ABSTRACT
Circadian rhythm disruption, as marked by circadian rhythm variability, eveningness (i.e., preference for later
sleep timing), and delayed sleep-wake phase disorder (DSPD, characterized by eveningness) are common
among adults with bipolar disorder (BD). Indeed, 65% of BD adults meet diagnostic criteria for DSPD during a
depressive episode, as compared to rates of 0.2-1.7% in the general population. Importantly, DSPD,
eveningness, and circadian rhythm variability are the most robust predictors of a poorer clinical course in BD,
including greater functional impairment and relapse to mood episodes across 1-5 years. The impact of an
episode in BD is profound; 60% of those experiencing their first episode fail to regain previous functioning at 2
years; over 50% of BD people experience disability; life expectancy is reduced by an average of 8-12 years.
Efficacious therapies such as Interpersonal and Social Rhythms Therapy (IPSRT) seek to improve outcomes in
BD by indirectly targeting the circadian system through stabilization of social rhythms. In this project, we build
vertically upon IPSRT by testing the mechanisms of a strategic intervention that directly targets the circadian
system disruptions observed in BD—low-dose afternoon supplemental melatonin plus time in bed scheduling.
With demonstrated efficacy for DSPD, this strategic intervention is low-burden to person, stabilizes
dysregulated sleep patterns, improves sleep, increases morningness, and normalizes circadian timing. The
advantages of melatonin as a strategic therapy for BD are significant: (1) available over-the-counter; (2)
inexpensive (~7 cents per pill); (3) easily administered/low patient burden; and (4) safe, with few side effects.
The proposed study is a randomized controlled trial of low-dose afternoon melatonin plus time in bed
scheduling relative to control (sleep hygiene education plus placebo pill) for DSPD in adults with BD and
clinically significant depressive symptoms to determine its engagement of the novel mechanistic target of
circadian timing. Specific aims are as follows: AIM 1: Determine the effect of low-dose afternoon melatonin
plus time in bed scheduling (n=25) vs. sleep hygiene education plus placebo pill (n=25) on the primary
mechanistic probe of circadian timing as measured by the gold-standard biomarker, dim light melatonin onset
(DLMO); AIM 2: Evaluate DLMO advance as a predictor of change in depression symptoms (self-reported and
Ecological Momentary Assessment, EMA); Evaluate exploratory mechanisms (increase in morningness and
reduction in sleep variability) as predictors of reduction in depression symptoms (self-reported and EMA); AIM
3. Evaluate DLMO advance as a predictor of exploratory outcomes (total sleep time, sleep-related impairment,
mania symptoms). Objective, in-home assessment of circadian timing and sleep enables mechanistic testing
focused on novel biomarkers. This proposal is consistent with NIMH Strategy 3 of targeting putative
mechanisms linking the Research Domain Criteria (RDoC) domain of the arousal/regulatory systems (e.g.,
circadian and sleep regulation) to poor outcomes in this impactful disorder.