0338 Evaluating Propofol-Induced Changes in Sleep Spindle Density in Late-Life Treatment-Resistant Depression

Introduction Sleep spindles are brief thalamocortical oscillations and markers of stage N2 sleep, which play a key role in maintaining sleep stability and supporting synaptic plasticity. Aging and neuropsychiatric illness are associated with reduced spindle expression. Propofol, a GABA-ergic anesthetic, induces spindle-like oscillations and slow-wave dynamics, suggesting potential modulation of these circuits. The SWIPED I trial (ClinicalTrials.gov NCT04680910) leveraged propofol as a mechanistic probe to enhance slow-wave expression in adults with late-life treatment-resistant depression (LL-TRD). We examined whether propofol modulated changes in spindle density and whether these changes were related to antidepressant effects. Methods Fifteen adults aged ≥60 years with treatment-resistant depression received two propofol infusions titrated to maximize slow-wave expression. Overnight polysomnography was conducted at baseline and the night of each infusion. Sleep spindles were quantified from stage N2 sleep using the personalized semi-automatic spindle detection (PSASD) algorithm, using baseline and infusion-night recordings. Spindle density was calculated as spindles per minute of N2 sleep. Depressive symptom severity was assessed at baseline, one, three, and ten weeks post-infusion via the Montgomery-Åsberg Depression Rating Scale (MADRS). Results Total propofol dose correlated with increases from baseline in N2 sleep spindle density on post-infusion nights (r = 0.62, p = 0.015). Other spindle characteristics (frequency, peak-to-peak amplitude, and duration) did not change (all p > 0.05). Increased spindle density correlated with reductions in depressive severity at 1 week (r = –0.61, p = 0.016) and 3 weeks (r = –0.60, p = 0.018) post-infusion, but not at 10 weeks (r = –0.26, p = 0.341). Duration of exposure to low and high modeled effect-site propofol concentrations (1–2 μg/mL or 2.5–4.5 μg/mL) did not correlate with spindle density changes (p > 0.05). Conclusion Serial infusions of propofol were associated with dose-dependent increases in spindle density and reductions in depressive symptoms. Spindle density may be an important marker or mediator of propofol antidepressant response. Future analyses incorporating N3 sleep and follow-up overnight recordings will determine the extent of spindle enhancement. A Phase II randomized controlled trial is now underway to examine the therapeutic potential of propofol-based sleep modulation in LL-TRD. Support (if any) NIH awards P50MH122351, U01MH128483, R01MH143055, Vagelos Undergraduate Research Fellowship