Personalized Integrated Chronotherapy for Perinatal Depression
Phase: NA
Conditions: Depression, Postpartum Depression, Prenatal Disorder, Circadian Dysregulation, Pregnancy Related, Sleep Disturbance
Sponsor: Rhode Island Hospital

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
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Cover Page:  
  
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
Protocol version: 03/20/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
2 
 
 
 
Background:  
 
Increasing evidence suggests a connection between mood disorders and circadian dysfunction, or 
dysfunction of the ‘internal body clock’ that helps regulate 24-hour cycles of sleep and 
wakefulness.1 Integrated chronotherapy is a treatment approach that integrates bright light 
therapy, an advance in timing of the sleep-wake schedule, sleep schedule stabilization, and sleep 
scheduling, to address circadian dysfunction and thus ameliorate symptoms of mood disorders.2 
Chronotherapy has been used and established as an effective treatment for patients with 
unipolar3,4 and bipolar5-9 depression outside of the perinatal period.2  
 
This multi-site study aims to assess the efficacy of personalized, integrated chronotherapy (PIC) 
in treating perinatal depression with or without concomitant anxiety. We hypothesize that 
women who suffer from depression/anxiety during their third trimester who receive PIC in 
addition to usual care (UC), (in comparison to women who receive UC only), will show 
improvement in depressive and anxiety symptoms throughout the remainder of their pregnancy 
into the postpartum period. Secondary hypotheses are that the women receiving PIC along with 
UC will in fact demonstrate changes to their circadian rhythms, and that these changes will 
mediate, or explain, any improvements in depression and anxiety symptoms.  
 
This R01 study aims to recruit 220 women across 5 sites to complete at least 176 participants. 
(This will accommodate a 20% screening failure and attrition rate.) Women with major 
depression will be recruited in the third trimester of pregnancy as verified by diagnostic 
measures. Subjects will be randomly assigned to UC or PIC+UC. PIC will entail that the subjects 
use a bright light box to expose themselves to light for 15-60 30 minutes each morning, follow 
an individualized sleep/wake schedule, keep a sleep/wake journal, and wear an actigraph (a wrist 
device resembling a wristwatch) to measure activity and light exposure throughout the day. 
Subjects in both groups will also have seven visits during their study enrollment, which will 
extend from 24-28 weeks’ gestation to eighteen weeks postpartum; At these visits, subjects will 
complete self-report measures and participate in mood assessments administered by a blinded 
clinician, their actigraph data will be downloaded and collected, and their prescribed sleep 
schedule will be adjusted as needed. At the beginning, middle, and end of the study, subjects will 
complete a sleep diary as well as provide three sets of saliva samples for evaluation of biological 
markers of circadian rhythm changes. The aim of this study is to assess the feasibility of 
integrating PIC into routine clinical care and to test whether the outcome of PIC is beneficial to 
both mother and infant. 
 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
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Specific Aims:  
 
Specific Aim 1: Examine the efficacy of PIC, acting through chronobiologic targets, to improve 
mood in women with major depression during third trimester (N=220). Hypothesis: Compared to 
women receiving UC for depression during pregnancy, women in the PIC+UC group will show 
greater improvement in dependent measures of depression (HAMD) and anxiety (HAMA) at 
pregnancy week 36 and postpartum week 6.  
Specific Aim 2: Examine hypothesized mechanisms of change to confirm that PIC engages and 
alters the RDoC domains targeted by chronotherapy (specifically DLMO, Sleep Onset, Sleep 
Offset, Phase Angle (PA), Light Levels), and to determine whether changes in targeted domains 
are associated with antidepressant response. Hypothesis 2a: Compared to UC, PIC+UC patients 
will have earlier circadian phase and bed/wake times and shorter PA at pregnancy week 36 and 
postpartum week 6. Hypothesis 2b: Decrease in HAMD and HAMA scores will be mediated by 
changes in DLMO, sleep onset, sleep offset, phase angle, and light levels.  
Exploratory Aims: (a) In 100 mother-infant pairs, examine if maternal DLMO is related to (i) 
melatonin levels and onset in breastmilk at postpartum week 6, and (ii) infant sleep measured 
with ankle actigraphy at 18 weeks; (b) Explore factors relevant to future widespread 
dissemination of perinatal PIC, including health care utilization in UC vs. PIC+UC groups and 
quality of PIC delivery by different health care providers.  
 
Eligibility Criteria:  
The study team intends to enroll 220 subjects, females who are 24 to 28 weeks pregnant at 
screening and who are seeking treatment for depressive/anxiety symptoms. This time frame was 
selected for both scientific and practical reasons (i.e., most pregnancies that gestate to this time 
point are viable, sleep disturbances are common at this stage, it is early enough in pregnancy to 
have an impact, and the resulting study duration is not a burden for participants). We will include 
pregnant women aged 18-45 years old inclusive, with a baseline Hamilton Depression Rating 
Scale (HAMD-17) score ³ 14 and a current DSM-5 diagnosis of MDD as determined with the 
Current Major Depressive Episode Module of the Structured Clinical Interview for DSM 
disorders (SCID-I/P) during the Screening Visit (V1). The rationale for involving the protected 
population of pregnant women in this study is that we are investigating the utility of a non-
pharmacologic antidepressant treatment option in the specific population of perinatal women 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
4 
and, therefore, must involve these women in the study. This will allow us to longitudinally gauge 
the efficacy of Integrated Chronotherapy in reducing perinatal depressive/anxiety symptoms. We 
will allow women with tobacco dependence to enroll. Furthermore, women’s preferred choice of 
either bottle feeding or breastfeeding will not affect her eligibility. We anticipate some 
participants will take antidepressant, anxiolytic, and/or mood stabilizing medications as part of 
usual care (UC). We will allow women who are taking medications to enroll because medication 
use for mood disorders during pregnancy reflects current medical practice and will improve 
generalizability. Integrated Chronotherapy as administered through this research study will 
merely supplement any clinical care women are receiving. However, the team will be mindful to 
only enroll participants who start an antidepressant before at least four weeks of scheduled 
Screening Visit. This measure is only to control for any prolonged onset of action that could lead 
to decreased depressive symptoms due to the antidepressant, rather than the study 
intervention(s). We will also enroll women who are not taking medications. Our goal is to recruit 
patients who can participate in the PIC intervention safely and who will be representative of 
women who present with depression/anxiety during pregnancy.  
 
The following factors will exclude participants from the study: active psychosis or suicidality 
contraindicating outpatient treatment as determined by the clinical judgement of the research 
team and as assessed with the B/C module of the SCID-I/P and the Columbia-Suicide Severity 
Rating Scale (C-SSRS), respectively; bipolar disorder (because sleep restriction can increase risk 
of conversion to mania); seizure disorder (because sleep restriction can increase seizure risk); 
self-report of frequent migraines/headaches precipitated by bright light or sleep deprivation; 
preexisting eye/skin disorders contraindicating light therapy; use of photosensitizing 
medications; primary Axis I diagnosis other than major depressive disorder (MDD); high risk 
pregnancy (e.g., conditions requiring mandatory bed rest or complex medical regimens that will 
interfere with study participation or conditions where poor infant outcomes are anticipated); 
starting antidepressants within four weeks prior to enrollment (see above); current employment 
as nightshift worker; Alcohol Use Disorders Identification Test (AUDIT) score > 8 and/or Drug 
Abuse Screening Test (DAST) > 1 indicating current alcohol or drug use disorders; women 
whose infants will not be living in the home or who will have a nighttime caregiver; Pittsburgh 
Sleep Quality Inventory (PSQI) < 5 (i.e., those who report no sleep complaints during third 
trimester of pregnancy and for whom an intervention targeting sleep might not be indicated; the 
PSQI has been validated in pregnant women); women who do not speak and read English 
because PIC research instruments are only available in English at this time. Women who 
experience fetal loss or stillbirth, as well as mothers whose infants are born before 36 weeks 
gestation or have NICU stays longer than five days, will be discontinued from the study but will 
continue to receive UC. 
 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
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Study Procedures:  
Following the initial pre-screening process to ascertain a woman’s eligibility, interested 
participants will be scheduled for Visit 1 (Screening) at 24-28 weeks gestation. The duration of 
this visit will be up to three hours. Study staff will thoroughly review the informed consent form 
with subject prior to the initiation of any protocol-specific procedures. If the woman provides her 
consent, she will be randomized to receive personalized bright light therapy and a prescribed 
sleep schedule (PIC) in addition to usual care (UC) (i.e. medications, talk therapy, etc.) or usual 
care (UC) alone. The PIC treatment will include both daily bright light therapy and personalized 
sleep prescriptions. 
 
Subjects will be required to complete a total of seven study visits as described below. Whenever 
possible, these visits will place at the research offices at the respective sites. Visits may be 
performed as virtual visits via telephone and/or video if necessary.  
 
Study Outline 
Visit 
Time 
Scheduling Window 
Measures 
Pregnancy Phase 
Visit 1 
(Screening, 
Consenting, 
and 
Randomization) 
24-28 
Weeks 
Pregnancy 
N/A 
Screening Interview and 
Forms 
Visit 2 
(Baseline) 
28-30 
Weeks 
Pregnancy 
28 Weeks, 0 Days – 30 
Weeks, 6 Days 
Home Sleep and Light 
Monitoring, Mood, Circadian 
Phase 1 
Visit 3 
33 Weeks 
Pregnancy 
33 Weeks, 0 Days – 33 
Weeks, 6 Days (+/- 6 Days) 
Home Sleep and Light 
Monitoring, Mood 
Visit 4 
36 Weeks 
Pregnancy 
36 Weeks, 0 Days – 36 
Weeks, 6 Days (+/- 6 Days) 
Home Sleep and Light 
Monitoring, Mood, Circadian 
Phase 2 
Postpartum Phase 
Visit 5 
2 Weeks 
Postpartum 
2 Weeks, 0 Days Postpartum 
– 2 Weeks, 6 Days 
Postpartum 
Home Sleep and Light 
Monitoring, Mood 
Visit 6 
6 Weeks 
Postpartum 
6 Weeks, 0 Days Postpartum 
– 6 Weeks, 6 Days 
Postpartum (+/- 6 Days) 
Home Sleep and Light 
Monitoring, Mood, Circadian 
Phase 3 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
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Visit 7 
18 weeks 
postpartum 
18 weeks, 0 days postpartum 
to 18 weeks, 6 days 
postpartum (+/- 6 days) 
Home Sleep and Light 
Monitoring, Mood assessment; 
debriefing. 
 
Throughout the study treatment (beginning after completing the baseline data collection at Visit 
2), women in the PIC+UC group will be asked to sit with a bright light box every morning. The 
starting prescription is to use the light box for 30 minutes within the first 45-60 minutes after 
waking. Personalized prescriptions will take into account individual participants’ schedules and 
morning responsibilities. Light duration may be adjusted within the range of 15-60 minutes 
depending on participant’s response. Women will be instructed to use the light every day with 
the light box positioned approximately 12-24 inches from the eyes. She may be permitted to 
read, watch TV and do other activities so long as it does not block her eyes from the light. 
Although the light box therapy has no known adverse effects to newborns, participating women 
will be instructed not to hold their newborn infants while they are undergoing bright light 
therapy. Language regarding this is included in the sleep prescription that will be completed by 
study staff and provided to the participant.  
 
Women will also be specifically prescribed a personalized sleep schedule based on their reported 
sleep patterns and constraints related to specific schedules.  
 
Continuous sleep and light monitoring through an actigraph will occur to estimate sleep times 
and light exposure. Women will be instructed to wear the actigraph at all times throughout study 
enrollment except in instances where it may be damaged (i.e. water exposure while 
showering/bathing).  
 
On weeks where melatonin saliva sampling is scheduled (baseline, pregnancy week 36 and 
postpartum week 6, see below), women will complete a daily sleep diary. Once the mother has 
delivered, the infant’s sleep patterns may also be collected on the diary.  
 
A total of three saliva sample sets will be collected as a part of this study at 28 Weeks Gestation, 
36 Weeks Gestation and 6 Weeks Postpartum (weeks of Visit 2, 4 and 6). This is to measure 
melatonin concentrations. Women will be asked to collect twelve saliva samples each evening 
every half hour at a time that is assigned based on their sleep patterns during the visit week. 
 
Infant assessments will be conducted at Postpartum Week 18, requiring participants to complete 
questionnaires on their infants’ sleep/behavior. Infants will also wear an actigraph on their ankle 
for one week to obtain an objective measure of sleep patterns.  
 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
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The 7 study center visits will include downloading of wrist monitor data, examination of sleep 
and activity data as measured through the actigraph versus what was reported in the sleep diary 
(during applicable weeks). Treatment sleep schedules will also be assigned and adjusted at study 
center visits. Questionnaires and blinded clinical assessments will be administered to measure 
mood, safety measures (e.g. suicidality and manic symptoms). 
Analytic Strategy Registered with AsPredicted.org 
 
1) Data collection:  
Have any data been collected for this study already? 
 It's complicated. We have already collected some data but explain in Question 8 why readers 
may consider this a valid pre-registration nevertheless. 
(Note:  Choices are ‘Yes, we already collected the data.’, ‘No, no data have been collected for 
this study yet.’ and the answer above.  Also, 'Yes' is not an accepted answer.) 
 
2) Hypothesis: 
What's the main question being asked or hypothesis being tested in this study?  
The primary aim of this single-blinded RCT is to test whether adding a personalized integrated 
chronotherapy intervention (PIC) to usual care (UC) for perinatal depression improves mood better 
than UC alone in individuals who meet criteria for major depression during 3rd trimester of 
pregnancy. Participants are females ages 18-45 years recruited at 24-28 weeks’ gestation across 5 
study sites. They are enrolled between 28-30 weeks of gestation and take part in the study through 
postpartum week 18. After the screening and consenting visit (V1), they are randomized to UC or 
PIC+UC and have 6 more study visits: baseline (V2), gestational week 33 (V3), gestational week 
36 (V4), postpartum week 2 (V5), postpartum week 6 (V6) and postpartum week 18 (V7). Sleep 
and mood are measured at Visits 2-7 and dim light melatonin onset is measured at Visits 2, 4, and 
6.  
Hypothesis: Compared to women receiving UC for depression during pregnancy, women in the 
PIC+UC group will show greater improvement in dependent measures of depression (HAMD) at 
postpartum week 6 
3) Dependent variable: 
Describe the key dependent variable(s) specifying how they will be measured.  

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
8 
The primary dependent variable is the score on the Hamilton Depression Rating Scale (HAMD-17) 
which is evaluated by blinded raters at the end of each study week.  We are also measuring the 
Hamilton Anxiety Rating Scale (HAMA). 
4) Conditions:  
How many and which conditions will participants be assigned to?  
Participants are randomized to usual care (UC) or personalized integrated chronotherapy 
(PIC)+UC. We are using urn randomization to allocate women to UC or PIC+UC while balancing 
for expectant mothers’ parity and whether women self-identify as declining pharmacologic 
treatment for perinatal depression. 
5) Analyses:  
Specify exactly which analyses you will conduct to examine the main question/hypothesis.   
Changes in HAMD from baseline will be compared using generalized estimating equations, 
treating follow-up points as discrete time points, having correlated error within patient. All study 
time points will be in the model, but our main hypothesis will be tested as an interaction involving 
the baseline time point and postpartum week 6. This will be carried out within the model using 
orthogonal linear contrasts. Distributions for each dependent variable will be based on: a) real-
world constraints, and b) model residual diagnostics. We will adjust for additional model 
misspecification using classical sandwich estimation. 
6) Outliers and Exclusions  
Describe exactly how outliers will be defined and handled, and your precise rule(s) for 
excluding observations.  
We will identify a data point as an outlier that should be excluded only if the value is 
impossible/implausible biologically or if there is corroborating evidence independent of the 
observation value that indicated a protocol deviation or concern related to data collection.  
7) Sample Size How many observations will be collected or what will determine sample size? 
No need to justify decision, but be precise about exactly how the number will be determined.  
We will continue enrolling through April 2024 and accept the sample size accrued at that point.   
8) Other Anything else you would like to pre-register?  
(e.g., secondary analyses, variables collected for exploratory purposes, unusual analyses 
planned?)  
 

 
Personalized Integrated Chronotherapy for Perinatal Depression 
    
NCT04364646 
   Uploaded: October 24, 2025 
 
 
 
9 
The official start date of this study was 02/02/2020. Required COVID restrictions and the 
relocation of one of our study sites limited participant recruitment. Thus, we have changed our 
analytic strategy. Our original plan was to conduct an interim two-tailed analysis after 100 
participants completed the study to test for early signs of confirmatory efficacy, with the plan to 
switch all patients to PIC+UC if the HAMD reduction between groups was significantly 
different at alpha=0.005 either at 36 weeks of pregnancy or 6 weeks postpartum. Absent that, 
we planned to use two-tailed tests of the HAMD change using an alpha of 0.02 at 36 weeks of 
gestation and 6 weeks postpartum. To avoid an underpowered study, we will now test a one-
tailed hypothesis at 6 weeks postpartum. We are therefore registering our one-tailed hypothesis 
while we are still enrolling participants and collecting data to establish our new a priori analytic 
plan.  
 
Our secondary aim is to examine putative mechanisms of change to confirm that PIC engages 
and alters the RDoC domains targeted by chronotherapy (specifically DLMO, Sleep Onset, 
Sleep Offset, Phase Angle (PA), and Light Levels) and to determine whether changes in 
targeted domains are associated with antidepressant response. For this aim, we hypothesize that 
(a) compared to UC, PIC+UC patients will have earlier circadian phase and bed/wake times and 
shorter PA at pregnancy week 36 and postpartum week 6; and (b) decrease in HAMD scores 
will be mediated by the changes in DLMO, Sleep Onset, Sleep Offset, Phase Angle, and Light 
Levels. 
 
9) Name 
Give a title for this AsPredicted pre-registration  
Personalized Integrated Chronotherapy for Perinatal Depression NCT04364646 
10) Type of study 
Experiment 
11) Data source  
Field experiment / RCT