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Original Investigation |

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder A Randomized Clinical Trial

Clemens W. Janssen, PhD1,2; Christopher A. Lowry, PhD3; Matthias R. Mehl, PhD4; John J. B. Allen, PhD4; Kimberly L. Kelly, MPA5,6; Danielle E. Gartner, BA5,7; Angelica Medrano, BA2,5; Tommy K. Begay, PhD1,2,5; Kelly Rentscher, MA4; Joshua J. White, BS5,8; Andrew Fridman, BS5; Levi J. Roberts, BA5; Megan L. Robbins, PhD9; Kay-u Hanusch, MSc10; Steven P. Cole, PhD11; Charles L. Raison, MD1,2,5,12
[+] Author Affiliations
1Department of Human Development and Family Studies, School of Human Ecology, University of Wisconsin–Madison
2Norton School of Family and Consumer Sciences, College of Agriculture, University of Arizona, Tucson
3Department of Integrative Physiology, Center for Neuroscience, University of Colorado–Boulder
4Department of Psychology, College of Science, University of Arizona, Tucson
5Department of Psychiatry, College of Medicine, University of Arizona, Tucson
6School of Anthropology, University of Arizona, Tucson
7Office of the Senior Vice President for Health Sciences, University of Arizona, Tucson
8Midwestern University, Glendale, Arizona
9Department of Psychology, University of California, Riverside
10University of Applied Science Fresenius Idstein Medical School, Idstein, Germany
11Research Design Associates Inc, Yorktown Heights, New York
12Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin–Madison
JAMA Psychiatry. 2016;73(8):789-795. doi:10.1001/jamapsychiatry.2016.1031.
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Importance  Limitations of current antidepressants highlight the need to identify novel treatments for major depressive disorder. A prior open trial found that a single session of whole-body hyperthermia (WBH) reduced depressive symptoms; however, the lack of a placebo control raises the possibility that the observed antidepressant effects resulted not from hyperthermia per se, but from nonspecific aspects of the intervention.

Objective  To test whether WBH has specific antidepressant effects when compared with a sham condition and to evaluate the persistence of the antidepressant effects of a single treatment.

Design, Setting, and Participants  A 6-week, randomized, double-blind study conducted between February 2013 and May 2015 at a university-based medical center comparing WBH with a sham condition. All research staff conducting screening and outcome procedures were blinded to randomization status. Of 338 individuals screened, 34 were randomized, 30 received a study intervention, and 29 provided at least 1 postintervention assessment and were included in a modified intent-to-treat efficacy analysis. Participants were medically healthy, aged 18 to 65 years, met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score of 16 or greater.

Interventions  A single session of active WBH vs a sham condition matched for length of WBH that mimicked all aspects of WBH except intense heat.

Main Outcomes and Measures  Between-group differences in postintervention Hamilton Depression Rating Scale scores.

Results  The mean (SD) age was 36.7 (15.2) years in the WBH group and 41.47 (12.54) years in the sham group. Immediately following the intervention, 10 participants (71.4%) randomized to sham treatment believed they had received WBH compared with 15 (93.8%) randomized to WBH. When compared with the sham group, the active WBH group showed significantly reduced Hamilton Depression Rating Scale scores across the 6-week postintervention study period (WBH vs sham; week 1: −6.53, 95% CI, −9.90 to −3.16, P < .001; week 2: −6.35, 95% CI, −9.95 to −2.74, P = .001; week 4: −4.50, 95% CI, −8.17 to −0.84, P = .02; and week 6: −4.27, 95% CI, −7.94 to −0.61, P = .02). These outcomes remained significant after evaluating potential moderating effects of between-group differences in baseline expectancy scores. Adverse events in both groups were generally mild.

Conclusions and Relevance  Whole-body hyperthermia holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit.

Trial Registration  clinicaltrials.gov Identifier: NCT01625546

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Figure 1.
CONSORT Flow Diagram for Whole-Body Hyperthermia (WBH) and Sham Groups
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Figure 2.
Effect of Whole-Body Hyperthermia (WBH) vs Sham Treatment on 17-Item Hamilton Depression Rating Scale (HDRS) Across the 6-Week Postintervention Period

The error bars indicate SEs. Means and SEs were derived from the raw data provided in Table 2.

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Balneotherapy as providing Whole Body Hyperthermia
Posted on July 23, 2016
Sinan Kardeş
Department of Medical Ecology and Hydroclimatology, İstanbul Faculty of Medicine, İstanbul University
Conflict of Interest: None Declared
Interesting article with attractive non-pharmacological treatment option! The results indicate that single session Whole Body Hyperthermia (core body temperature reach 38.5°C) improves symptoms of major depressive disorder. This improvement persists throughout the entire 6-week duration of follow-up.

The whole body hyperthermia can also be reached by immersion of whole body (head-out immersion) in thermal water. This approach as a balneotherapy is widely used in many European countries and Turkey [1-3].

The beneficial effects of balneotherapy or spa therapy in reducing depressive symptoms or stress have demonstrated in several studies conducting in fibromyalgia patients [4-6] and in healthy people [7-9].

In balneotherapy trials observed clinical effects are of course mainly attributed to the balneotherapy. On the other hand, in spa therapy trials the observed clinical effects may also mainly attributed to the balneotherapy because it is main and and core intervention in spa therapy; however, the other interventions included in spa therapy regimens (i.e Turkish bath (hamam), mud-pack therapy, massage, physical therapy modalities, and aquatic/land based exercise…) and the other factors (climatotherapy, changes in environmental and social milieu…) must be taken into account as contributing factors to the clinical benefits when interpreting the results of spa therapy trials. Indeed, most spa therapy trials have aimed to evaluate efficacy of spa therapy as a whole rather than focusing each individual components of spa therapy separately as a responsible factor for improvement of symptoms [4, 10, 11].

In short, spa therapy regimens comprising balneotherapy may considered as providing whole body hyperthermia for the management of the depressive disorders in many European countries and Turkey where these therapies are widely available and reimbursed by health health insurance systems.

1) Karagülle M, Karagülle MZ. Effectiveness of balneotherapy and spa therapy for the treatment of chronic low back pain: a review on latest evidence. Clin Rheumatol. 2015;34:207-14. 7.
2) Karagülle MZ, Karagülle M. [Balneotherapy and spa therapy of rheumatic diseases in Turkey: a systematic review]. Forsch Komplementarmed Klass Naturheilkd. 2004;11:33-41.
3) Karagülle M, Kardeş S, Dişçi R, Gürdal H, Karagülle MZ. Spa therapy for elderly: a retrospective study of 239 older patients with osteoarthritis. Int J Biometeorol. 2016 published on 26 Jan 2016. doi: 10.1007/s00484-016-1138-7
4) Zijlstra TR, van de Laar MA, Bernelot Moens HJ, Taal E, Zakraoui L, Rasker JJ. Spa treatment for primary fibromyalgia syndrome: a combination of thalassotherapy, exercise and patient education improves symptoms and quality of life. Rheumatology (Oxford). 2005;44:539-46.
5) Dönmez A, Karagülle MZ, Tercan N et al. SPA therapy in fibromyalgia: a randomised controlled clinic study. Rheumatol Int. 2005 Dec;26:168-72.
6) Ozkurt S, Dönmez A, Zeki Karagülle M, Uzunoğlu E, Turan M, Erdoğan N. Balneotherapy in fibromyalgia: a single blind randomized controlled clinical study. Rheumatol Int. 2012;32:1949-54.
7) Rapolienė L, Razbadauskas A, Sąlyga J, Martinkėnas A. Stress and Fatigue Management Using Balneotherapy in a Short-Time Randomized Controlled Trial. Evid Based Complement Alternat Med. 2016;2016:9631684.
8) Matzer F, Nagele E, Bahadori B, Dam K, Fazekas C. Stress-relieving effects of short-term balneotherapy - a randomized controlled pilot study in healthy adults. Forsch Komplementmed. 2014;21:105-10.
9) Latorre-Román PÁ, Rentero-Blanco M, Laredo-Aguilera JA, García-Pinillos F. Effect of a 12-day balneotherapy programme on pain, mood, sleep, and depression in healthy elderly people. Psychogeriatrics. 2015;15:14-9.
10) van Tubergen A, Landewé R, van der Heijde D, Hidding A, Wolter N, Asscher M, Falkenbach A, Genth E, Thè HG, van der Linden S. Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: a randomized controlled trial. Arthritis Rheum. 2001;45:430-8.
11) Karagülle M, Kardeş S, Karagülle O, Dişçi R, Avcı A, Durak İ, Karagülle MZ. Effect of spa therapy with saline balneotherapy on oxidant/antioxidant status in patients with rheumatoid arthritis: a single-blind randomized controlled trial. Int J Biometeorol. 2016 published on 21 Jun 2016. doi: 10.1007/s00484-016-1201-4
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