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.