Precision Targeting of Propofol-induced Electroencephalographic Slow Waves: a Novel Phase I Paradigm for Treatment-resistant Major Depressive Disorder
Phase: PHASE1
Conditions: Treatment-resistant Depression
Sponsor: Washington University School of Medicine

 
 
 
Slow Wave Induction by Propofol to Eliminate 
Depression (SWIPED) Trial: Phase I 
 
Washington University Human Research Protection Office Protocol: 202008037 
National Clinical Trial (NCT) Identified Number:  NCT04680910 
Principal Investigators: Ben J.A. Palanca, M.D., Ph.D., M.Sc. & Eric J. Lenze, M.D. 
Sponsor: Washington University School of Medicine in St. Louis 
 
Funded by: National Institute of Mental Health Grant U01MH128483 
Version Number:  v.3.1.5 
30 January 2023 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
2.3.31.3, 
2.3.3, 8.2 
Suicide Risk Management Protocol 
triggered by MADRS or C-SSRS 
Change timing and number of MADRS, C-
SSRS, and SHAPS 
Broadening of trigger for Suicide Risk 
Management Protocol  
Capture acute changes in depression, 
anhedonia, and suicidality, with 
consideration that best time is likely 7 days 
after second infusion 
1.3., 10.1.5 
Approximate range for data collection, 
update of team roster 
Increase flexibility for participants and staff. 
New team members added 
1.3, 3, 8.2, 9, 
10.2  
Incorporate NIH Toolbox and PVT to assess 
cognition 
Assess feasibility for Phase II.  
1.1, 1.3 
Evaluate depression at 10 weeks 
Comparison with other antidepressant trials 
5,1, 7.3 
EMR check for eligibility Email reminders 
Address unresponsive patient 

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema .................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background ........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................. 14 
2.3.1 
Known Potential Risks ................................................................................................... 14 
2.3.2 
Known Potential Benefits .............................................................................................. 15 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 15 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 18 
4 
STUDY DESIGN ........................................................................................................................................... 19 
4.1 
Overall Design .................................................................................................................................... 19 
4.2 
Scientific Rationale for Study Design .............................................................................................. 19 
4.3 
Justification for Dose ......................................................................................................................... 20 
4.4 
End of Study Definition ...................................................................................................................... 20 
5 
STUDY POPULATION ................................................................................................................................. 20 
5.1 
Inclusion Criteria................................................................................................................................. 20 
5.2 
Exclusion Criteria ............................................................................................................................... 20 
5.3 
Lifestyle Considerations .................................................................................................................... 21 
5.4 
Screen Failures .................................................................................................................................. 21 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 21 
6 
STUDY INTERVENTION ............................................................................................................................. 22 
6.1 
Study Intervention(s) Administration ............................................................................................... 22 
6.1.1 
Study Intervention Description ..................................................................................... 22 
6.1.2 
Dosing and Administration ............................................................................................ 22 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 23 
6.2.1 
Acquisition and accountability ...................................................................................... 23 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 23 
6.2.3 
Product Storage and Stability ....................................................................................... 23 
6.2.4 
Preparation ...................................................................................................................... 24 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................................................... 24 
6.4 
Study Intervention Compliance ........................................................................................................ 24 
6.5 
Concomitant Therapy ........................................................................................................................ 25 
6.5.1 
Rescue Medicine ............................................................................................................ 25 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 25 
7.1 
Discontinuation of Study Intervention ............................................................................................. 25 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 26 
7.3 
Lost to Follow-Up ............................................................................................................................... 26 
8 
STUDY ASSESSMENTS AND PROCEDURES...................................................................................... 27 
8.1 
Efficacy Assessments ....................................................................................................................... 27 
8.2 
Safety and Other Assessments ....................................................................................................... 27 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 31 

  
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 31 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 31 
8.3.3 
Classification of an Adverse Event .............................................................................. 31 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 33 
8.3.5 
Adverse Event Reporting .............................................................................................. 33 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 33 
8.4 
Unanticipated Problems .................................................................................................................... 34 
8.4.1 
Definition of Unanticipated Problems (UP)................................................................. 34 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 34 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 35 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................... 35 
9.1 
Statistical Hypotheses ....................................................................................................................... 35 
9.2 
Sample Size Determination .............................................................................................................. 36 
9.3 
Statistical Analyses ............................................................................................................................ 36 
9.3.1 
General Approach .......................................................................................................... 36 
9.3.2 
Analysis of the Primary Endpoint(s) ............................................................................ 36 
9.3.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 37 
9.3.4 
Safety Analyses .............................................................................................................. 37 
9.3.5 
Baseline Descriptive Statistics ..................................................................................... 37 
9.3.6 
Planned Interim Analyses ............................................................................................. 37 
9.3.7 
Sub-Group Analyses ...................................................................................................... 37 
9.3.8 
Tabulation of Individual participant Data .................................................................... 37 
9.3.9 
Exploratory Analyses ..................................................................................................... 38 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 38 
10.1 
Regulatory, Ethical, and Study Oversight Considerations........................................................... 38 
10.1.1 
Informed Consent Process ........................................................................................... 38 
10.1.2 
Study Discontinuation and Closure ............................................................................. 38 
10.1.3 
Confidentiality and Privacy ........................................................................................... 39 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 40 
10.1.5 
Key Roles and Study Governance .............................................................................. 40 
10.1.6 
Safety Oversight ............................................................................................................. 42 
10.1.7 
Clinical Monitoring .......................................................................................................... 43 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 43 
10.1.9 
Data Handling and Record Keeping ............................................................................ 43 
10.1.10 
Protocol Deviations ........................................................................................................ 44 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 44 
10.1.12 
Conflict of Interest Policy............................................................................................... 45 
10.2 
Abbreviations ...................................................................................................................................... 46 
10.3 
Protocol Amendment History ........................................................................................................... 48 
11 
REFERENCES .............................................................................................................................................. 50 
 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
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CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Institute of Mental Health Terms and Conditions of Award. The Principal Investigator(s) will assure that 
no deviation from, or changes to the protocol will take place without and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SWIPED: Phase I 
Version 3.1.5 
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WU HRPO Protocol 202008037 
 
 
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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Slow Wave Induction by Propofol to Eliminate Depression Trial (SWIPED): Phase I 
Study Description: 
This is Phase I of a two-phase clinical trial to evaluate whether serial infusions of 
propofol can enhance slow wave sleep (SWS) and lead to improvements in 
cognition and depression. Phase I evaluates the safety and feasibility of 
targeting electroencephalographic (EEG) slow waves in 15 geriatric patients 
with treatment-resistant depression. If pre-specified milestones are met, a 
Phase II randomized controlled trial will evaluate short- and long-term effects 
on sleep structure, cognitive impairment, and depression severity in 70 geriatric 
patients. 
Objectives: 
 
Primary: Establish that propofol can safely 1) induce EEG slow waves during 
infusion and 2) promote the presence and persistence of SWS measures on 
subsequent nights in geriatric TRD patients  
Secondary: Inform design of Phase II to identify optimal dosing frequency, 
persistent of effects and recruitment criteria. 
Primary Endpoints: 
Safety: Number of adverse events and serious adverse events directly 
attributable to infusions. Feasibility: 1) EEG slow waves during the propofol 
infusions (sedation slow wave activity) and 2) Measures of slow wave sleep 
(sleep slow wave activity). 
Secondary 
Endpoints: 
Safety: Changes in suicidality (C-SSRS), in cognitive performance (MoCA). 
Feasibility: Changes in duration of N3 and REM sleep and proportion of total 
sleep time for these stages. Delta sleep ratio. 
Tertiary Endpoints: 
Changes in circadian rhythm, affect, anhedonia, depression symptoms 
Study Population: 
Inclusion: Age 60 or greater, English-speaking, TRD (non-responsiveness to at 
least two adequate trials of oral antidepressants for current episode). 
Exclusion: Symptomatic coronary artery disease, marked congestive heart 
failure/cardiomyopathy (NYHA > Class III, LVEF <40%, or greater than mild RV 
systolic dysfunction), prior reaction to propofol, resting heart rate < 50 bpm, 
ECT/TMS/vagal nerve stimulation in the past 6 weeks, body mass index >35, C-
SSRS of 4 or greater, MoCA score <23, non-prescribed used of amphetamines, 
opioids, marijuana, cocaine, or phencyclidine, intake of > 14 beers/week (or 
equivalent), anesthetic exposure in past 4 weeks, concurrent use of 
benzodiazepines > 2 mg/day lorazepam or equivalent, trazodone > 50 mg/day, 
or gabapentin > 600 mg/day. 
Phase: 
Phase I – 15 participants at single site 
Description of Sites: 
Clinical Coordinating Center/Data Coordinating and Statistical Center/Clinical 
Site: Washington University School of Medicine in St. Louis (WUSM) 
Description of Study 
Intervention: 
Intravenous propofol will be administered on two study sessions monitored by 
a board-certified anesthesiologist. With the aid of pharmacokinetic modeling, 
the dose will be titrated at an individual level to elicit safe induction of 
electroencephalographic (EEG) slow waves monitored during 64-channel EEG 
acquisition. The dosing from the first infusion will be used to facilitate rapid 
targeting for the second infusion. Infusions will last approximately 1-2 hours. 
Study Duration: 
1 Year 
Participant Duration: 
13 weeks: Study duration 3 weeks, 2-week of follow up, 10-week follow up 

SWIPED: Phase I 
Version 3.1.5 
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WU HRPO Protocol 202008037 
 
 
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1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. PICOT (Participant, Intervention, Control, Outcomes, Timing) Summary of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Phase I Goals: (a) Establish proof of concept: Does propofol dosed to induce slow waves, enhance SWS post-
infusion during nightly sleep? (b) Determine how many post-infusion days SWS is restored during nightly sleep. 
Rationale: This follows the design of experiments in ketamine infusions for TRD1,2, in which single infusion 
studies determined the duration of antidepressant effect; this duration was used to calculate the frequency of 
repeated infusions (2x/week). 
Phase I Design:  
Participants (n=15): 
Age 60+ 
Current MDD 
2 failed trials of antidepressants 
Slow Wave-induction with propofol:  
1 dose-titration infusion, then  
1 infusion dosed to induce EEG Slow waves  
Duration: Two infusions in one week, then two weeks’ at-home measurement of SWS 
High-density EEG during each infusion to confirm and quantify slow wave activity. 
Dreem EEG at home for 3 nights during the post-infusion week to confirm and measure duration of SWS 
enhancement; this duration is used to determine frequency of infusions in Phase II. 

SWIPED: Phase I 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
 Phone Screening 
Day -14 to -1 
Enrollment/Baseline 
Visit 1, Day 1 
Enrollment/Baseline Call 
At home, Day 1 +2 days 
Pre-infusion 1 
At home, Day 1-7 
Pre-infusion 2* 
At home, Day 2-7 
Study Visit 2 
Day 5 +/- 7 days 
Study Visit 3 
Day 9 +/-7 days 
Post-infusion 2 
 At home, Day 11 +/-6 days 
Post-infusion 3 
At home, Day 14 +/-6 days 
Post-infusion 4 
At home, Day 17 +/-9 days 
Post-infusion 5 
At home, Day 20 +/-5 days 
Post-infusion 6 
At home, Day 23 +/-5 days 
Follow up Study Visit 4 
Day 30 +/-1 week 
Final Follow up 
 At home, Day 80 +/-1 week 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Night Sleep Recording a 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administer propofol 
infusion 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Physical exam (including 
height and weight) 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
MADRS 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
SHAPS 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
PHQ-9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HD-EEG 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
Feeling Scale 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
MoCA 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
NIH Cognition Toolbox 
Battery and PVT 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse event review and 
evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Draw * 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
Wrist actigraphy 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Sleep diary 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
MEQ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STOP-BANG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Case Report 
Forms 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a: At home sleep recording using Dreem headband 
* Asterisk indicates optional study procedures for added flexibility 
C-SSRS: Columbia-Suicide Severity Rating Scale 
MADRS: Montgomery-Asberg Depression Rating Scale 
SHAPS: Snaith-Hamilton Pleasure Scale 
PHQ-9: Patient Health Questionnaire-9 
HD-EEG: High-density Electroencephalography 
MoCA: Montreal Cognitive Assessment 
MEQ: Morningness-Eveningness Questionnaire 
STOP-BANG: Snoring, Tired, Observed Apnea, high blood Pressure, Body mass index, Age, Neck circumference, male Gender Questionnaire 
PVT: Psychomotor Vigilance Test 
Table 1: Schedule of Activities. 
 
 
 
 

SWIPED: Phase I 
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WU HRPO Protocol 202008037 
 
 
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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Treatment-resistant depression (TRD) in older adults is a leading cause of disability, excess mortality from 
suicide, and dementia. Cognitive problems and sleep disturbances are common, contributing to 
recurrence and poor long-term outcomes. Disrupted slow wave sleep is at the nexus of depression and 
cognitive dysfunction in older adults. Novel approaches to target this core pathophysiology are lacking. 
Our mechanistic project is designed to elucidate the relationships between TRD and sleep disturbances in 
older adults. Through personalized infusions targeting electroencephalographic (EEG) patterns, we aim 
for a systematic characterization of the relationships between the propofol-induced EEG slow waves and 
enhancement of slow wave sleep. Through the repurposing of propofol as a therapeutic probe, this 
innovative proposal will establish whether EEG slow waves are a viable therapeutic target for novel 
antidepressant approaches.  
 
2.2 
BACKGROUND  
A. Significance 
A.1. Major Depressive Disorder: A Major Health Problem That Contributes to Poor Cognitive Outcomes  
Treatment-resistant depression (TRD) in older adults is a leading cause of disability3, excess mortality 
from suicide4,5, and dementia6-8. With the aging population, the prevalence of late life TRD (LL-TRD) is 
likely to increase over time9,10. Using failure of two oral antidepressant classes as a defining characteristic 
of TRD, we demonstrated that additional trials of traditional antidepressants such as venlafaxine are 
futile11. Moreover, long-term outcomes are dismal, with high recurrence rates12,13. While ECT14,15 and 
TMS16 are alternatives for some, novel treatments are desperately needed. New treatments should target 
core pathophysiology; an important candidate is sleep disruption17 that contributes not only to difficult-
to-treat depression18 but also deficits in alertness and executive function19. Therefore, derangements in 
sleep architecture have been posited as a treatment target for novel interventions in LL-TRD.  
Cognitive problems are common in LL-TRD. Executive functions (EF) are cognitive processes involved in 
goal-directed behavior20,21. They impact everyday function, including activities involved in medical and 
self-care22. EF include inhibition of prepotent responses, set-shifting (cognitive flexibility), and working 
memory23, governed by distinct but connected prefrontal cortex (PFC) regions21,24-26. EF impairment often 
coexists with LL-TRD21,27, posited as due to microvascular lesions affecting white matter tracts connecting 
prefrontal and subcortical structures28. EF impairments are associated with poor responses to oral 
antidepressant treatment, including nonresponse to aripiprazole augmentation12,20,22,29-32. Cognitive 
disturbances are associated with poor functionality, progression to Alzheimer’s disease and related 
dementias, and survival.  
Related to EF, impairments in alertness and processing speed are commonly seen in those with depression 
and sleep disturbances. Psychomotor vigilance testing allows quantitation of both psychomotor speed 
and lapses in alertness33,34. Depressive mood is associated with more lapses and longer reaction times34. 
Furthermore, analyses of the Wisconsin Sleep Cohort study have demonstrated an association with 
depression and psychomotor response speed, following adjustments for age and sex33. Additional analysis 
of this cross-sectional cohort showed that those with depression have more lapses. Intrasubject 
longitudinal measurements demonstrated that slower psychomotor speed was associated with a higher 

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Version 3.1.5 
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WU HRPO Protocol 202008037 
 
 
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odds ratio for the development of depression. Thus, psychomotor speed and lapses (reduced alertness) 
may reflect core sleep-related cognitive difficulties in depression. 
A.2. Disrupted Slow Wave Sleep (SWS) is at the Nexus of Depression and Cognitive Dysfunction in Older 
Adults 
Sleep is a daily critical period for restoration of physiologic and brain function, and for good mental health. 
It is divided into rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. SWS, also 
known as NREM Stage 3 (N3)35, is linked to the subjective feelings of restorative sleep36, reduced 
neurohumoral stress response37, and memory consolidation38. SWS is defined by the dominance of 
electroencephalographic (EEG) sleep slow waves, whose measurement provides markers of synaptic 
plasticity39-41. SWS plays an important role in memory processing; during SWS memories appear to be 
replayed through hippocampal-dependent pathways42. Synaptic remodeling for learning and memory 
occurs during SWS, potentially through release of brain-derived neurotrophic factor (BDNF)43. The 
squared amplitude, or power in these slow waves of SWS can be quantified as the slow wave activity 
(SWA). From a neurophysiologic standpoint, SWA is potentiated by a longer duration of wakefulness but 
dissipates over the course of sleep44. Changes in SWA between subsequent cycles of SWS are thought to 
reflect dissipation of sleep pressure and synaptic homeostasis45. SWA is a putative marker of homeostatic 
processes required for modeling neural connections based on recent experience. Early evidence suggests 
that enhancement of SWS may improve memory46,47. 
More recently, the electrophysiologic waves of SWS have been shown to regulate the biochemical milieu 
within the brain through the glymphatic system48 by stimulating cerebrospinal fluid waves49 that flush out 
lactate50. Proper functioning of this system may prevent deposition of pathology underlying Alzheimer’s 
disease and related dementias by allowing drainage of amyloid-beta48,51 and tau52. Power in these slow 
waves is inversely correlated with tau and amyloid-beta deposition in older adults, suggesting utility as a 
prognostic/diagnostic marker for cognitive impairment53. Anesthetic induction of states resembling SWS, 
with high EEG delta power have been correlated with greater glymphatic influx54,55, opening the door for 
pharmacologic targeting of slow waves to manipulate metabolic and physiologic processes that may 
protect against long-term cognitive impairment.  
Quality of SWS is reduced by stress and likely impacts depression. The proportion of SWS declines with 
each decade of aging such that the aged are at particular risk of deficiency. Chronic deficits in SWS 
potentially contribute to a cycle of future deficits through damage to circuitry regulating sleep and 
circadian rhythms. Reduced SWS is also a risk factor for recurrence of depression56. Overall, SWS is 
important for physiologic homeostasis and cognitive processes, with an unmet need in the those with LL-
TRD. 
A.3. Electroencephalographic Sleep Slow Waves are Novel Targets for Antidepressants 
Abnormalities in sleep slow wave expression have long been associated with depression. Reduced 
nighttime SWA, particularly in the first cycle57-62, has been considered as part of the core pathophysiology, 
even when accounting for age63. Delta sleep EEG metrics during N2 (Figure 2A) and SWS/N3 (Figure 2B) 
accounted for the largest proportion of variance in depression symptoms64, particularly for depressed 
mood. Furthermore, patients with depression tend to show higher peak SWA not at the first N3 cycle but 
later, consistent with the hypothesis that patients with depression have impaired homeostasis of synaptic 
plasticity65. Thus, the delta sleep ratio (DSR) is computed by dividing the SWA for the 1st N3 cycle by the 
SWA of the 2nd N3 cycle66, with a ratio > 1.5 observed in those without depression. DSR has also been used 
as a predictor for treatment response and vulnerability to recurrence. Shifting of SWA to the early part of 
sleep with imipramine predicted antidepressant response62. Low DSR predicted antidepressant 
responsiveness to ketamine67. Lower DSR (< 1.1) was associated with early recurrence of unipolar MDD 

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following discontinuation of antidepressant therapy66 or vulnerability to depression after interferon alpha 
treatment68. In concordance, older antidepressants augment slow wave sleep; these include lithium69-71, 
trazodone, nefazodone, mirtazapine72, sertraline73, and clomipramine62. Furthermore, newer 
antidepressants, such as ketamine74 and agomelatine75 augment time in SWS or SWA metrics. Despite 
these observations, no studies have specifically targeted SWS to treat TRD and cognitive function in older 
adults. 
Restoration of SWS to the early cycles of overnight sleep coincides with normalization of REM (Figure 2C) 
sleep architecture. SWS normally predominates in early sleep cycles, with replacement of REM later in the 
evening. Intrusion of REM into early sleep cycles and greater durations are commonly observed in patients 
with depression, with subsequent delay and reduced duration observed with antidepressant response. 
Overall, objective metrics based on EEG sleep slow waves are associated with depression, treatment 
response, and cognitive functioning. The potential for increasing SWS with pharmacological treatments 
opens the possibility of SWA and SWS enhancement as a pathway for novel antidepressant 
management strategies aimed at normalizing REM sleep architecture. 
A.4. Propofol induces EEG slow waves during infusion and alleviates N3 sleep deficiency on nights 
following infusion 
Propofol is a commonly 
used 
sedative 
in 
anesthetic practice. Low 
doses 
induce 
a 
shift 
toward lower frequencies 
in the EEG with some 
resemblance to N2 (Figure 
2D). Higher doses induce 
EEG 
slow 
waves 
resembling 
those 
of 
N3/SWS76 
(Figure 
2E), 
while even greater doses 
induce burst suppression 
(Figure 2F). The ability of 
propofol to recapitulate 
states resembling SWS in 
humans is aligned with the 
ability of propofol to fulfill 
rodent deficits of SWS77. 
Prolonged 
infusion 
in 
rodents 
reduced 
delta 
band power in the early 
sleep cycles78. The ability of propofol to provide subjective feelings of restorative sleep has motivated use 
as a treatment for refractory insomnia79,80. In adult patients with chronic refractory insomnia, five days of 
a 2-hour propofol infusion led to SWS enhancement (from 10 to 20% of total sleep time) with persistent 
augmentation 6 months after therapy80. From a safety standpoint, the pharmacokinetic modeling of 
propofol is well-established81-85. Sedation at projected serum concentrations of 3-4 mcg/ml without 
airway or cardiovascular support has been safely employed in young volunteers to elucidate the neural 
circuitry of propofol EEG slow waves76,86,87. The ability of propofol to recapitulate electrophysiologic and 
homeostatic properties of SWS has not yet been linked to antidepressant effects. 
Figure 2. EEG Patterns During Natural Sleep and Propofol Sedation From a 71-
year-old female with TRD. These data demonstrate the similarities and 
differences in EEG patterns across varied states of arousal. A. EEG during N2 sleep. 
B. Large amplitude slow waves during N3/SWS. C. REM Sleep with large amplitude 
deflections due to rapid eye movement artifacts. F7-F8 EEG data were recorded 
using a wireless wearable headband (Dreem). D. Non-slow wave EEG patterns 
with minimal slow waves during propofol infusion. E. Slow wave EEG patterns, 
resembling N3 sleep, during the same infusion. F. At higher infusion rates of 
propofol, burst suppression is induced. D-F were recorded using 64-channel high-
density EEG. All data were 0.1-0.6 Hz bandstop- and 0.5-40 Hz bandpass-filtered. 

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These data demonstrating a favorable side effect profile during routine clinical use, titratability, and 
effects of propofol on sleep architecture place it in a unique position as an experimental therapeutic 
probe for temporally linking target engagement of electroencephalographic markers and clinical 
effects.  
A.5. Additional putative antidepressant actions of propofol 
Antidepressant effects of propofol, independent of SWS induction/enhancement, have been suggested. 
While binding to GABA receptors is its primary mechanism88,89, propofol has additional molecular 
mechanisms that include antagonism of NMDA90 and action at AMPA receptors91,92. In rodent models, 
propofol pretreatment augmented the antidepressant effects of ketamine93 and moderate-dose ECT.94 
In surgical patients and those undergoing endoscopies, propofol exposure sometimes produces transient 
improved mood and euphoria95,96, amorous behavior97,98, and elation99 which can last for several hours100. 
These effects appear to be dose-dependent; low-dose sub-anesthetic propofol infusions targeting plasma 
concentrations of 0.9 mcg/ml yielded no improvements in mood 4 hours after infusion101. Higher doses of 
propofol capable of inducing burst suppression (Figure 2F) in humans has been associated with 
improvements in depression scores102 with some antidepressant responses sustained for up to 3 months. 
Since propofol has several potential antidepressant actions–SWS induction and enhancement as well as 
NMDA antagonism and AMPA receptor agonism–it will be important to delineate effects that are 
attributable to changes in sleep architecture from other effects. This requires a Phase I study to determine 
the ability of propofol to induce EEG slow waves and restore SWS in LL-TRD patients, and then a Phase II 
clinical trial to assess the association of SWS enhancement with cognitive and clinical outcomes.  
B. Innovation 
B.1. Theoretical and Experimental: Pharmacologic targeting of neurophysiologic states during 
unconsciousness and sleep 
Traditional monoaminergic antidepressants target specific molecular receptors and ion channels. In doing 
so, they disrupt multiple adaptive processes regulated by these receptors, but may not directly correct 
the underlying pathophysiology. These medications must be given chronically, and downsides of this 
approach include side effects and potential risks in medically ill individuals103. In contrast, we are utilizing 
propofol as a probe to both target EEG states resembling sleep and to increase the propensity for 
subsequent N3 sleep. In this way, our goal is to facilitate endogenous neural circuitry to restore normal 
architecture of sleep. We anticipate that this approach will yield new pharmacologic and non-
pharmacologic avenues for alleviating TRD.  
In this proposal, we are shifting the focus from targeting the monoaminergic neurotransmitter system, 
toward the restoration of SWS to correct a core pathophysiology. This is similar to the efforts with other 
novel antidepressants such as ketamine74 and the neurosteroid brexanolone104, which are thought to 
correct pathophysiology associated with TRD and post-partum depression, respectively. These states may 
facilitate the relearning of interactions between patients and the external world to reconfigure pathologic 
circuits underlying depression. In this study, propofol is being repurposed for its ability to induce states 
that address deficiencies of SWS and tested for its longer-term ability to alleviate depression and 
associated cognitive dysfunction. 
B.2. Experimental: High-density EEG provide biomarkers for target engagement during propofol 
infusion. Wireless wearable EEG devices provide biomarkers of treatment effect on sleep post-infusion 
Personalized medicine105 requires dosing based on individualized need. Here, neurophysiologic markers 
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target engagement (i.e., induction of EEG slow waves during the infusion). High-density EEG maximizes 
signal-to-noise and allows secondary analyses on circuits during propofol infusions. Furthermore, we will 
leverage the potential of at-home sleep EEG recordings as a report of the effects on brain circuitry. The 
use of wireless wearable devices (Figure 3)106,107 addresses feasibility issues of cost, logistics, 
interpretability, and instrumentation—all issues that hamper longitudinal investigation of sleep 
architecture. 
B.3. Theoretical and Experimental: Targeting of depression through direct manipulation of SWS 
Disorder of REM sleep 
expression has been 
posited as a marker 
and 
mechanism 
contributing to TRD. 
Patients 
with 
abnormal 
REM 
commonly express a 
short 
time 
interval 
(latency) 
between 
sleep onset and REM, 
and 
a 
greater 
proportion 
of 
total 
sleep 
time. 
Dysregulation of REM 
sleep, 
via 
early 
expression 
or 
overexpression, both 
yield deficiency in N3. 
The 
restoration 
of 
N3/REM 
sleep 
architecture has been 
posited 
as 
a 
contributor to antidepressant effect. This proposal is innovative in targeting SWS expression, given that 
deficits in this stage may contribute to damage in thalamocortical and limbic circuitry critical for cognition 
and emotional regulation.  
B.4. Theoretical and Experimental: Investigation of circuit markers related to underlying mechanisms 
We view propofol as a drug that can either be repurposed as a possible treatment for depression, but 
more likely be used as a therapeutic probe to understand the relationship between SWS enhancement 
and antidepressant effects. We address key steps in the FAST-FAIL approach for new drug discovery109. 
Published data (§A) and preliminary data (§C) show preclinical/clinical evidence supporting target 
engagement for therapeutics. EEG slow waves during infusion represent our biomarker for compound 
activity at neurobiological target and dosing-based target engagement. We propose dosing congruent 
with clinical anesthesia and volunteer studies for safe and efficacious target engagement. Phase II studies 
are proposed to address behavioral outcomes (alertness, executive function, and fluid cognition 
composite) as well as biomarkers of effect (N3 sleep). These studies will lay the groundwork for sleep slow 
wave enhancement via pharmacologic and non-pharmacologic interventions.  
B.5. Experimental: Repurposing of anesthetic agents to improve cognitive outcomes  
Figure 3. Wireless wearable headbands for serial at-home unattended overnight 
sleep recordings. A. Our group has been utilizing the Dreem headband to record sleep 
from geriatric patients prior to cardiac surgery107. The device has dry EEG electrodes 
(F7, Fpz, F8, O1, O2), accelerometers, and infrared plethysmography. B. Example EEG 
markers recorded by the Dreem to allow sleep staging. Vertex Sharp Waves for N1, 
Sleep spindles and K-complexes for N2, Slow waves for N3. Sawtooth Waves for REM, 
Posterior dominant rhythm (PDR) for wakefulness (W). Through use of the Dreem to 
record preoperative sleep of 90 cardiac surgical patients (age 60 or greater), the 
proportion of sleep time was 17.8% REM, 8% N1, 70.8% N2, 0.4% N3, consistent with 
previous literature108. Among 26 geriatric patients with two recordings, paired 
Wilcoxon sign-rank tests showed no significant difference in proportion of total sleep 
time for any stage (all p > 0.05). 

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Sedative anesthetics have been associated with acute confusion and cognitive decline in the perioperative 
setting. Here we are addressing the provocative hypothesis that these agents may improve cognitive 
outcomes either directly (addressing acute/chronic sleep deprivation) or indirectly through alleviating the 
cognitive impairments of depression. This complements our work in repurposing anesthetics as 
antidepressants110,111. 
C.1. Preliminary Studies 
C.1.1. Infrastructure for Recruitment of TRD Patients 
Data: Our group has a large pool of geriatric patients for recruitment, including a recently completed 
large-scale trial of LL-TRD (OPTIMUM) and a geriatric depression clinic. These referral sources have been 
successful for the pilot stages of the proposed work. Since the initiation of recruitment (1/12/21), we 
approached 4 older adults with TRD and completed infusions in two participants. One remains active for 
future participation. 
Relevance: Excellent feasibility of recruiting geriatric TRD patients into a protocol requiring infusions and 
at-home sleep recordings. 
C.1.2. Cognitive Task Performance and the Psychomotor Vigilance Test 
Data: We (Dr. Lenze) have previous experience with evaluating both measures of executive function and 
global cognition using the NIH Toolbox Cognition Battery32. We have previously utilized the NIH Toolbox 
Cognition Battery Fluid Composite in a randomized placebo-controlled investigation that evaluated 
whether vortioxetine improved cognitive training112. One-hundred participants, age 65 years or older, 
were randomly assigned to take either placebo or 10 mg vortioxetine for a 26-week interval with a target 
cognitive training engagement of 150 minutes/week. The NIH Toolbox Cognition battery was 
administered at 4-, 12-, and 26-weeks following randomization. The computer-based instrument allowed 
assessment of fluid and crystallized cognition through the following five component tests (and tested 
cognitive domains): The Flanker Inhibitory Control Test (executive function-sustained attention and 
inhibitory control), the Dimensional Change Card Sort test (executive function-cognitive flexibility), the 
List Sorting Working Memory Test (working memory), the Picture Sequence Memory Test (episodic 
memory), and the Pattern Comparison Processing Test (processing speed). We utilized age-corrected 
standardized scores, excluding participants who failed to complete a 2-week lead-in period and those who 
had scores above 10a determined cutoff of one standard deviation above age-matched controls. At 12 
weeks, we observed greater improvement in the estimated Fluid Cognition Composite Change from 
Baseline (+4.19 favoring vortioxetine over placebo, with a standard error of 1.52, p = 0.0063, Cohen’s d 
effect size of 0.57). Smaller effects were noted at 4- and 26-weeks.  

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The Psychomotor Vigilance Test (PVT)114 is a common task used to assess vigilance/alertness in the 
context of poor sleep and psychiatric illness. Adaptions 
allowing short testing bouts of a few minutes have been 
validated 115, all the way to 3 minutes116,117. The PVT 
requires the participant to respond as quickly as 
possible and to maintain sustained vigilance due to the 
incorporation of a random intertrial interval of several 
seconds. The task generates a right skewed distribution 
in reaction time (RT), that can be assessed in terms of 
lapses (outliers) as well as overall metrics of speed (the 
reciprocal of reaction time, RRT). With sleep 
deprivation, there are an increased number of lapses 
(reaction time > 500 ms)118. We (Dr. Palanca) have prior 
experience with the execution of a 3-minute 
computerized version of the PVT in healthy non-
depressed study participants undergoing general 
anesthesia (Figure 4)113. We (Drs. Palanca, Lenze, and 
Farber) have extended our experience in patients with 
TRD undergoing electroconvulsive therapy (ECT)119.  
Relevance: These data demonstrate 1) successful longitudinal administration of the NIH Cognition 
Toolbox in the geriatric population, 2) ability to detect change in the global fluid cognition following an 
intervention, 3) successful implementation of the 3-minute computerized versions of the PVT.  
These data will be important for a future planned Phase II study. 
C.1.3. Precision Targeting of Propofol EEG Slow Waves During High-density EEG 
Data: We have carried out serial infusions on two participants with LL-TRD and have demonstrated 
proof of concept of the proposed work. Both participants underwent two propofol infusions lasting 2 
hours. Estimated propofol target effect-site concentrations were projected using published 
pharmacokinetic models85 implemented in an iOS application, AnestAssist. The infusion bolus and rates 
were tailored to the patients’ sex, age, height, and weight. The first infusion session was utilized to 
evaluate safety endpoints and EEG changes in response to propofol bolus and infusions. This dose-
titration session facilitated the second infusion sessions, focused on establishing safe and stable target 
engagement of EEG slow waves. An anesthesiologist controlled the infusion rate (80-200 mcg/kg/min) 
while monitoring participant safety with a study nurse. Minimal airway support (chin lift) and 
supplemental oxygen were supplied to further augment safety. Fasting and monitoring guidelines were 
followed according to society guidelines. High-density EEG data were acquired using a 
MagStim/Philips/EGI system and 64-channel GSN nets. Elefix conductive gel was injected within the 
Ag/AgCl electrode sensors to minimize impedances above 100 kOhms/electrode. Data (500 Hz sampling) 
were acquired with a Net Amps 400 amplifier and Net Station version 5.0 via a Late 2012 Mac Pro 
Workstation.  
We have induced targeted EEG slow waves in two participants, extending proof of concept. Example 
EEG data for the first participant are included in Figure 2C-E. Data from the second participant’s dose-
titration session are shown in Figure 5. While Non-Slow Wave EEG patterns are noted at lower targeted 
Figure 4. Return to baseline PVT response time 
following general anesthesia. Change in baseline 
scores are plotted for 30 healthy volunteers 
following 3-hours of isoflurane anesthesia 
(purple) or following 3-hours of watching videos 
(black)113.    

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effect site concentrations of propofol 1.5-2 mcg/ml (Figure 5A-B), Slow Wave EEG patterns noted at higher 
concentrations (Figure 5C-D) were targeted during the remainder of the infusion (effect-site 
concentration of 2.3-2.4 mcg/ml, as demonstrated in the time-frequency power spectrogram (Figure 5E). 
This contour plot graphs the power at each frequency as a function of time. The persistence of the 
combination of power at low frequency oscillations (<4 Hz) and “spindle-like” activity at 13-14 Hz is 
observed. 
Relevance: These data demonstrate our ability to 1) safely administer serial infusions of propofol and 2) 
target propofol dosing to induce EEG slow waves in the outpatient setting. 
Figure 5. Targeting of Slow Wave EEG During 
Propofol Infusion for a 77-year-old male with 
TRD. Propofol was administered intravenously 
during the first infusion/dose-titration session. 
A. During short boluses of propofol, Non-Slow 
Wave EEG patterns were observed with mixed 
alpha (8-13 Hz) and beta (13-30 Hz) activity and 
minimal slow wave oscillations. B. Lack of slow 
waves is also noted in a 30-second epoch, where 
the effect site concentration is estimated to be 2 
mcg/ml. Period in A is highlighted in purple, with 
similar activity as in Figure 2D. C. Low frequency 
EEG oscillations resembling sleep slow waves are 
induced during the maintenance of targeted 
propofol effect site concentration. D. Additional 
examples of slow waves are in this 30-second 
epoch, with period in C in red shading. These EEG 
slow waves resemble Figure 2E. The effect site 
concentration is ~2.4 mcg/ml. E. Time-frequency 
spectrogram of EEG data from the Fp1-Cz channel shows the distribution of power at different frequencies as a 
function of time. Epochs for A-B and C-D are indicated by purple and red arrows, respectively, with the latter portion 
of the infusion targeting Slow Wave EEG patterns.  
C.1.4. At-home Sleep Recordings and Potentiation of Sleep SWA Following Propofol Infusions 
Data: We have years of experience utilizing wireless wearable devices to longitudinally record sleep EEG 
markers in elderly cardiac surgical patients. The Dreem (Figure 3A) has been the main vehicle for collecting 
EEG data for the prospective observational investigation of perioperative sleep in geriatric cardiac surgical 
patients, 
“Prognosticating 
Delirium 
Recovery 
Outcomes 
Using 
Wakefulness 
and 
Sleep 
Electroencephalography (P-DROWS-E, ClinicalTrials.gov NCT03291626, NIA R01AG057901, PI Palanca). 
Each Dreem has dry EEG sensors including Fpz (ground), F7, F8, O1 and O2 for recording multichannel 
EEG. Additionally, it has an infrared light source and sensor to measure heart rate and a 3-axis set of 
accelerometers for tracking head position and respiratory effort. Accelerometers are utilized to provide 
actigraphy data to assist in automatic sleep staging, detection of arousals, and head position. Using the 
Dreem, we have recorded over 471 overnight sessions from 100 patients in probing putative relationships 
between postoperative delirium and sleep EEG markers (slow waves and spindles). Geriatric patients are 
trained to instrument themselves with the device and record their own overnight sleep records. 
Deidentified data are preprocessed by the device manufacturer and imported by research staff into 
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raw data are down-sampled to 250 Hz and frequency bandpass filtered at 0.5-50 Hz using EEGLAB120, an 
open-source analysis toolbox. European data format (EDF) records are imported into Respironics 
Sleepware G3 software (version 3.7.1., Philips Respironics, Inc., Murrysville, PA, USA) and evaluated by 
American Academy of Sleep Medicine (AASM) certified sleep technologists who scored greater than 90% 
agreement on assessments through the AASM inter-scorer reliability program. Manual scoring proceeded 
for 30-second epochs, using modified AASM scoring rules previously developed for single frontal EEG 
analyses121 and described recently106. The sleep stages are aligned with quantitative EEG analytical 
measures. Scorable preoperative records were provided by 82% of patients while 94% completed 
recordings after surgery. Data from 26 patients who recorded multiple nights of in-home recordings 
showed no differences in sleep stage durations, suggesting that only one night is required for establishing 
baseline sleep structure. We have extended our use of the Dreem to a current investigation on EEG 
markers of sleep for weeks over the index course of ECT (CET-REM study). These sleep data, from a 
consumer grade device designed for comfort during sleep, reinforce the feasibility of repeated use 
following one or more weeks of serial propofol infusions. 
Leveraging this approach, a 71-year-old female recorded her own overnight sleep for two nights prior to 
propofol infusions (Figure 6A). The two hypnograms demonstrate transitions among AASM stages of 
wakefulness (W), stages of NREM (N1, N2, and N3/SWS), and REM (R). These two recordings are consistent 
with: 1) prolonged overnight recordings with adequate quality for sleep staging, 2) cycling into deep stages 
of (R), 3) dominance of N1 and N2 sleep with a paucity of N3 sleep at baseline despite a long TST. Overnight 
sleep was also monitored using the Dreem on the evenings of the first and second propofol infusions 
(Figure 6B). Progressive augmentation of the total duration of N3 sleep and proportion of total sleep time 
were noted after each propofol session. 
Relevance: These data demonstrate the following: 1) Success in leveraging innovative technology 
required for conducting longitudinal sleep studies, 2) Ability to augment N3 sleep through propofol 
infusions, and 3) The possibility of persistence of effects in that successive propofol infusions may have a 
synergistic effect in augmenting sleep slow waves on subsequent nights. We are in a key position to probe 
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2.3 
RISK/BENEFIT ASSESSMENT   
   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Propofol Infusion: 
Propofol is a commonly used sedative in anesthetic practice and critical care medicine.  
Per the propofol package insert122, the most common risk associated with propofol infusions includes 
burning/stinging or pain at injection site, bradycardia, arrhythmia, hypotension, hypertension, 
hypoxemia, hypercapnia, airway obstruction and apnea. Less likely risk (< 1%) include 
anaphylaxis/anaphylactoid reaction, premature atrial contractions, syncope, hypertonia/dystonia, 
paresthesia, myalgia, pruritus, amblyopia, and cloudy urine. While case of rare anaphylactic123-126 or 
anaphylactoid127-129 reactions have been reported, allergic reactions occur at an estimated 1:60,000 
exposures130. There have been previous anecdotal connections to food allergies, but recent data shows 
no association between propofol allergy and allergies to egg, soy, or peanuts131. 
Adverse events (AEs) related to propofol are commonly encountered by anesthesiologists in clinical 
practice performing procedures such as colonoscopies or transesophageal echocardiographic studies. 
Patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are safely 
anesthetized with propofol. Finally, serious adverse events (SAEs) include hospitalization, anaphylaxis, 
cardiac arrest, stroke, or death. Patients will be attended by a board-certified anesthesiologist during each 
sedation session, with all standard sedation and airway management equipment available should any 
adverse events occur. 
IV Placement and Blood Draws: 
Patients will undergo serial propofol infusions via an intravenous catheter (IV). The placement of the IV 
could cause tenderness or bruising at the insertion site, as well as dizziness or fainting. Blood can be drawn 
from the IV catheters or through separate venipuncture, with similar risk as for IV placement. 
Dreem EEG:  
Patients will be asked to sleep with the Dreem device at home for up to 1 week prior to their first propofol 
infusion session, as well as the night after each infusion session. Patients may also be asked to sleep with 
the Dreem device for up to 2 weeks following their final infusion session. We have observed no definitive 
Figure 6. Potentiation of SWS Following Propofol Infusions Monitored Through Wireless Wearable Headbands. 
A. Hypnograms demonstrate sleep structure of two overnight recordings from a 71-year-old female with TRD, 
recorded on the week before propofol infusion sessions. Consistent with prior literature, N3 was sparse, 
accounting for only 3 minutes/0.6% total sleep time (TST) or 0.5 minutes/0.2% TST. B. Overnight sleep recordings 
from the same participant demonstrates augmentation of N3 sleep on the night of the first propofol infusion 
session (Post-infusion 1, 6 minutes/2.5% TST) and night of the second infusion session (Post-infusion 2, 14 
minutes/6.2% TST). C. Frontal EEG tracings at time indicated by purple arrow in B, from a representative N3 epoch 
of the Post-infusion 1 overnight recording. The traces demonstrate sleep slow waves in Fpz-F7 and F8-F7 channels. 
D. Expansion of blue highlighted period in C. Epoch Labels: W, Wakefulness; NS, Non-scorable; R, REM; N1, NREM 
Stage 1; N2, NREM Stage 2; N3, NREM Stage 3/SWS. All data were obtained using the Dreem and scored according 
to our recently published modified AASM criteria106. 

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abrasions or skin irritation related to hundreds of Dreem recording acquired from over 150 geriatric 
cardiac surgical patients106,107.  
Skin irritation may occur from wearing the dry electrodes on the Dreem headband. Some discomfort may 
also occur, particularly those over patient’s hair. Some individuals have reported difficulty sleeping while 
wearing the device. 
Genetic Research: 
There may be information obtained from the genetic testing that indicates that the participant, or 
potentially a family member (since we inherit genes from our parents, and pass genes on to our children) 
are at risk for a particular disease or condition.  For example, genetic sequencing may indicate that an 
individual is more prone to develop certain types of cancer or other types of diseases, (e.g. Alzheimer’s or 
other inherited diseases). This information might harm the participant if shared with employer or 
insurance carrier. Depending on the test and result, participants may also be uncomfortable with the 
findings of the genetic research. 
High-Density EEG: 
Risk of injury related to high-density EEG acquisition during propofol infusion is minimal. Skin abrasions 
from scalp electrode placement or discomfort upon removal of scalp electrodes may occur.  
STOP-BANG/MADRS/SHAPS/PHQ-9/C-SSRS/MoCA/MEQ/NIH Cognitive Toolbox Battery:  
There 
are 
no 
known 
risks 
associated 
with 
assessment 
of 
obstructive 
sleep 
apnea 
risk/depression/anhedonia/suicidal ideation via surveys. Patients may become uncomfortable should 
their self-rated severity not improve at the desired rate. Moreover, patients may be uncomfortable 
conveying thoughts of death. We are not aware of any risks with serial cognitive assessments. 
Breach of Confidentiality: 
The risk of unintended release of personal health information (PHI) exists.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
There is no benefit to individual subjects in this study. Society may benefit from a better understanding 
of the interaction between propofol sedation, slow wave sleep and depression.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
This mechanistic clinical trial addresses a critical nexus between sleep, mood, and cognition in the geriatric 
population. We expect the successful outcomes of this research to open a pathway for novel 
pharmacologic and non-pharmacologic interventions to promote SWS enhancement. Propofol could be 
further exploited as a therapeutic probe to elucidate relationships between sleep structure and 
antidepressant response. This research addresses questions that have profound implications for society. 
With the rise in the aging population, we hope to provide translatable biomarkers and approaches for 
future precision medicine, with a long-term goal of improving public health and quality of life for those 
afflicted with TRD. 
We hope that enrolled patients may benefit from the study through promotion of sleep quality and 
lowering of depressive symptom severity. Patients with treatment-resistant depression can build agency 
by knowing that they are contributing to helping others through scientific research. We are also in a key 

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position to educate study participants on the importance of sleep. We will also share data with patients 
regarding their brain activity and sleep structure. The study will require multiple infusions of propofol, a 
sedative commonly used for clinical procedures. Propofol is well-tolerated when monitored by qualified 
practitioners based on patient vital signs and comorbidities. 
Overall, we feel that the potential benefits outweigh potential risks, and there is sufficient clinical 
equipoise to justify conducting research. 
Propofol adverse events: 
A board-certified anesthesiologist with ACLS certification will supervise propofol infusions with 
collaboration of a certified registered nurse anesthetist or anesthesia trainee. The anesthesiologist will be 
physically present until the patient is awake and recovering from the anesthetic. Patients will have 
adhered to ASA fasting and monitoring guidelines. Medications, including narcotics and benzodiazepines, 
will be continued ad libitum—except angiotensin converting enzyme inhibitors or angiotensin receptor 
blockers, which are normally held prior to procedures requiring sedation or general anesthesia. Patients 
with obstructive sleep apnea or COPD will not be excluded, as propofol sedation remains safe. ASA 
standard monitoring (blood pressure pulse oximetry, ECG, CO2 capnography, suction, airway, and 
resuscitation equipment) will be employed. Bolus dosing of propofol will be done carefully to minimize 
risk of apneic events.  
The potential benefits of mitigating depression, cognitive impairment, and poor sleep in the geriatric 
population justify this greater than minimal risk study intervention.  
Bruising/bleeding/nerve injury/infection related to venipuncture: 
Only qualified nursing and physician staff will carry out these procedures. Aseptic technique will be utilized 
to minimize risk of skin and blood stream infection. Venipuncture for IV placement is necessary for the 
propofol infusion and possible rescue medications. Blood biobanking will be useful for future substudies. 
Genetic Research: 
Results of genetic testing will not be shared with insurers or employers. Participant anonymity in the study 
will maintained using study code to separate PHI and genetic test results. Genetic analyses will not be 
shared with study patients who request their own findings. 
Abrasions from HD-EEG and Dreem sleep recordings: 
The coordinators undergo rigorous training in high-density EEG acquisition, as well as in utilization of the 
Dreem EEG headband. Scalp will be monitored before cap placement to evaluate any vulnerability. Scalp 
will be inspected after cap removal to assess for any abrasions. Participant satisfaction and absence of 
scalp pain will be evaluated by research staff.  
Patients will be instructed on proper use of the Dreem to minimize discomfort and possibility of abrasions 
during serial overnight recordings. Locations of dry electrodes will be varied over time to minimize the 
possibility of repeated pressure to the exact same scalp locations. Devices will be cleaned with 3% 
hydrogen peroxide spray and wipes between uses to minimize the risk of skin pathogen transmission. 
Follow-up will evaluate for any discomfort or disruption of sleep. Participants with significant 
discomfort/poor sleep quality will be closely evaluated and rescreened/rescheduled for study infusion 
days to ensure that representative sleep baseline data and post-infusion data will be acquired.  
Breach of Confidentiality: 
To minimize breach of confidentiality risk, the minimum necessary data will be collected to achieve the 
study objectives, datasets will be de-identified after study completion, and data and code keys will be 

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stored in password-protected databases. All electronic documents are stored on secure servers that are 
password protected and have various state-of-the art firewall protections with frequent upgrades of these 
protections. The study coordinator and team members will ensure that all paper documents are locked in 
a filing cabinet in a locked office of a member of the study team. Access to all study documents is limited 
to members of the research team and will be controlled by the principal investigators.  
Suicide: 
Patients who are identified as being acutely suicidal will be excluded from the study. Nevertheless, since 
the rate of completed suicide in the USA remains high (i.e., about twice the rate of homicide) and most 
Americans who commit suicide suffer from depression, all participants eligible to participate in this study 
are at a statistically higher risk for suicide than the general population. However, the participants’ absolute 
risk for completing suicide during this brief study remains very low (i.e., about 1 in 3,000 to 10,000) and 
participation in the study does not create or increase the risk of completed suicide. Most experts believe 
that one of the most efficient ways to decrease suicidal risk in older depressed individuals is to treat their 
depression. Furthermore, all participants will be formally assessed frequently throughout the study.  
We 
will 
use 
the 
rater-administered 
Columbia 
Suicide 
Severity 
Rating 
Scale 
(C-SSRS, 
https://cssrs.columbia.edu/wp-content/uploads/C-SSRS1-14-09-Baseline.pdf) to assess severity and 
intensity of suicidal ideation both current (past month) and lifetime.  
At different assessment points, the research staff will assess for passive death wish, and suicidal ideation, 
intent, or plan when they administer the MADRS. The first items of the C-SSRS will also be assessed and 
reviewed (using past week as range). A MADRS 2+ score on item 10 or a C-SSRS score of 4 or greater 
(active suicidal ideation with some intent to act with or without a specific plan) would be an exclusion for 
the study; instead, these individuals would be referred for psychiatric management. The study psychiatrist 
(Dr. Lenze) would review these patients and any individual with lifetime suicide attempt, to determine the 
participant is safe to participate/continue in the study and what additional risk management procedures 
are needed, if any. The patient’s outpatient psychiatric care provider would be contacted.  
If a participant endorses suicidal ideation, intent, or plan, the trained raters will follow an operationalized 
protocol that has been developed to manage high-risk participants in other study of depressed 
participants potentially at risk for suicide. This protocol has already been used successfully by the 
investigators to manage several acutely suicidal patients. Briefly, the protocol entails a specific 
determination of the suicidal risk and prescribes a set of actions. For instance, when a participant is 
determined to be at high and immediate risk, the rater is instructed to stay with the participant until he 
or she has contacted a study psychiatrist to discuss the situation and to devise a plan according to standard 
procedure. For this reason, raters will have cell phones, and at least one study psychiatrist will be 
reachable at all times. In case of extreme emergency, raters are instructed to call their hospital security 
team or 911 for immediate help and to initiate commitment proceedings. This may lead to a clinical 
intervention that is lifesaving and may not have occurred had the participant not been participating in the 
study. 
 
 
 
 
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
1. Safety: Evaluate 
whether the 
intervention is safe 
and well-tolerated  
 
 
2. Feasibility: Evaluate 
whether propofol 
infusions allow (A) 
Efficient induction of 
SWA and (B) promote 
the expression and 
persistence of sleep 
slow waves  
1. Adverse events and serious adverse 
events, including incidence, severity, and 
likelihood of relation to intervention. 
 
 
 
2. A) Sedation slow wave activity (SWA, 0.5-
4 Hz EEG power) during propofol sedation. 
 
B) Change in sleep slow wave activity 
during N2/N3 Sleep (post-infusion – pre-
infusion) 
1. Evaluate whether serial 
propofol infusions are safe 
(<5% serious adverse events 
directly attributable to 
infusions) 
 
2. Evaluate in geriatric TRD 
patients that propofol 
infusions can (A) efficiently 
induce EEG slow waves during 
infusion (SWA for most of the 
sedation time) and (B) 
augment total sleep SWA in 
greater or equal to 40% of 
study completers. 
Secondary 
 
 
1. Safety: Evaluate 
whether propofol 
infusions are 
associated with 
augmented (A) 
suicidality or (B) 
cognitive impairment. 
  
2. Feasibility: Evaluate 
changes in sleep 
structure 
1. (A) Change in Suicidality (C-SSRS),  
(B) Change in Cognitive Performance 
(MoCA), and (C) NIH Toolbox Cognition 
Battery 
 
 
 
 
2. Changes in duration of N3 and REM sleep 
and proportion of total sleep time for these 
stages. Delta sleep ratio (DSR, calculated as 
the SWA of the 1st N3 cycle divided by the 
SWA of the 2nd N3 cycle). 
 
 
1. (A) Suicidality screening for 
need of emergency psychiatric 
care. (B) Examine changes in 
cognition that may be 
associated with propofol 
infusion. 
 
 
2. Established markers for 
sleep macrostructure. 
Tertiary/Exploratory  
 
 
Examine feasibility of 
acquiring propofol-
associated changes in 
(A) circadian rhythms, 
(B) affect, (C) 
anhedonia, (D) 
depression symptoms 
(A) Circadian rhythms using wrist 
actigraphy/molecular markers/MEQ, and 
sleep diary, (B) Measure of affect (feeling 
scale), (C) Measure of anhedonia (SHAPS), 
(D) Measure of Depressive Symptoms 
(MADRS) 
 
These measures are important 
for evaluating feasibility of 
collection in Phase II. 
 
 
 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Our hypothesis is that targeted propofol infusion in TRD patients will induce slow wave activity during 
sedation and augment subsequent sleep slow wave activity. We will recruit 15 participants for this open 
label single arm Phase I trial. All participants will undergo two propofol infusions 2-6 days apart, with each 
infusion maximizing expression of EEG slow waves. To minimize bias, there will be no specific gender or 
ethnic background consideration for enrollment. This will be a single site investigation at Washington 
University Medical Center.   
 
Study Intervention 
Propofol will be infused through a peripheral IV, with the assistance of target-controlled infusion software 
and pumps, with an anticipated infusion duration of 1-2 hours. Concurrent high-density EEG will be 
acquired as in §C.1.3. but with an updated recording rig and sensor nets that use either Elefix conductive 
gel or salt solution. An Axis P3364LV network camera, synchronized to EEG recordings, will provide video 
for post-hoc analysis. Participants will be discharged home after nurse monitoring and fulfillment of post-
anesthetic care unit criteria132. 
Patients will be instructed by staff on operation of the Dreem headband for at-home overnight sleep EEG 
recordings. Patients will demonstrate ability to successfully wear the Dreem and initiate recordings 
without assistance. The device, charger, instruction sheet, and a link to a 2-minute instructional video will 
be provided to patients. This paradigm has been successful in the acquisition of preoperative sleep 
recordings in over 150 geriatric cardiac surgical patients106,107 and eight patients who underwent ECT for 
TRD (ClinicalTrials.gov NCT04451135).  
Dreem recordings will be obtained prior to the first propofol infusion and on evenings of propofol 
infusions. Additionally, recordings will be obtained for up to 6 nights within a 2-week period after the final 
infusion, to evaluate persistence of restoration of sleep architecture. Participants will exchange the device 
with staff during each in-person visit, to allow device examination and data download.   
Planned subgroup analyses include stratification by sex and age. For the purposes of Phase II of the study, 
additional subgroup analyses will be performed based on baseline sleep structure (e.g. total sleep time 
and proportion of time in N3 sleep), and time interval separating the two infusions. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This non-controlled study is a Phase I trial for gauging the safety and feasibility prior to the launch of a 
Phase II randomized placebo-controlled trial of 70 participants to evaluate the effect of serial propofol 
infusions on slow wave sleep, cognition, and depression. 
 
The overall investigation is modeled after the FAST Trials by establishing 1) safe target-engagement of a 
physiologic biomarker (EEG sleep slow waves) through propofol and 2) EEG slow waves as a novel 
antidepressant engagement target for future pharmacologic and non-pharmacologic therapies. 
 
 

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Progression milestones to the Phase II trial include: 1) Safe (<5% infusions with serious adverse events 
directly attributable to propofol), 2) Successful induction of SWA during propofol infusions in ≥60% of 
all participants, and 3) Enhancement of SWS in ≥40% of all participants over the subsequent week. 
Phase I data will also strengthen execution of Phase II by identifying optimal dosing frequency, 
persistence of SWS enhancement, and optimal recruitment strategies. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
For propofol, standard clinical administration is via the intravenous route. From a safety standpoint, the 
pharmacokinetic modeling of propofol is well-established85. Sedation at projected serum concentrations 
of 3-4.5 mcg/ml without airway or cardiovascular support has been safely employed to elucidate the 
neural circuitry of EEG slow waves76,86,87. Dosing of propofol will be established by safe induction of EEG 
slow waves tailored to the individuals response and vital signs; no specific dose is predetermined at a 
patient level. For further details on dosing strategy. For detailed dosing strategy, please refer to section 
6.1.2. 
 
4.4 
END OF STUDY DEFINITION 
 
A study completer will be defined as a participant who has safely completed the baseline sleep 
recording, both propofol infusions, and both post-sedation sleep recordings. 
 
The end of study will be reached when the last participant has completed the last study visit or 
procedure listed in the Schedule of Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
To be eligible for study participation, an individual must meet all following criteria: 
 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Age 60 or greater 
4. English speaking (as an interpreter will not be readily available should a participant need to 
convey any safety concerns during the propofol infusion sessions or require guidance on 
conducting at-home sleep recordings) 
5. Treatment-resistant Depression (non-responsive to at least two adequate trials of oral 
antidepressants for current episode). 
 
When available, electronic medical records over the previous five years will be used to confirm safety 
and eligibility. Women and members of minority groups will be included in accordance with the NIH Policy on 
Inclusion of Women and Minorities as Participants In Research Involving Human Subjects.  
 
5.2 
EXCLUSION CRITERIA 
 

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An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Presence of symptomatic coronary artery disease 
2. Presence of marked congestive heart failure/cardiomyopathy (NYHA > Class III, LVEF <40%, 
greater than mild RV systolic dysfunction) 
3. Prior reaction to propofol 
4. Resting heart rate < 50 bpm 
5. Treatment with Electroconvulsive therapy/Transcranial Magnetic Stimulation/vagal nerve 
stimulation within 6 weeks 
6. Body mass index > 35 
7. C-SSRS of 4 or greater (active suicidal ideation with some intent and with/without a specific 
plan) 
8. MoCA score < 23 (at least mild dementia) 
9. Non-prescribed used of amphetamines, opioids, marijuana, cocaine, or phencyclidine  
10. Intake of > 14 beers/week (or equivalent) 
11. Anesthetic exposure in the past 4 weeks  
12. Concurrent use of benzodiazepines > 2 mg/day lorazepam or equivalent, trazodone > 50 
mg/day, or gabapentin > 600 mg/day. 
 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
In accordance with ASA Guidelines for perioperative fasting, study participants are asked to: 
• 
Abstain from food at least 8 hours before start of propofol infusions. 
• 
Abstain from clear fluids at least 2 hours before start of propofol infusions. 
• 
Avoid non-prescribed used of amphetamines, opioids, marijuana, cocaine, or phencyclidine or 
high alcohol intake to maintain study eligibility. 
 
Participants will also be asked to continue all medications throughout the study period, except angiotensin 
converting enzyme (ACE) inhibitors and angiotensin receptor blockers. These medications are commonly 
held on the morning of anesthetic sedation to reduce the possibility of hypotension. 
 
5.4 
SCREEN FAILURES 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of failure to 
meet inclusion/exclusion criteria may be rescreened. Rescreened participants will be assigned the same 
participant number as for the initial screening if they are able to follow study procedures at a future time. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Target sample size for this Phase I trial is 15 TRD male and female patients aged 60 or greater with an 
expected 20% attrition rate. Our group has a large pool of geriatric patients for recruitment, including a 
recently completed large-scale trial of LL-TRD (OPTIMUM) and a geriatric depression clinic. These referral 
sources have been successful for the pilot stages of the proposed work. Additionally, we will employ 
recruitment services through Volunteers for Health, Facebook ads, and Centerwatch.  

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Potential participants will be contacted by phone and/or email to gauge interest and preliminary 
screening. 
The following strategies will be employed to maximize retention: 1) Participants will be contacted by their 
preferred method on the day before any study visits for reminder and confirmation, 2) Study staff will 
contact patients on day of at-home sleep recordings to remind them to initiate sleep recording, and the 
next day to address and questions/concerns, and 3) a portable internet modem will be sent home with 
participants to allow for remote monitoring of at-home sleep recordings, to minimize attrition due to data 
loss/poor quality data.  
 
Participants will be compensated for their time and effort. Compensation is broken down as follows: 
• 
$30 for each baseline home sleep study (2 maximum) 
• 
$15 for each sedation session (2 maximum) 
• 
$25 for each post sedation home sleep study (7 maximum) 
• 
$40 for follow up study questionnaires/test 
• 
$305 possible for completion of all study procedures 
Payment will be prorated based on the number of completed study procedures list above. Upon retrieval 
of study devices and completion of the final study visit, payment will be processed and sent to the 
participants’ residence in form of a check. Transportation is commonly a limitation for involvement. 
Remuneration for drivers ($20) will be employed, if needed. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Propofol is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia 
or sedation122. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal 
excitation, usually within 40 seconds from the start of injection. The half time of the blood-brain 
equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. The 
mechanism of action is poorly understood; however, propofol is thought to produce its 
sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter 
GABA through the ligand gated GABAA receptor.  
6.1.2 DOSING AND ADMINISTRATION 
 
Propofol will be administered intravenously in a post-anesthesia recovery unit or clinical trials research 
unit, concordant with clinical practice and requisite monitoring and safety guidelines. 
Pharmacokinetic models will be used to generate a preliminary bolus and infusion schedule. Infusion bolus 
and rates will be tailored to the participants’ sex, age, height, and weight. To precisely target EEG slow 
waves with concurrent spontaneous ventilation we anticipate the need for infusion rates ranging from 20 
mcg/kg/min to 200 mcg/kg/min, with starting infusion rates ranging between 150 and 200 mcg/kg/min. 
Infusion rates above 100 mcg/kg/min will be restricted for short periods designated to quickly raise effect 
site concentrations while maintaining safety in the monitored anesthetic setting, based on effect site 

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concentrations projected by the pharmacokinetic model85. During periods of stable pharmacokinetics, 
infusion rates are anticipated to be under 100 mcg/kg/min, as observed during acquisition of our pilot 
data (2 participants, 2 infusion sessions each), targeting propofol effect site concentrations of 3-4.5 
mcg/ml projected by the pharmacokinetic model85. This range is consistent with infusion rates used to 
maintain sedation in the ICU during mechanical ventilation (former) and for total intravenous anesthesia 
during surgical procedures. 
The first propofol infusion will be utilized to evaluate safety endpoints and EEG changes in response to 
propofol bolus and infusions. This dose-titration session will facilitate the second infusion session, which 
will focus on establishing safe and stable target engagement of EEG slow waves. There is no maximum 
dose of propofol to propose based on existing literature. 
Safety for study participants will be ensured through continual supervision of a board-certified 
anesthesiologist for the duration of all study drug infusions. The anesthesiologist will be physically present 
until the patient is awake and recovering from the anesthetic. When available, a certified registered nurse 
anesthetist (CRNA) will also assist with supervised drug infusion, clinical monitoring, and airway 
interventions. The infusions sessions will be conducted in rooms of the Washington University Clinical 
Trials Research Unit (CTRU), supplemental nursing staff and resuscitation equipment are readily available.  
Following cessation of propofol, the participant will continue to be monitored by nursing staff until they 
meet standard post-anesthesia care unit (PACU) discharge criteria132. Based on clinical practice and our 
pilot participants, the recovery period is projected to take 60-90 minutes. As per institutional guidelines, 
the patient will need to be taken home by a responsible adult. Rideshare services (i.e. Uber or cab will be 
available but a study team member or trusted individual will need to accompany the participant to their 
residence). 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Propofol will be acquired and stored by the Principal Investigator. The study medication is stored in a 
locked medication cabinet. Access is only available to physician and nurse research team members. A log 
is maintained to register inventory and dispensing, with entries signed and dated. Annual lab inspections 
by the WUSM Environmental Health and Safety (EHS) are also in place to ensure safe and secure storage 
of study medications.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Propofol (Diprivan, Fresenius-Kabi) is formulated in a white, oil-in-water emulsion. The pKa is 11. The 
octanol/water partition coefficient for propofol is 6761:1 at a pH of 6 to 8.5. In addition to the active 
component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5mg/mL), egg 
lecithin (12 mg/mL), disodium edetate (0.005%), and sodium hydroxide to adjust pH122. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Propofol will be stored according to guidelines between 4° to 25°C (40° to 70°F) in a locked cabinet 
accessible only by study physicians and nurses. Stability of the drug will be inspected visually for 
particulate matter and discoloration prior to administration. Each propofol vial is intended for a single 
use. 

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6.2.4 PREPARATION 
 
Infusion tubing will be primed with propofol and infused into crystalloid (Lactated Ringers solution) 
utilized as a carrier fluid.  
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
To minimize bias, study team members scoring overnight sleep recordings will be blinded to the interval 
between day of infusion and data acquisition. In addition, masking of total drug infused and infusion rates 
will be extended to those performing depression, behavioral, and cognitive assessments. Finally, all raters 
and those performing statistical analyses will be blinded to timing of the data acquisition (pre/post- 
propofol, timing of acquisition relative to the day of infusion). This will minimize the possibility that the 
hypothesis of sleep slow wave augmentation biases detection of sleep slow waves/scoring of N3/SWS 
epochs. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
An in-person adherence reminder session will take place at the initial study visit. This session will include: 
• 
The importance of following study guidelines for adherence to serial at-home sleep recordings 
and fasting guidelines.  
• 
Instructions about the purpose, use, and care of the Dreem headband and Dreem internet 
modem. 
• 
Instructions regarding wear of the Dreem including timing, importance of charging the Dreem for 
data verification, and what to do in the event of a missed night. 
• 
Instructions to complete a daily sleep diary entry. 
• 
Notification that participants will be contacted regularly throughout study period for adherence 
reminders. 
• 
Importance of contacting the research team if experiencing problems with the Dreem headband 
and/or internet modem. 
 
Study team will contact patients 1) on the evening before initiation of overnight sleep recordings, 2) on 
the day following the overnight recordings, 3) as need to check satisfaction and troubleshoot recordings 
after the 2nd infusion of propofol. Participants will be asked about any problems they are having using the 
Dreem devices and be reminded to charge the headband. By sending participants home with both 
headband and internet modem, research team members will be able to remotely monitor and acquire the 
sleep EEG data once participants connect the headband to a power source after each recording.  
 
Multiple methods will be employed to assess at-home sleep recording adherence: 1) phone call/email 
contact on evening of at-home night recording and day following, 2) daily sleep diary entries, 3) remote 
monitoring and acquisition of at-home sleep EEG recordings (Dreem-viewer), and 4) reasons for non-
compliance. Successful completion of at-home sleep recordings or reasons for missing data will be 

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recorded on the appropriate case report forms. Sleep EEG data from Dreem-viewer will be downloaded 
into a designated, secure data storage drive.  
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) on 
enrollment and study infusion days include concomitant prescription medications, over-the-counter 
medications, and supplements. 
Prescribed antidepressants and other psychotropic medications will be continued by participants. These 
medications will be recorded in case report forms. While acute administration of opioids and 
benzodiazepines can augment the possibility of respiratory depression with propofol, the team does not 
expect chronic use to affect safety of participants. Patients taking commonly prescribed medications that 
affect N3 sleep (benzodiazepines, trazodone, and gabapentin) above dose-related thresholds will be 
excluded from participation. 
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) will be held on 
the day of study infusions in mitigate hypotension risk. 
 
6.5.1 RESCUE MEDICINE 
 
In the unlikely event that they are needed, rescue medication and airway equipment to treat any 
anticipated or unanticipated side effect will be immediately available. Resuscitation capabilities will be 
immediately available. The following rescue medications will be available glycopyrrolate, phenylephrine, 
ephedrine, epinephrine, and crystalloids for interventions if needed. Patients requiring repeated boluses 
of ephedrine (total dose > 50 mg) for persistent hypotension would be replaced after study session 
termination. The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication will be recorded on the appropriate CRF. 
 
An automatic external defibrillator is also available on site for emergencies. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from propofol infusion does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant finding 
is identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
Propofol infusion will be stopped for the following AE refractory to clinician interventions: 
 
• 
Profound treatment-resistant bradycardia, defined as a heart rate less than 40 beats per minute 
for more than three minutes 

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• 
Profound treatment-resistant hypotension, defined as a 30% decrease from baseline MAP for 
more than 10 minutes 
• 
Inability to maintain a patent airway and/or sustained decrease in SpO2 below 92% despite the 
use of simple airway maneuvers and supplementation of up to 6 liters per minute of oxygen  
• 
Sustained cardiac conduction abnormalities 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Vital signs will be monitored on recorded on appropriate CRF until resolution of clinically 
significant event. 
• 
Participants will be contacted 1 day, 1 week, and 2 weeks after the clinically significant event to 
monitor for adverse events, serious adverse events, and/or unanticipated problems.  
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study procedure non-compliance (e.g. lack of fasting on the morning prior to propofol 
infusion) 
• 
Poor tolerance of study procedures (e.g. discomfort during Dreem overnight sleep recordings). 
• 
Patients requiring repeated boluses of ephedrine (total dose > 50 mg) for persistent hypotension 
would be replaced after study session termination.  
 
Participants withdrawn or discontinued before both propofol infusions have been completed will be 
replaced and will not count towards recruitment target or milestones. 
 
The PI reserves the right to discontinue the study protocol at any time for patient safety. The reason for 
participant discontinuation or withdrawal from the study will be recorded on the appropriate Case Report 
Form (CRF). 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit with 1 week and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). Up 
to three emails will be sent over the course of a month. These contact attempts should be 
documented in the participant’s medical record or study file.  
 

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Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Not applicable. Data for this Phase I study only concern safety and feasibility. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Preliminary screening (At home): 
• 
Phone screening script  
• 
Patient Health Questionnaire-9 (PHQ-9) 
 
Visit 1: Enrollment/Baseline: 
• 
Verify inclusion/exclusion criteria 
• 
Written informed consent 
• 
Contact information and demographic information 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Snaith-Hamilton Pleasure Scale (SHAPS) 
• 
Montreal Cognitive Assessment (MoCA) 
• 
NIH Cognition Toolbox Battery and Psychomotor Vigilance Test (PVT) 
• 
Morningness-Eveningness Questionnaire (MEQ) 
• 
Snoring, Tired, Observed Apnea, high blood Pressure, Body mass index, Age, Neck 
circumference, male Gender (STOP-BANG) Questionnaire to screen for obstructive sleep apnea 
risk133,134 to screen for possible obstructive sleep apnea. 
• 
Urine drug screen and direct screening for illicit drug use (non-prescribed used of 
amphetamines, opioids, marijuana, cocaine, or phencyclidine). 
• 
History and focused physical examination comparable to that preoperative assessment. The 
history will focus on adverse reactions to propofol, other anesthetics, and airway/intubation 
history. The physical examination will focus on airway, cardiac, pulmonary, and neurological 
systems to evaluate for signs of acute cardiopulmonary illnesses warranting deferral of study 
procedures. 
 
Pre-Infusion (At home): 
• 
Overnight sleep EEG recording using the Dreem device 
• 
Sleep diary 
• 
Wrist actigraphy 
 
Visit 2: Propofol Infusion – Titration and EEG Slow Wave Induction: 
• 
High-density EEG recorded before and throughout infusion 

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• 
Identification of optimal dosing to induce EEG slow waves 
• 
Feeling Scale, before induction and after return of consciousness 
• 
Blood draw 10-15 mls by study physician or nurse (optional) 
Post-infusion (At-home): 
• 
Overnight sleep EEG recording using the Dreem device on night of infusion 
• 
Sleep diary 
• 
Wrist actigraphy 
 
Visit 3: Propofol Infusion – EEG Slow Wave Induction: 
• 
High-density EEG recorded before and throughout infusion 
• 
Optimal dosing to induce EEG slow waves 
• 
Feeling Scale, before induction and after return of consciousness 
• 
Blood draw 10-15 mls by study physician or nurse (optional) 
 
Post-Infusion (At home): 
• 
Overnight sleep EEG recording using the Dreem device on night of infusion 
• 
Overnight sleep EEG recording using the Dreem device for up to 5 additional nights during the 2-
week period after the final infusion 
• 
Sleep diary 
• 
Wrist actigraphy 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Snaith-Hamilton Pleasure Scale (SHAPS) 
 
Visit 4: Follow up 1: 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Snaith-Hamilton Pleasure Scale (SHAPS) 
• 
Montreal Cognitive Assessment (MoCA) 
• 
NIH Cognition Toolbox Battery and Psychomotor Vigilance Test (PVT) 
• 
High-density EEG 
• 
Blood draw 10-15 mls by study physician or nurse (optional) 
 
Visit 5: Final follow up (In person or at home): 
• 
Montgomery-Asberg Depression Rating Scale (MADRS) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Snaith-Hamilton Pleasure Scale (SHAPS) 
 
Participants will also be asked to wear a wrist actigraphy watch starting on the first pre-infusion sleep 
recording throughout the study until the final visit. 
 
 
Propofol Infusion Sessions with Concurrent High-density EEG 
A board-certified anesthesiologist with ACLS certification will supervise propofol infusions with 
collaboration of a certified registered nurse anesthetist or anesthesia trainee. Patients will have adhered 

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to ASA fasting and monitoring guidelines. Medications, including narcotics and benzodiazepines, will be 
continued ad libitum—except angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 
which are normally held prior to procedures requiring sedation or general anesthesia. Patients with 
obstructive sleep apnea or COPD will not be excluded, as propofol sedation remains safe. ASA standard 
monitoring (blood pressure pulse oximetry, ECG, CO2 capnography, suction, airway, and resuscitation 
equipment) will be employed. Propofol will be infused through a peripheral IV, with the assistance of 
target-controlled infusion software and pumps, with an anticipated infusion duration of 1-2 hours. High-
density EEG will be acquired as in §C.1.3. but with an updated recording rig. An Axis P3364LV network 
camera, synchronized to EEG recordings, will provide video for post-hoc analysis. Participants will be 
discharged home after nurse monitoring and fulfillment of post-anesthetic care unit criteria132.  
At-home Overnight Sleep EEG Recordings 
Patients will be instructed by staff on initiating recordings with the Dreem. Patients will demonstrate 
ability to successfully wear the Dreem and initiate recordings without assistance. The device, charger, 
instruction sheet, and a link to a 2-minute instructional video will be provided to patients. This paradigm 
has been successful in the acquisition of preoperative sleep recordings in over 150 geriatric cardiac 
surgical patients106,107 and eight patients who underwent ECT for TRD (ClinicalTrials.gov NCT04451135).  
EEG Data Preprocessing and Spectral Analysis 
Dreem EEG data will undergo preprocessing (§C.1.4). Briefly, raw data will be down-sampled and filtered 
using EEGLAB120. EDF records will be imported into Respironics Sleepware G3 software and evaluated by 
AASM-certified sleep technologists. Manual scoring will proceed for 30-second epochs, using modified 
AASM scoring rules previously developed for single frontal EEG121. These approaches have been detailed 
in a recent protocol on an ongoing delirium investigation (ClinicalTrials.gov NCT03291626, NIH 
R01AG057901)106. N2 and N3 (sleep slow waves present in > 20% epoch) will be utilized in quantitation of 
EEG metrics. Eye movements in frontal EEG will allow scoring of REM sleep epochs. To maximize rigor and 
reproducibility, staff will be blinded to the timing of acquisition for clinical/cognitive outcomes during 
sleep staging and EEG quantitative analyses. 
High-density EEG data will also be preprocessed in EEGLAB120. As previously described for preprocessing 
of SWA, data will be lowpass filtered at 40 Hz prior to decimation to 125 Hz. A 0.1-0.6 bandstop filter will 
be applied to remove respiratory artifact prior to high pass filtering at 0.5 Hz53. 
Measurement of SWA and Delta Sleep Ratio (DSR)  
Multitaper methods will be used for power spectral analysis using the MATLAB Chronux toolbox135. 
Spectral estimates will be based on 6-second non-overlapping time windows, time-bandwidth product of 
3, and 5 tapers. Distributions of power in the 20-30 Hz and 1-4.5 Hz bands will be utilized in a 
semiautomated fashion to reject artifactual epochs53. SWA for each night will be quantified during the 
first and second cycles of N3, using custom-written MATLAB scripts that average total power spectral 
estimates within the 0.5-4 Hz frequency band at one minute intervals136. Secondary analyses will rely on 
the delta sleep ratio (DSR) for each night of sleep, which will be computed by dividing the SWA of the 
first N3 cycle by the quantity of the second N3 cycle. 
Depressive/Anhedonia/Suicidality/Affect Symptoms 
The Montgomery-Åsberg Depression Rating Scale (MADRS)137 will be administered to study participants 
on enrollment and on follow up in-person or telephone appointments. We have conducted thousands of 
MADRS assessments and have training and reliability testing methods to ensure excellent interrater 
reliability. Additionally, severity of anhedonia will also be assessed using the Snaith-Hamilton Pleasure 

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Scale (SHAPS)138, while the C-SSRS will be employed for suicidality screening and need for emergency 
psychiatric care. Affect before and after each infusion will be assessed using the Feeling Scale139. 
Cognitive Symptoms 
The Montreal Cognitive Assessment (MoCA)140 will be administered to study participants on enrollment 
and again at the final follow up visit. The MoCA test subjects for the presence of impairments. 
The brief and pragmatic NIH Toolbox Cognitive Battery32 will be employed. Its use is recommended for 
all NIH-funded neurocognitive studies to maximize rigor and reproducibility. Administration will occur on 
the iPad, based on our previous experience112. The Flanker Inhibitory Control Test requires subjects to 
focus on an arrow stimulus while inhibiting attention to stimuli that arise on either flank. During the 
Dimensional Change Card Sort Test, participants match bivalent test pictures to target pictures while 
switching between dimensions of color and shape. For the List Sorting Working Memory Test, subjects 
are first asked to order objects (either food or animals) from smallest to largest and then presented with 
both food and animals. The task is then to report food in size order and then animals in size order. For the 
Picture Sequence Memory Test, participants are asked to recall a series of pictures that progressively 
increase in length. For the Pattern Comparison Processing Test, subjects are asked to determine whether 
two objects presented side-by-side are identical. The Fluid Cognition Composite Score will be computed 
from performance on these tasks. As effects of depression and sleep disruption have been noted on the 
Flanker Inhibitory Control Test, scores on that task will be used as a measure of executive function. We 
acknowledge that Fluid Cognition is not the exact same construct as executive function (it also contains 
some memory and attention tasks) but it is a pragmatic and widely-used construct which corresponds 
highly with executive function141. 
The psychomotor vigilance test (PVT) will be administered on an iPad. Participants are asked to 
immediately touch the screen when a counter starts incrementing. Task metrics will be downloaded. The 
reciprocal of the median reaction time (RT) will be computed to yield the RRT (psychomotor speed). The 
number of lapses (RT >500 ms) will also be counted for secondary analyses. These assessments will be 
performed following consent, on treatment sessions prior to propofol infusion, and at follow up 
assessments. There is no transmission of data to 3rd parties. 
Wrist Actigraphy for Assessment of Circadian Rhythms 
Patients will be offered the ActTrust 2 wrist actigraph (Condor Instruments, São Paulo, Brazil) which allows 
collection of longitudinal non-dominant wrist actigraphy measures of rest and activity from the point of 
enrollment to the follow up 4th Study Visit. These signals will be analyzed to evaluate circadian rhythms 
and changes induced by propofol. A sleep diary will be completed by participants to corroborate with 
physiologic signals. The Morningness-Eveningness Questionnaire (MEQ)142, completed at enrollment, will 
be compared to these data. 
Blood Biobanking (Optional) 
Optional blood sampling will occur at Study Visits 2, 3, and 4. These will be done near the beginning and 
middle of the propofol infusions, as well as at the follow up visit. Following centrifugation, plasma will be 
banked. Samples may also be processed for storage in PAXGene RNA tubes for future gene expression 
analyses. Overall, no more than 50 mls of blood/5-10 teaspoons will be drawn over the course of the 
study. Biomarkers to be assayed include RNAseq gene expression to allow detection of differences 
between internal circadian time and true time143, proteomic analysis via Olink Neurology 384 Explore to 
measures levels of inflammatory cytokines (e.g. IL-6, IL-8) and markers axonal injury (neurofilament light 
chain), or genotyping of sleep/circadian loci (e.g. adenosine deaminase or adenosine receptor typing). 
   

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an investigational 
study or protocol regardless of causality assessment.  An adverse event can be an unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, syndrome or disease associated 
with or occurring during the use of an investigational product whether or not considered related to the 
investigational product. 
Examples of adverse events include dizziness, fainting, skin irritation, pain (IV site, airway maneuvers, or 
EEG recording), disrupted sleep from overnight EEG recordings, hypotension, or respiratory 
depression/apnea.  
 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, or a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of SAEs would include need for hospitalization, anaphylaxis, cardiac arrest, stroke, or death. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 

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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
Expected adverse events are those adverse events that are listed in the protocol, the Investigator’s 
Brochure (current edition), drug labeling or in the study informed consent document. These will include 
bradycardia, hypotension, hypercapnia, airway obstruction, and apnea. 

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Unexpected adverse events are those that 1) are not described in the Investigator's Brochure or drug 
labeling, 2) are not anticipated in the study informed consent.  This includes adverse events for which the 
specificity or severity is not consistent with the description in the informed consent. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Adverse events will be reported to the IRB at the continuing review and to the NIMH DSMB and NIMH 
annually. 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
SAEs would be reported to the WU Human Research Protection Office (IRB) within 24 hours. Resumption 
of the study would only occur after approval of the IRB. 
Reporting of events to the NIMH DSMB will follow the NIMH’s reportable events policy. The following 
table outlines the NIMH’s reportable events policy for AEs, SAEs, death, unanticipated problems, 
protocol deviations, non-compliance, suspensions and terminations. 
 

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Reportable Event 
When is Event Reported to the NIMH 
Reported By 
IRB/ISM/DSMB/OHRP/FDA 
Suspensions or Terminations 
Any suspension or termination of approval must 
include a statement of the reason(s) for the action and 
must be reported promptly to the NIMH PO within 
3 business days of receipt. 
Regulatory or 
Monitoring Entity and 
Investigator 
Deaths related to study 
participation 
Deaths must be reported within 5 business days of the 
Principal Investigator first learning of the death. 
Investigator 
Unexpected Serious Adverse 
Events related to study 
participation 
Reported to the NIMH PO within 10 business days of 
the study team becoming aware of the SAE. 
Investigator 
Unanticipated Problems 
Involving Risks to Subjects or 
Others 
Reported to the NIMH PO within 10 business days of 
the investigator learning of the event. 
Investigator 
Serious or Continuing 
Noncompliance 
http://videocast.nih.gov/pdf/
ohrp072414.pdf 
Reported to the NIMH PO within 10 business days of 
IRB determination. 
Institution 
Adverse Event 
For all AEs and SAEs that are deemed expected and/or 
unrelated to the study, a summary should be 
submitted to the NIMH PO with the annual progress 
report. (SAEs will be documented for the NIMH DSMB 
in reports for thrice-yearly meetings.)  
Investigator 
Protocol Deviations 
With the annual progress report  
Investigator 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the WU HRPO (IRB), NIMH DSMB, and NIMH. 
The UP report will include the following information: 

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• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and NIMH PO/DSMB within 
10 business days of the investigator becoming aware of the event.  
• 
Ups involving risk to subjects or others will be reported to the IRB and NIMH PO/DSMB within 10 
business days of learning of any events suggesting that the research procedures place participants 
or others at an unanticipated greater risk of harm. 
• 
Any other UP will be reported to the IRB under continuing review. 
 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Full disclosure of unanticipated problems will be disclosed by the principal investigator. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Safety/feasibility Endpoint(s):  
• 
Adverse events and serious adverse events, including incidence, severity, and likelihood of 
relation to propofol infusion. Hypothesis: Serial propofol infusions will be safe and well-tolerated 
in study participants, with less than 5% serious adverse events directly attributable to infusions. 
• 
Measure of slow wave activity during propofol infusion. Hypothesis: Propofol infusion will 
efficiently induce EEG SWA during sedation in at least 60% of participants. 
• 
Change in total slow wave activity during N2/N3 sleep post-infusion compared to pre-infusion. 
Hypothesis: Propofol infusion will augment total sleep SWA over the subsequent week in at least 
40% of study completers.  
 
Secondary Safety/feasibility Endpoint(s): 
• 
Measure of suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS). Hypothesis: 
There will be no significant changes in suicidality associated with propofol infusions. 
• 
Measure of cognitive performance using the Montreal Cognitive Assessment (MOCA), NIH 
Toolbox Cognition Battery and Psychomotor Vigilance Test (PVT). Hypothesis: There will be no 
significant changes in cognitive performance associated with propofol infusions. 
• 
Measures of duration of N3 and REM sleep and proportion of total sleep time for these stages, 
delta sleep ratio. 
 

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Tertiary Endpoint(s):  
• 
Changes in circadian rhythm study period using wrist actigraphy and blood biomarkers. 
Hypotheses: Propofol infusions with increase amplitude of circadian rhythms or enhance 
circadian rhythmicity. Morningness-eveningness will modulate whether sleep SWA is potentiated 
by propofol infusions.  
• 
Measure of affect using the Feeling Scale. Hypothesis: Affect will be improved after propofol 
infusion. 
• 
Measure of anhedonia using the Snaith-Hamilton Pleasure Scale (SHAPS). Hypothesis: Anhedonia 
will not be exacerbated post-infusion compared to baseline. 
• 
Feasibility measure of propofol induced SWA to alleviate depressive symptom using the 
Montgomery-Asberg Depression Rating Scale (MADRS). Hypothesis: Depressive symptoms will 
not worsen post-infusion compared to baseline. 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
We carried out a sample size calculation based on the two pre-treatment and two post-treatment sleep 
recordings obtained from our first participant (Figure 4A-B). We utilized a mean N3 duration (minutes) of 
1.75 (pre-treatment) and 10 (post-treatment) and combined standard deviation of 4.19. For paired 
measurements within participants, these estimates would only lead to a sample size of 6. This first 
participant had an > 400% augmentation of her baseline N3 duration, which may be greater compared to 
others in Aim 1. Furthermore, we expect a 20% attrition such that targeting 15 participants seems 
compatible with a convenience sample size for gauging safety, feasibility, and persistence of post-
intervention sleep SWA promotion. 
 
 
9.3 
STATISTICAL ANALYSES 
 
 
 
9.3.1 GENERAL APPROACH 
Given the small sample size for this exploratory study, only descriptive statistics will be performed. 
The small sample size and lack of normative values for SWA/SWS measures present challenges in 
evaluating enhancement of SWA. Many adults older than 60 years of age do not show any SWS, thus an 
augmentation of at least 1 minute of SWS relative to baseline would constitute enhancement for this 
initial study. 
 
9.3.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
Number of AE and SAE will be tabulated across participants. SAE frequency will be compared to the 
milestone threshold of 5%. 
Slow Wave Activity (SWA) will be calculated as the total EEG 0.5-4 Hz power/minute during propofol 
treatment (sedation SWA) and during overnight SWS (sleep SWA). Sleep SWA will be measured from at-
home recording taken before and following infusions, contingent on recordings meeting quality metrics. 

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Descriptive statistics will evaluate rates of tolerability and adverse events, duration of sedation SWA and 
sleep SWA (median and interquartile ranges).  
We have set a feasibility threshold of augmentation of sleep SWA for 40% of study completers. A targeted 
treatment that works well in 40% of depressed older adults would be of high public health significance, 
particularly among those with TRD. For comparison, the recent OPTIMUM study results found that the 
top-performing agent, aripiprazole, brought about remission in 33% of completers. It is our hope that the 
research will allow us to better pre-select individuals that are particularly likely to benefit. 
 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
We will perform descriptive statistics on C-SSRS and MoCA scores, respectively.  
 
For sleep structure measures (N3 and REM total duration/proportion of total sleep time, DSR), we 
perform descriptive statistics (median and interquartile ranges) at each respective time point. 
 
9.3.4 SAFETY ANALYSES 
 
See sections 9.4.2. and 9.4.3. 
 
 
9.3.5 BASELINE DESCRIPTIVE STATISTICS 
 
Descriptive statistics will be compiled for age, sex, years of depression 
No inferential statistical analyses will be carried out on baseline measures. 
 
9.3.6 PLANNED INTERIM ANALYSES  
 
Interim analyses are not planned for this open-label study. 
 
9.3.7 SUB-GROUP ANALYSES 
Primary and secondary safety/feasibility endpoints will be analyzed based on age, sex, time separating 
propofol infusions. Additional analyses will be based on medical comorbidity (Cumulative Illness Rating 
Scale Score), baseline MOCA score (23-26 for cognitively impaired) vs (26-30 for cognitively intact), and 
age of onset of first episode of MDD (to address the importance of late onset depression). 
Additionally, structure of baseline sleep (e.g. duration and proportion of total sleep time for N3 and REM) 
will be utilized in sub-group analysis. If high variance in SWS enhancement is observed, we could perform 
univariate regression analyses to evaluate for the presence of covariates driving the high variance. Such 
analyses would be useful to determine whether the intervention is better targeted for particular 
subgroups (e.g. patients with a low, but non-zero proportion of N3, or infusions separated by longer 
intervals of greater than 5 days may be less effective than treatments separated by 2-3 days).  
These analyses will be helpful in targeting enrollment for Phase II. 
 
9.3.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 

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For visualization, individual participant data (sleep SWA, DSR, MADRS, C-SSRS, SHAPS, and feeling scale) 
will be listed by time point. 
 
9.3.9 EXPLORATORY ANALYSES 
 
Not applicable. Tertiary exploratory data will be acquired to confirm feasibility of acquisition for Phase II. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: Informed consent document and telephone screening questionnaire. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the signed 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 

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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, the NIMH, and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and the NIMH. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
NIMH, and WUSM. This confidentiality is extended to cover testing of biological samples and clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored on site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Individual participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified. 
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to disclose 
identifying information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from 
being compelled to disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies by helping 

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assure confidentiality and privacy to participants. This certificate may not be effective for information held 
in foreign countries.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data obtained for this study will be de-identified, analyzed, and stored for use in studies conducted in the 
future. De-identified data may be shared with other researchers including those outside of the study. 
Permission to store and share data will be included in the informed consent. Bank biospecimens will be 
stored for up to 5 years after publication on the primary outcomes. Genetic testing will be conducted for 
patients who agree to the optional blood draw component. 
To date, there are no publicly accessible sleep data sets acquired from geriatric patients with depression. 
These are needed to facilitate future research and enhance reproducibility and rigor in this field. We will 
share our data with the National Sleep Research Resource within three years after completion of the 
study. Furthermore, we will share our data on the NIMH Data Archive twice per year. To maximize rigor, 
we will publish a protocol of our approach and pre-specified analyses by the end of Year 2 of funding.  
We will upload our data in a timely manner to the NIMH Data Archive (NDA) as per notice NOT-MH-19-
033, to enable us to share our data with other investigators in the research community. The NDA will 
include the following Data Structures in the project’s Data Dictionary: 1) Sedation Slow Wave Activity, 2) 
Sleep Slow Wave Activity, 3) NIH Toolbox Cognition Battery Executive Function Score, 4) Psychomotor 
Vigilance Task median reaction time, 5) NIH Toolbox Cognition Battery Fluid Cognition Measure Score, 6) 
Montgomery-Åsberg Rating Scale Score, 7) Snaith-Hamilton Pleasure Scale (SHAPS) Score, 8) Columbia-
Suicide Severity Rating Scale (C-SSRS) Score, 9) Delta Sleep Ratio. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Co-Principal Investigator 
Co-Principal Investigator 
Ben Julian A. Palanca, M.D., Ph.D., M.Sc. 
Associate Professor of Anesthesiology and Psychiatry 
Eric J. Lenze, M.D. 
Wallace and Lucille K. Renard Professor of 
Psychiatry, Professor of Anesthesiology 
Washington University School of Medicine in St. 
Louis 
Washington University School of Medicine in 
St. Louis 
660 S. Euclid Avenue, Campus Box 8054 
660 S. Euclid Avenue, Campus Box 8134 
314-323-1902 
314-362-3794 
palancab@wustl.edu 
lenzee@wustl.edu 
 
Study Team and Roles/Responsibilities 
Washington University School of Medicine / Barnes-Jewish Hospital (BJH) 
Co-Principal Investigator: Ben Julian A. Palanca, M.D., Ph.D., M.Sc., Associate Professor of Anesthesiology 
and Psychiatry 
As 
a 
cardiothoracic 
anesthesiologist 
and 
translational 
neuroscientist 
with 
expertise 
in 
electroencephalographic (EEG) changes induced by sleep, anesthesia, and delirium – together with Dr. 
Lenze, Dr. Palanca will be responsible for the overall design and execution of the proposed studies, 
oversight and management of the project, ensuring timely progression to meet milestones. 
Co-Principal Investigator: Eric J. Lenze, M.D., Professor of Psychiatry and Anesthesiology 

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As a geriatric psychiatrist with a distinguished program as clinical trialist on mental and cognitive 
disorders – together with Dr. Palanca will be responsible for the overall study design, coordination with 
the surgical teams, and will provide general oversight and management of the project, ensuring timely 
progression to meet milestones. 
Co-Investigator: ShiNung Ching, Ph.D., Associate Professor of Electrical Systems Engineering and 
Biomedical Engineering 
A dynamic systems and control engineer and expert on pharmacologic modeling of anesthetic effects 
on the electroencephalogram, Dr. Ching will provide expertise on precision targeting of propofol-
induced EEG slow waves through open loop technology and real-time processing of scalp EEG, and signal 
processing. 
Co-Investigator: Nuri B. Farber, M.D., Professor of Psychiatry 
A senior psychiatrist on the electroconvulsive therapy (ECT) service with extensive experience with 
treatment-resistant depression and a complementary background in NMDA antagonists, Dr. Farber will 
provide guidance on study execution, patient recruitment, training of staff for administration of the 
MADRS, data analysis, data interpretation, and manuscript preparation. 
Co-Investigator: Brendan P. Lucey, M.D., MSCI, Associate Professor of Neurology 
As the section head for Sleep Medicine and an expert on the relationships between sleep disorders and 
Alzheimer’s disease, he will provide assistance with study design, technical expertise of sleep recordings 
from wireless wearable devices, data collection, analysis, and interpretation. 
Co-Investigator: S. Kendall Smith, M.D., Ph.D., Assistant Professor of Anesthesiology 
Given her experience on TimeSignature and circadian rhythms, she will contribute to acquisition and 
analysis of physiologic and molecular markers for substudies on changes in circadian rhythms induced 
by the intervention. 
Co-Investigator: Nan Lin, Ph.D., Professor of Mathematics and Statistics 
Dr. Lin will serve as the biostatistician for the study. He will perform statistical analysis of the data. He 
and the research team have collaborated multiple prior projects. 
Clinical Lab Manage/Data Manager: TBN 
This team member will serve a key role in coordinating staff, effort, and products related to the 
proposed investigation, given Dr. Palanca’s clinical commitments. A master’s or Ph.D.-trained 
professional with background in neuroscience will be recruited. They will be in charge of maintaining 
study compliance, data acquisition, analysis, and manuscript drafting. 
Research Coordinators: Emily Lenard, M.S.W., Aris Perez, Jennifer Wulfers  
These team members will support participant recruitment, screening, and intake. With her 
experience in administering the MADRS, SHAPS, and the C-SSRS, they will assist in data collection of 
these outcomes, and manuscript preparation. 
Research Coordinators: Orlandrea Hyche, B.S.; Allyson Quigley  
Ms. Hyche and Quiqley will score sleep stages of EEG data recorded by Dreem devices. They will 
review the efficacy of automatic detection of slow waves and sleep spindles and will assist in 
modifying the algorithms as needed. Augmentation of effort will be needed in Year 4 to aid in data 
dissemination. 
Clinical Research Nurse Coordinator: TBN 

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A Nurse Coordinator will assist in recruitment, managing clinical outcomes, and patient monitoring for 
adverse events. She will coordinate filings with the IRB and ClinicalTrials.gov. This team member will be 
guided by Drs. Lenze and Farber’s staff on analysis and interpretation of the MADRS.  
Postdoctoral Research Fellow: TBN 
They will also contribute to the recording and quantitative analysis of sleep and high-density EEG 
data. The postdoctoral fellow will supplement research assistant efforts and work with Dr. Ching on 
precision targeting of propofol-induced EEG slow waves, data analysis, and manuscript drafting. 
Certified Registered Nurse Anesthetists: TBN 
Certified registered nurse anesthetists (CRNAs) will collaborate with attending anesthesiologists during 
propofol study sessions to maximize safety. They will aid in airway maneuvers, clinical monitoring, and 
manipulation of propofol infusion rates. 
University of Pittsburgh Medical Center 
Consultant: Charles F. Reynolds, III, M.D., Distinguished Professor Psychiatry 
A world expert on the contributions of sleep abnormalities to mental illness and as a distinguished 
clinical trialist, he will provide guidance on study design, data analysis, interpretation, and manuscript 
preparation. 
 
10.1.6 SAFETY OVERSIGHT 
 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.   
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) convened by 
NIMH. The DSMB includes experts in scientific disciplines needed to monitor the data and ensure patient 
safety during the conduct of this study, including addiction and mental health experts, clinical trial experts, 
biostatisticians, and bioethicists. DSMB members have no association with the project investigators, and 
no conflicts of interest with study outcomes. The DSMB will meet at least three times a year to assess 
safety and data of the study. The DMSB will operate under the rules of an approved charter. The DSMB 
will provide its input to NIMH staff.  
DSMB procedures conform with usual standards, including reviewing emerging trial data and maintaining 
confidentiality. The main responsibilities of the NIMH DSMB include, but are not limited to the following: 
(1) reviewing the research protocol, consent form(s) and plans for data and safety monitoring prior to the 
initiation of the study; (2) monitoring of the progress of the study, including data quality, timeliness, 
recruitment and retention of study participants, adverse events, serious adverse events (SAEs), reasons 
for participant withdrawal, adherence to the timeline of the study, protocol deviations, performance 
across study sites, and factors that may affect the risks and benefits of the study such as emerging 
literature; and (3) making directives about the continuation, modification, or termination of the study, 
based on the balance of adverse events and beneficial outcomes. Throughout the study, notification of 
SAEs as well as any proposed investigator-initiated changes in the protocol will be submitted to the NIMH 
DSMB. Based on its review of the protocol, the NIMH DSMB will identify the data parameters and format 
of the information to be regularly reported. The NIMH DSMB may at any time request additional 
information from the Principal Investigators. 
All SAEs and adverse events (AEs will only be reported to the NIMH DSMB annually) will be tabulated and 
submitted to the NIMH DSMB in the triannual DSMB data reports. Based on review of safety data, the 

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NIMH DSMB will issue directives concerning the conduct of the study. Recommendation/directives made 
by the DSMB may include amending safety monitoring procedures, modifying the protocol or consent, 
terminating the study, or continuing the study as designed.  
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
• 
Monitoring for this study will be performed by Department of Anesthesiology Division of Clinical 
and Translational Research. 
• 
An initial review will be performed after the first 3 participants have completed study procedures. 
• 
Regulatory staff will be provided copies of monitoring reports within 7 days of visit. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
We will perform internal quality management of study conduct, data and biological specimen collection, 
documentation, and completion.   
 
Following written Standard Operating Procedures (SOPs), the study staff will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Research Electronic Data Capture (REDCap), a 21 
CFR Part 11-compliant data capture system. The data system includes password protection and internal 

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quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 3 years after the study is completed and closed by the 
IRB. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations.  
All deviations must be addressed in study source documents, reported to the NIMH Program 
Official/DSMB and Washington University Human Research Protection Office. Protocol deviations must 
be sent to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
Sharing of participant data (EEG, sleep studies, and blood samples) is mandatory for enrollment. 
Permission for further use of these data and samples can be withdrawn by study participants at any time. 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Data from this study may be requested from other researchers after the completion of the 
primary endpoint by contacting the principal investigators. 
 

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In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the NIMH has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
 
 

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10.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ACLS 
Advanced Cardiovascular Life Support 
AMPA 
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 
ANCOVA 
Analysis of Covariance 
ASA 
American Society of Anesthesiologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DSR 
Delta Sleep Ratio 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
EF 
Executive Function 
eCRF 
Electronic Case Report Forms 
EEG 
Electroencephalography 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HD-EEG 
High-density electroencephalography 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
IV 
Intravenous 
LL-TRD 
Late Life Treatment Resistant Depression 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
Major Depressive Disorder 
MEQ 
Morningness-Eveningness Questionnaire 
MoCA 
Montreal Cognitive Assessment 

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MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
N3 
Non-rapid Eye Movement Sleep Stage 3 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PHI 
Personal Health Information 
PHQ-9 
Patient Health Questionnaire-9 
PFC 
Prefrontal Cortex 
PVT 
Psychomotor Vigilance Test 
QA 
Quality Assurance 
QC 
Quality Control 
REM 
Rapid Eye Movement Sleep 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
STOP-
BANG 
Snoring, Tired, Observed Apnea, high blood Pressure, Body mass index, Age, Neck circumference, 
male Gender Questionnaire 
SWA 
Slow Wave Activity 
SWS 
Slow Wave Sleep 
TRD 
Treatment-Resistant Depression 
UP 
Unanticipated Problem 
US 
United States 
WUSM 
Washington University School of Medicine 
 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
 
 
Version 
Date 
Description of Change  
Brief Rationale 
2 
4/2/22 
Clarification of terms and 
procedures. 
Preparation for DSMB initial 
review. 
2.1 
4/11/22 
Addition to section 2.3.1, 2.3.3., 
10.1.11 
Addressed risk of genetic 
testing and mitigation 
measures, sharing 
3.1 
6/21/22 
Additions to 1.1, 1.3, 2.3, 2.3.3, 4.1, 
4.2, 5.2, 6.1, 9.3  
Revision of exclusion criteria, 
assess for possible OSA as 
confounder, screen for illicit 
drug use, addressing propofol 
risks, monitoring during study, 
analytical plan of descriptive 
statistics only, transparency on 
“go” criteria for further study 
3.1.1 
9/7/22 
6.1.2, 5.3, 6.5.1, 8.2 
Improved clarity of propofol 
dosing and wording 
3.1.2 
9/28/22 
1.3, 2.3.1, 8.2, 10.2 
Inclusion of the PHQ-9 in phone 
screen, EEG recording on follow 
up 
3.1.3 
10/4/22 
1.3, 2.3.3, 8.2, 10.1.5 
Change timing and number of 
MADRS, C-SSRS, and SHAPS; 
update team roster 
3.14 
11/2/22 
5.5 
Correction of remuneration to 
be consistent with SOA and 
maximize retention to study 
follow up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
1. 
aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous 
ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139-145. 
2. 
Singh JB, Fedgchin M, Daly EJ, et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-
Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am 
J Psychiatry. 2016;173(8):816-826. 
3. 
Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with 
physical disability: a review of the literature and prospectus for future research. Am J Geriatr 
Psychiatry. 2001;9(2):113-135. 
4. 
Wolkowitz OM, Reus VI, Mellon SH. Of sound mind and body: depression, disease, and accelerated 
aging. Dialogues Clin Neurosci. 2011;13(1):25-39. 
5. 
Szanto K, Lenze EJ, Waern M, et al. Research to reduce the suicide rate among older adults: 
methodology roadblocks and promising paradigms. Psychiatr Serv. 2013;64(6):586-589. 
6. 
Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer 
disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 
2006;63(5):530-538. 
7. 
Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7(6):323-
331. 
8. 
Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF, 3rd. Late-life depression and risk of 
vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-
based cohort studies. Br J Psychiatry. 2013;202(5):329-335. 
9. 
Thomas L, Mulsant BH, Solano FX, et al. Response speed and rate of remission in primary and 
specialty care of elderly patients with depression. Am J Geriatr Psychiatry. 2002;10(5):583-591. 
10. 
Mulsant BH, Blumberger DM, Ismail Z, Rabheru K, Rapoport MJ. A systematic approach to 
pharmacotherapy for geriatric major depression. Clin Geriatr Med. 2014;30(3):517-534. 
11. 
Buchalter ELF, Oughli HA, Lenze EJ, et al. Predicting Remission in Late-Life Major Depression: A 
Clinical Algorithm Based Upon Past Treatment History. J Clin Psychiatry. 2019;80(6). 
12. 
Deng Y, McQuoid DR, Potter GG, et al. Predictors of recurrence in remitted late-life depression. 
Depress Anxiety. 2018;35(7):658-667. 
13. 
Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. 
2009;23(8):627-647. 
14. 
Kellner CH, Husain MM, Knapp RG, et al. Right Unilateral Ultrabrief Pulse ECT in Geriatric 
Depression: Phase 1 of the PRIDE Study. Am J Psychiatry. 2016;173(11):1101-1109. 
15. 
Kellner CH, Husain MM, Knapp RG, et al. A Novel Strategy for Continuation ECT in Geriatric 
Depression: Phase 2 of the PRIDE Study. Am J Psychiatry. 2016;173(11):1110-1118. 
16. 
Conelea CA, Philip NS, Yip AG, et al. Transcranial magnetic stimulation for treatment-resistant 
depression: Naturalistic treatment outcomes for younger versus older patients. J Affect Disord. 
2017;217:42-47. 
17. 
Murphy MJ, Peterson MJ. Sleep Disturbances in Depression. Sleep Med Clin. 2015;10(1):17-23. 
18. 
Schroder CM, O'Hara R. Depression and Obstructive Sleep Apnea (OSA). Ann Gen Psychiatry. 
2005;4:13. 
19. 
Holanda FWNJ, de Almondes KM. Sleep and executive functions in older adults: A systematic 
review. Dement Neuropsychol. 2016;10(3):185-197. 
20. 
Cristancho P, Lenze EJ, Dixon D, et al. Executive Function Predicts Antidepressant Treatment 
Noncompletion in Late-Life Depression. J Clin Psychiatry. 2018;79(3). 

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Version 3.1.5 
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30 January 2023 
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WU HRPO Protocol 202008037 
 
 
51 
21. 
Snyder HR. Major depressive disorder is associated with broad impairments on 
neuropsychological measures of executive function: a meta-analysis and review. Psychol Bull. 
2013;139(1):81-132. 
22. 
Burdick DJ, Rosenblatt A, Samus QM, et al. Predictors of functional impairment in residents of 
assisted-living facilities: the Maryland Assisted Living study. J Gerontol A Biol Sci Med Sci. 
2005;60(2):258-264. 
23. 
Diamond A. Executive functions. Annu Rev Psychol. 2013;64:135-168. 
24. 
Duncan J, Owen AM. Common regions of the human frontal lobe recruited by diverse cognitive 
demands. Trends Neurosci. 2000;23(10):475-483. 
25. 
Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 
2001;24:167-202. 
26. 
Rajji TK, Sun Y, Zomorrodi-Moghaddam R, et al. PAS-induced potentiation of cortical-evoked 
activity in the dorsolateral prefrontal cortex. Neuropsychopharmacology. 2013;38(12):2545-2552. 
27. 
Mulsant BH, Ganguli M. Epidemiology and diagnosis of depression in late life. J Clin Psychiatry. 
1999;60 Suppl 20:9-15. 
28. 
Alexopoulos GS, Murphy CF, Gunning-Dixon FM, et al. Microstructural white matter abnormalities 
and remission of geriatric depression. Am J Psychiatry. 2008;165(2):238-244. 
29. 
Galvin JE, Roe CM, Coats MA, Morris JC. Patient's rating of cognitive ability: using the AD8, a brief 
informant interview, as a self-rating tool to detect dementia. Archives of neurology. 
2007;64(5):725-730. 
30. 
Kaneriya SH, Robbins-Welty GA, Smagula SF, et al. Predictors and Moderators of Remission With 
Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression: An Analysis of the IRL-
GRey Randomized Clinical Trial. JAMA Psychiatry. 2016;73(4):329-336. 
31. 
Lowe B, Unutzer J, Callahan CM, Perkins AJ, Kroenke K. Monitoring depression treatment 
outcomes with the patient health questionnaire-9. Med Care. 2004;42(12):1194-1201. 
32. 
Weintraub S, Dikmen SS, Heaton RK, et al. Cognition assessment using the NIH Toolbox. 
Neurology. 2013;80(11 Suppl 3):S54-64. 
33. 
Plante DT, Hagen EW, Ravelo LA, Peppard PE. Impaired neurobehavioral alertness quantified by 
the psychomotor vigilance task is associated with depression in the Wisconsin Sleep Cohort study. 
Sleep Med. 2020;67:66-70. 
34. 
Yun CH, Kim H, Lee SK, et al. Daytime sleepiness associated with poor sustained attention in 
middle and late adulthood. Sleep Med. 2015;16(1):143-151. 
35. 
Berry RBB, R.; Gamaldo, C.E.; Harding, S.M.; Lloyd, R.M.; Marcus, C.L.; Vaughn, B.V. The AASM 
Manual for Scoring of Sleep and Associated Events: Rules, Terminology and Technical 
Specifications, Version 2.3. Darien, Illinois: American Academy of Sleep Medicine; 2015. 
36. 
Akerstedt T, Hume K, Minors D, Waterhouse J. Good sleep--its timing and physiological sleep 
characteristics. J Sleep Res. 1997;6(4):221-229. 
37. 
Tasali E, Leproult R, Ehrmann DA, Van Cauter E. Slow-wave sleep and the risk of type 2 diabetes 
in humans. Proc Natl Acad Sci U S A. 2008;105(3):1044-1049. 
38. 
Molle M, Yeshenko O, Marshall L, Sara SJ, Born J. Hippocampal sharp wave-ripples linked to slow 
oscillations in rat slow-wave sleep. J Neurophysiol. 2006;96(1):62-70. 
39. 
Esser SK, Hill SL, Tononi G. Sleep homeostasis and cortical synchronization: I. Modeling the effects 
of synaptic strength on sleep slow waves. Sleep. 2007;30(12):1617-1630. 
40. 
Riedner BA, Vyazovskiy VV, Huber R, et al. Sleep homeostasis and cortical synchronization: III. A 
high-density EEG study of sleep slow waves in humans. Sleep. 2007;30(12):1643-1657. 
41. 
Vyazovskiy VV, Riedner BA, Cirelli C, Tononi G. Sleep homeostasis and cortical synchronization: II. 
A local field potential study of sleep slow waves in the rat. Sleep. 2007;30(12):1631-1642. 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
30 January 2023 
CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
52 
42. 
Rasch B, Buchel C, Gais S, Born J. Odor cues during slow-wave sleep prompt declarative memory 
consolidation. Science. 2007;315(5817):1426-1429. 
43. 
Deuschle M, Schredl M, Wisch C, et al. Serum brain-derived neurotrophic factor (BDNF) in sleep-
disordered patients: relation to sleep stage N3 and rapid eye movement (REM) sleep across 
diagnostic entities. J Sleep Res. 2018;27(1):73-77. 
44. 
Dash MB. Infraslow coordination of slow wave activity through altered neuronal synchrony. Sleep. 
2019;42(12). 
45. 
Achermann P, Dijk DJ, Brunner DP, Borbely AA. A model of human sleep homeostasis based on 
EEG slow-wave activity: quantitative comparison of data and simulations. Brain Res Bull. 
1993;31(1-2):97-113. 
46. 
Marshall L, Molle M, Hallschmid M, Born J. Transcranial direct current stimulation during sleep 
improves declarative memory. J Neurosci. 2004;24(44):9985-9992. 
47. 
Marshall L, Helgadottir H, Molle M, Born J. Boosting slow oscillations during sleep potentiates 
memory. Nature. 2006;444(7119):610-613. 
48. 
Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain 
parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 
2012;4(147):147ra111. 
49. 
Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and 
cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631. 
50. 
Lundgaard I, Lu ML, Yang E, et al. Glymphatic clearance controls state-dependent changes in brain 
lactate concentration. J Cereb Blood Flow Metab. 2017;37(6):2112-2124. 
51. 
Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of 
Alzheimer's disease. Neurobiol Dis. 2016;93:215-225. 
52. 
Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau 
pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180-16193. 
53. 
Lucey BP, McCullough A, Landsness EC, et al. Reduced non-rapid eye movement sleep is 
associated with tau pathology in early Alzheimer's disease. Sci Transl Med. 2019;11(474). 
54. 
Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx is correlated with high EEG delta 
power and low heart rate in mice under anesthesia. Sci Adv. 2019;5(2):eaav5447. 
55. 
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 
2013;342(6156):373-377. 
56. 
Buysse DJ, Frank E, Lowe KK, Cherry CR, Kupfer DJ. Electroencephalographic sleep correlates of 
episode and vulnerability to recurrence in depression. Biol Psychiatry. 1997;41(4):406-418. 
57. 
Ganguli R, Reynolds CF, 3rd, Kupfer DJ. Electroencephalographic sleep in young, never-medicated 
schizophrenics. A comparison with delusional and nondelusional depressives and with healthy 
controls. Arch Gen Psychiatry. 1987;44(1):36-44. 
58. 
Kupfer DJ, Ulrich RF, Coble PA, et al. Application of automated REM and slow wave sleep analysis: 
II. Testing the assumptions of the two-process model of sleep regulation in normal and depressed 
subjects. Psychiatry Res. 1984;13(4):335-343. 
59. 
Reynolds CF, 3rd, Kupfer DJ. Sleep research in affective illness: state of the art circa 1987. Sleep. 
1987;10(3):199-215. 
60. 
Gillin JC, Duncan W, Pettigrew KD, Frankel BL, Snyder F. Successful separation of depressed, 
normal, and insomniac subjects by EEG sleep data. Arch Gen Psychiatry. 1979;36(1):85-90. 
61. 
Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. A meta-analysis. 
Arch Gen Psychiatry. 1992;49(8):651-668; discussion 669-670. 
62. 
Ehlers CL, Havstad JW, Kupfer DJ. Estimation of the time course of slow-wave sleep over the night 
in depressed patients: effects of clomipramine and clinical response. Biol Psychiatry. 
1996;39(3):171-181. 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
30 January 2023 
CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
53 
63. 
Gillin JC, Duncan WC, Murphy DL, et al. Age-related changes in sleep in depressed and normal 
subjects. Psychiatry Res. 1981;4(1):73-78. 
64. 
Perlis ML, Giles DE, Buysse DJ, Thase ME, Tu X, Kupfer DJ. Which depressive symptoms are related 
to which sleep electroencephalographic variables? Biol Psychiatry. 1997;42(10):904-913. 
65. 
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. 
Neuropsychopharmacology. 2008;33(1):88-109. 
66. 
Kupfer DJ, Frank E, McEachran AB, Grochocinski VJ. Delta sleep ratio. A biological correlate of early 
recurrence in unipolar affective disorder. Arch Gen Psychiatry. 1990;47(12):1100-1105. 
67. 
Duncan WC, Jr., Selter J, Brutsche N, Sarasso S, Zarate CA, Jr. Baseline delta sleep ratio predicts 
acute ketamine mood response in major depressive disorder. J Affect Disord. 2013;145(1):115-
119. 
68. 
Lotrich FE, Germain A. Decreased delta sleep ratio and elevated alpha power predict vulnerability 
to depression during interferon-alpha treatment. Acta Neuropsychiatr. 2015;27(1):14-24. 
69. 
Kupfer DJ, Reynolds CF, 3rd, Weiss BL, Foster FG. Lithium carbonate and sleep in affective 
disorders. Further considerations. Arch Gen Psychiatry. 1974;30(1):79-84. 
70. 
Billiard M. Lithium carbonate: effects on sleep patterns of normal and depressed subjects and its 
use in sleep-wake pathology. Pharmacopsychiatry. 1987;20(5):195-196. 
71. 
Friston KJ, Sharpley AL, Solomon RA, Cowen PJ. Lithium increases slow wave sleep: possible 
mediation by brain 5-HT2 receptors? Psychopharmacology (Berl). 1989;98(1):139-140. 
72. 
Doghramji K, Jangro WC. Adverse Effects of Psychotropic Medications on Sleep. Psychiatr Clin 
North Am. 2016;39(3):487-502. 
73. 
Jindal RD, Friedman ES, Berman SR, Fasiczka AL, Howland RH, Thase ME. Effects of sertraline on 
sleep architecture in patients with depression. J Clin Psychopharmacol. 2003;23(6):540-548. 
74. 
Duncan WC, Sarasso S, Ferrarelli F, et al. Concomitant BDNF and sleep slow wave changes indicate 
ketamine-induced plasticity in major depressive disorder. Int J Neuropsychopharmacol. 
2013;16(2):301-311. 
75. 
Quera Salva MA, Vanier B, Laredo J, et al. Major depressive disorder, sleep EEG and agomelatine: 
an open-label study. Int J Neuropsychopharmacol. 2007;10(5):691-696. 
76. 
Murphy M, Bruno MA, Riedner BA, et al. Propofol anesthesia and sleep: a high-density EEG study. 
Sleep. 2011;34(3):283-291A. 
77. 
Tung A, Bergmann BM, Herrera S, Cao D, Mendelson WB. Recovery from sleep deprivation occurs 
during propofol anesthesia. Anesthesiology. 2004;100(6):1419-1426. 
78. 
Tung A, Lynch JP, Mendelson WB. Prolonged sedation with propofol in the rat does not result in 
sleep deprivation. Anesth Analg. 2001;92(5):1232-1236. 
79. 
Rabelo FA, Braga A, Kupper DS, et al. Propofol-induced sleep: polysomnographic evaluation of 
patients with obstructive sleep apnea and controls. Otolaryngol Head Neck Surg. 
2010;142(2):218-224. 
80. 
Xu Z, Jiang X, Li W, Gao D, Li X, Liu J. Propofol-induced sleep: efficacy and safety in patients with 
refractory chronic primary insomnia. Cell Biochem Biophys. 2011;60(3):161-166. 
81. 
Shafer A, Doze VA, Shafer SL, White PF. Pharmacokinetics and pharmacodynamics of propofol 
infusions during general anesthesia. Anesthesiology. 1988;69(3):348-356. 
82. 
Tackley RM, Lewis GT, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT. Computer controlled 
infusion of propofol. Br J Anaesth. 1989;62(1):46-53. 
83. 
Marsh BJ, Morton NS, White M, Kenny GN. A computer controlled infusion of propofol for 
induction and maintenance of anaesthesia in children. Can J Anaesth. 1990;37(4 Pt 2):S97. 
84. 
Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in 
children. Br J Anaesth. 1991;67(1):41-48. 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
30 January 2023 
CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
54 
85. 
Schnider TW, Minto CF, Gambus PL, et al. The influence of method of administration and 
covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology. 
1998;88(5):1170-1182. 
86. 
Mhuircheartaigh RN, Rosenorn-Lanng D, Wise R, Jbabdi S, Rogers R, Tracey I. Cortical and 
subcortical connectivity changes during decreasing levels of consciousness in humans: a 
functional magnetic resonance imaging study using propofol. J Neurosci. 2010;30(27):9095-9102. 
87. 
Ni Mhuircheartaigh R, Warnaby C, Rogers R, Jbabdi S, Tracey I. Slow-wave activity saturation and 
thalamocortical isolation during propofol anesthesia in humans. 
Sci Transl Med. 
2013;5(208):208ra148. 
88. 
Peduto VA, Concas A, Santoro G, Biggio G, Gessa GL. Biochemical and electrophysiologic evidence 
that propofol enhances GABAergic transmission in the rat brain. Anesthesiology. 1991;75(6):1000-
1009. 
89. 
Irifune M, Takarada T, Shimizu Y, et al. Propofol-induced anesthesia in mice is mediated by 
gamma-aminobutyric acid-A and excitatory amino acid receptors. Anesth Analg. 2003;97(2):424-
429, table of contents. 
90. 
Orser BA, Bertlik M, Wang LY, MacDonald JF. Inhibition by propofol (2,6 di-isopropylphenol) of 
the N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J 
Pharmacol. 1995;116(2):1761-1768. 
91. 
Mao LM, Hastings JM, Fibuch EE, Wang JQ. Propofol selectively alters GluA1 AMPA receptor 
phosphorylation in the hippocampus but not prefrontal cortex in young and aged mice. Eur J 
Pharmacol. 2014;738:237-244. 
92. 
Krampfl K, Cordes AL, Schlesinger F, Wolfes H, Bufler J. Effects of propofol on recombinant AMPA 
receptor channels. Eur J Pharmacol. 2005;511(1):1-7. 
93. 
Wang X, Yang Y, Zhou X, et al. Propofol pretreatment increases antidepressant-like effects induced 
by acute administration of ketamine in rats receiving forced swimming test. Psychiatry Res. 
2011;185(1-2):248-253. 
94. 
Luo J, Min S, Wei K, Zhang J, Liu Y. Propofol interacts with stimulus intensities of electroconvulsive 
shock to regulate behavior and hippocampal BDNF in a rat model of depression. Psychiatry Res. 
2012;198(2):300-306. 
95. 
O'Toole DP, Milligan KR, Howe JP, McCollum JS, Dundee JW. A comparison of propofol and 
methohexitone as induction agents for day case isoflurane anaesthesia. Anaesthesia. 
1987;42(4):373-376. 
96. 
McDonald NJ, Mannion D, Lee P, O'Toole DP, O'Boyle C, Keane PK. Mood evaluation and 
outpatient anaesthesia. A comparison between propofol and thiopentone. Anaesthesia. 1988;43 
Suppl:68-69. 
97. 
Canaday BR. Amorous, disinhibited behavior associated with propofol. Clin Pharm. 
1993;12(6):449-451. 
98. 
Kent EA, Bacon DR, Harrison P, Lema MJ. Sexual illusions and propofol sedation. Anesthesiology. 
1992;77(5):1037-1038. 
99. 
Kim JH, Byun H, Kim JH. Abuse potential of propofol used for sedation in gastric endoscopy and 
its correlation with subject characteristics. Korean J Anesthesiol. 2013;65(5):403-409. 
100. 
D'Haese J, Camu F, Dekeyzer PJ, D'Haenen HA. Propofol and methohexitone anaesthesia: effects 
on the profile of mood state. Eur J Anaesthesiol. 1994;11(5):359-363. 
101. 
Whitehead C, Sanders LD, Oldroyd G, et al. The subjective effects of low-dose propofol. A double-
blind study to evaluate dimensions of sedation and consciousness with low-dose propofol. 
Anaesthesia. 1994;49(6):490-496. 
102. 
Mickey BJ, White AT, Arp AM, et al. Propofol for Treatment-Resistant Depression: A Pilot Study. 
Int J Neuropsychopharmacol. 2018;21(12):1079-1089. 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
30 January 2023 
CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
55 
103. 
Maslej MM, Bolker BM, Russell MJ, et al. The Mortality and Myocardial Effects of Antidepressants 
Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis. Psychother Psychosom. 
2017;86(5):268-282. 
104. 
Luscher B, Mohler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic 
deficit hypothesis of depression and may foster resilience. F1000Res. 2019;8. 
105. 
Lenze EJ, Nicol GE, Barbour DL, et al. Precision clinical trials: a framework for getting to precision 
medicine for neurobehavioural disorders. J Psychiatry Neurosci. 2021;46(1):E97-E110. 
106. 
Smith SK, Nguyen T, Labonte AK, et al. Protocol for the Prognosticating Delirium Recovery 
Outcomes Using Wakefulness and Sleep Electroencephalography (P-DROWS-E) study: a 
prospective observational study of delirium in elderly cardiac surgical patients. BMJ Open. 
2020;10(12):e044295. 
107. 
Kafashan MM, Hyche O, Nguyen T, et al. Perioperative sleep in geriatric cardiac surgical patients: 
a feasibility study using a wireless wearable device. Br J Anaesth. 2021;126(6):e205-e208. 
108. 
Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and 
relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284(7):861-
868. 
109. 
Krystal AD, Pizzagalli DA, Mathew SJ, et al. The first implementation of the NIMH FAST-FAIL 
approach to psychiatric drug development. Nat Rev Drug Discov. 2018;18(1):82-84. 
110. 
Nagele P, Palanca BJ, Gott B, et al. A phase 2 trial of inhaled nitrous oxide for treatment-resistant 
major depression. Sci Transl Med. 2021;13(597). 
111. 
Siegel JS, Palanca BJA, Ances BM, et al. Prolonged ketamine infusion modulates limbic connectivity 
and induces sustained remission of treatment-resistant depression. Psychopharmacology (Berl). 
2021. 
112. 
Lenze EJ, Stevens A, Waring JD, et al. Augmenting Computerized Cognitive Training With 
Vortioxetine for Age-Related Cognitive Decline: A Randomized Controlled Trial. Am J Psychiatry. 
2020;177(6):548-555. 
113. 
Mashour GA, Palanca BJ, Basner M, et al. Recovery of consciousness and cognition after general 
anesthesia in humans. Elife. 2021;10. 
114. 
Dinges DF, Powell JW. Microcomputer analyses of performance on a portable simple visual RT 
task during sustained operations. Behavior Research Methods & Instrumentation. 1985;17:652-
655. 
115. 
Basner M, Dinges DF. An adaptive-duration version of the PVT accurately tracks changes in 
psychomotor vigilance induced by sleep restriction. Sleep. 2012;35(2):193-202. 
116. 
Basner M, Mollicone D, Dinges DF. Validity and Sensitivity of a Brief Psychomotor Vigilance Test 
(PVT-B) to Total and Partial Sleep Deprivation. Acta Astronaut. 2011;69(11-12):949-959. 
117. 
Basner M, Rubinstein J. Fitness for duty: a 3-minute version of the Psychomotor Vigilance Test 
predicts fatigue-related declines in luggage-screening performance. J Occup Environ Med. 
2011;53(10):1146-1154. 
118. 
Doran SM, Van Dongen HP, Dinges DF. Sustained attention performance during sleep deprivation: 
evidence of state instability. Arch Ital Biol. 2001;139(3):253-267. 
119. 
Palanca BJA, Maybrier HR, Mickle AM, et al. Cognitive and Neurophysiological Recovery Following 
Electroconvulsive Therapy: A Study Protocol. Front Psychiatry. 2018;9:171. 
120. 
Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics 
including independent component analysis. J Neurosci Methods. 2004;134(1):9-21. 
121. 
Lucey BP, McLeland JS, Toedebusch CD, et al. Comparison of a single-channel EEG sleep study to 
polysomnography. J Sleep Res. 2016;25(6):625-635. 
122. 
Kabi F. Propofol Package Insert. In:2014. 

SWIPED: Phase I 
Version 3.1.5 
NIMH U01MH128483 
30 January 2023 
CT.gov NCT04680910 
WU HRPO Protocol 202008037 
 
 
56 
123. 
de Leon-Casasola OA, Weiss A, Lema MJ. Anaphylaxis due to propofol. Anesthesiology. 
1992;77(2):384-386. 
124. 
Laxenaire MC, Gueant JL, Bermejo E, Mouton C, Navez MT. Anaphylactic shock due to propofol. 
Lancet. 1988;2(8613):739-740. 
125. 
Tsai MH, Kuo PH, Hong RL, Yang PC. Anaphylaxis after propofol infusion for Port-A-Cath insertion 
in a 35-year old man. J Formos Med Assoc. 2001;100(6):424-426. 
126. 
Koul A, Jain R, Sood J. A critical incident report: Propofol triggered anaphylaxis. Indian J Anaesth. 
2011;55(5):530-533. 
127. 
Laxenaire MC, Mata-Bermejo E, Moneret-Vautrin DA, Gueant JL. Life-threatening anaphylactoid 
reactions to propofol (Diprivan). Anesthesiology. 1992;77(2):275-280. 
128. 
McHale SP, Konieczko K. Anaphylactoid reaction to propofol. Anaesthesia. 1992;47(10):864-865. 
129. 
Ducart AR, Watremez C, Louagie YA, Collard EL, Broka SM, Joucken KL. Propofol-induced 
anaphylactoid reaction during anesthesia for cardiac surgery. J Cardiothorac Vasc Anesth. 
2000;14(2):200-201. 
130. 
Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg. 
2003;97(5):1381-1395. 
131. 
Asserhoj LL, Mosbech H, Kroigaard M, Garvey LH. No evidence for contraindications to the use of 
propofol in adults allergic to egg, soy or peanutdagger. Br J Anaesth. 2016;116(1):77-82. 
132. 
Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth. 1995;7(1):89-91. 
133. 
Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. High STOP-Bang score indicates a high 
probability of obstructive sleep apnoea. Br J Anaesth. 2012;108(5):768-775. 
134. 
Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive 
sleep apnea. Anesthesiology. 2008;108(5):812-821. 
135. 
Mitra PP, Bokil H. Observed Brain Dynamics. 1st ed. New York: Oxford University Press; 2008. 
136. 
Latta F, Leproult R, Tasali E, Hofmann E, Van Cauter E. Sex differences in delta and alpha EEG 
activities in healthy older adults. Sleep. 2005;28(12):1525-1534. 
137. 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J 
Psychiatry. 1979;134:382-389. 
138. 
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment 
of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167(1):99-103. 
139. 
Hardy CJ, Rejeski WJ. Not what, but how one feels: the measurement of affect during exercise. J 
Sport Exerc Psychol. 1989;11:304-317. 
140. 
Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699. 
141. 
Roca M, Parr A, Thompson R, et al. Executive function and fluid intelligence after frontal lobe 
lesions. Brain. 2010;133(Pt 1):234-247. 
142. 
Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in 
human circadian rhythms. Int J Chronobiol. 1976;4(2):97-110. 
143. 
Braun R, Kath WL, Iwanaszko M, et al. Universal method for robust detection of circadian state 
from gene expression. Proc Natl Acad Sci U S A. 2018;115(39):E9247-E9256.