Whole Body Hyperthermia and Major Depression (MDD)

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