Slow Wave Induction by Propofol to Eliminate Depression (SWIPED)

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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, 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 criteria. 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 patients 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.

Official Title
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Precision Targeting of Propofol-induced Electroencephalographic Slow Waves: a Novel Phase I/2 Paradigm for Treatment-resistant Major Depressive Disorder

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: Propofol
* Diagnostic Test: Electroencephalography (EEG)
* Diagnostic Test: Slow-Wave Activity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Age 60 or greater 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) Treatment-resistant Depression (non-responsive to at least two adequate trials of oral antidepressants for current episode). Exclusion Criteria: Presence of symptomatic coronary artery disease Presence of marked congestive heart failure/cardiomyopathy (NYHA > Class III, LVEF <40%, greater than mild RV systolic dysfunction) Prior reaction to propofol Resting heart rate < 50 bpm Treatment with Electroconvulsive therapy/Transcranial Magnetic Stimulation/vagal nerve stimulation within 6 weeks Body mass index > 35 C-SSRS of 4 or greater (active suicidal ideation with some intent and with/without a specific plan) MoCA score < 23 (at least mild dementia) Non-prescribed used of amphetamines, opioids, marijuana, cocaine, or phencyclidine Intake of > 14 beers/week (or equivalent) Anesthetic exposure in the past 4 weeks Concurrent use of benzodiazepines > 2 mg/day lorazepam or equivalent, trazodone > 50 mg/day, or gabapentin > 600 mg/day.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot Study for safety and feasibility and then randomized controlled trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propofol infusion - moderate dose<br>Serial propofol infusions to maximally and safely induce unconsciousness and EEG slow waves while minimizing burst suppression. | Drug: Propofol<br>* Targeted propofol infusion in TRD patients will induce sedation. Dosage of propofol is determined based upon EEG markers and treatment arm.<br>* Other names: anesthetic;Diagnostic Test: Electroencephalography (EEG)<br>* EEG will be recorded during propofol infusion and during overnight sleep. Sleep EEG data will be acquired for a minimum of one night prior to the first sedation session, providing a baseline measure. Additional overnight sleep recordings will be performed on day of sedation and subsequent nights.<br>Diagnostic Test: Slow-Wave Activity<br>* Duration of slow waves during sedation will be evaluated using automated approaches. SWA during sedation will be calculated as the total power in the 0.5-4 Hz frequency band/total time in minutes. SWA during N2/N3 sleep will be calculated as the total power in the 0.5-4 Hz frequency band/total time in minutes in the N2 and N3 sleep stages. Delta sleep ratio will be computed from the SWA measured during the first and second N2/N3 cycles.<br>|
| Active Comparator: Propofol infusion - low dose<br>Serial propofol infusions to safely induce unconsciousness while minimizing EEG slow waves and burst suppression. | Drug: Propofol<br>* Targeted propofol infusion in TRD patients will induce sedation. Dosage of propofol is determined based upon EEG markers and treatment arm.<br>* Other names: anesthetic;Diagnostic Test: Electroencephalography (EEG)<br>* EEG will be recorded during propofol infusion and during overnight sleep. Sleep EEG data will be acquired for a minimum of one night prior to the first sedation session, providing a baseline measure. Additional overnight sleep recordings will be performed on day of sedation and subsequent nights.<br>Diagnostic Test: Slow-Wave Activity<br>* Duration of slow waves during sedation will be evaluated using automated approaches. SWA during sedation will be calculated as the total power in the 0.5-4 Hz frequency band/total time in minutes. SWA during N2/N3 sleep will be calculated as the total power in the 0.5-4 Hz frequency band/total time in minutes in the N2 and N3 sleep stages. Delta sleep ratio will be computed from the SWA measured during the first and second N2/N3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Propofol Infusion | Adverse events and serious adverse events, including incidence, severity, and likelihood of relation to intervention. Evaluate whether serial propofol infusions are safe (<5% serious adverse events directly attributable to infusions) | Up to one week after propofol infusions | 
| Feasibility of Propofol Infusion - Propofol SWA | Evaluate in geriatric TRD patients that propofol infusions can efficiently induce EEG slow waves during infusion (SWA for most of the sedation time) Sedation slow wave activity (SWA, EEG power within 0.5-4 Hz frequency band) during propofol sedation. | During two-hour propofol infusions | 
| Feasibility of Propofol Infusion - Sleep SWA | Evaluate Change in sleep slow wave activity during N2/N3 Sleep (post-infusion - pre-infusion) Evaluate whether propofol can augment total sleep SWA in greater or equal to 40% of study completers. | Over three-week period of pre- and post- infusion sleep recordings | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Affects on suicidality | Evaluate whether propofol infusions are associated with augmented suicidality Change in Suicidality (C-SSRS) Suicidality screening for need of emergency psychiatric care. | Up to 10 weeks after second infusion | 
| Affects sleep structure | Evaluate changes in sleep structure 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 NREM cycle divided by the SWA of the 2nd NREM cycle). Established markers for sleep macrostructure. | Over three-week period of pre- and post- infusion sleep recordings | 
| Affects on cognition (MoCA) | Evaluate changes in cognitive function Change in Cognitive Performance on the MoCA. Examine potential positive or negative changes cognition that may be associated with propofol infusion. | comparison of baseline measure to up to 3 weeks after second infusion | 
| Affects on cognition (Fluid Cognition) | Evaluate changes in cognitive function Change in Cognitive Performance on the NIH Toolbox Cognition Battery Examine potential positive or negative changes cognition that may be associated with propofol infusion. | comparison of baseline measure to up to 3 weeks after second infusion |