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Published in final edited form as: Brain Behav Immun. 2024 Apr 26;119:801–806. doi: 10.1016/j.bbi.2024.04.040

The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway

Naoise Mac Giollabhui 1, Christopher A Lowry 2, Maren Nyer 1, Simmie L Foster 1, Richard T Liu 1, David G Smith 3, Steven P Cole 4, Ashley, E Mason 5, David Mischoulon 1, Charles L Raison 6,7,8
PMCID: PMC11670333  NIHMSID: NIHMS1993900  PMID: 38677624

Abstract

There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18–65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n=12; 75% female; age=37.9 years (SD=15.3) or sham [n=14; 57.1% female; age=41.1 years (SD=12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72)=11.73, p<.001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B=–229.44, t=−3.82, p<.001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.

Keywords: Depression, Randomized Clinical Trial, Whole-body Hyperthermia, interleukin-6, Soluble Interleukin-6, Mechanism, Treatment

1. Introduction

Depression is the leading cause of global disability (Friedrich, 2017) and is projected to be the greatest contributor to global disease burden by 2030 (Hock et al., 2012). Existing antidepressant treatments are only modestly effective (Trivedi et al., 2006), highlighting the importance of identifying new antidepressant treatments and understanding their mechanism of action.

Fever-range whole-body hyperthermia (WBH) produces a rapid and sustained antidepressant effect (Beever, 2010; Hanusch et al., 2013; Naumann et al., 2017; Nyer et al., 2019), as previously reported in the primary outcomes paper of this clinical trial (Janssen et al., 2016). Subsequent secondary analysis from this clinical trial examining the impact of WBH on circulating inflammatory cytokines found that WBH was associated with an acute and transitory increase in plasma concentrations of the cytokine interleukin-6 (IL-6), but not other cytokines (e..g., tumor necrosis factor-alpha, IL-1α, IL-1β, IL-4, IL-8), and that increased IL-6 was associated with the antidepressant effect of WBH (Flux et al., 2023). That increased IL-6 signaling in the context of WBH may exert an antidepressant effect appears counterintuitive as circulating IL-6 concentrations are markedly elevated in medical conditions associated with depression (e.g., autoimmune diseases/COVID-19 infection) (Irwin and Miller, 2007; Mac Giollabhui et al., 2022; Potere et al., 2021) and milder elevations are reliably observed in depression (Kohler et al., 2017; Mac Giollabhui et al., 2021; Miller and Raison, 2016). Paradoxically, however, WBH and a number of other interventions with antidepressant effects (e.g., electroconvulsive therapy, ketamine, physical exercise, fasting, sleep deprivation and sunlight exposure) have been observed to induce acute increases in IL-6 (Gay et al., 2021; Li et al., 2017; Raison et al., 2018).

A resolution of this paradox may lie in the fact that IL-6 signals via at least two pathways: a classical anti-inflammatory pathway that is activated when IL-6 binds to the membrane-bound IL-6 receptor (IL-6R) to form a complex on the relatively few cells that express membrane-bound IL-6R (e.g., monocytes, neutrophils, macrophages, some T cells) and a proinflammatory trans-signaling pathway that is activated when a soluble IL-6R (sIL-6R)/IL-6 complex binds with the ubiquitously expressed glycoprotein-130. An ongoing challenge in psychoneuroimmunology research is interpreting high levels of IL-6 when elevated levels of IL-6 can exert both pro- and anti-inflammatory effects depending on whether increased IL-6 activates membrane-bound or soluble IL6Rs (this simplification is broadly accurate but ignores other important processes, such as trans-presentation and the role of soluble glycoprotein 130 – for excellent reviews, see (Del Giudice and Gangestad, 2018; Rose-John et al., 2023). The therapeutic relevance of selectively inhibiting specific IL-6 signaling pathways has been demonstrated in preclinical and autoimmune conditions (e.g., inflammatory bowel disease) (Rose-John, 2021). Although preliminary reports suggest an important positive association between biomarkers of IL-6 trans-signaling and depressive symptoms, the relative roles of classical vs. trans IL-6 signaling in the context of depression remains untested.

The current study investigated whether the previously observed association between increased IL-6 and reduced depression following WBH reflects of preferential activation of the anti-inflammatory classical signaling pathway. In a double-blind, randomized, sham-controlled 6-week trial of WBH in adults with major depressive disorder, we hypothesized that a biomarker of higher levels of classical IL-6 signaling (the ratio of IL-6:sIL-6R) immediately following WBH (but not prior to WBH) would be associated with greater reductions in clinician-rated depression severity across the post-intervention study period (Weeks 1, 2, 4, 6). This proxy for classical IL-6 signaling has previously been reported on (Villar-Fincheira et al., 2021) and assumes that an increase in IL-6 above and beyond levels of sIL-6R (i.e., IL-6:sIL-6R ratio) is more likely to bind with membrane-bound IL-6R to activate anti-inflammatory signaling pathways (rather than sIL-6R-mediated trans-signaling).

2. Material and methods

2.1. Participants

Complete details on this clinical trial, including study design, recruitment, inclusion/exclusion criteria, primary behavioral and cytokine-based outcomes, and adverse events, have been reported elsewhere (Flux et al., 2023; Janssen et al., 2016). Participant flow is described in Supplementary Figure 1. Briefly, the study was approved by the University of Arizona Institutional Review Board and pre-registered on ClinicalTrials.gov (NCT01625546).

Participants provided signed informed consent following a full description of study procedures, risks and potential benefits and prior to conducting any study procedures. Participants were medically healthy males and females aged 18–65 years who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a major depressive episode of ≥4 weeks duration at screening with a baseline 17-item Hamilton Depression Rating Scale (HDRS) score ≥16. Participants were free of psychotropic medications at study entrance and for the duration of the study.

2.2. Study Design

Participants were randomized with 1-to-1 allocation in blocks of 6 to receive a single WBH versus sham WBH session. For the active condition, a Heckel HT3000 system delivered WBH at the level of the chest by infrared lights and at the level of the lower extremities by infrared heating coils until the participant’s core body temperature reached 38.5°C/101.3°F; this was followed by a 60-min cool-down phase. The sham procedure was identical to the active condition, except that the Heckel HT3000’s primary infrared lights were not turned on, and lighting/noise were added to simulate the active condition. Exposure duration was matched in active and sham conditions.

Depressive symptoms were assessed on intervention day prior to study intervention and at post-intervention weeks 1, 2, 4 and 6 by trained raters using the HDRS. A baseline blood draw occurred on the morning of the intervention; blood was drawn ≤30 minutes of intervention completion and during the morning at weeks 1/4 post-intervention. The blood draw and the evaluation of depressive symptoms both occurred on the same day for intervention day, week 1 and week 4 assessments; blood was drawn between 8:30AM and 9:30AM to control for potential circadian variation (except for the post-intervention blood draw). Plasma concentrations of IL-6 were assessed using recommended guidelines; methods and data have been previously reported in detail (Flux et al., 2023).

2.3. Assessment of Plasma Concentrations of the Plasma Soluble IL-6 Receptor

Plasma sIL-6R concentrations were assessed using enzyme-linked immunoassay (Life Sciences, Cat. no. KHR0061; intra-assay%CV, 5.8; inter-assay%CV, 9.4). As a proxy measure, (Villar-Fincheira et al., 2021), classical IL-6 signaling was indexed as the ratio of plasma IL-6 (pg/mL) to plasma sIL-6R (pg/mL) (IL-6:sIL-6R ratio). For descriptive statistics on plasma concentrations of IL-6/sIL-6R over time, see Supplementary Table 1.

2.4. Statistical Analyses

In this secondary analysis, participants were included if they completed ≥2 blood draws (pre- and post-intervention) and HDRS assessments (baseline and at least observation post-intervention). Missing data were imputed using expectation maximization; Little’s MCAR tests indicated that missingness of the data was independent of both the observed and unobserved data. (Little, 1988).

Of the 14 sham participants, 9 had complete IL-6:sIL-6R ratio data and 11 had complete HDRS data. All WBH participants had complete data. Group differences in baseline sociodemographic/clinical variables were investigated using independent-sample t-tests and chi-square tests. Differences in IL-6:sIL-6R ratios over time were determined using repeated measures ANOVA; pairwise comparisons tested for differences at each timepoint. Hierarchical linear models (HLM) were used to determine the effect of the IL-6:sIL-6R ratio by treatment group on HDRS score over time. Models included as covariates baseline HDRS score, linear function of time, and HDRS scores at weeks 1, 2, 4, and 6 as repeated measures. Partial correlation coefficients were calculated in the whole sample between the residual of IL-6:sIL-6R ratio (post-WBH) regressed on HDRS baseline score and HDRS score at weeks 1, 2, 4, and 6 regressed on HDRS baseline score.

From the 34 randomized subjects: 4 did not receive the intervention; 1 subject did not have immune biomarkers before or after the intervention; 1 subject exhibited extreme values across multiple variables of central interest to this study; and 2 subjects were missing data on the Hamilton Depression Rating Scale. Specifically, the multivariate outlier exhibited baseline IL-6 (49.32 pg/mL) prior to WBH that was 28.3 SDs above the mean as well as the highest levels of baseline depression (31) and treatment response (week 6 HDRS = 4). Modified intent-to-treat analyses were conducted imputing data for 2 subjects who were missing data on the Hamilton Depression Rating Scale.

3. Results

Participant characteristics (N=26) are reported in Supplemental Table 1. When compared to the sham condition, active WBH significantly increased the IL-6:sIL-6R ratio immediately post-treatment [F(3,72)=11.73, p<.001, d=1.40; the mean difference in the IL-6:sIL-6R ratio at the post-intervention assessment point when comparing the active group with the sham was .046, F(1,24)=26.07, (p<.001), d=2.09 (Figure 1). No group differences in the biomarker of classical signaling were observed at baseline or at post-intervention weeks 1 and 4. HLM indicated that increases in the IL-6:sIL-6R ratio following WBH moderated HDRS-assessed depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:sIL-6R ratio were associated with decreased HDRS-assessed depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active WBH compared to sham treatment (B=−229.44, t(26)=−3.82, p<.001, d=1.51; controlling for days in study and baseline depressive symptoms). Increased IL-6:sIL-6R ratio before treatment with WBH was not associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 (B=−313.30, t(26)=−1.89, p=.07, d=0.79; controlling for days in study and baseline depressive symptoms) for either treatment group. Partial correlations of post-intervention values of the IL-6:sIL-6R ratio and change in depressive symptoms in the whole sample for weeks 1, 2, 4 and 6 were: Week 1, r(20)=−.44 (p=.03); Week 2, r(20)=−.61 (p=.001); Week 4, r(20)=−.55 (p=.005); and Week 6, r(20)=−.09 (p=.67). Figure 2 provides an illustrative example of the association at Week 2 by treatment allocation. In additional modified intent-to-treat analyses, no substantial difference in the pattern of result was observed (see Supplemental Material for complete details).

Figure 1: IL-6:sIL-6R ratio by randomization group over time.

Figure 1:

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Footnote: Error bars represent standard deviations; IL-6 = interleukin-6; WBH = whole-body hyperthermia. IL-6:sIL-6R ratio is defined as the ratio of plasma IL-6 to plasma sIL-6R (IL-6/ sIL-6R).

Figure 2. Partial correlation of IL-6:sIL-6R ratio post-WBH and depressive symptoms at week 2.

Figure 2.

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Footnote: Partial correlation of depressive symptoms at week 2 that are adjusted for baseline depressive symptoms (y-axis) and IL-6:sIL-6R ratio immediately post-WBH that is adjusted for pre-WBH IL-6:sIL-6R ratio (x-axis).

This study examines an immune mechanism that contributes to the antidepressant effects of whole-body hyperthermia

Whole-body hyperthermia led to an acute, time-limited increase in the ratio of interleukin-6 (IL-6):soluble IL-6 receptor

Increased ratio of IL-6:soluble IL-6 receptor was associated with the anti-depressant effect of whole-body hyperthermia

4. Discussion

This post hoc analysis of a double-blind, randomized, sham-controlled trial found that WBH treatment, but not sham treatment, led to an acute, time-limited, increase in the ratio of IL-6 to sIL-6R. This was consistent with our study hypothesis and suggests that WBH preferentially activates anti-inflammatory classical IL-6 signaling. Differential activation of IL-6’s anti-inflammatory potential may reflect the time-limited nature of WBH’s effect on the cytokine, given that 24 hours are required for IL-6R to be fully cleaved from cell membranes to constitute sIL-6R, thereby differentially increasing classical signaling (Rose-John, 2012). Also supporting a primarily anti-inflammatory role for IL-6 in the context of WBH is the observation that WBH does not acutely increase other proinflammatory cytokines, such as IL-1β and tumor necrosis factor (Flux et al., 2023; Raison and Miller, 2013), that precipitate initiation of IL-6 trans-signaling (Del Giudice and Gangestad, 2018).

This study suggests that differential activation of the classical versus trans IL-6 signaling pathway may mediate—at least in part—the sham-adjusted antidepressant effects of WBH. These data help resolve the paradox that increased plasma concentrations of IL-6 – a proinflammatory cytokine typically associated with increased risk for depression (Kohler et al., 2017; Mac Giollabhui et al., 2021) – are associated with better treatment response in WBH. Convergent support for this possibility comes from studies suggesting that acute increases in IL-6 seen across anti-inflammatory interventions (e.g., electroconvulsive therapy, ketamine, fasting, exercise) generally show antidepressant potential (Köhler et al., 2014). Nonetheless, to our knowledge this is the first study to examine whether an antidepressant modality that acutely increases plasma concentrations of IL-6 is associated with a biomarker of classical signaling.

The 3-fold increase in IL-6 concentrations observed following WBH is comparable to the 2.7-fold increase observed following 35 minutes of high-intensity training (Cullen et al., 2017) and is indicative of potential health benefits and may hold particular relevance where barriers to exercise exist. It is notable that elevated IL-6 concentrations were not observed at weeks 1 or 4. This suggests that alterations in IL-6 concentrations are transient and that the physiological changes responsible for the more persistent antidepressant effect are downstream from the initial bolus of IL-6. It has long been known that IL-6 also plays a critical role in controlling local and systemic inflammatory responses to prevent (Xing et al., 1998). It is likely that, as in the case of exercise, IL-6 in the context of WBH promotes anti-inflammatory activity via increases in IL-1R antagonist, soluble TNF-R and IL-10 and inhibition of TNF-α and IL-1(Petersen and Pedersen, 2005). There are data suggesting that IL-6 may act on macrophages to produce macrophages IL-1Ra (Tilg et al., 1994); however, the cellular mechanism by which WBH exerts an anti-inflammatory effect have not been fully explored. Interpretation of these results should be considered within the context of the study limitations.

In addition to the importance of replicating findings from the current study in larger prospective trials of WBH, direct assessment of where increased circulating IL-6 binds (i.e., to membrane-bound IL-6R) is needed to confirm the role of classical signaling hypothesized in this study. Moreover, a substantial number of randomized individuals were not included in primary analyses and non-trivial amounts of data were missing – we cannot exclude the possibility that missing data bias the results presented here and, as such, results from this study should be considered preliminary. Should this be confirmed, 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.

Supplementary Material

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Supplementary Table 1

Acknowledgments

We gratefully acknowledge Tommy K. Begay, PhD for collection, processing, storage, and shipping of plasma for assessment of plasma biomarkers.

Funding/Support

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, Harvard University’s Mind Brain Behavior Interfaculty Initiative, and from Barry and Janet Lang and Arch and Laura Brown. Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number K23MH132893. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A Heckel – HT 3000 Whole Body Hyperthermia System was provided free of charge to Dr. Raison for use in the current study, by heckel medizintechnik GmbH in Germany. A similar device has been provided to Dr. Mischoulon for use in two ongoing studies extending the work reported here.

Declaration of interest

C.A.L. is Cofounder, Board Member, and Chief Scientific Officer of Mycobacteria Therapeutics Corporation, and is a member of the faculty of the Integrative Psychiatry Institute, Boulder, Colorado, the Institute for Brain Potential, Los Banos, California, and Intelligent Health Ltd, Reading, UK. A.E.M is a scientific advisor to Oura Health. C.L.R (Raison) serves as a consultant for Usona Institute, Novartis and Otsuka. R.T.L. is a consultant for Relmada Therapeutics. Drs. Mac Giollabhui, Nyer, Foster, Smith, Cole, and Mischoulon report no financial relationships with commercial interests.

Footnotes

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REFERENCES

  1. Beever R, 2010. The effects of repeated thermal therapy on quality of life in patients with type II diabetes mellitus. The Journal of alternative and complementary medicine 16, 677–681. [DOI] [PubMed] [Google Scholar]
  2. Cullen AE, Tappin BM, Zunszain PA, Dickson H, Roberts RE, Nikkheslat N, Khondoker M, Pariante CM, Fisher HL, Laurens KR, 2017. The relationship between salivary C-reactive protein and cognitive function in children aged 11–14years: Does psychopathology have a moderating effect? Brain. Behav. Immun 66, 221–229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Del Giudice M, Gangestad SW, 2018. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain. Behav. Immun 70, 61–75. [DOI] [PubMed] [Google Scholar]
  4. Flux MC, Smith DG, Allen JJ, Mehl MR, Medrano A, Begay TK, Middlemist BH, Marquart BM, Cole SP, Sauder CJ, 2023. Association of plasma cytokines and antidepressant response following mild-intensity whole-body hyperthermia in major depressive disorder. Transl Psychiatry 13, 132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Friedrich MJ, 2017. Depression is the leading cause of disability around the world. JAMA 317, 1517–1517. [DOI] [PubMed] [Google Scholar]
  6. Gay F, Romeo B, Martelli C, Benyamina A, Hamdani N, 2021. Cytokines changes associated with electroconvulsive therapy in patients with treatment-resistant depression: a Meta-analysis. Psychiatry Res 297, 113735. [DOI] [PubMed] [Google Scholar]
  7. Hanusch K-U, Janssen CH, Billheimer D, Jenkins I, Spurgeon E, Lowry CA, Raison CL, 2013. Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling. Am. J. Psychiatry 170, 802–804. [DOI] [PubMed] [Google Scholar]
  8. Hock RS, Or F, Kolappa K, Burkey MD, Surkan PJ, Eaton WW, 2012. A new resolution for global mental health. Lancet 379, 1367–1368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Irwin MR, Miller AH, 2007. Depressive disorders and immunity: 20 years of progress and discovery. Brain. Behav. Immun 21, 374–383. [DOI] [PubMed] [Google Scholar]
  10. Janssen CW, Lowry CA, Mehl MR, Allen JJ, Kelly KL, Gartner DE, Medrano A, Begay TK, Rentscher K, White JJ, 2016. Whole-body hyperthermia for the treatment of major depressive disorder: a randomized clinical trial. JAMA Psychiatry 73, 789–795. [DOI] [PubMed] [Google Scholar]
  11. Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, Stubbs B, Solmi M, Veronese N, Herrmann N, Raison CL, Miller BJ, Lanctot KL, Carvalho AF, 2017. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand 135, 373–387. [DOI] [PubMed] [Google Scholar]
  12. Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J, 2014. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71, 1381–1391. [DOI] [PubMed] [Google Scholar]
  13. Li Y, Shen R, Wen G, Ding R, Du A, Zhou J, Dong Z, Ren X, Yao H, Zhao R, Zhang G, Lu Y, Wu X, 2017. Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration. Front. Pharmacol 8, 139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Little RJ, 1988. A test of missing completely at random for multivariate data with missing values. Journal of the American statistical Association 83, 1198–1202. [Google Scholar]
  15. Mac Giollabhui N, Foster S, Lowry CA, Mischoulon D, Raison CL, Nyer M, 2022. Interleukin-6 receptor antagonists in immunopsychiatry: Can they lead to increased interleukin-6 in the central nervous system (CNS) and worsening psychiatric symptoms? Brain. Behav. Immun 103, 202–204. [DOI] [PubMed] [Google Scholar]
  16. Mac Giollabhui N, Ng TH, Ellman LM, Alloy LB, 2021. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol. Psychiatry 26, 3302–3314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miller AH, Raison CL, 2016. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol 16, 22–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Naumann J, Grebe J, Kaifel S, Weinert T, Sadaghiani C, Huber R, 2017. Effects of hyperthermic baths on depression, sleep and heart rate variability in patients with depressive disorder: a randomized clinical pilot trial. BMC Complement. Altern. Med 17, 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nyer M, Hopkins LB, Farabaugh A, Nauphal M, Parkin S, McKee MM, Miller KK, Streeter C, Uebelacker LA, Fava M, 2019. Community-Delivered Heated Hatha Yoga as a Treatment for Depressive Symptoms: An Uncontrolled Pilot Study. The Journal of Alternative and Complementary Medicine 25, 814–823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Petersen AMW, Pedersen BK, 2005. The anti-inflammatory effect of exercise. J. Appl. Physiol 98, 1154–1162. [DOI] [PubMed] [Google Scholar]
  21. Potere N, Batticciotto A, Vecchié A, Porreca E, Cappelli A, Abbate A, Dentali F, Bonaventura A, 2021. The role of IL-6 and IL-6 blockade in COVID-19. Expert Rev. Clin. Immunol 17, 601–618. [DOI] [PubMed] [Google Scholar]
  22. Raison CL, Knight JM, Pariante C, 2018. Interleukin (IL)-6: A good kid hanging out with bad friends (and why sauna is good for health). Brain. Behav. Immun 73, 1–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Raison CL, Miller A, 2013. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol. Psychiatry 18, 15–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rose-John S, 2012. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int. J. Biol. Sci 8, 1237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rose-John S, 2021. Therapeutic targeting of IL-6 trans-signaling. Cytokine 144, 155577. [DOI] [PubMed] [Google Scholar]
  26. Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J, 2023. Targeting IL-6 trans-signalling: past, present and future prospects. Nature Reviews Immunology, 1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW, 1994. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83, 113–118. [PubMed] [Google Scholar]
  28. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, 2006. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR* D: implications for clinical practice. Am. J. Psychiatry 163, 28–40. [DOI] [PubMed] [Google Scholar]
  29. Villar-Fincheira P, Paredes AJ, Hernández-Díaz T, Norambuena-Soto I, Cancino-Arenas N, Sanhueza-Olivares F, Contreras-Briceño F, Mandiola J, Bruneau N, García L, 2021. Soluble interleukin-6 receptor regulates interleukin-6-dependent vascular remodeling in long-distance runners. Front. Physiol 12, 722528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK, 1998. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J. Clin. Invest 101, 311–320. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

MMC4
NIHMS1993900-supplement-MMC4.docx (19.8KB, docx)
MMC2
NIHMS1993900-supplement-MMC2.doc (39.5KB, doc)
MMC1
NIHMS1993900-supplement-MMC1.docx (13.5KB, docx)
Supplementary Table 1
NIHMS1993900-supplement-Supplementary_Table_1.docx (14.4KB, docx)

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