the role of immune function and inflammation in MDD have led to the recognition that MDD is associated with chronic inflammation. Meta-analysis reviews have found increased levels of depression in patients with depressionTNF-α, IL-6, IL-13, IL-18, IL-12, IL-1 receptor antagonist and serum soluble TNF receptor 2 (sTNFR2), along with reduced levels of the proinflammatory cytokine IFN-γ.3Immune-targeted therapies such as anti-IL-6 and anti-TNF agents have been shown to improve symptoms of depression and fatigue in patients.4Research into the effects of pharmacological agents such as selective serotonin reuptake inhibitors (SSRIs) andSerotonin-norepinephrine reuptake inhibitors (SNRIs) on inflammatory cytokines have had mixed results. A meta-analysis of human studies foundResearchers found that antidepressants reduce IL-1β,IL-4, IL-6 and IL-10although the effects are not consistent across drug classes.5
In this study, most inflammatory cytokines were not affected by WBHT. Only IL-6 showed a significant increase immediately after WBHT treatment but normalized in future measurements. Even more interestingly, these observed changes in IL-6 concentrations directly correlated with improvements in participants' HDRS scores. Improvement in symptoms was maximal 2 weeks after WBHT treatment. This was not what the researchers expected, and the results led them to believe that acute changes in IL-6 may have an impact on mood that is yet to be understood. A plausible explanation is that the transient increase in IL-6 is more similar to an exercise-induced increase in IL-6, which is known to have unique cellular effects compared to chronic high IL-6 effects. The researchers acknowledge that some changes in inflammatory cytokines compared to the control group may have been missed because patients in the control group received a sham treatment consisting of mild warming. This mild heating served as a low-temperature WBHT and ultimately was not a true zero 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, unproductive inflammation.6Clinically, we often treat 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 areas of aging and chronic/degenerative diseases has shown that disruption of immune rhythms is the key to dysregulation. A recent review on this 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.7Future research in this area should focus on methods to restore productive immune/inflammatory pathways. WBHT and other temporary antipyretic therapies may represent useful clinical tools not only in the treatment of depression but also in other chronic inflammatory diseases by helping to restore this important biological function.