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# The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway Brain Behav Immun. 2024 Jul:119:801-806. doi: 10.1016/j.bbi.2024.04.040. Epub 2024 Apr 26. ### Authors [Naoise Mac Giollabhui](https://pubmed.ncbi.nlm.nih.gov/?term=Mac+Giollabhui+N&cauthor_id=38677624) [1](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-1 "Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: nmacgiollabhui@mgh.harvard.edu.") , [Christopher A Lowry](https://pubmed.ncbi.nlm.nih.gov/?term=Lowry+CA&cauthor_id=38677624) [2](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-2 "Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.") , [Maren Nyer](https://pubmed.ncbi.nlm.nih.gov/?term=Nyer+M&cauthor_id=38677624) [3](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-3 "Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.") , [Simmie L Foster](https://pubmed.ncbi.nlm.nih.gov/?term=Foster+SL&cauthor_id=38677624) [3](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-3 "Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.") , [Richard T Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+RT&cauthor_id=38677624) [3](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-3 "Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.") , [David G Smith](https://pubmed.ncbi.nlm.nih.gov/?term=Smith+DG&cauthor_id=38677624) [4](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-4 "Center for Single Cell Biology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.") , [Steven P Cole](https://pubmed.ncbi.nlm.nih.gov/?term=Cole+SP&cauthor_id=38677624) [5](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-5 "Research Design Associates, Yorktown Heights, NY, USA.") , [Ashley E Mason](https://pubmed.ncbi.nlm.nih.gov/?term=Mason+AE&cauthor_id=38677624) [6](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-6 "Department of Psychiatry, University of California, San Francisco, CA, USA.") , [David Mischoulon](https://pubmed.ncbi.nlm.nih.gov/?term=Mischoulon+D&cauthor_id=38677624) [3](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-3 "Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.") , [Charles L Raison](https://pubmed.ncbi.nlm.nih.gov/?term=Raison+CL&cauthor_id=38677624) [7](https://pubmed.ncbi.nlm.nih.gov/38677624/#affiliation-7 "Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Vail Health Behavioral Health, Edwards, CO, USA; Department of Spiritual Health, Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA.") ### Affiliations - 1 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: nmacgiollabhui@mgh.harvard.edu. - 2 Department of Integrative Physiology, University of Colorado, Boulder, CO, USA. - 3 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. - 4 Center for Single Cell Biology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. - 5 Research Design Associates, Yorktown Heights, NY, USA. - 6 Department of Psychiatry, University of California, San Francisco, CA, USA. - 7 Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Vail Health Behavioral Health, Edwards, CO, USA; Department of Spiritual Health, Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA. - PMID: [38677624](https://pubmed.ncbi.nlm.nih.gov/38677624/) - PMCID: [PMC11670333](https://pmc.ncbi.nlm.nih.gov/articles/PMC11670333/) - DOI: [10\.1016/j.bbi.2024.04.040](https://doi.org/10.1016/j.bbi.2024.04.040) ## 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; Interleukin-6; Mechanism; Randomized Clinical Trial; Soluble Interleukin-6; Treatment; Whole-body Hyperthermia. Copyright © 2024 Elsevier Inc. All rights reserved. ## Publication types - Randomized Controlled Trial ## MeSH terms - Adolescent - Adult - Aged - Antidepressive Agents / pharmacology - Antidepressive Agents / therapeutic use - Double-Blind Method - Female - Humans - Hyperthermia - Hyperthermia, Induced / methods - Interleukin-6\* / blood - Major Depressive Disorder\* / therapy - Male - Middle Aged - Receptors, Interleukin-6\* / metabolism - Signal Transduction\* / drug effects - Treatment Outcome - Young Adult ## Substances - Interleukin-6 - Receptors, Interleukin-6 - IL6 protein, human - Antidepressive Agents ## Grants and funding - [K23 MH132893/MH/NIMH NIH HHS/United States](https://pubmed.ncbi.nlm.nih.gov/?term=K23+MH132893%2FMH%2FNIMH+NIH+HHS%2FUnited+States%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant K23 MH132893/MH/NIMH NIH HHS/United States")

Brain Behav Immun. 2024 Jul:119:801-806. doi: 10.1016/j.bbi.2024.04.040. Epub 2024 Apr 26. ### Affiliations - 1 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: nmacgiollabhui@mgh.harvard.edu. - 2 Department of Integrative Physiology, University of Colorado, Boulder, CO, USA. - 3 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. - 4 Center for Single Cell Biology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. - 5 Research Design Associates, Yorktown Heights, NY, USA. - 6 Department of Psychiatry, University of California, San Francisco, CA, USA. - 7 Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Vail Health Behavioral Health, Edwards, CO, USA; Department of Spiritual Health, Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA. - PMID: [38677624](https://pubmed.ncbi.nlm.nih.gov/38677624/) - PMCID: [PMC11670333](https://pmc.ncbi.nlm.nih.gov/articles/PMC11670333/) - DOI: [10\.1016/j.bbi.2024.04.040](https://doi.org/10.1016/j.bbi.2024.04.040) ## 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; Interleukin-6; Mechanism; Randomized Clinical Trial; Soluble Interleukin-6; Treatment; Whole-body Hyperthermia. Copyright © 2024 Elsevier Inc. All rights reserved. ## Publication types - Randomized Controlled Trial ## MeSH terms - Adolescent - Adult - Aged - Antidepressive Agents / pharmacology - Antidepressive Agents / therapeutic use - Double-Blind Method - Female - Humans - Hyperthermia - Hyperthermia, Induced / methods - Interleukin-6\* / blood - Major Depressive Disorder\* / therapy - Male - Middle Aged - Receptors, Interleukin-6\* / metabolism - Signal Transduction\* / drug effects - Treatment Outcome - Young Adult ## Substances - Interleukin-6 - Receptors, Interleukin-6 - IL6 protein, human - Antidepressive Agents