HypErthermia as an Additional Treatment for the Biology and Experience of Depression: The HEATBED Study
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of California, San Francisco

 
 
 
 
 
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STUDY PROTOCOL & STATISTICAL ANALYSIS PLAN  
 
Official Title:  
 
HYPERTHERMIA AS AN ADDITIONAL TREATMENT 
FOR THE BIOLOGY AND EXPERIENCE OF 
DEPRESSION: THE HEATBED STUDY 
Clinicaltrials.gov # 
NCT05041361 
Date 
8 April 2024 
Development Phase: 
Feasibility & Acceptability 
Sponsor: 
Ashley E. Mason, PhD & Frederick M. Hecht, MD 
UCSF Osher Center for Integrative Health 
School of Medicine 
1545 Divisadero Street Suite 301 
San Francisco CA 94115 
Principal Investigator: 
Name: Ashley E. Mason, PhD 
 
 
 
E-mail: Ashley.Mason@ucsf.edu  
 
Co-Principal 
Investigator 
Name: Frederick M. Hecht, MD 
 
 
 
 
E-mail: Rick.Hecht@ucsf.edu 
 
Medical Monitor: 
Name: Frederick M. Hecht, MD 
 
 
 
 
E-mail: Rick.Hecht@ucsf.edu 
 
 
 
 
 
 

 
 
 
 
 
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BACKGROUND 
Depression recovery is not uniformly linear; people who recover from depression often 
experience acute improvements, termed ‘sudden gains,’ early in treatment. Data suggest 
that participants with clinical depression who receive whole body heating (Hanusch et al., 
2013; Janssen et al., 2016) and participants who receive cognitive behavioral therapy 
(CBT) treatment (Aderka et al., 2012; Tang et al., 1999) show sudden gains. Ascertaining if 
a treatment comprising both sauna sessions and CBT sessions is feasible and tolerable will 
allow for further research of this integrative mind-body treatment as a potentially effective 
and disseminable treatment for clinical depression.  
Prior work has demonstrated that whole body heating to an internal temperature of 38.5 °C 
(101.3 °F) using a head out infrared heating device is tolerable by healthy adults and is 
associated with significant reductions in clinical depression (Hanusch et al., 2013; Janssen 
et al., 2016) that characterize sudden gains. This prior work administered a single sauna 
session in a Heckel heating device, a medical hyperthermia device, and reported 
improvements in depression symptoms within 1 week of this session. This prior work did 
not ascertain if additional sauna sessions led to further decreases in depression; a dose-
escalation study has not yet been performed. Our earlier pilot project established (in N=25 
participants) that a readily accessible, commercially available sauna, which the UCSF IRB 
granted NSR designation, can achieve a core temperature of 101.3 °F without serious 
adverse events.  
In addition to the body-based approach of using sauna as a possible treatment for 
depression symptoms, we will provide the current gold standard psychotherapy 
intervention, cognitive behavioral therapy (CBT) to participants. Cognitive behavioral 
therapy (CBT) is an efficacious, highly disseminable evidence-based treatment for 
depression. Many therapy modalities can elicit sudden gains; however, sudden gains in 
cognitive behavioral therapy (CBT) are more frequent and durable than those observed in 
non-CBT therapies (Aderka et al., 2012). Meta-analytic data suggest that the effects of 
sudden gains on depression symptoms in the context of CBT treatment are larger (Hedges’s 
g=0.74) and longer lasting than those occurring in the context of non-CBT treatment 
(Hedges’s g=0.23; Aderka et al., 2012). The conceptual framework of sudden gains 
suggests that such gains can lead to cognitive changes that then lead to further symptom 
reduction, sparking a positive feedback loop termed an “upward spiral” (Tang & DeRubeis, 
1999). Sudden gains in CBT generally follow from “critical” therapy sessions characterized 
by substantial cognitive change. CBT is an effective manualized psychotherapy that a 
diverse range of mental health clinicians, including marriage and family therapists (MFTs) 
and clinical social workers (CSWs), can provide. In many areas, MFTs and CSWs are more 
readily available and affordable than clinical psychologists. Hence, optimizing an 
intervention that includes a psychotherapy modality that a range of mental health clinicians 
can provide strengthens the potential for dissemination. 
 
 

 
 
 
 
 
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References:  
Aderka IM, Nickerson A, Bøe HJ, Hofmann SG. Sudden gains during psychological 
treatments of anxiety and depression: A meta-analysis. J Consult Clin Psychol. 
2012;80(1):93. 
Hanusch, K.-U., Janssen, C. H., Billheimer, D., Jenkins, I., Spurgeon, E., Lowry, C. A., & 
Raison, C. L. (2013). Whole-body hyperthermia for the treatment of major depression: 
Associations with thermoregulatory cooling. American Journal of Psychiatry, 170(7), 802–
804.  
Janssen, C. W., Lowry, C. A., Mehl, M. R., Allen, J. J. B., Kelly, K. L., Gartner, D. E., ... 
Raison, C. L. (2016). Whole-Body Hyperthermia for the Treatment of Major Depressive 
Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 73(8), 789–795.  
Tang TZ, DeRubeis RJ. Sudden gains and critical sessions in cognitive-behavioral therapy 
for depression. J Consult Clin Psychol. 1999;67(6):894 
 
 
TITLE 
EXAMINING THE FEASIBILITY AND ACCEPTABILITY OF 
SAUNA SESSIONS AND COGNITIVE BEHAVIORAL THERAPY 
(CBT) FOR PARTICIPANTS WITH CLINICAL DEPRESSION 
SPONSOR 
Ashley E. Mason, PhD 
CO-SPONSOR 
Frederick M. Hecht, MD 
NUMBER OF 
SITES 
1 
RATIONALE 
Depression recovery is not uniformly linear; people who recover from 
depression often experience acute improvements, termed ‘sudden 
gains,’ early in treatment. Data suggest that participants with clinical 
depression who receive whole body heating (Hanusch et al., 2013; 
Janssen et al., 2016) and participants who receive cognitive behavioral 
therapy (CBT) treatment (Aderka et al., 2012; Tang et al., 1999) show 
sudden gains. Ascertaining if a treatment comprising both sauna 
sessions and CBT sessions is feasible and tolerable will allow for 
further research of this integrative mind-body treatment as a 
potentially effective and disseminable treatment for clinical 
depression. 
STUDY DESIGN Single-arm, unblinded pilot trial 

 
 
 
 
 
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PRIMARY 
OBJECTIVE 
Develop a whole-body heating (WBH) + Cognitive Behavioral 
Therapy (CBT) treatment. We will enroll 16 participants with clinical 
depression and deliver *4 biweekly WBH (sauna) sessions and 8 
weekly CBT sessions. After the first half of enrollment (~n=8) is 
complete, we will use participant and staff feedback to refine 
procedures for the remaining enrollment (we will submit any 
refinements or changes to the treatment to the UCSF IRB approval 
before implementing them).  
 
*Of note, after n=6 participants had completed participation, we 
reduced the number of WBH sessions from 8 weekly sessions to 4 bi-
weekly (every-other-week) sessions for the remaining 10 participants.  
SECONDARY 
OBJECTIVES 
To pilot test the feasibility of all assessment procedures in anticipation 
of a larger trial.  
NUMBER OF 
PARTICIPANT
S 
16  
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Age of at least 18 years old 
2. Current major depressive episode of at least 2 weeks duration as 
assessed by the Structured Clinical Interview for DSM-5 (SCID) 
and a Beck Depression Inventory-II (BDI-II) score ≥ 21 at 
screening 
3. Able to understand the nature of the study and able to provide 
written informed consent prior to conduct of any study procedures 
4. Must have smartphone onto which they can download an app from 
Apple App or Google Play stores 
5. Ability to lie supine (on back) for 2 hours (required for sauna 
sessions) 
6. Must be fully vaccinated against COVID-19 
Exclusion Criteria: 
1. >30% reduction in BDI-II score between Screen #1 and Screen #2 
(conducted ~1 week after Screen #1). 
2. Suicide attempt in the past 12 months defined using the SAMHSA 
suicidality question during the clinician-administered interview or 
active suicidal ideation as indexed by a score of 3 on the BDI-II 
suicidality item during the clinician-administered interview. 
3. Any of the following medical conditions: cardiovascular disease 
(other than controlled hypertension), seizure disorder, history of 
cerebrovascular accident (CVA) or other serious neurological 
condition (e.g. Parkinson’s disease, multiple sclerosis, or 
dementia), current neoplasia, any active enclosed infection (e.g. 
dental abscess, joint infection), hemophilia or other cause for 

 
 
 
 
 
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excessive bleeding (e.g. platelet disorder), or other medical 
condition that in the opinion of investigators may increase the risk 
of WBH 
4. Comorbid psychiatric conditions or history of comorbid 
psychiatric conditions that might better explain depressive 
symptoms, including schizophrenia, schizoaffective disorder, 
Bipolar Disorder I, Obsessive Compulsive Disorder, Anorexia 
Nervosa, Bulimia Nervosa, Alcohol Dependence, or Drug 
Dependence 
5. Known hypersensitivity to hyperthermia and/or infrared exposure 
6. Inability to fit into the sauna device 
7. Breast implants 
8. Pregnancy, active lactation or intention to become pregnant during 
the study period 
9. Use of any medication that might impact thermoregulatory 
capacity, including:  
• diuretics, barbiturates 
• beta-blockers 
• antipsychotic agents 
• anti-cholinergic agents or chronic use of antihistamines 
• aspirin (other than low-dose ASA for prophylactic 
purposes) 
• medication prescribed for the treatment of depression 
(antidepressant medication [ADM]) including but not 
limited to: selective serotonin reuptake inhibitors [SSRIs], 
Serotonin and norepinephrine reuptake inhibitors [SNRIs], 
Monoamine oxidase inhibitors [MAOIs], Tricyclics 
[TCAs], and atypical antipsychotic and antidepressant 
medications (participants must have been free of these 
medications for at least 4 weeks)  
• antibiotics (past 14 days), pain medication (opioids) due to 
procedure, e.g., dental procedure (past 14 days), 
Emergency contraception pill (past 14 days) 
• any other medication that in the judgment of the PI would 
increase risk of study participation or introduce excessive 
variance into physiological or behavioral responses to 
WBH 
• recent use (multiple consecutive doses) of: non-steroidal 
anti-inflammatory drugs (NSAIDs), systemic 
corticosteroids, cytokine antagonists 
10. Regular use of any nicotine products, including cigarettes, vapes, 
chewing tobacco, or other forms of nicotine (if use is not regular, 
must be willing to refrain for 24 hours before and 24 hours after 
sauna session) 
11. Unwilling to refrain from using marijuana products and alcohol 
for the 24 hours before and 24 hours after sauna sessions  

 
 
 
 
 
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12. Unwilling to refrain from heavy exercise on the day of sauna 
sessions 
13. Unwilling to refrain from engaging with sauna, hot yoga, cold 
plunges, cryotherapy, and hot tub/jacuzzi outside of study 
(prospective participant must not have engaged with any of these 
activities for 30 days prior to their baseline study visit). 
14. Has begun new psychotherapy treatment in the prior 6 weeks 
 
*Note: All medications reported by potential subjects will be 
reviewed by medical monitor Frederick Hecht, MD. If the medication 
is determined to not have meaningful impacts on bodily 
thermoregulatory processes and to not interact with whole body 
heating, the subject may participate.    
TEST 
PRODUCT, 
DOSE, AND 
ROUTE OF 
ADMINISTRAT
ION 
Portable Sauna Dome – One Person 
Supine sauna device, head out, body inside of sauna 
Sauna session approx. 80 – 140 minutes, maximum 140 minutes  
Manufactured by Clearlight Infrared  
CONTROL 
PRODUCT, 
DOSE AND 
ROUTE OF 
ADMINISTRAT
ION 
N/A, all participants receive the same treatment 
 
DURATION OF 
PARTICIPANT 
PARTICIPATIO
N AND 
DURATION OF 
STUDY 
This is a single-center, single-arm, non-randomized experimental 
study that will include 16 participants. Participants will be in the study 
for approximately 10 weeks. Total time involved will be 
approximately ~33.5 hours:  
• E-Screen: Web-based eligibility screen for self-report eligibility 
criteria 
o ~10 minutes 
• Phone Screen: Phone call to review eligibility, schedule study 
visits 
o ~30 minutes  
• Online Depression Screen: Web-based depression screen  
o ~10 minutes 
• In-Person Screen / Baseline Visit: Participant to complete 
screening procedures, provide informed written consent and 
receive bill of rights, download Oura Ring app, complete self-
report questionnaires and anthropometric assessments 
o ~150 minutes 
• Daily depression assessment: Brief web-based surveys assessing 
depression symptoms each morning  
o ~2 minutes each 

 
 
 
 
 
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• Sauna Visits 1-4: In-person visits, participant (if female) to 
complete pregnancy screen if the participant thinks there is a 
possibility of pregnancy, COVID-19 rapid test, complete 
questionnaires (all sauna visits), provide blood and saliva samples 
(Sauna Visits 1, 3 and 4), and complete sauna session 
o ~240-260 minutes each 
• Cognitive Behavioral Therapy (CBT) Visits 1-8: In-person visits, 
participant to receive 50-minute CBT session and complete self-
report measures 
o ~75 minutes each 
• Close-out visit: In-person visit, participant to complete 
questionnaires, complete clinician-administered assessment, 
provide blood and saliva samples if the participant does not 
complete a 4th sauna visit, return Oura Ring 
o ~85 minutes 
CONCOMMITA
NT 
MEDICATIONS 
Allowed: 
• All medications reported by potential participants will be 
reviewed by medical monitor Frederick Hecht, MD. If the 
medication is determined to not have meaningful impacts on 
bodily thermoregulatory processes and to not interact with 
whole body heating, the participant may participate.   
Prohibited: 
1. Use of any medication that might impact thermoregulatory 
capacity, including: diuretics, barbiturates, beta-blockers, 
antipsychotic agents, anti-cholinergic agents or chronic use of 
antihistamines, cytokine antagonists 
2. Current antidepressant medications (all classes) or use within 
the past 30 days 
3. Recent use (multiple consecutive doses) of systemic 
corticosteroids 
4. Needing to use antihistamines, aspirin (other than low-dose 
ASA for prophylactic purposes), non-steroidal anti-
inflammatory drugs (NSAIDs), or systemic corticosteroids, on 
Study Visit days 
5. Use of any other medication that in the judgment of the PI 
would increase risk of study participation or introduce 
excessive variance into physiological or behavioral responses 
to WBH 
6. Regular use of any nicotine products, including cigarettes, 
vapes, chewing tobacco, or other forms of nicotine 
7. The following medications in these timeframes: Antibiotics 
(past 14 days), Pain medication (opioids) due to procedure, 
e.g., dental procedure (past 14 days), Emergency contraception 
pill (past 14 days) 

 
 
 
 
 
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EFFICACY 
EVALUATIONS 
See below for primary and secondary endpoints. 
PRIMARY 
ENDPOINT 
Primary outcomes. The primary endpoint is the average number of 
planned WBH sessions completed. We have selected this as the 
primary outcome because prior studies have not assessed the 
acceptability of multiple sauna sessions and we believe it is important 
to verify acceptability of multiple sauna sessions before including it in 
further steps.  
SECONDARY 
ENDPOINTS 
Secondary outcomes. The secondary endpoints are the average number 
of planned BDI-II assessments completed and the change in the BDI-II 
from baseline to the final assessments (12 weeks).  
OTHER 
EVALUATIONS 
N/A 
SAFETY 
EVALUATIONS 
Incidence of unexpected adverse events. We will monitor participants 
for unexpected adverse events and serious adverse events during and 
following the sauna sessions.   
PLANNED 
INTERIM 
ANALYSES  
Due to the current study design and safety profile of this test product 
(portable sauna dome – one person) and cognitive behavioral therapy 
(CBT; a standard depression psychotherapy treatment), we do not plan 
any interim analyses. 
STATISTICS 
Primary Analysis 
Plan 
Primary outcome: We initially planned to quantify the number of 
planned WBH sessions completed and provide this information as the 
mean number of sessions with the corresponding standard deviation. 
Because, with Sponsor oversight and permission, we changed the 
number WBH sessions offered from 8 WBH sessions to 4 WBH 
sessions to optimize feasibility midway through enrollment, we 
analyzed the primary outcome separately for participants offered 8 
WBH sessions and participants offered 4 WBH sessions. 
Secondary outcome: We quantified the number of BDI-II assessments 
completed and provide this information as the mean number of 
assessments completed with the corresponding standard deviation. All 
participants were administered 10 BDI-II assessments.  
Secondary outcome: We calculated the change in BDI-II scores from 
the baseline BDI-II assessment to the final BDI-II assessment (12 
weeks) by computing a paired t-test using the final assessment and the 
baseline assessment, and provide 95% confidence intervals around the 
mean difference. All participants who completed participation were 
administered the baseline and final BDI-II assessments. 
Rationale for 
Number of 
Participants 
This study (which is funded by NIH/NCCIH and gift funding) will 
recruit 16 participants and aims to assess feasibility and acceptability 
of the planned sauna + CBT treatment. We are not aiming to test 
efficacy in these studies as we do not have adequate sample size. If 14 
of 16 participants complete at least 80% of their assigned WBH 
sessions (87.5%), the 95% CI for this rate will be 71% to 100% 
(normal approximation to the binomial), which we believe will 

 
 
 
 
 
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provide adequate precision for feasibility testing.