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. 2024 May 30;14(5):e087516.
doi: 10.1136/bmjopen-2024-087516.

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial

Rachel Lynn Rios  1 , Michael Green  1 , S Kendall Smith  1   2 , MohammadMehdi Kafashan  1   2 , ShiNung Ching  3 , Nuri B Farber  4 , Nan Lin  5 , Brendan P Lucey  2   6 , Charles F Reynolds  7 , Eric J Lenze  1   4 , Ben Julian Agustin Palanca  8   2   4   9   10 ; SWIPED Study Team
Collaborators, Affiliations

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial

Rachel Lynn Rios et al. BMJ Open. .

Abstract

Introduction: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series.

Methods and analysis: SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion.

Ethics and dissemination: The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial.

Trial registration number: NCT04680910.

Keywords: Adult anaesthesia; Cognition; Depression & mood disorders; Electroencephalography; GERIATRIC MEDICINE; Sleep medicine.

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Conflict of interest statement

Competing interests: BJAP has a patent on control of anaesthetic state modulation and an agreement with Elemind on the use of non-pharmacological potentiation of EEG slow waves. EL reports consulting fees from Merck, Boehringer-Ingelheim, Pritikin ICR, IngenioRx and Prodeo, grant funding from Janssen, the COVID Early Treatment Fund and FastGrants, and a patent pending on sigma-1 receptor agonists for COVID-19. BPL reports consulting fees from Eisai, Eli Lilly, OrbiMed and the GLG Group. He has also received research funding from Eisai and serves on the Scientific Advisory Board for Beacon Biosignals and a Data Safety Monitoring Board for Eli Lilly. RLR and MK have no conflicts to disclose concerning any product mentioned or concept discussed in this article. MK, BPL, EL and BJAP have received funding from the National Institutes of Health.

Figures

Figure 1
Figure 1
Electroencephalographic (EEG) slow waves and burst suppression evoked from a single participant. During natural sleep, the predominance of high amplitude EEG slow waves in the delta band (delta waves) define slow wave sleep (SWS)/stage 3 non-rapid eye movement sleep (N3) (A). EEG slow waves can also be induced during propofol general anaesthesia (B). With high doses of propofol, EEG burst suppression arises (C). Data were acquired from a 71-year-old woman during the pilot study.
Figure 2
Figure 2
Study timeline. 15 study participants will undergo two 2-hour propofol infusions, high-density EEG, serial at-home unattended sleep studies, cognitive assessments and evaluations of depression, anhedonia and suicidality. Participants will complete a sleep diary. A blood biobanking study is optional, as marked by asterisks. C-SSRS, Columbia Suicide Severity Rating Scale; EEG, electroencephalography; HD, high density; MADRS, Montgomery-Åsberg Depression Rating Scale; MoCA, Montreal Cognitive Assessment; NIH, National Institutes of Health; PHQ-9, Patient Health Questionnaire-9; PVT, Psychomotor Vigilance Test; SHAPS, Snaith-Hamilton Pleasure Scale.
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