Whole Body Hyperthermia and Major Depression (MDD)
Whole Body Hyperthermia and Major Depression (MDD)
Major depressive disorder (MDD) is predicted to be the second leading cause of disability
 worldwide by the year 2020. The economic burden of depression in the United States is
 significant: $83.1 billion in 2000 and increasing. Much of this burden comes from the high
 rate of sub-optimal treatment outcomes associated with the disorder. Indeed, only 50% of MDD
 patients recover in less than 12 weeks with adequate treatment, and up to 20% of patients
 will fail to adequately respond to all currently available interventions. Moreover, current
 treatments come at the cost of significant central nervous system (CNS) side effects, further
 highlighting the need for more effective treatments with fewer side effects. This study will
 compare temperature ranges from the investigators preliminary studies involving
 thermoafferent pathways resulting in antidepressant actions with lower temperature ranges not
 expected to activate these pathways as a control condition, with the goal to evaluate whether
 previous observations were related to the temperature range in question or can be achieved
 with other levels.
We will conduct a placebo controlled clinical trial to determine if Whole Body Hyperthermia
 has antidepressant effects in medically healthy patients with moderate to severe MDD. We plan
 to recruit a sample of 30 medically healthy individuals with MDD who will be randomized to
 examine whether WBH will demonstrate an antidepressant effect when compared to a control-WBH
 condition that will be comprised of very mild heating in the WBH machine (Heckel HT3000). To
 determine acute and sustained effects of WBH on depression severity, the study will include
 basic clinical and psychiatric assessments 5 days before and after WBH and follow-up
 assessments at 2, 4, and 6 weeks following WBH. Additionally, assessments will be conducted
 during the optional open treatment, 1 week following the open treatment, and at the 3 month
 follow up. To assess whether WBH affects how individuals relate to other people in their
 environment, as well as how they spend their time in general and to assess social processes,
 the study will employ the Electronically Activated Recorder (EAR). Participants will wear the
 EAR device during the day, while going about their lives over the weekend. This weekend
 monitoring also includes an actigraphy assessment during which participants will wear an
 actigraphy device during their waking and sleeping hours. In addition, blood will be obtained
 at multiple time points to assess plasma concentrations of biological predictors or response
 and mechanism of action for WBH. This study challenges the existing paradigm by determining
 if peripheral afferent sensory pathways can be accessed to treat MDD and thus avoid problems
 of exposing all of the brain to non-selective drugs.
Inclusion Criteria for MDD patients:

 1. Male or female outpatients aged 18-65.

 2. Able to understand the nature of the study and able to provide written informed
 consent prior to conduct of any study procedures.

 3. In the investigator's opinion, has met DSM-IV-TR criteria for Major Depressive
 Disorder for at least 4 weeks prior to signing consent, single or recurrent episode,
 without psychotic features, as the subject's primary psychiatric disorder.

 4. Able to communicate in English with study personnel.

 5. Has a Hamilton Depression Rating Scale (HDRS) score ≥18 at screening and ≥14 on
 intervention day.

 6. For women of child-bearing potential (i.e., one who is biologically capable of
 becoming pregnant), must be willing to use a medically acceptable form of birth
 control or practice abstinence for the duration of her participation in the trial.

 Exclusion Criteria for MDD patients:

 1. Symptoms of depression which, in the investigator's opinion, are better accounted for
 by a diagnosis other than Major Depressive Disorder.

 2. Any of the following diagnoses, as identified by the psychiatric evaluation or study
 assessments:

 -  A current DSM-IV-TR Axis I diagnosis of Dementia; or

 -  Any current DSM-IV-TR Axis II diagnosis (i.e. personality disorder) that would
 suggest potential noncompliance with the protocol; or

 -  A lifetime history of Schizophrenia, Schizoaffective Disorder, or a Bipolar
 Disorder Type 1; or

 -  A diagnosis claustrophobia severe enough that it would impair ability to be in
 the Heckel HT3000 hyperthermia device

 -  A current (or within 12 months prior to the Screening visit) diagnosis of
 Anorexia Nervosa or Bulimia Nervosa

 3. Subject has met DSM-IV criteria for Substance Abuse in the 3 months prior to screening
 visit, or non-remitted Substance Dependence in the 6 months prior to screening visit.

 4. A diagnosis of an anxiety disorder that is considered by the investigator to be of
 greater source of distress or functional impairment than the patient's depressive
 symptoms. Subjects with comorbid anxiety disorders not excluded above and considered
 to be of secondary importance will be permitted in the study.

 5. Participation in concurrent formal psychotherapy during the trial, or in the 2 weeks
 prior to the screening visit.

 6. Individuals with a history of having difficulty swallowing food or large capsules will
 be excluded from participating in the assessment of core body temperature (because
 swallowing a large sensor pill is required). The ingestible temperature capsules will
 not be used in subjects with any known or suspected obstructive disease of the
 gastrointestinal tract including, but not limited to esophageal stricture,
 diverticulosis and inflammatory bowel disease (IBD), peptic ulcer disease, Crohn's
 disease, ulcerative colitis; previous gastrointestinal surgery.

 7. Subject has a medical condition or disorder that:

 -  Is unstable and clinically significant, or:

 -  Could interfere with the accurate assessment of safety or efficacy of treatment,
 including:

 1. individuals who are using prescription drugs that may impair
 thermoregulatory cooling, including diuretics, barbiturates, and
 beta-blockers, or antihistamines,

 2. individuals with cardiovascular conditions or problems (uncontrolled
 hypertension, congestive heart failure, or documented evidence of coronary
 artery disease)

 3. individuals with chronic conditions/diseases associated with a reduced
 ability initiate thermoregulatory cooling, including Parkinson's, multiple
 sclerosis, central nervous system tumors, and diabetes with neuropathy,

 4. hemophiliacs/individuals prone to bleeding,

 5. individuals with a fever the day of study intervention,

 6. individuals with hypersensitivity to heat,

 7. individuals with recent acute joint injury,

 8. individuals with enclosed infections, be they dental, in joints, or in any
 other tissues.

 8. Clinically significant, in the investigator's opinion, abnormal findings on screening
 laboratory tests or physical exam.

 9. Presence of clinically significant suicide risk, based on the investigator's opinion,
 or a Columbia Suicide Severity Risk Scale (C-SSRS) suicidal ideation score of 4 or 5.
 Any suicide attempt within 3 months of the Screening visit is exclusionary.

 10. Use of any psychotropic medications for 2 weeks (8 weeks for fluoxetine) prior to
 initiation of the study, with the exception of hypnotic medications (zolpidem,
 zaleplon, eszopiclone).

 11. Need for any non-protocol psychotropic medication during the trial, with the exception
 of hypnotics used up to four nights per week.

 12. Use of any psychoactive dietary or herbal products in the 2 weeks prior to screening
 visit 2, or at any time during the trial.

 13. Women who are pregnant (HCG pregnancy test at screening, or lactating, or who plan to
 become pregnant during the study.

 14. Current participation in any clinical trial that might impact results of this one,
 which includes participation in another clinical trial for depression, as well as drug
 trials with agents that might affect mood or regulation of body temperature.

 15. Reasonable likelihood for non-compliance with the protocol for any other reason, in
 the opinion of the Investigator, prohibits enrollment of subject into the study.

 16. Obesity and overall size of subject. It will be up to the PI's discretion will
 consider BMI, waist circumference, and body fat composition when determining
 eligibility and safety of the individual.

 17. History of peripheral circulatory disease, for example peripheral vascular disease,
 deep vein thrombosis (DVT), or lymphedema.

 18. History of a cerebral vascular accident

 19. History of stroke, epilepsy or cerebral aneurisms

 20. Cancer in the last five years.

 21. Diabetes mellitus types I or II

 22. Any clinically significant autoimmune disease (compensated hypothyroidism allowed)

 23. Active alcohol or drug abuse/dependence in the 3 months prior to screening