Chronobiological Basis of Depression during the Menopause Transition - Project Summary/Abstract The 2017 Nobel Prize in Physiology and Medicine was awarded for work on circadian rhythm (CR) regulation. Now the challenge is to translate these basic science principles to clinical populations. Significant hormonal changes during the perimenopause (P-M) may disrupt CRs, manifesting as mood, sleep and activity dysfunction, increasing depressive illness risk. In this proposal we 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, ultimately we 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), we 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 we 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, we 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, we 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, non- pharmacological, 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.
