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Letters to the Editor   |    
Whole-Body Hyperthermia for the Treatment of Major Depression: Associations With Thermoregulatory Cooling
Kay-U Hanusch, M.Sci.; Clemens H. Janssen, M.S.; Dean Billheimer, Ph.D.; Isaac Jenkins, M.S.; Erin Spurgeon; Christopher A. Lowry, Ph.D.; Charles L. Raison, M.D.
Am J Psychiatry 2013;170:802-804. doi:10.1176/appi.ajp.2013.12111395
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Mr. Hanusch and Mr. Janssen have received consulting fees from Health Vertical of Etruvian Hamburg GmbH. Dr. Lowry has received consulting fees from Enlight Biosciences. Dr. Raison has received advisory board, development, or travel fees from Eli Lilly, CME Incite, Johnson & Johnson, the North American Center for Continuing Education, Pamlab, and Pfizer. Dr. Billheimer, Mr. Jenkins, and Ms. Spurgeon report no financial relationships with commercial interests.

Support provided from Barry and Janet Lang and from Heckel Medizintechnik GmbH.

From the Department of Physiotherapy, Aeskulap-Clinic, Brunnen, Switzerland; the Norton School of Family and Consumer Sciences and the Department of Agricultural and Biosystems Engineering, College of Agriculture and Life Sciences, University of Arizona, Tucson; BIO5 Institute, University of Arizona, Tucson; the Department of Psychiatry, College of Medicine, University of Arizona, Tucson; and the Department of Integrative Physiology and Center for Neuroscience, University of Colorado, Boulder.

Copyright © 2013 by the American Psychiatric Association

Accepted March , 2013.

To the Editor: Converging preclinical data suggest that stimulating a warm-sensitive thermoafferent spinoparabrachial pathway that projects from the skin (and other epithelial linings) to specific midbrain serotonergic nuclei produces antidepressant-like effects in animal models, while simultaneously inducing thermoregulatory cooling (1). Interestingly, several lines of evidence indicate that major depressive disorder may be characterized by suboptimal activity in this pathway, based on repeated observations that the disorder is associated with increased core body temperature, reduced thermoregulatory cooling (e.g., sweating), and alterations in peripheral measures of serotonin (5-HT) activity, all of which are expected manifestations of impaired activity in the skin-to-brain-to-skin thermoregulatory circuit within which the ascending spinoparabrachial pathway and its CNS projections form core components (1).

We used ongoing clinical activities at a private alternative treatment hospital in Switzerland to evaluate the relevance of these observations for the treatment of depression by examining the acute antidepressant effects of mild whole-body hyperthermia in 16 medically healthy adults who were clinically diagnosed with major depressive disorder. Our interest in whole-body hyperthermia was based on animal data from our group demonstrating that exposure to warm temperature activates the spinoparabrachial pathway and the midbrain 5-HT nuclei to which it projects (1).

Mild-intensity whole-body hyperthermia was induced using a Heckel 2000 device, which uses water-cooled infrared lamps to heat the body (Heckel Medizintechnik GmbH, Esslingen, Germany). Using the Centers for Epidemiologic Studies Depression Scale (CES-D) (2), we found that a single session (mean session time, 126.7 minutes [SD=18.0]) induced a rapid, robust, and sustained reduction in depressive symptoms (CES-D score before treatment, mean=29.9 [SD=10.6]; 5 days after treatment, mean=19.2 [SD=12.3]; t=4.53, df=15, p<0.001, effect size=1.13). Thirteen of these patients received no other pharmacologic or psychotherapeutic intervention during the 5 days following whole-body hyperthermia, whereas three patients were being chronically treated with a selective serotonin reuptake inhibitor (SSRI), with no change in dosage during the study period. Interestingly, when examined separately, whole-body hyperthermia appeared to have no effect in the three individuals receiving SSRI treatment. With these three individuals removed from analysis, the effect size of the hyperthermia increased (t=5.15, df=12, p<0.001, effect size=1.4).

Mean core body temperature data were obtained in 12 patients before whole-body hyperthermia and in seven patients both before and 5 days after the intervention. Core temperature was assessed with either an indwelling temperature sensor (EndoTherm GmbH) inserted rectally in male patients or vaginally in female patients or by hourly measurement of rectal temperature while awake. The same method was used for both assessments in patients who had their core body temperature measured twice (i.e., before and 5 days after whole-body hyperthermia). The treatment induced significant and persistent thermoregulatory cooling, as reflected by a drop in mean core body temperature from 37.3°C (SD=0.24) before treatment to 37.0°C (SD=0.14) 5 days after treatment (t=5.5, df=6, p=0.002, effect size=2.1). Moreover, a trend-level large effect size correlation was observed between reductions in CES-D scores and reductions in mean core body temperatures in the same period (r=0.73, df=4, p=0.06) (Figure 1A). Finally, higher mean core body temperature prior to hyperthermia strongly correlated with degree of antidepressant response 5 days after treatment (r=0.62, df=9, p=0.043), with one statistical outlier removed (Figure 1B).

 
Anchor for JumpAnchor for Jump
FIGURE 1.Associations Between 24-Hour Mean Core Body Temperature and Depressive Symptom Response to Whole-Body Hyperthermiaa

a Panel A depicts the correlation between decreases in score on the Center for Epidemiologic Studies Depression Scale (CES-D) and decreases in 24-hour mean core body temperature from before treatment to 5 days after treatment with whole-body hyperthermia. Panel B depicts the correlation between 24-hour mean core body temperature before treatment and changes in CES-D depression scores from before treatment to 5 days after treatment, with one outlier removed (indicated by a green box with an “x” through it).

Taken together, these findings suggest that whole-body hyperthermia provides rapid and sustained relief of depressive symptoms and may do so by sensitizing physiological pathways important for thermoregulatory cooling that also affect brain regions implicated in the regulation of mood. Although this is the first study, to our knowledge, to examine this intervention specifically for major depressive disorder, our findings are consistent with reports that hyperthermia improves mood and quality of life when used in medically ill patients (3, 4).

Hale  MW;  Raison  CL;  Lowry  CA:  Integrative physiology of depression and antidepressant drug action: implications for serotonergic mechanisms of action and novel therapeutic strategies for treatment of depression.  Pharmacol Ther 2013; 137:108–118
[CrossRef] | [PubMed]
 
Orme  JG;  Reis  J;  Herz  EJ:  Factorial and discriminant validity of the Center for Epidemiological Studies Depression (CES-D) scale.  J Clin Psychol 1986; 42:28–33
[CrossRef] | [PubMed]
 
Koltyn  KF;  Robins  HI;  Schmitt  CL;  Cohen  JD;  Morgan  WP:  Changes in mood state following whole-body hyperthermia.  Int J Hyperthermia 1992; 8:305–307
[CrossRef] | [PubMed]
 
Beever  R:  The effects of repeated thermal therapy on quality of life in patients with type II diabetes mellitus.  J Altern Complement Med 2010; 16:677–681
[CrossRef] | [PubMed]
 
References Container

FIGURE 1. Associations Between 24-Hour Mean Core Body Temperature and Depressive Symptom Response to Whole-Body Hyperthermiaa

a Panel A depicts the correlation between decreases in score on the Center for Epidemiologic Studies Depression Scale (CES-D) and decreases in 24-hour mean core body temperature from before treatment to 5 days after treatment with whole-body hyperthermia. Panel B depicts the correlation between 24-hour mean core body temperature before treatment and changes in CES-D depression scores from before treatment to 5 days after treatment, with one outlier removed (indicated by a green box with an “x” through it).

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References

Hale  MW;  Raison  CL;  Lowry  CA:  Integrative physiology of depression and antidepressant drug action: implications for serotonergic mechanisms of action and novel therapeutic strategies for treatment of depression.  Pharmacol Ther 2013; 137:108–118
[CrossRef] | [PubMed]
 
Orme  JG;  Reis  J;  Herz  EJ:  Factorial and discriminant validity of the Center for Epidemiological Studies Depression (CES-D) scale.  J Clin Psychol 1986; 42:28–33
[CrossRef] | [PubMed]
 
Koltyn  KF;  Robins  HI;  Schmitt  CL;  Cohen  JD;  Morgan  WP:  Changes in mood state following whole-body hyperthermia.  Int J Hyperthermia 1992; 8:305–307
[CrossRef] | [PubMed]
 
Beever  R:  The effects of repeated thermal therapy on quality of life in patients with type II diabetes mellitus.  J Altern Complement Med 2010; 16:677–681
[CrossRef] | [PubMed]
 
References Container
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