Chronobiological Basis of Menopausal Depression: Correcting Misaligned Circadian Rhythms With Sleep and Light Interventions

The goal of this clinical trial is to learn more about mood, sleep, and activity during menopause. The main question it aims to answer is: can mood and sleep dysfunction in menopause be improved by resetting misaligned circadian rhythm through one night of strategic sleep timing adjustment and two weeks of exposure to bright light at a certain time of day? Researchers will compare sleep timing (earlier vs. later) and bright white light exposure (morning or evening) to investigate the effect of melatonin levels on mood, sleep, and activity. Participants will 1) submit urine samples to measure melatonin levels, 2) be assigned to advance or delay their sleep for one night, 3) sit in front of a light box for 30 minutes per day (morning or evening) for 14 days, 4) complete questionnaires about their mood and sleep, and 5) wear a device that will measure their activity.

Significant hormonal changes during perimenopause (P-M) may disrupt circadian rhythm (CR), manifesting as mood, sleep and activity dysfunction, increasing depressive illness risk. In this proposal, the investigators aim to test further a hypothesis of CR dysregulation in P-M mood and sleep dysfunction by administering critically-timed sleep + light interventions (SLI) designed to target and correct CR misalignment, and thereby improve mood and sleep. By this approach, the investigators aim to optimize P-M health and prevent disease and disability.

Hypotheses are: 1) SLI which phase-advance (shift earlier) vs phase-delay (shift later) CRs, best measured by melatonin, will ameliorate mood and sleep dysfunction, and 2) A corrective phase-shift in the primary biological target, melatonin timing, will be a significant mediator of improved function. In P-M depressed participants (DP) vs normal controls (NC), the investigators recently reported increased plasma melatonin secretion and delayed morning melatonin offset associated with mood and sleep disturbances; correcting the phase-delayed melatonin CR with critically-timed sleep (wake therapy) + light interventions improved mood and sleep within 1-2 weeks, correlating significantly with melatonin phase-advance.

To confirm target engagement and intervention mechanisms, in P-M women the investigators will compare 1) an Active Phase-Advance Intervention (PAI): phase-advanced restricted sleep (sleep 9pm-1am) for 1 night, followed by 2 weeks of phase-advancing morning (AM) bright white light (BWL) for 30 min/day starting within 30 min of wake time, vs 2) a Control Phase-Delay Intervention (PDI): phase-delayed restricted sleep (sleep 3-7am) for 1 night, followed by 2 weeks of phase-delaying evening (PM) BWL for 30 min/day ending 30 min before bedtime. In pilot data, the investigators found relatively inert effects of Control PDI on melatonin and nonsignificant (non-worsening) effects on mood and sleep. Combining SLI hastens, potentiates and maintains their beneficial effects. In a randomized parallel design in 100 P-M women with mood and sleep/activity dysfunction, the investigators will administer either PAI or PDI at home (to enhance ecological validity), assessing effects on psychometric measures, urinary 6-sulfatoxy-melatonin (6-SMT) and actigraphy sleep/activity.

This innovative combination of SLI identifies novel targets for health and disease prevention and addresses an unmet therapeutic need in P-M women. It extends to the P-M our investigations of CR dysregulation and its restoration with SLI in other mood and sleep disorders associated with hormonal change in premenstrual and peripartum depression. This approach potentially offers a safe, efficacious, rapid-acting, well-tolerated, nonpharmacological, sustainable, affordable, home, and thus effective, intervention that can reduce health disparities. This work also forms the basis for future trials, aiming to optimize treatment outcomes by identifying chronobiological targets specific to an individual, the goal of personalized, preventative medicine.