Alternative Treatments for Premenstrual Dysphoric Disorder
Phase: NA
Conditions: Premenstrual Dysphoric Disorder
Sponsor: University of California, San Diego

Study Product Guidelines and Considerations 
1 of 53 
Version 1.0 
 
 
29 MAR 2012 
Clinical Intervention Study 
Protocol  
 
FULL PROTOCOL TITLE 
Alternative Treatments for Premenstrual Dysphoric Disorder 
(Subtitle:  A randomized, masked, 40-subject clinical trial of combination 
wake and light therapy in the treatment of Premenstrual Dysphoric Disorder) 
 
Study Chairman or Principal Investigator:   
Principal Investigator: Barbara L. Parry, M.D., Professor of Psychiatry UCSD 
 
Supported by:  
The National Center of Complementary and Alternative Medicine  
NIH Study Number: RO1 AT007169-01A1 
 
Study Intervention Provided by:  
There is no support provided by pharmaceutical companies or device manufacturers. 
This project is not an IND/IDE study. 
Sponsor of IND (IDE):  
N/A 

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Tool Revision History 
Version Number: 1 
Version Date: 3/27/13 
Summary of Revisions Made: Original document 
Version Number: 2 
Version Date: 6/21/13 
Summary of Revisions Made: These revisions are a response to NCCAM Comments and 
Queries to the Investigator from the October, 2012 Council.   
Version Number: 3 
Version Date: 8/12/13 
Summary of Revisions Made: These revisions are a response to NCCAM’s responses and 
further questions to version 2.   
Version Number: 4 
Version Date: 9/25/2013 
Summary of Revisions Made: These final revisions are our biostatistician’s (Shahrokh Golshan, 
Ph.D.) response to NCCAM queries from 8/30/13.   
 
Version Number: 5 
Version Date: 12/20/2013 
Summary of Revisions Made: These final revisions amend the memo format of the language in 
section 6.2.6 to be in line with the standard protocol template; and also to reflect that we will 
perform secondary analyses on completers. 
 

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TABLE OF CONTENTS 
Page 
FULL PROTOCOL TITLE .......................................................................................................... 1 
Tool Revision History ............................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................ 3 
STUDY TEAM ROSTER ........................................................................................................ 6 
PARTICIPATING STUDY SITES ........................................................................................... 7 
PRÉCIS ................................................................................................................................. 7 
1. STUDY OBJECTIVES ........................................................................................................... 8 
1.1 
Primary Objective ....................................................................................................... 8 
1.2 
Secondary Objectives ................................................................................................. 9 
2. BACKGROUND AND RATIONALE....................................................................................... 9 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 9 
2.2 
Study Rationale .........................................................................................................10 
3. STUDY DESIGN ...................................................................................................................11 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ......................................................14 
4.1 
Inclusion Criteria ........................................................................................................14 
4.2 
Exclusion Criteria .......................................................................................................15 
4.3 
Study Enrollment Procedures ....................................................................................16 
5. STUDY INTERVENTIONS ....................................................................................................18 
5.1 
Interventions, Administration, and Duration ...............................................................18 
5.2 
Handling of Study Interventions .................................................................................19 
5.3 
Concomitant Interventions .........................................................................................20 
5.3.1 Allowed Interventions .............................................................................................20 
5.3.2 Required Interventions ...........................................................................................20 
5.3.3 Prohibited Interventions .........................................................................................20 
5.4 
Adherence Assessment .............................................................................................20 
6. STUDY PROCEDURES ........................................................................................................20 
6.1 
Schedule of Evaluations ............................................................................................21 
6.2 
Description of Evaluations .........................................................................................22 
6.2.1 Screening Evaluation .............................................................................................22 
6.2.2 Enrollment, Baseline, and/or Randomization .........................................................23 
6.2.3 Blinding ..................................................................................................................25 
6.2.4 Treatment Visits .....................................................................................................25 
6.2.5 Washout Visit .........................................................................................................25 

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6.2.6 Follow-up/Final Evaluation .....................................................................................26 
7. SAFETY ASSESSMENTS ....................................................................................................27 
7.1 
Specification of Safety Parameters ............................................................................27 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ....28 
7.3 
Adverse Events and Serious Adverse Events ............................................................28 
7.4 
Reporting Procedures ................................................................................................29 
7.5 
Followup for Adverse Events .....................................................................................30 
7.6 
Safety Monitoring .......................................................................................................30 
8. INTERVENTION DISCONTINUATION .................................................................................30 
9. STATISTICAL CONSIDERATIONS ......................................................................................31 
9.1 
General Design Issues ..............................................................................................31 
9.2 
Sample Size and Randomization ...............................................................................31 
Treatment Assignment Procedures ...................................................................................32 
9.3  
Definition of Populations ............................................................................................33 
9.4 
Interim Analyses and Stopping Rules ........................................................................34 
9.5 
Outcomes ..................................................................................................................35 
9.5.1 Primary Outcome ...................................................................................................35 
9.5.2 Secondary Outcomes ............................................................................................35 
9.6 
Data Analyses ...........................................................................................................36 
10. DATA COLLECTION AND QUALITY ASSURANCE .........................................................38 
10.1 
Data Collection Forms ...............................................................................................38 
10.2 
Data Management .....................................................................................................38 
10.3 
Quality Assurance .....................................................................................................39 
10.3.1 
Training ..............................................................................................................39 
10.3.2 
Quality Control Committee .................................................................................39 
10.3.3 
Metrics ...............................................................................................................40 
10.3.4 
Protocol Deviations ............................................................................................41 
10.3.5 
Monitoring ..........................................................................................................41 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ............................................................41 
11.1 
Institutional Review Board (IRB) Review ....................................................................41 
11.2 
Informed Consent Forms ...........................................................................................41 
11.3 
Participant Confidentiality ..........................................................................................42 
11.4 
Study Discontinuation ................................................................................................42 
12. COMMITTEES ....................................................................................................................42 
13. PUBLICATION OF RESEARCH FINDINGS .......................................................................42 

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14. REFERENCES ...................................................................................................................43 
15. SUPPLEMENTS/APPENDICES .........................................................................................52 
I. Procedures Schedule 

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STUDY TEAM ROSTER  
Barbara L. Parry, M.D., Professor of Psychiatry in Residence, Principal Investigator 
 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-5592 
(fx) 619-543-7519 
bparry@ucsd.edu 
Richard Hauger, M.D., Professor of Psychiatry in Residence, Co-Investigator 
 
9500 Gilman Drive, MC9116A 
La Jolla, California 92093-9116 
(ph) 858-552-8585 x 3471 
rhauger@ucsd.edu 
Henry Orff, Ph.D., Clinical Rater 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-7957 
(fx) 619-543-7849 
horff@ucsd.edu 
Shahrokh Golshan, Ph.D., Project Scientist, Co-Investigator 
9500 Gilman Drive, MC9151A 
La Jolla, California 92093-9151 
(ph) 858-642-1264 
sgolshan@ucsd.edu 
Charles Meliska, Ph.D., Project Scientist, Quality Assurance Officer, Professor Level, 
Co-Investigator 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-6345 
(fx) 619-543-7849 
cmeliska@ucsd.edu 
Diane Sorenson, M.P.H., Recruitment Officer and Clinic Coordinator 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-5575 
(fx) 619-543-7849 

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dsorenson@ucsd.edu 
L. Fernando Martínez, B.A., Research Associate 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-7917 
(fx) 619-543-7849 
lfmartinez@ucsd.edu 
Ana Lopez, B.S., Data Manager 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-6507 
(fx) 619-543-7849 
amlopez@ucsd.edu 
Alan Turken, B.S., Senior Research Technician 
9500 Gilman Drive, MC9151 
La Jolla, California 92093-9151 
(ph) 858-552-8585 x 7109 
aturken@ucsd.edu 
Gary Lyasch, Project Assistant 
9500 Gilman Drive, MC0804 
La Jolla, California 92093-0804 
(ph) 619-543-5592 
(fx) 619-543-7519 
glyasch@ucsd.edu 
 
PARTICIPATING STUDY SITES 
University of California, San Diego Medical Center in Hillcrest.   
200 West Arbor Drive. 
San Diego, CA 92103 
(ph) 619-543-6222 
PRÉCIS  
Study Title  
Alternative Treatments for Premenstrual Dysphoric Disorder 
 

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Objectives  
The primary aim of this study is to examine the effects of co-administered wake 
therapy followed by light treatment on mood and circadian rhythms to test the 
hypothesis that critically timed chronotherapy improves mood by correcting phase 
disturbances in melatonin and sleep in women with Premenstrual Dysphoric Disorder 
(PMDD). 
 
Design and Outcomes   
40 women with Premenstrual Dysphoric Disorder ages 18-45 will be randomized 
to a cross-over design contrasting one night of Late Wake Therapy followed by 7 
days of morning Bright-White Light (LWT+AM BWL) vs. one night of Early Wake 
Therapy followed by evening Bright-White Light (EWT+PM BWL) administered in the 
luteal phase of two separate menstrual cycles. Treatment will be preceded by 2 
evaluation months to determine diagnosis and collect baseline mood, sleep, 
actigraphy and endocrine measures. To lessen the patient’s burden, the 1-night EWT 
or LWT and the following 7-day BWL interventions will be conducted at home, given 
at a fixed point in each menstrual cycle, from day 1 to 7 after the mid-cycle LH surge. 
We anticipate that LWT+7 days of AM BWL (vs. EWT+PM BWL) will produce much 
greater mood benefits and larger physiological responses, than the one-time light 
pulses used in our earlier phase-shift studies. 1, 2 
 
Interventions and Duration  
Using a randomized cross-over design, in the luteal phase of their menstrual 
cycles, PMDD women will receive either 1) one night of LWT (sleep 21:00-01:00 h, 
followed by wakefulness) plus 7 days of AM BWL (light-emitting diode-LED 
administered for 60 minutes, starting within 30 minutes of habitual wake time) or 2) 
EWT (wakefulness until 03:00 h, then sleep 03:00-07:00 h) plus 7 nights of PM BWL 
(administered 90 minutes before habitual sleep onset, for 60 minutes).  Following this 
first intervention, patients will undergo one washout month with no intervention.  The 
second intervention will be completed in the luteal phase of the following month and 
will be the treatment opposite the one previously performed.  Total study duration, 
including evaluations and washout, will be 5 months (see Figure 1, Section 3, for 
detailed study flow diagram). 
 
Sample Size and Population  
In order to achieve the targeted enrollment goal of 40 completed subjects 
allowing for a 20% drop-out rate, 48 PMDD women ages 18-45 will be recruited to 
participate in the study. 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
We will assess the effects of the proposed study interventions on mood, urinary 
melatonin, sleep and activity to test the following specific hypothesis: 
For PMDD patients in the symptomatic luteal phase, LWT+AM BWL, compared 

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with EWT+PM BWL, will: A) Improve mood on rating scales; B) Phase-advance 
urinary melatonin timing measures in relation to clock time and sleep measures; C) 
The magnitude of the mood change will correlate with the magnitude of the phase-
advance in melatonin. 
1.2 
Secondary Objectives 
We will assess the effects of the proposed interventions on reproductive 
hormones. In addition, we will test the effects of expectation, 
morningness/eveningness and seasonality on primary outcome measures of mood, 
melatonin and sleep. We will evaluate subjective assessments of side effects to 
treatment and effectiveness. 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
PMDD is a devastating illness, causing extensive personal suffering, disruption in 
interpersonal and family relationships and occupational impairment. It can progress 
to major depressive disorder (MDD)3, 4 and exacerbate the course of bipolar illness,5, 
6 pregnancy, postpartum and menopausal depression.7 The incidence of women with 
severe premenstrual mood symptoms who meet criteria for a mental disorder has 
been estimated at 5-8%.8-10 In addition, 20% to 80% of women report some mood, 
cognitive, and behavioral disturbances associated with their menstrual cycle.3 
Current treatments of PMDD are marginal (< 60% response).11 Many women do not 
want to use, or cannot tolerate, chronic antidepressant medications for a periodic 
illness. Consequently, enhanced treatment approaches are needed to improve 
health outcomes.12 The NIH Office of Research for Women’s Health (Planning the 
Women’s Health Agenda for the 21st Century, November, 1997, Bethesda, MD) 
targeted PMDD as an area for increased research on women's mental health, now 
mandated by Congress. PMDD was a DSM-IV8 criterion set designated for further 
study in the appendix,13 but will be incorporated into the DSM-5.14 
Women are underrepresented in studies of sleep and circadian rhythms.15, 16 A 
translational comprehensive approach to studying the chronobiological abnormalities 
in PMDD can serve to develop new, alternative non-pharmacological treatment 
strategies of sleep and wake therapies. The key to establishing synchronized 
rhythms associated with healthy mood states is intervention at critical clock times. To 
achieve this objective, a better understanding of the optimal timing of wake and light 
interventions is needed. Elucidating the factors contributing to PMDD also will 
enhance our understanding and treatment of other female-specific mood disorders 
that involve alteration of reproductive hormones (e.g., pregnancy, postpartum and 
menopausal depression). Another positive outcome may be optimization of sleep 
and wake therapies applied to other types of depression with chronobiological 
disturbances, given the similarity of their phenomenology and possible pathogenic 
mechanisms. 
This proposal is innovative in providing new, alternative and possibly complementary 
treatment interventions as well as in providing a conceptual model to understand the 
mechanisms by which wake therapy and light treatment exert their antidepressant 
effects. The benefits of combined sleep and light therapies have been confirmed in 
mood disorders,17-31 but combined wake therapy and light treatment have not been 
used previously to treat PMDD, or those women who do not respond to, cannot 

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tolerate, or desire alternatives to antidepressant or other treatments for PMDD. Using 
wake therapy alone is limited by the relapse that often occurs after subsequent 
sleep; and light treatment alone in non-seasonal mood disorders is limited by the 
duration of treatment required to elicit a therapeutic response (at least 4-6 weeks). 
The combined treatment proposed here is innovative because wake therapy 
enhances the effect of light treatment and reduces the time needed to elicit a 
therapeutic response, and light treatment maintains mood benefits of wake therapy 
lost after subsequent sleep. This approach is in response to a call for the 
development of novel combination therapies to improve treatment responses.32 
Before combining treatments, it is best that each treatment be tested alone.32 Our 
research team previously has applied wake therapy alone or light treatment alone, 
yet no group has used these combined treatments in PMDD. Thus this proposal 
represents a reasonable next step and a creative synthesis of the two treatment 
approaches. Also, although chronobiological mechanisms have been proposed as 
the neurobiologic basis for mood disorders,29, 33-35 the chronobiologic basis of PMDD 
has not been investigated systematically by research groups other than our own. 
Frederick Goodwin, Peter Whybrow, Anna Wirz-Justice and Siegfried Kasper,33 as 
well as a position statement by the Committee on Chronotherapeutics of the 
International Society for Affective Disorders,34 endorsed a broader view of 
chronobiological factors (e.g., circadian phase and sleep disturbances) in mood 
disorders, emphasizing that sleep and light therapies are rapid and effective 
antidepressants for first-line treatment of MDD.30 We designed our proposed study to 
provide crucial evidence on whether sleep and light therapies in combination provide 
enhanced benefits in PMDD. 
2.2 
Study Rationale 
Interventions: The wake therapy and light interventions proposed in this 
application are based on our previous studies in PMDD 36-39 and key published 
experiments by other investigators that indicate that the combined interventions are 
efficacious in other mood disorders after one week of treatment and maintained at 9-
months follow-up.17-31 To provide optimal timing of interventions, we will administer 
wake therapy in the early-night vs. late-night and light pulses in the AM vs. PM at 
selected times in relation to sleep (within 30 min of waking and 90 min before sleep 
onset, respectively). These times were selected to examine phase-advance and 
phase-delay responses without disrupting sleep. Successful light treatment is 
associated with a phase-shift of the melatonin rhythm as noted by Epperson et al.40 
in a randomized trial of bright light therapy for antepartum depression and by Terman 
et al.41 in winter depression. In this proposal focusing on mood effects, we will 
administer 7 days of AM or PM light after wake and before sleep, respectively, for 60 
min using a light-emitting diode (LED) device. The advantage of LEDs over 
conventional light boxes (fluorescent or incandescent) is that LEDs can be selected 
to emit light with energy concentrated at wavelengths of 450-480nm to which the 
human circadian system is most sensitive.42-44 Thus LEDs are not only more efficient, 
but smaller and light-weight, further enhancing patient compliance. Clinical effects on 
mood generally occur within 3-4 days after the onset of treatment, and expire within 
3-4 days after discontinuation of treatment.45, 46 
A crossover treatment design will be employed to compare LWT+AM BWL vs. 
EWT+PM BWL responses within the same individual. As wake interventions lose 
effectiveness after 1 day, and light treatment effects after 3-4 days, we anticipate 
minimal carry-over effects of the wake plus light interventions administered a month 

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apart. To further ensure no carry-over effects, there will be a month of no-
intervention between the 1st and 2nd treatments. Because our previous studies 
clearly indicated differences between PMDD and NC subjects occurred primarily in 
the luteal menstrual cycle phase, we will treat during this menstrual cycle phase 
rather than in the follicular phase.  
Melatonin measures: To make the study more clinically feasible on an outpatient 
basis and to reduce subject burden, instead of plasma melatonin measures requiring 
now expensive inpatient admissions, we will obtain two overnight collections (30+ h) 
of urinary 6-sulfatoxymelatonin (6-SMT) pre- and post-intervention. Since light 
suppresses melatonin acutely (within 30 minutes), melatonin measures will be 
obtained after completion of the light treatment to avoid confounding the suppressive 
effects with the phase-shifting effects of light. Based on previous work,1, 47, 48 we 
know melatonin profiles are stable and consistent within an individual when 
measured at different time points. These characteristics make melatonin one of the 
best markers for circadian rhythmicity in humans in non-constant routine conditions, 
if light is controlled appropriately. We will not use a constant routine, as it is not 
needed to obtain informative circadian parameters from rhythms in urinary 6-SMT, is 
burdensome, not clinically feasible for depressed patients in an outpatient setting, 
and has less potential therapeutic application. Melatonin is also a very useful marker 
because it is little masked by exercise, sleep, diet or stress when compared with 
other circadian parameters such as temperature, cortisol or activity measurements. 
Measuring 6-SMT in the urine has similar advantageous characteristics, and is less 
expensive and burdensome to patients compared with plasma measures. Moreover, 
the power of this method has been clearly and extensively demonstrated at UCSD by 
our collaborators Drs. Elliott, Kripke and colleagues.49, 50  
Other biological rhythm measures such as sleep and activity may be 
independently regulated, but coupled. Therefore, it is informative also to measure 
these components of the circadian system in order to better quantify and understand 
the circadian response to treatment and its impact on mood and sleep.  
3. STUDY DESIGN 
Forty PMDD subjects will be recruited. Menstrual cycle phase will be established 
by measuring the mid-cycle LH surge using a urinary colorimetric assay (Clearblue® 
colorimetric LH assay, Princeton, New Jersey). Failure to ovulate will exclude the 
subject from participating that month, and the study will be postponed until a 
following month when ovulation can be documented. 
Overall Design (see Figure 1): Month 1 consists of a screening evaluation using 
daily mood ratings (DMR) (see Section 6: Subject Selection). In Month 2, evaluations 
are continued, the Structured Clinical Interview for DSM-IV (SCID)51, 52 and 
documentation of ovulation by the LH surge (approximately menstrual cycle day 14) 
are performed. In the Month 2 luteal phase, PMDD subjects will collect overnight 
urine samples for 6-SMT and reproductive hormones (RH) (estradiol, progesterone, 
FSH, LH, prolactin) starting 8-9 days after the LH surge (approximately menstrual 
cycle days 22-23). These baseline urine sample collections are timed to coincide 
with post-intervention measures in months 3 and 5. Starting in Month 3, after the LH 
surge (luteal phase), subjects will undergo a night of LWT (sleep 21:00-01:00 h, 
followed by wake) vs. EWT (wake until 03:00 h followed by sleep until 07:00 h) at 
home. We selected the specific wake and sleep times based on our previous work in 

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PMDD.36, 37 The following day, subjects will receive the light intervention for 7 
consecutive days: days 1-7 after the LH surge (approximately menstrual cycle days 
15-21). We will randomize subjects to 60 min of either AM bright white light (LED of 
1350 lux at 20 inches) starting within 30 minutes of their habitual wake time, or PM 
bright white light ending 30 min before their habitual sleep onset time. After 
completing seven days of light exposure, subjects again will collect 30+ hours of 
urine samples over 2 nights (between days 8-9 after the LH surge, approximately 
menstrual cycle day 22-23). The following Month 4 (Washout) will be a month of no 
intervention to prevent any carry-over effects from the Month 3 intervention affecting 
measures in Month 5. Mirroring Month 3 timing, in the luteal phase of Month 5, 
subjects will receive the alternate wake therapy (LWT or EWT) and light exposure 
(AM or PM), followed by 2 overnight collections of urinary 6-SMT and RH samples. 
See Fig. 1, below. 
This design allows us to complete the studies at least two days before the next 
expected menstrual period. Measuring the circadian profile of urinary melatonin over 
2 nights for 30+ h will allow us to assess phase, duration and amplitude changes of 
melatonin reflective of the underlying circadian pacemaker. In addition, we will 
assess phase-shift responses of melatonin to light in relation to other critical 
biological rhythm measures of sleep and activity. To document the sleep/wake cycle 
and exposure to light intensity and spectra, we will use the Actiwatch device (see 
description below). 
Figure 1. Study flow: The luteinizing hormone surge (LHS) documents ovulation, c. menstrual 
cycle day (CD) 14. Urine samples for 6-sulphatoxy-melatonin (6-SMT) and reproductive 
hormones (RHs) will be collected for 30+ hours over 2 nights between days 8-9 after the LH 
surge (c. CD 22-23) in months 2,3,5; actigraphy will begin the day of LHS and continue until 
day 10 after the LHS (CD 14-24) of months 2,3,5; late wake therapy (LWT) or early wake 
therapy (EWT) will be administered at home on the night of the LHS; bright morning (AM) or 
evening (PM) light will be administered on days 1-7 after the LHS (CD 15-21) in a 
counterbalanced, cross-over design in months 3 and 5. Mood ratings (HRSD+BDI) will be 
collected as follows: Months 1 & 2 – once per week; Months 3 & 5 – LHS + 0 (Pre-
Intervention 1 
 
Washout 
 
 Intervention 2 
I N T E R V E N T I O N 
Month 2
Month 1
EVALUATION 
Month 4
Month 5
Month 3
LHS
c. CD 14 
LHS
c. CD 14 
LHS
c. CD 14 
ACTIGRAPHY 
 
LHS +0 → LHS +10 
URINE 6-SMT & RH 
 
 
 
6-SMT/RH (30+ hours)) 
LHS +8 → LHS +9 
LWT+AM Light vs. EWT+PM Light 
      
 
 
LWT/EWT at home, LHS +0 
 
     Bright White Light 
     LHS +1 → LHS +7 

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LWT/EWT), daily LHS +1 → LHS + 2 and once the evening after last treatment (LHS +7/8). 
Visual Analogue Scales (VAS) for depressed mood, anxiety, affective lability, irritability (Daily 
Mood Ratings)(core PMDD symptoms) collected daily during Months 1 & 2, and twice daily 
on LHS + 0 through LHS + 2 (for wake therapy effects) and daily LHS + 3 through LH + 10 
(for light treatment effects) in Months 3 & 5. HRSD will be collected once during Month 4 and 
a once a month after Intervention 2 to monitor relapse. 
 
Urinary Collections for 6-SMT and RH: For urine collections, subjects will 
measure and record the time and total volume of each urine voided over a 30-hour 
interval starting with the last urination before going to bed one evening and ending 
on the morning of the second day thereafter. Two 2 ml aliquots from each voiding will 
be frozen at home in duplicate using labeled and numbered vials, and later stored at 
-70 C in the lab until assay. Subjects will receive thorough instruction regarding 
accurate recording of time and volume and proper collection and storage of the 
aliquots associated with each sample, including hands-on experience. Subjects also 
will be encouraged to drink extra fluids during waking hours (~ 200 ml every 2 hours) 
to remain well-hydrated and to facilitate more frequent voiding. Subjects will receive 
an oversupply of duplicate sample vials, each with easily read numbers on the 
printed label which are repeated on the vial tops to ensure correct identification of 
each sample with the associated time and volume on the record sheet. They also will 
be supplied with 1000 ml plastic bottles for refrigerator storage of samples collected 
during awakenings at night (so that volume measurement and transfer to freezer 
vials can be postponed until morning). The above urine collection methods have 
served us well for many years.49, 50, 53 
Actigraphy Measures: Measures of activity and illumination using the Actiwatch 
Spectrum device will be obtained for 10 days in the luteal phase starting on the day 
of the LH surge during the 2nd month of screening evaluation and during each 
subsequent intervention month. The Actiwatch Spectrum, developed by 
Respironics®, a subsidiary of Royal Philips Electronics, is a small device (48.5 x 
36.7 x 13.8 mm and weighing 29.8 g with band) containing a piezoelectric linear 
accelerometer (sensitive to 0.003 g and above), log-linear photometric transducer 
(sensitive from <0.01 lux to >100,000 lux), 3 photon flux and irradiance color sensors 
in the red, green, and blue bands of visible light, a microprocessor with 2 Mbits RAM 
memory that allows for 36 days continuous recording of 1-minute epochs, and 
associated circuitry. The orientation and sensitivity of the accelerometer are 
optimized for highly effective sleep-wake inference from wrist activity. The 
illumination measurements are roughly log-linear from a range below moonlight to 
the brightest summer day at noon. An important innovative feature of this device is 
an off-the-wrist sensor, which distinguishes when the participant has removed the 
device for any reason. The Actiwatch Spectrum also allows us to determine spectral 
composition of light, which may differentially affect phase-shift, and therefore, 
treatment responses.45  
Sleep Interventions: Adherence to appropriate sleep and wake times during the 
EWT and LWT interventions will be documented by actigraphy. Compliance with 
wake therapy also will be monitored by having patients leave a message on an 
answering machine once every half-hour while awake. As they are only awake for 4 
hours during wake therapy, they will make 8 calls.  
Light Interventions: Subjects will sit in front of a portable (5.5” x 6.25”) Litebook ® 
Model 1.2 light box (an array of 60 cool white light-emitting diodes behind a clear 

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plastic screen)(The Litebook Company Ltd., Alberta Canada) with an intensity of 
1,350 lux and an irradiance of 2.41x10-9 w/cm2 at 20 in, and spectral emission peaks 
at 464 nm and 564 nm. Subjects will gaze at the light source for a minute every few 
minutes for 30 min. The distance of the subject from the light source will be 
calibrated individually for each light box by use of a Meterman LM631 Digital Light 
Meter (Meterman Test Tools, Everett, WA) to produce an intensity of 1,350 lux at 
20.0 in. Ambient light intensity and spectra will be documented by the Actiwatch 
Spectrum. A research assistant will provide a measuring tape to ensure proper 
distance between light source and patient, check the Actiwatch recordings to ensure 
compliance, as well as the Litebook’s built-in compliance monitor recordings.  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
Subjects for these experiments over 5 years will include: Forty women with 
premenstrual dysphoric disorder (PMDD). As only women have menstrual cycles, only 
women will be sought. As women generally do not develop significant premenstrual 
mood symptoms until late adolescence, and the menstrual cycle may become irregular 
during the perimenopause, only women age 18-45 years will be studied. For these 
reasons, children and adolescents under the age of 18 and peri- and post-menopausal 
women will be excluded. All ethnic groups will be represented (Caucasian, Asian, Black, 
Hispanic and Other). We will focus on recruiting subjects representative of the 
community: approximately 54% Caucasian, 30% Hispanic, 10% Asian, 5% African 
American and 1% Other. The UCSD Medical Center serves a clientele in which 
minorities are over-represented. All subjects will be adults individually competent to 
execute written informed consent.  
Recruitment of minority subjects: We will take pains to recruit women of color and 
other minorities working with the Women’s Center, the Cross Cultural center, the 
Lesbian, Gay, Bi-Sexual and Transgender (LGBT) Resource Center, Queer People of 
Color (QPOC) Center and the Native American Student Alliance on the University of 
California campus. 
 
 
Caucasian 
Hispanic 
Asian 
Black 
Other 
Female 
54% 
30% 
10% 
5% 
1% 
 
4.1 
Inclusion Criteria 
PMDD women wishing to participate in this study must meet the following 
inclusion criteria: 
 
Age: 18-45 years. 
 
Women with regular ovulatory menstrual cycles 26-32 days in length (for at 
least the previous six months). 
 
A history of a depressive (but not bipolar) mood disorder, but not an ongoing 
episode (symptom free for the last 12 months). 
 
Patients must meet DSM-IV criteria for Premenstrual Dysphoric Disorder (that 
includes irritability). 
 
Objective ratings: mean of HRSD total scores across evaluation weeks 1-8 < 
7 for follicular phase (day 5-10 of cycle after menses); mean of total HRSD 

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scores across evaluation weeks 1-8  > 14 for premenstrual (luteal) phase (6 
days prior to onset of menses onward). 
 
Subjective ratings: mean of Beck Depression Inventory total scores across 
evaluation weeks 1-8 < 10 follicular phase; > 10 premenstrual (luteal) phase.  
 
Daily ratings: minimal symptoms (mean less than 50 on 100mm scale) 
follicular phase; at least a 30% increase in mean affective symptom ratings, 
premenstrual (luteal) phase. 
 
By clinical assessment and ratings, the patient has reported a history (for at 
least the last six months) of recurrent, moderate to severe premenstrual 
mood symptoms that impair some aspect of social or occupational functioning 
and that remit within a few days after the onset of menses. This pattern is 
prospectively documented with subjective daily mood ratings (DMR – visual 
analogue scale) during at least two consecutive symptomatic cycles. 
Symptom severity will also be documented with objective and subjective 
ratings over that time. Patients must demonstrate a consistency of symptoms 
and a long enough duration of symptoms (7-10 days) to allow for study. 
 
Subjects willing to endure the rigors of a long-term (up to 6 months) research 
study. 
4.2 
Exclusion Criteria 
Participants meeting any of the following exclusion criteria at baseline will be 
excluded from study: 
 
Subjects with significant medical illness including hepatic (abnormal liver 
function tests), neurological, renal, cardiac, pulmonary, hematologic, 
gastrointestinal, or metabolic disorders. 
 
Subjects who are lactating, are within 6 months postpartum, or have an 
irregular sleep- wake cycle, e.g., from having very young children in the 
home. 
 
Subjects who are using hormonal contraception (within six months prior to the 
study).  
 
Subjects using medication that may affect outcome measures of mood, 
circadian rhythms or hormone levels (6-sulphatoxy-melatonin, estradiol, 
progesterone, FSH, LH, prolactin) within one month of initiating the study or 
anytime during the study. Such medications include OTC medication 
(excluding Tylenol), antidepressants, anti-anxiety, antihypertensive, beta 
blockers, and asthma medications. Vaccinations, vitamins/mineral 
supplements (excluding St. John’s Wart, melatonin and valerian) and/or short 
course antibiotics will not be considered exclusionary. 
 
Subjects with significant psychiatric disorder (schizophrenia, bipolar disorder, 
anxiety disorders, eating disorders, personality disorders, sleep disorders). 
An ongoing major depressive episode within the last year is reason for 
exclusion, although a previous history of a depressive episode is not (using 
DSM-IV diagnostic criteria for a major depressive episode). 
 
Subjects with a recent history (within the past year) of drug or alcohol abuse. 

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 
Subjects with a history of anemia, liver, kidney, cardiopulmonary, metabolic 
or thyroid disease within one year of participation (per patient-reported 
medical history).  
 
Subjects with irregular menstrual cycles (cycle lengths vary greater than 3 
days or who fail to ovulate for 2 consecutive months). 
 
Subjects unlikely to cooperate with the requirements of the study. 
 
Subjects needing frequent or continuous use of any medication or drugs that 
may affect outcome measures, including alcohol (>1 drink daily) and nicotine 
(> 5 cigarettes daily). 
 
Subjects whose prospective DMR ratings do not show cyclic variation in 
association with the menstrual cycle (as per inclusion criteria). 
 
Subjects with an irregular sleep schedule, extreme chronotypes or a sleep-
wake cycle that does not correspond to the environmental light-dark cycle 
(e.g., subjects within 2 weeks of transmeridian travel, night shift workers, or 
those with significant advanced or delayed sleep phase syndromes). To 
enhance precision of the timing of the light stimulus on circadian phase 
(temporal resolution), we will exclude women with habitual sleep onset times 
after midnight or wake times after 9 am. 
4.3 
Study Enrollment Procedures  
Subject Selection: Before entering the study, all subjects undergo a diagnostic 
evaluation for 2-3 months to establish that they meet criteria for PMDD, as required 
by DSM-IV:  
A. In most menstrual cycles during the past year, five (or more) of the following 
symptoms were present for most of the time during the last week of the luteal 
phase, which began to remit within a few days after the onset of the menstrual 
flow, and were absent in the week post-menses, with at least one of the five 
symptoms being from among those numbered 1, 2, 3 or 4. 
1. markedly depressed mood, feelings of hopelessness, or self-deprecating 
thoughts 
2. marked anxiety, tension, feelings of being "keyed up" or "on edge" 
3. marked affective lability (e.g., feeling suddenly sad or tearful or increased 
sensitivity to rejection) 
4. persistent and marked anger or irritability or increased interpersonal conflicts 
5. decreased interest in usual activities (e.g., work, school, friends, hobbies) 
6. subjective sense of difficulty in concentrating 
7. lethargy, easy fatigability, or marked lack of energy 
8. marked change in appetite, overeating, or specific food cravings 
9. hypersomnia or insomnia 
10. a subjective sense of being overwhelmed or out of control 
11. other physical symptoms, such as breast tenderness or swelling, headaches, 
joint or muscle pain, a sensation of bloating," weight gain 
B. The disturbance markedly interferes with work or school or with usual social 
activities and relationships with others (e.g., avoidance of social activities, 
decreased productivity and efficiency at work or school). 

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C. The disturbance is not merely an exacerbation of the symptoms of another 
disorder, such as major depression disorder, panic disorder, dysthymia disorder 
or a personality disorder (although it may be superimposed on any of these 
disorders.) 
D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least 
two consecutive symptomatic cycles.  
Note: Although the criteria for PMDD are in the main body of the text and 
formatted slightly differently in DSM-5, the diagnostic criteria for PMDD have not 
changed between DSM-IV and DSM-5.  Thus, no alterations to the DSM-IV SCID 
criteria are needed to establish diagnosis. 
Participants will begin the Evaluation Period at any time during their menstrual 
cycle.  Patients will monitor their cycle days and collect ratings until two consecutive 
symptomatic menstrual cycles occur, per diagnostic criteria (outlined in pg.16, 
section 4.3).  As we expect variation in menstrual cycle lengths among patients, we 
cannot establish a strict temporal schedule for this evaluation period. Nevertheless, 
we anticipate its duration to be no less than 2 (provided evaluation begins proximal 
to their first cycle day and they have regular, continuously symptomatic cycles) and 
no greater than 3 months (to allow for detection of 2 full symptomatic cycles). 
Scheduling the start of this evaluation period according to patients’ first cycle day 
would increase patient burden and be prohibitive to recruitment efforts.   
To facilitate understanding of study flow and design (see section 6.1), we refer to 
the Evaluation Period as Month 1 and Month 2 (as there are 2 full consecutive 
menstrual cycles within this period). 
We recruit subjects through referral sources from the UCSD Dept. of Psychiatry 
Outpatient Services and Women’s Mood Disorders Clinic, the Reproductive and 
Family Medicine Clinics, the Internal Medicine Group, the Student Health Service 
and the Counseling and Psychological Service (with all of whom the PI has a 
longstanding collaborative relationship -- see attached letters). Through the UCSD 
public affairs office, we place advertisements in local newspapers, mail flyers to local 
San Diego zip codes, make on-line announcements for UCSD employees/students, 
and place flyers or brochures at clinics, libraries and on campus bulletin boards in 
the San Diego area. After subjects complete an initial telephone and written 
screening questionnaire (Menstrual Assessment Form), we obtain a medical and 
psychiatric history from every subject selected for possible inclusion in the proposed 
study. A Clinical Rater (trained clinician) with established inter-rater reliability (kappa 
coefficient = 0.90) will conduct SCID52 interviews. During the telephone screening we 
will inquire on history of anemia, kidney, cardiopulmonary, metabolic, liver or thyroid 
disease within one year of screening.  Those endorsing positive history of any of 
these conditions will be excluded from participation.  No lab test or physical 
examinations are required to verify history.  We will not test for existence of these 
medical conditions at the time of study since it would be cost prohibitive and an 
unreasonable burden for patients to obtain labs via outside sources, thus hindering 
recruitment efforts.  We will obtain a urine toxicology screen and a pregnancy test. In 
addition, each subject will receive a thorough explanation of the study before being 
asked to personally sign informed written consent under supervision of the UCSD 
Committee on Investigations Involving Human Subjects. 

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During an initial 2-3 month evaluation period, subjects will complete twice-daily 
self ratings of mood (including core PMDD symptoms of depression, anxiety, 
affective lability, irritability) using a 100 mm visual analogue scale (Daily Mood 
Ratings form-DMR).54, 55 Individual items on the DMRs will be measured, scored and 
plotted using GraphPad Prism (GraphPad Software, Inc. La Jolla, CA) to observe the 
daily progression of mood symptoms (both in the morning and evening from day to 
day in the follicular and luteal phase) throughout the evaluation phase and in relation 
to the woman’s menses to ensure proper diagnosis based on DSM-IV criteria. 
Women also will visit the clinic on a weekly basis where the project coordinator will 
collect the daily rating forms, and a trained clinician, blind to treatment condition, will 
interview the subjects using the 24-item Hamilton Rating Scale for Depression 
(HRSD).56 At this time the subjects also will complete a Beck Depression and Anxiety 
Inventory.57, 58 In addition, we will ask them to complete a screening questionnaire on 
their sleep patterns, to keep daily sleep logs and to adhere to their habitual sleep 
schedule. This evaluation period will establish the diagnosis of PMDD and will 
provide information as to when symptoms are likely to occur. It also helps us to 
design a study schedule based on each patient's individual symptom patterns, and to 
establish each individual’s sleep schedule prior to interventions. As in our previous 
studies and those of others,59  we expect about 5% of patients screened to meet 
criteria. We especially will recruit women who are non-responsive to other 
interventions for PMDD, or who seek alternatives to pharmacological or chronic 
treatments for PMDD.   
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Treatment 1 will occur during the menstrual cycle immediately following the 2 
menstrual cycles studied in the evaluation period. Washout will occur the following 
menstrual cycle, and Treatment 2 the menstrual cycle immediately following 
Washout.  As we establish the Evaluation Period as Month 1 and Month 2, we will 
refer to Treatment 1 as occurring in Month 3, Washout in Month 4, and Treatment 2 
in Month 5 (see section 6.1).   
During Month 3, qualified participants will sign the Study Consent between cycle 
days 1 and 10, be randomized to treatment and receive all necessary instructions, 
forms and equipment to continue with the treatment phase. On the day of their 
luteinizing hormone (LH) surge (luteal phase), subjects will undergo a night of Late 
Wake Therapy (LWT) (sleep 21:00-01:00 h, followed by wake) vs. Early Wake 
Therapy (EWT) (wake until 03:00 h followed by sleep until 07:00 h) at home. We 
selected the specific wake and sleep times based on our previous work in PMDD.36, 
37 The following day, subjects will receive the light intervention for 7 consecutive 
days: days 1-7 after the LH surge (approximately menstrual cycle days 15-21). 
Depending on their randomization schedule, subjects will receive, at home, 60 min of 
either AM bright white light (LED of 1350 lux at 20 inches) starting within 30 minutes 
of their habitual wake time (for those undergoing LWT), or PM bright white light 
ending 30 min before their habitual sleep onset time (for those undergoing EWT). 
The following Month 4 (Washout) will be a month of no intervention to prevent any 
carry-over effects from the Month 3 intervention affecting measures in Month 5. 
Mirroring Month 3 timing, in the luteal phase of Month 5, subjects will receive the 
alternate wake therapy (LWT or EWT) and light exposure (AM or PM) (see Fig. 1, 
above). 

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Sleep Interventions: Appropriate sleep and wake times during the EWT and LWT 
interventions will be documented by actigraphy. Compliance with wake therapy also 
will be monitored by having patients leave a message on an answering machine 
once every half-hour while awake. As they are only awake for 4 hours during wake 
therapy, they will make 8 calls. The potential risks of wake therapy include fatigue.  
Subjects will be encouraged to stay at home the day after wake therapy or, if driving, 
arrange alternative transportation.  In previous studies of one night of total wake 
therapy in PMDD patients, subjects felt energized and wished to return to work or 
other daily activities.  Previous studies also included two consecutive nights of partial 
wake therapy.  We anticipate fewer problems in this study with only one night of 
partial wake therapy. Sleep and activity measures are non-invasive, but may cause 
some skin irritation and/or discomfort on the wrist where the Actiwatch Spectrum 
(Philips Respironics, Bend Oregon) is worn. 
Light Interventions: Subjects will sit in front of a portable (5.5” x 6.25”) Litebook ® 
Model 1.2 light box (an array of 60 cool white light-emitting diodes behind a clear 
plastic screen)(The Litebook Company Ltd., Alberta Canada) with an intensity of 
1,350 lux and an irradiance of 2.41x10-9 w/cm2 at 20 in, and spectral emission peaks 
at 464 nm and 564 nm. Subjects will gaze at the light source for a minute every few 
minutes for 60 min. The distance of the subject from the light source will be 
calibrated individually for each light box by use of a Meterman LM631 Digital Light 
Meter (Meterman Test Tools, Everett, WA) to produce an intensity of 1,350 lux at 
20.0 in. Ambient light intensity and spectra will be documented by the Actiwatch 
Spectrum. A research assistant will provide a measuring tape to ensure proper 
distance between light source and patient, check the Actiwatch recordings to ensure 
compliance, as well as the Litebook’s built-in compliance monitor recordings. Since 
most of us are exposed to fluorescent light in our everyday lives, we do not anticipate 
that exposure to bright light per se will pose any special physical, psychological, 
social or legal risks.  The intensity planned is less intense than bright sunlight, which 
normally exceeds 10,000-50,000 lux.  Although 1,350 lux is more intense than 
common indoor room lighting during a 16-hour day, the average patient would 
receive more radiation from room lighting than from 1-2 hours of special lighting.  
Thus, the treatment is expected to be less hazardous than going for a walk or going 
to the beach.  No special side effects apart from mild sleepiness (the patient needs 
to be awake for the light exposure and evening light may potentially disrupt sleep 
onset) are anticipated.  It should be noted that sleep deprivation has been reported 
to benefit depressed patients.  The possibility that the bright light treatment might 
potentiate a depressed patient’s risk of switching into mania is recognized, although 
we have not seen this effect in previous studies of PMDD patients and we will 
exclude bipolar patients with mania from the study.  If hypomania occurs, the light 
would be discontinued and appropriate referral and treatment with psychotropic 
medication, if needed, would be given. 
Duration: Intervention phase will require a minimum of 3 months, provided 
patients have regular menstrual cycles and we can detect an LH surge (ovulation) in 
months 3 and 5.  If a patient fails to ovulate in either month 3 or 5, she will be asked 
to repeat ovulation testing the following month.  Two consecutive months with no 
ovulation will result in discontinuation of participation.   
5.2 
Handling of Study Interventions  
After randomization, the research associate will prepare all necessary equipment 
and recording logs necessary for patients to complete the study. The study 

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coordinator and research associate, unmasked to the treatment condition, will 
provide the necessary instructions to ensure proper administration of treatment.  
Light boxes, binders, calendars and checklists will be provided in office to 
facilitate patient adherence to time-specific study protocols, completion of forms, 
collection of required measures and at-home self-administration of the study 
intervention. 
5.3 
Concomitant Interventions  
As we will study mood and endocrine effects of the intervention from baseline to 
post-treatment, use of hormonal contraception (within six months prior to study) and 
other medication (within one month prior to study) will be prohibited.  
5.3.1 Allowed Interventions 
Acetaminophen (Tylenol) 650 mg po every 4 hours prn pain or headache. 
5.3.2 Required Interventions 
N/A 
5.3.3 Prohibited Interventions 
Hormonal contraception (within six months prior to study) and other medication 
(within one month prior to study or at any time during the study) that may affect 
outcome measures of mood, circadian rhythms or hormone levels (6-sulphatoxy-
melatonin, estradiol, progesterone, FSH, LH, prolactin) will be prohibited. Such 
medications include Over-the-Counter (OTC) medication (excluding Tylenol), 
antidepressants, anti-anxiety, antihypertensive, beta blockers, and asthma 
medications. Vaccinations, vitamins/mineral supplements (excluding St. John’s Wart, 
melatonin and valerian) and/or short course antibiotics will not be considered 
exclusionary. 
5.4 
Adherence Assessment  
Utilizing itemized checklists outlining each study requirement, study staff will 
review all data collection forms/logs on an ongoing basis for completeness and 
accuracy as well as compliance to study protocol. Binders, calendars and checklists 
will be provided to facilitate patient adherence to time-specific study protocols, 
completion of forms and collection of required measures. Staff will calculate 
adherence to protocol and continuously tabulate the results to ensure adherence to 
wake therapy is 100% and light is at least 85% (completing at least 6 of 7 days of 
light therapy).  Appropriate sleep and wake times during the EWT and LWT 
interventions will be documented by actigraphy. Compliance with wake therapy also 
will be monitored by having patients leave a message on an answering machine 
once every half-hour while awake. As they are only awake for 4 hours during wake 
therapy, they will make 8 calls. To ensure compliance with light protocols, a research 
associate will provide a measuring tape to ensure proper distance between light 
source and patient, check the Actiwatch recordings during time of intervention, as 
well as the Litebook’s built-in compliance monitor recordings. 
6. STUDY PROCEDURES  

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6.1 
Schedule of Evaluations 

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6.2 
Description of Evaluations  
 
Evaluations will be performed at various times during the multiple steps of this 5-
month study:  Screening, Evaluation Period (months 1 and 2), Treatment 1 (month 
3), Washout (month 4), Treatment 2 (month 5) and Follow-up/Final Visit.  In the 
Schedule of Evaluations figure above, LHS refers to luteinizing hormone surge 
detected via ovulation testing (performed for 7 days starting on menstrual cycle day 
10 in months 2, 3 and 5).   
Objective ratings (HRSD and SCID) will be administered, collected, scored and 
reviewed by the Clinical Rater immediately upon completion by the patient. 
Subjective ratings (BDI, BAI, PGWI, Daily Mood Ratings (VAS), SPAQ, 
Expectation Form, Horne and Ostberg Scale, PSQI, Sleep Quality Ratings, Side 
Effects Checklists, Global Assessment of Treatment Effectiveness) will be collected 
and scored by the Research Associate for review by the Clinical Rater upon 
completion by the patient. 
6.2.1 Screening Evaluation 
Screening evaluations will be collected weekly in clinic during months 1 and 2.  
Baseline mood, endocrine and sleep measures will also be collected during 
evaluation month 2. 
Screening 
All subjects will be screened via telephone to ensure they meet study criteria as 
defined in sections 4.1 (Inclusion Criteria) and 4.2 (Exclusion Criteria) above. Those 
that meet criteria will be scheduled for a screening interview with the Study 
Coordinator. Inclusion and exclusion criteria must be maintained throughout the 
study.  Any deviation will be reported to the Study Coordinator and conveyed to the 
PI for evaluation and outcome determination. 
During their initial screening visit in clinic, patients will complete a Menstrual 
Screening Form to assess mood and somatic symptoms, medication use and 
personal and family medical and psychological history.  In addition we will obtain a 
urine toxicology screen and a pregnancy test.   
Consenting Procedure 
A written informed Screening Consent will be obtained from each subject at entry 
into the study to proceed with participation in the evaluation phase.  After completion 
of the evaluation phase, qualified participants will sign a Study Consent before 

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proceeding with the treatment phase.  Informed consent is obtained by the following 
process: 
1. The subject will be asked to review the screening consent form. 
2. The PI, Study Coordinator and/or one of their associates will meet with the 
subject to review the form, to confirm and to answer any questions the 
subject might have.  The UCLA Office of Protection of Research Studies 
“Evaluation to Sign a Consent form for Research” will be administered to 
insure that all participants have understood the consent document, before 
they are asked to sign it. 
3. Once the subject demonstrates understanding of the study and agrees to 
participate in the study, the consent will be signed in the presence of the 
Study Coordinator or a Research Associate and a witness. 
6.2.2 Enrollment, Baseline, and/or Randomization 
Baseline Assessments 
In accordance with the Schedule of Evaluations (section 6.1 above), baseline 
measures will be collected in Evaluation Month 2 as follows: 
 
Hamilton:  The Hamilton Rating Scale for Depression (HRSD)56 (as a validated 
objective, interview-based assessment of depression). Atypical depression 
symptoms as part of the Structured Interview Guide for the Hamilton Depression 
Rating Scale, Seasonal Affective Disorders version (SIGH-SAD )60 (as atypical 
symptoms in particular respond to light treatment61) Mania62 ratings (to document 
any clinical induction of manic symptoms by the wake or light interventions) – 
once weekly for 8 weeks, 
 
Beck Depression Inventory (BDI)57 (as a validated subjective assessment of 
depression) – once weekly for 8 weeks, 
 
Beck Anxiety Inventory (BAI)58 (as many women with PMDD report anxiety 
symptoms)63  – once weekly for 8 weeks, 
 
The Psychological General Well-Being Index (PGWI)64  – once weekly for 8 
weeks, 
 
Daily mood self-ratings (DMR)54 that include core PMDD symptoms of anxiety 
and irritability – daily for 8 weeks, 
 
Expectation form measuring patient expectation for change with the interventions 
(100 mm line from “much worse” to “much better”) – completed once,  
 
Horne-Östberg scales to assess morningness and eveningness65 – completed 
once,  
 
Seasonal Pattern Assessment Questionnaire (SPAQ)66 – completed once, 
 
Pittsburgh Sleep Quality Index (PSQI)67 to assess subjective sleep quality – once 
in month 1 and month 2,  
 
Visual analogue scale68 to assess subjective sleep quality – once in month 1 and 
month 2, 

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 
Structured Clinical Interview for DSM-IV (SCID)51, 52 – completed once to 
establish diagnosis in evaluation week 8, 
 
Ovulation testing performed for 7 days starting on menstrual cycle day 10 in 
month 2 to determine luteinizing hormone surge (LHS).  Participants will contact 
Study Coordinator with their time of first menses (cycle day 1) to determine cycle 
day 10 and schedule appointment for collecting study forms and equipment, 
 
Actigraphy will be collected for 10 days starting the day of LHS to monitor 
baseline sleep, light and activity measures at home, 
 
Urine collection for 30 hrs performed between days 8-9 after LHS. 
Enrollment 
Enrollment in the evaluation phase of the study occurs at the time of first 
screening visit when patients sign a Screening Consent form.   
Enrollment in the treatment phase occurs during a clinic visit scheduled between 
cycle days 1 and 10 of the menstrual cycle immediately following successful 
completion of the evaluation phase (Month 3), provided they are qualified to 
participate and they sign a Study Consent form.  During this visit, they will also be 
assigned an individual participant identifier (Master Code Number) and be 
randomized to the first of two treatment conditions. Enrollment ascertainment for the 
treatment phase and randomization occur at the same time.  
Randomization 
All subjects for this study will be enrolled in the evaluation phase of the study at 
the time of the first screening visit when patients sign a Screening Consent form.  
Enrollment in the treatment phase occurs during a clinic visit scheduled between 
cycle days 1 and 10 of the menstrual cycle immediately following successful 
completion of the evaluation phase (Month 3), provided the subject is qualified to 
participate.  During this visit, we will randomize subjects to the first of two treatment 
conditions. Starting on the day of ovulation, subjects will be randomized to either 1) 
one night of Late Wake Therapy (LWT: sleep 21:00-01:00 h, followed by 
wakefulness) plus 7 days of AM Bright White Light (BWL: light-emitting diode-LED 
administered for 60 minutes, starting within 30 minutes of habitual wake time) or 2) 
Early Wake Therapy (EWT: wakefulness until 03:00 h, then sleep 03:00-07:00 h) 
plus 7 nights of PM BWL (administered 90 minutes before habitual sleep onset, for 
60 minutes).  The problem of randomization imbalance, observed particularly when 
independent groups (such as group 1 receiving only treatment A and group 2 
receiving only treatment B) are used, will be addressed by two processes.  First, this 
study uses a cross-over design and subjects will be assigned to the other treatment 
in the luteal phase of their next menstrual cycle after a one-month washout period.  
Second, subjects will be randomized to study treatment group in a 1:1 ratio with 
variably-sized block design.  This randomization will be done using SAS programs 
that we have used for many of our clinical trial studies.  The block sizes are known 
only to the study statistician.  The randomization table will be prepared prior to the 
initiation of the study.  
Note, only subjects who meet all of the inclusion criteria and none of the 
exclusion criteria after successful completion of the evaluation phase are eligible for 
randomization into the treatment phase. 

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In addition to violations of inclusion and exclusion criteria, we also will document 
in the patient’s chart reasons for randomization failure, any protocol deviations and 
reasons why subjects were lost to follow-up, voluntarily withdrew and/or were 
terminated from the study. 
Participants will be assigned for study between cycle days 1 and 10 of Month 3 
and will begin the wake therapy component of Treatment 1 at time of ovulation, 
which may occur between cycle days 10 and 17. Treatment 2 will occur in Month 5, 
approximately two months after randomization.  If a patient does not ovulate, 
treatment will be delayed until the following menstrual cycle, thereby increasing the 
time between randomization and each treatment condition by approximately 1 
month, the maximum allowable period.  
6.2.3 Blinding 
The principal investigator and clinical rater will remain blind to treatment condition 
until completion or discontinuation of participant from study.  As patients will be 
coded, one statistician and technician and supervisor running assays also will be 
blind to patient name and treatment condition. Members of the Data Safety 
Monitoring Committee will review records in which patient names are coded, unless 
the code needs to be broken in the event of an adverse outcome.  All other lab 
personnel will not be blind to treatment as the study coordinator and research 
associate prepare patient equipment and instruct patients on proper completion of 
the treatment protocol, the data manager and quality assurance officer enter all data 
into the database (including treatment condition). Due to the nature of the treatment 
(sleep, light intervention), patients will not be blind to condition.  
6.2.4 Treatment Visits 
In accordance with the Schedule of Evaluations (section 6.1 above), treatment-
related measures will be collected in months 3 and 5 as follows: 
 
Hamilton:  The Hamilton Rating Scale for Depression (HRSD)56 (as a validated 
objective, interview-based assessment of depression). Atypical depression 
symptoms as part of the Structured Interview Guide for the Hamilton Depression 
Rating Scale, Seasonal Affective Disorders version (SIGH-SAD )60 (as atypical 
symptoms in particular respond to light treatment61) Mania62 ratings (to document 
any clinical induction of manic symptoms by the wake or light interventions) – on 
ovulation night (LSH), daily on LHS+1 – LHS+2 (during intervention) and once 
after light treatment on LHS+8-9 (post-intervention assessment). 
 
Beck Depression Inventory (BDI)57 (as a validated subjective assessment of 
depression) – on ovulation night (LSH), daily on LHS+1 – LHS+2 (during 
intervention) and once after light treatment on LHS+8-9 (post-intervention 
assessment), 
 
Beck Anxiety Inventory (BAI)58 (as many women with PMDD report anxiety 
symptoms)63  – on ovulation night (LSH), daily on LHS+1 – LHS+2 (during 
intervention) and once after light treatment on LHS+8-9 (post-intervention 
assessment), 
 
The Psychological General Well-Being Index (PGWI)64  – on ovulation night 
(LSH), daily on LHS+1 – LHS+2 (during intervention) and once after light 
treatment on LHS+8-9 (post-intervention assessment), 

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 
Daily mood self-ratings (DMR)54 that include core PMDD symptoms of anxiety 
and irritability – collected daily on LHS+0 through LHS+2 (for wake therapy 
effects) and daily LHS+3 through LHS+10 (for light treatment effects), 
 
Pittsburgh Sleep Quality Index (PSQI)67 to assess subjective sleep quality – once 
on LHS+8-9 (post-intervention assessment),  
 
Visual analogue scale68 to assess subjective sleep quality – once on LHS+8-9 
(post-intervention assessment), 
 
Ovulation testing performed for 7 days starting on menstrual cycle day 10 in 
months 3 and 5 to determine luteinizing hormone surge (LHS).  Participants will 
contact Study Coordinator with their time of first menses (cycle day 1) to 
determine cycle day 10 and schedule appointment for collecting study forms and 
equipment, 
 
Actigraphy will be collected for 10 days starting the day of LHS to monitor 
baseline sleep, light and activity measures at home, 
 
Urine collection for 30 hrs performed between days 8-9 after LHS. 
 
Objective assessments (HRSD) collected during intervention and post-
intervention will be performed by telephone, to reduce patient burden, on the same 
day the patients complete the subjective assessment forms (BDI, BAI, PGWI, DMR, 
PSQI, sleep quality) during the times indicated above.   
 
6.2.5 Washout 
During washout Month 4, subjects will again perform the urine toxicology 
screening, Hamilton, BDI, BAI and PGWI ratings (once during the luteal phase, 
around the same time in the patient’s cycle as the post treatment 2 ratings 
were collected). 
6.2.6 Follow-up/Final Evaluation 
During final visit, subjects will again perform the Hamilton, BDI, BAI and PGWI 
ratings (once).  They will also complete the Global Assessment of Treatment 
Effectiveness form.  Final evaluation of inclusion/exclusion criteria will be performed 
at this time. 
After completion of the study (final visit), participants will be followed up for 1 
month to monitor relapse. The Clinical Rater will telephone the patient at home 
during the luteal phase, around the same time in the patient’s cycle as the post 
treatment 2 ratings were collected, to collect follow-up mood ratings (Hamilton, BDI, 
BAI and PGWI). 
None of the subjects will be excluded from analysis, and their data will be 
analyzed according to the randomization scheme. Different hypotheses are included 
for different phases of the study.  All subjects will be included in any baseline 
analyses regardless of their final study status.  In addition to the baseline data, at 
least one other data point is needed in order to provide a valid estimation of a 
parameter for change throughout the study. The Random Regression Model was 
selected due to the flexibility of this method that includes all subjects with any valid 
data point in the analyses, as opposed to a method that is designed to examine just 

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the completers, such as a Repeated Measures Analysis of Variance. All subjects will 
be included in the analyses and we will not focus only on subjects who complete the 
study.  Secondary analyses will be performed on data from completers.  Our 
methods for data analyses include all subjects with any valid data points in the 
analyses (see Section 9.6. General Approach to Data Handling and Statistical 
Analyses). 
7. SAFETY ASSESSMENTS  
Participant safety will be monitored once an individual is enrolled for screening in 
the study.  
7.1 
Specification of Safety Parameters 
Risks to patients in this protocol are low and are detailed as follows: 
Affect and Anxiety:  
Premenstrual symptoms may become worse leading to depression, anxiety, 
irritability and rarely suicidality. It is anticipated that these studies will not be greatly 
different from spending nights at home with some added measurements and 
interventions. The added measures may add some disruption and anxiety to daily 
schedules. 
Urine Collection, Sleep/Activity:   
The risks of urine collection are minimal and may include inconvenience with 
collection of samples and completion of forms.  Sleep and activity measures are non-
invasive, but may cause some skin irritation and/or discomfort on the wrist where the 
Actiwatch is worn. 
Effects of Bright Light Treatment: 
Since most of us are exposed to fluorescent light in our everyday lives, we do not 
anticipate that exposure to bright light per se will pose any special physical, 
psychological, social or legal risks.  The intensity planned is less intense than bright 
sunlight, which normally exceeds 10,000-50,000 lux.  Although 1,350 lux is more 
intense than common indoor room lighting during a 16-hour day, the average patient 
would receive more radiation from room lighting than from 1-2 hours of special 
lighting.  Thus, the treatment is expected to be less hazardous than going for a walk 
or going to the beach.  No special side effects apart from mild sleepiness (the patient 
needs to be awake for the light exposure and evening light may potentially disrupt 
sleep onset) are anticipated.  It should be noted that sleep deprivation has been 
reported to benefit depressed patients.  The possibility that the bright light treatment 
might potentiate a depressed patient’s risk of switching into mania is recognized, 
although we have not seen this effect in previous studies of PMDD patients and we 
will exclude bipolar patients with mania from the study.  If hypomania occurs, the 
light would be discontinued and appropriate referral and treatment with psychotropic 
medication, if needed, would be given. 
Effects of Wake Therapy or Partial Sleep Deprivation: 
The potential risks include fatigue.  Subjects will be encouraged to stay at home 
the day after wake therapy or, if driving, arrange alternative transportation.  In 
previous studies of one night of total wake therapy in PMDD patients, subjects felt 
energized and wished to return to work or other daily activities.  Previous studies 
also included two consecutive nights of partial wake therapy.  We anticipate fewer 
problems in this study with only one night of partial wake therapy. 

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The following risk-management procedures will be used:  
Depression, Anxiety, Suicidality, Mania:  
To guard against adverse effects, all subjects will have a complete psychiatric 
history administered by a certified clinician. By monitoring mood twice daily and by 
providing weekly ratings by trained clinicians, we expect to detect any problems with 
mood before they become severe.  Known bipolar patients are excluded to reduce 
the risk of mania occurring.  Suicidal ideation will be monitored by the Clinical Rater 
at the time of HRSD administration.  Patients are instructed to call the Rater, Study 
Coordinator, Research Associate or on-call psychiatrist if these symptoms occur. 
Suicidal ideation will be evaluated by both the Clinical rater and PI to determine the 
best course of action.  A licensed psychiatrist will always be on-call to subjects 
should any psychiatric emergency arise.  If needed, patients will be referred for 
appropriate treatment including inpatient hospitalization if warranted. 
Urine Collections:  
Trained staff will instruct participants in the proper method of urine collections. 
Wake Therapy:  
To ensure sufficient wakefulness after the wake therapy interventions, the patient 
is encouraged to stay at home, not drive or operate machinery and arrange for 
alternate transportation, for which they will be reimbursed.  To avoid the induction of 
mania, bipolar patients are excluded.  
Actiwatch:  
Equipment will be checked regularly and its use by subjects overseen by 
specifically trained personnel to ensure maximum safety and comfort.  
Pregnancy:  
Subjects are warned not to rely on "time of the month" for contraception.  
 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Timing of assessment and reporting of adverse events are detailed in items 7.3 
and 7.4 below.  We will utilize a Data Safety and Monitoring Committee and will 
immediately report any unanticipated or adverse events affecting subjects or others 
to the Institutional Review Board (IRB) of the University of California, San Diego to 
determine whether further information or protocol changes are needed. Any study 
modifications required by the IRB would be reported to the NCCAM/NIH program 
officer immediately. 
7.3 
Adverse Events and Serious Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a subject during 
participation in the clinical study or with use of the experimental agent being studied. 
An adverse finding can include a sign, symptom, abnormal assessment (laboratory 
test value, vital signs, electrocardiogram finding, etc.), or any combination of these. 
A serious adverse event (SAE) is any adverse event that results in one or more 
of the following outcomes: 
 
Death 

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 
A life-threatening event 
 
Inpatient hospitalization or prolongation of existing hospitalization  
 
A persistent or significant disability/incapacity 
 
A congenital anomaly or birth defect 
 
An important medical event based upon appropriate medical judgment 
 
AEs will be categorized according to the likelihood that they are related to the 
study intervention as follows: 
 
 
 
 
0 – Definitely unrelated:  
AE is clearly not related to the investigational 
agent(s) 
1 – Unlikely:  
AE is doubtfully related to the investigational agent(s) 
2 – Possibly related:  
AE may be related to the investigational agent(s) 
3 – Probably related:  
AE is likely related to the investigational agent(s) 
4 – Definitely related:  
AE is clearly related to the investigational agent(s) 
All AEs (and SAEs) will be recorded by the study coordinator, research associate 
or other staff member as they occur.  Reports that include onset time, duration, 
severity, etc., will be sent to PI for review to determine actions to be taken, 
relatedness to study and monitoring of outcomes. 
Mood ratings and side effects checklists will be utilized to assess treatment 
safety.  
 
7.4 
Reporting Procedures 
As detailed in the Data and Safety Monitoring Plan (DSMP) for an Independent 
Monitoring Committee, AEs (and SAEs) will be labeled by level of severity in 
accordance with the grading system stipulated in the U.S. Department of Health and 
Human Services’ Common Terminology Criteria for Adverse Events (CTCAE) – 
Version 4.0 (v4.03: June 14, 2010).1 Grades range from 1 to 5 and are based on the 
AE’s impact on the patient as 1) Mild, 2) Moderate, 3) Severe, 4) Life-threatening, 
and 5) Death.  Attribution of each AE will be determined by PI according to the above 
criteria. 
AEs will be followed up weekly for 3 months, once every 2 weeks for 2 months, 
and once per month for 1 month (total of 6 months). 
The Independent Monitoring Committee (IMC), composed of a clinician with 
expertise in women’s mental health and the reproductive cycle, a physician with 
expertise in clinical trials and a biostatistician will review adverse event rates yearly. 
A yearly Study Safety Report listing individual AEs, frequency/severity of treatment-
related side effects and out-of-range scores will be provided to the IMC, the UCSD 
IRB and NIH/NCCAM. 
                                                 
 
1 U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Center. Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 – Published: May 28, 2009 (v4.03: June 14,2010) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 

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SAEs that are unanticipated, serious, and possibly related to the study 
intervention will be reported to the IMC, IRB and NCCAM in accordance with 
requirements.   
 
Unexpected fatal or life-threatening AEs related to the intervention will be 
reported to the NCCAM Program Officer within 7 days. Other serious and 
unexpected AEs related to the intervention will be reported to the NCCAM 
Program Official within 15 days. 
 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the IMC, IRB, NCCAM, and other oversight organizations in 
accordance with their requirements. In the annual AE summary, the Independent 
Monitor Report will state that they have reviewed all AE reports. 
7.5 
Followup for Adverse Events 
AEs will be followed weekly for 3 months, once every 2 weeks for 2 months, and 
once per month for 1 month (total of 6 months). 
7.6 
Safety Monitoring  
The independent monitors comprising the IMC for this study are Dr. James Lohr, 
with expertise in clinical trials, Dr. Kathryn Hirst, with clinical expertise in women’s 
mental health related to the reproductive cycle and Dr. Wesley Thompson, a 
biostatistician. They are not associated with this research project and thus work 
independently of the PI, Dr. Barbara L. Parry. Drs. Lohr, Hirst and Thompson are not 
a part of the key personnel involved in this grant and are qualified to review the 
patient safety and data generated by this study because of their expertise in the 
following areas:  
As professor and vice chair of clinical affairs in the UCSD Department of 
Psychiatry, director of the VA Center of Excellence for Stress and Mental Health, and 
executive director of the UCSD Psychopharmacology Research Initiatives Center of 
Excellence, Dr. Lohr has extensive experience in human subjects research 
monitoring and disease expertise.  Dr. Hirst’s experience is in Family Medicine and 
Psychiatry with a focus on women's mental health and the reproductive cycle. 
Dr. Thompson’s research interests center on the adaptation and application of 
statistical models of a dynamic covariation of multiple functional processes in order 
to identify potentially causal relationships between brain function, depression, and 
physical health. He is also interested in developing statistical models that may 
explain the underlying mechanisms of healthy cognitive aging. 
8. INTERVENTION DISCONTINUATION   
If complications develop from the urine collection, sleep, activity or light studies, the 
procedure would be discontinued and all appropriate measures taken to provide the 
necessary care and follow up (unless otherwise requested by patient). 
Participation in research is entirely voluntary.  Patients may refuse to participate or 
withdraw at any time without jeopardy to the medical care they will receive at this institution 
or loss of benefits to which they are entitled. The investigator also may withdraw patients 
from participation if they become pregnant or otherwise loose qualification for participation 
(see sections 4.1 and 4.2 for inclusion and exclusion criteria, respectively).  The PI can 

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withdraw patients from the study without their consent if they fail to comply with important 
study requirements, such as keeping appointments or if they become so ill that they need to 
be referred for outside treatment. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
The design is a randomized cross-over contrasting LWT+AM bright light vs. 
EWT+PM bright light administered in the luteal phase of two separate menstrual 
cycles, and preceded by 2 evaluation months. To lessen the patient’s burden, the 1-
night EWT or LWT and the following 7-day BWL interventions will be conducted at 
home, given at a fixed point in each menstrual cycle, from day 1 to 7 after the mid-
cycle LH surge. We anticipate that LWT+7 days of AM BWL (vs. EWT+PM BWL) will 
produce much greater mood benefits and larger physiological responses, than the 
one-time light pulses used in our earlier phase-shift studies. 
The wake therapy and light interventions proposed in this application are based 
on our previous studies in PMDD and key published experiments by other 
investigators that indicate that the combined interventions are efficacious in other 
mood disorders after one week of treatment and maintained at 9-months follow-up. 
To provide optimal timing of interventions, we will administer wake therapy in the 
early-night vs. late-night and light pulses in the AM vs. PM at selected times in 
relation to sleep (within 30 min of waking and 90 min before sleep onset, 
respectively). 
A crossover treatment design is employed to compare LWT+AM BWL vs. 
EWT+PM BWL responses within the same individual. As wake interventions lose 
effectiveness after 1 day, and light treatment effects after 3-4 days, we anticipate 
minimal carry-over effects of the wake plus light interventions administered a month 
apart. To further ensure no carry-over effects, there will be a month of no-
intervention between the 1st and 2nd treatments. Because our previous studies 
clearly indicated differences between PMDD and NC subjects occurred primarily in 
the luteal menstrual cycle phase, we will treat during this menstrual cycle phase 
rather than in the follicular phase.  
Hypothesis (H) 1: For PMDD patients in the luteal phase, LWT+AM BWL, 
compared with EWT+PM BWL, will A) Decrease scores on SIGH-SAD, BDI, BAI, 
and DMR, and increase global assessment of treatment effectiveness from baseline 
to post-intervention; B) Phase-advance urinary melatonin timing measures 
(acrophase, onset and offset time) in relation to clock time and to sleep measures 
(onset, end time and mid-sleep times); C) The magnitude of the phase-advance (B, 
above) will correlate with the magnitude of the symptom changes (A, above) by 
linear regression. 
9.2 
Sample Size and Randomization 
For our primary outcome measures of mood, based on our earlier data reflecting 

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seven days of light exposure alone2 (i.e., without the ‘priming’ effect of wake 
therapy), we predict the following changes in mood in PMDD subjects (N = 40) after 
Late Wake Therapy plus AM Light vs. Early Wake Therapy plus PM Light:  A 
significantly greater improvement (decrease in raw score) will be detected at the p = 
.05 level with (a) 71% power in Hamilton Rating Scale for Depression (HRSD) Score 
(Mean difference 3.15+9; effect size = .324); (b) > 99% power in atypical score 
(Mean difference 4.45+5; effect size = .78); (c) > 99 % power in Structured Interview 
Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders 
(SIGH-SAD) Items (Mean difference 7.0+11; effect size = .627); (d) 86% power in 
Beck Depression Inventory (BDI) score (Mean difference 6.30+15; effect size = 
.378).  
For the recovery criterion of > 50% decrease from baseline (Chi Square 
analyses): (a) 97% power for HRSD score (difference in proportions: .44); (b) 70% 
power for atypical score (difference in proportions: .30); (c) 86% for SIGH-SAD score 
(difference in proportions: .325); and (d) 93% power for BDI score (difference in 
proportions: .40). For the remission criterion of reduction to a score of < 8 (Chi 
Square analyses): (a) 89% power for the SIGH-SAD score; (b) 44% power for the 
BDI score. All tests are two-tailed. 
We also performed power analyses for the primary hypotheses, incorporating the 
longitudinal nature of the design for the proposed Random Regression model (also 
known as Multilevel Models, or Growth Curve Models). Procedures describes by 
Hedeker et al.69 for Random Regression Models, with the above data, was used for 
the proposed study to estimated needed sample size. We assume a Type-I error 
level (alpha-level) of 0.05, drop-out rate of 10% to 15% and an autoregressive 
covariance structure, with correlation between sequential assessments set at 0.45 
(based on our previous data). We are confident based on our results from these two 
separate approaches that the proposed study will have minimum power of 80% to 
yield a statistically significant result for a medium effect size. Here, medium effect 
size is defined as a treatment difference increasing linearly from 0 at baseline to .5 
SD units at the last time point. Type 1 error will be controlled by correcting the p-
value per domain. 
 
Treatment Assignment Procedures  
We will study subjects pre- and post-intervention to determine the optimal phase-
relationship between melatonin and sleep. Using a randomized cross-over design, 
PMDD and NC in the luteal phase will receive either 1) one night of LWT (sleep 
21:00-01:00 h, followed by wakefulness) plus 7 days of AM BWL (light-emitting 
diode-LED administered for 60 minutes, starting within 30 minutes of habitual wake 
time) or 2) EWT (wakefulness until 03:00 h, then sleep 03:00-07:00 h) plus 7 nights 
of PM BWL (administered 90 minutes before habitual sleep onset, for 60 minutes). 
Subjects will be cross-over to the other treatment in the luteal phase of their next 
menstrual cycles after one month of washout period. 
Study statistician, Dr. Golshan, will prepare randomization table prior to startup of 
                                                 
 
2 Parry BL, Berga SL, Mostofi N, Klauber MR, Resnick A. Plasma melatonin circadian rhythms during the 
menstrual cycle and after light therapy in premenstrual dysphoric disorder and normal control subjects. J Biol 
Rhythms. 1997;12(1):47-64. 

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the study. 
For blinding, see section 6.2.3 above. 
9.3  
Definition of Populations 
Forty women with DSM-IV diagnoses of premenstrual dysphoric disorder 
(PMDD) will be selected for the study. Before entering the study, patients will be 
screened using standardized questionnaires and the Structured Clinical Interview for 
Diagnosis (SCID), complete daily mood self-ratings for two months (required to 
confirm a DSM-IV diagnosis) and visit our clinic weekly for Hamilton, Beck, atypical 
and mania ratings to observe individual changes in symptoms over the menstrual 
cycle that include symptoms of anxiety, irritability, mood lability and physical 
discomfort. Eligibility, inclusion and exclusion criteria are listed below. All subjects 
with valid baseline and at least one post baseline measurement will be included in 
the analysis. 
 
PMDD Subjects: Eligibility, Inclusion and Exclusion Criteria: 
Inclusion criteria 
1) 
Age: 18-45 years. 
2) 
Women with regular ovulatory menstrual cycles 26-32 days in length (for at 
least the previous six months). 
3) 
A history of a depressive (but not bipolar) mood disorder, but not an ongoing 
episode (symptom free for the last 12 months). 
4) 
Patients must meet DSM-IV criteria for Premenstrual Dysphoric Disorder (that 
includes irritability). 
5) 
Objective ratings: mean of HRSD total scores across evaluation weeks 1-8 < 
7 for follicular phase (day 5-10 of cycle after menses); mean of total HRSD 
scores across evaluation weeks 1-8  > 14 for premenstrual (luteal) phase (6 
days prior to onset of menses onward). 
6) 
Subjective ratings: mean of Beck Depression Inventory total scores across 
evaluation weeks 1-8 < 10 follicular phase; > 10 premenstrual (luteal) phase.  
7) 
Daily ratings: minimal symptoms (mean less than 50 mm on 100mm scale) 
follicular phase; at least a 30% increase in mean affective symptom ratings, 
premenstrual (luteal) phase. 
8) 
By clinical assessment and ratings, the patient has reported a history (for at 
least the last six months) of recurrent, moderate to severe premenstrual 
mood symptoms that impair some aspect of social or occupational functioning 
and that remit within a few days after the onset of menses. This pattern is 
prospectively documented with subjective daily mood ratings (DMR – visual 
analogue scale) during at least two consecutive symptomatic cycles. 
Symptom severity will also be documented with objective and subjective 
ratings over that time. Patients must demonstrate a consistency of symptoms 
and a long enough duration of symptoms (7-10 days) to allow for study. 
9) 
Subjects willing to endure the rigors of a long-term (up to 6 months) research 
study.  
 
 
Exclusion Criteria 
1) 
Subjects with significant medical illness including hepatic (abnormal liver 
function tests), neurological, renal, cardiac, pulmonary, hematologic, 
gastrointestinal, or metabolic disorders. 

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2) 
Subjects who are lactating, are within 6 months postpartum, or have an 
irregular sleep- wake cycle, e.g., from having very young children in the 
home. 
3) 
Subjects who are using hormonal contraception (within six months prior to the 
study).  
4) 
Subjects using medication that may affect outcome measures of mood, 
circadian rhythms or hormone levels (6-sulphatoxy-melatonin, estradiol, 
progesterone, FSH, LH, prolactin) within one month of initiating the study or 
anytime during the study. Such medications include OTC medication 
(excluding Tylenol), antidepressants, anti-anxiety, antihypertensive, beta 
blockers, and asthma medications. Vaccinations, vitamins/mineral 
supplements (excluding St. John’s Wart, melatonin and valerian) and/or short 
course antibiotics will not be considered exclusionary. 
5) 
Subjects with significant psychiatric disorder (schizophrenia, bipolar disorder, 
anxiety disorders, eating disorders, personality disorders, sleep disorders). 
An ongoing major depressive episode within the last year is reason for 
exclusion, although a previous history of a depressive episode is not (using 
DSM-IV diagnostic criteria for a major depressive episode). 
6) 
Subjects with a recent history (within the past year) of drug or alcohol abuse. 
7) 
Subjects with a history of anemia, kidney, cardiopulmonary, metabolic, liver 
or thyroid disease within one year of participation (per patient-reported 
medical history). 
8) 
Subjects with irregular menstrual cycles (cycle lengths vary greater than 3 
days or who fail to ovulate for 2 consecutive months). 
9) 
Subjects unlikely to cooperate with the requirements of the study. 
10) 
Subjects needing frequent or continuous use of any medication or drugs that 
may affect outcome measures, including alcohol (>1 drink daily) and nicotine 
(>5 cigarettes daily). 
11) 
Subjects whose prospective DMR ratings do not show cyclic variation in 
association with the menstrual cycle (as per inclusion criteria). 
12)       Subjects with an irregular sleep schedule, extreme chronotypes or a sleep-
wake cycle that does not correspond to the environmental light-dark cycle 
(e.g., subjects within 2 weeks of transmeridian travel, night shift workers, or 
those with significant advanced or delayed sleep phase syndromes). 
 
9.4 
Interim Analyses and Stopping Rules  
This study will be stopped prior to its completion if: (1) the intervention is 
associated with adverse effects that call into question the safety of the intervention; 
(2) difficulty in study recruitment or retention will significantly impact the ability to 
evaluate the study endpoints; (3) any new information becomes available during the 
trial that necessitates stopping the trial; or (4) other situations occur that might 
warrant stopping the trial. 
 
No interim analysis is planned. 
 

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9.5 
Outcomes  
9.5.1 Primary Outcome   
 
Treatment-Related Mood Rating Changes from Baseline (month 2) to post 
intervention (months 3,5) : 
Mood ratings include Hamilton Rating Scale for Depression (HRSD), Beck 
Depression Inventory (BDI), atypical depression symptoms as part of the 
Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal 
Affective Disorders version (SIGH-SAD), Beck Anxiety Inventory (BAI), mania 
ratings, the Psychological General Well-Being Index (PGWI) and daily mood self-
ratings (DMR) that include core PMDD symptoms of anxiety and irritability as 
required during diagnostic evaluation, before, during and after each wake and 
light intervention at the same time of day (between 15:00-17:00 h). To assess 
more acute effects on mood that may occur more rapidly during the wake 
interventions, subjects will complete DMRs twice daily beginning the evening 
before the wake therapy intervention and continuing until the morning after the 
recovery night of sleep. 
 
Treatment-Related Urinary 6-sulfatoxymelatonin (6-SMT) Changes from Baseline 
(month 2) to post intervention (months 3,5) :  
6-SMT is a principal melatonin metabolite that is abundant in urine, well 
correlated with plasma melatonin, and serves as an excellent marker for 
circadian phase response. 
 
Treatment-related changes in objective and subjective sleep measures: 
Using actigraphy, we will obtain objective measures of the sleep/wake cycle to 
ensure appropriate sleep/wake times during wake therapy, and during the light 
interventions as it is an important biological rhythm with which to compare the 
intervention-induced melatonin rhythm changes. To assess subjective sleep 
quality, we will use the Pittsburgh Sleep Quality Index (PSQI) and a visual 
analogue scale. 
 
9.5.2 Secondary Outcomes   
 
Effects of expectation, morningness/eveningness and seasonality on primary 
outcome measures: 
Prior to entering the study, subjects will complete expectation forms measuring 
their expectation for change with the interventions (100 mm line from "much 
worse" to "much better") as well as Horne-Östberg scales to assess morningness 
and eveningness, as these variables may mediate or moderate primary outcome 
measures. To determine whether seasonality affects outcome, subjects will 
complete the Seasonal Pattern Assessment Questionnaire (SPAQ). 
 
Treatment-related changes from baseline (month 2) and 1-2 days post 
intervention (months 3,5) in reproductive hormones: 
We will obtain overnight urinary samples for estradiol, progesterone, 
gonadotropins and prolactin (obtained at the same time of 6-SMT overnight 
collections in baseline and intervention months). 
 
Subjective visual analog scale-based global assessment of treatment 
effectiveness: 

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Following both treatment interventions, subjects will complete a visual analog 
scale-based global assessment of treatment effectiveness. 
 
Subjective assessment of side effects to treatment: collected 1-2 days post 
intervention (months 3,5)   
Following each treatment interventions, subjects will complete an assessment of 
side effects using the Side Effects Checklist. 
As delineated in our Data and Safety Monitoring Plan, the Independent 
Monitoring Committee will meet on an annual basis to review outcome data.  The 
committee will be masked to a participant’s intervention group assignment. 
9.6 
Data Analyses  
Analysis will be performed on data from subjects qualified for participation in 
accordance to DSM-IV criteria for PMDD (see section 4.3 for criteria and symptoms) 
as confirmed prospectively by Daily Mood Ratings (DMR).  
Mood and Other Ratings: In study month 3 (first treatment), month 4 (washout), 
month 5 (second treatment) and month 6 (follow-up), we will examine objective 
(HRSD, atypical, mania – to evaluate symptom severity) and subjective (Beck– to 
evaluate symptom severity, visual analogue scale-DMR) mood (including irritability 
and anxiety) and physical symptom ratings as a function of diagnosis and time of 
wake/light interventions.  
6-SMT data processing and circadian analyses: From the 6-SMT 
concentration, urine volume, and the collection times, the 6-SMT excretion rate 
(ng/h) is computed for each collection interval (the interval between one voiding and 
the next). Circadian parameters then are computed from analyses of the full time 
series of 5-min intervals representing each overnight collection. The best-fitting 24-
hour cosine curve (for an assumed period of 24 h) is estimated with a least-squares 
technique to yield the acrophase time (peak), amplitude (1/2 height) and mesor 
(mean excretion rate (ng/h)) of the fitted curve. To further describe changes in 
circadian phase and waveform, we use the actual ng/h curve to estimate the 
circadian timing of nocturnal 6-SMT onsets and offsets algebraically from upward 
(onset) and downward (offset) crossings of the cosine mesor.  
Reproductive Hormones: Levels will be correlated with circadian measures and 
mood ratings to determine reproductive hormonal influences on circadian physiology 
and mood. 
Daily Sleep Logs will be analyzed for rhythm stability (consistency of standard 
deviations of sleep onset and offset times from night to night), before vs. after the 
interventions.  
Actiwatches: Activity and illumination will be examined to determine time-in-bed 
and any naps that occur during the day. Daily total sleep time, wake time, number of 
awakenings and distribution of lengths of awakenings for night and day separately in 
each 24 h period will be determined using the automated sleep-wake scoring 
algorithm and custom SAS procedures that we have developed.70 Extended cosinor 
analyses70 will be done to determine the mesor, amplitude and acrophase of activity 
and illumination and the f-statistic (with higher values representing more robust and 
synchronized rhythms that we expect to correlate with improved mood). The mean 
and maximum light intensities (in lux) and the number of minutes above 1,000 lux 

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also will be examined. Analyses then will be done comparing activity, sleep and light 
exposure between groups and time of light intervention with the light and activity 
summary variables as continuous covariates. Baseline pre-intervention values and 
post-intervention activity and illumination values also can be compared for a specific 
light pulse. These analyses will determine if the following variables predict the 
magnitude of treatment and phase-shift responses: 1) The timing of activity onset 
and offset, 2) The amplitude of activity at baseline, 3) The illumination levels at 
baseline.1   For young adults, the Actiwatch is an accurate method for recording both 
the in-bed interval and for estimating the time asleep.71 Although presumably less 
accurate on a nightly basis than PSG, the Actiwatch is capable of several weeks of 
round-the clock recording, which would not be feasible with PSG either in the CTRI 
or at home. 
General Approach to Data Handling and Statistical Analyses: Care will be 
taken to insure the confidentiality, complete recording, and accurate computerization 
of the data. Items will be subject to range and relational checks. Crosscheck 
programs will be used to provide a 100% check of data entry. Descriptive statistics 
will be calculated on all data items. Distributions, means, medians, standard 
deviations, ranges, skewness and kurtosis will be calculated for all measurements. 
Missing data values will be minimized by intensive training of the interviewers in 
techniques of clarifying answers and checking questionnaires while participants are 
on-site.  When missing values are identified, several approaches such as 
rescheduling tests or interviews will be used to acquire the necessary data.  
Furthermore, missing data will be examined to assess randomness.  We expect 
missing data to be randomly distributed and will impute appropriate values.  Missing 
data (i.e. loss to follow-up) will be tested to determine if it is informative, and the 
methods developed by Diggle72 and Ridout73 to test for completely random dropouts 
will be applied.  All available data will be used in our data analysis without any need 
to estimate missing data (see below). 
Specifically, data for hypothesis 1.A. will be analyzed using a Random 
Regression Model (RRM), a generalized linear model described by Gibbons et al.,74 
Hedeker et al.69 and Laird.75  The random effects method has several advantages 
over more traditional analytic approaches such as a change score, end-point or 
repeated measures analysis of variance.  This method allows the inclusion of 
subjects with missing data or those who were terminated early in the study, without 
relying on data imputation procedures.  This method provides an estimate of the 
individual variability around the population trend, the variability of the individual 
intercepts (baseline values) and slopes (changes across time), and the correlation 
between them.  A fully saturated treatment by time model will be utilized for 
inference.  Co-variance structure will be chosen based on Akaikes Information 
Criterion (AIC).  Random treatment effects also will be evaluated for importance 
based on the model AIC.  This plan allows for any group level effects to be 
incorporated into the model.  Denominator degrees of freedom will be calculated 
using the Kenward-Roger small sample correction.  All subjects will be included in 
the analyses, and we will not focus only on subjects who complete the study.  Our 
methods for data analyses include all subjects with any valid data points in the 
analyses.  Secondary analyses will be performed on data from completers. Type 1 
error will be controlled by correcting the p-value per domain.  For hypothesis 1.B, an 
individual’s slope for each of the dependent variables listed above will be calculated 
and will be used for correlational analysis using the Pearson method.  In addition, we 
will examine the number of responders.  The operational definition of the criteria for 

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response on the mood measures, the HRSD, SIGH-SAD and the BDI, is a decrease 
of > 50% in the pre-treatment/baseline score, while the remission criterion will be a 
decline to a value < 8 on the SIGH-SAD and BDI as per Terman et al.41  We will 
compare percentages of PMDD subjects achieving the Terman criteria in groups 
receiving different interventions using Chi Square analysis.  Results from Expectation 
Forms and Horne-Ostberg Scales will be examined in relation to the magnitude of 
mood change after interventions as assessed by mood ratings, the Psychological 
General Well-Being Index (PGWI), and side effects checklists.  We also will examine 
the effect of diagnosis and light intervention on measures of subjective sleep quality 
as measured by the Pittsburgh Sleep Quality Index (PSQI), and differences between 
groups or intervention on outcome measures as a function of the phase-angle 
difference (PAD) between melatonin timing (acrophase, onset, offset) and sleep 
(onset, end-time, mid-sleep) measures. Data for hypothesis 1.C will be analyzed 
similar to hypothesis 1.B.  Data for hypothesis 2.A will be analyzed similar to 
hypothesis 1.A using RRM.  Data from LWT + AM BWL, however, will be used only.  
Data for hypothesis 2.B will be analyzed similar to hypothesis 1.B by using individual 
slope in the correlational analysis. Data for hypothesis 3.A will be analyzed similar to 
hypothesis 1.B, and for hypothesis 3.B, similar to hypothesis 1.A using only EWT 
+PM BWL treatment data.  
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms   
Data will be collected according to the schedule outlined in section 6.1. The blind 
clinical rater will collect all mood forms (Hamilton, BDI, BAI, PGWI, DMRs, SCID, 
etc.).  All other forms (screening, consents, actigraphy, urine collection, side effects, 
urine toxicology, ovulation, etc.) will be collected by the study coordinator and/or 
research associate, who are not blind to the study condition. Forms will not contain 
any patient identifiers; only patient numbers corresponding to each participant in 
accordance to the confidentiality protocols stipulated in section 11.3 below.  
10.2 
Data Management  
The data monitor will review all data collection forms on an ongoing basis for 
completeness and accuracy as well as compliance with study protocol. She will enter 
patient data into a central database, which will be verified against the original source 
document by independent lab personnel.  The quality assurance officer will oversee 
the completeness and accuracy of this central database prior to proceeding with 
statistical analyses. 
Data forms for this study are as follows: 
 
Menstrual Assessment Questionnaire to collect patient’s menstrual, medical and 
psychiatric history during screening, 
 
Hamilton:  The Hamilton Rating Scale for Depression (HRSD)56 (as a validated 
objective, interview-based assessment of depression). Atypical depression 
symptoms as part of the Structured Interview Guide for the Hamilton Depression 
Rating Scale, Seasonal Affective Disorders version (SIGH-SAD )60 (as atypical 
symptoms in particular respond to light treatment61) Mania62 ratings (to document 
any clinical induction of manic symptoms by the wake or light interventions), 

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 
Beck Depression Inventory (BDI)57 (as a validated subjective assessment of 
depression), 
 
Beck Anxiety Inventory (BAI)58 (as a subjective assessment of anxiety 
symptoms)63, 
 
The Psychological General Well-Being Index (PGWI)64  (as a subjective 
assessment of general well-being), 
 
Daily Mood Ratings (DMR)54 (as a subjective 100 mm visual analogue scale that 
include core PMDD symptoms of anxiety and irritability), 
 
Expectation form measuring patient expectation for change with the interventions 
(100 mm line from “much worse” to “much better”),  
 
Horne-Östberg subjective scales to assess morningness and eveningness65,  
 
Seasonal Pattern Assessment Questionnaire (SPAQ)66 to subjectively assess 
seasonality, 
 
Pittsburgh Sleep Quality Index (PSQI)67 to assess subjective sleep quality,  
 
Sleep Quality Ratings68 (a 100 mm visual analogue scale to assess subjective 
sleep quality), 
 
Structured Clinical Interview for DSM-IV (SCID)51, 52 (a detailed objective  
questionnaire to establish diagnosis), 
 
Actiwatch Log to record subjective sleep times (bed time, wake time, naps, etc.) 
and assist in editing and analyzing objective sleep data, 
 
Urine Collection Log to record time and total urination volume associated with 
each collected urine sample and necessary for post-assay data analysis, 
 
Side- Effects Checklist to record potential side effects from treatment.  Forms will 
be used to assess treatment safety, 
 
Global Assessment of Treatment Effectiveness (subjective assessment). 
 
10.3 
Quality Assurance  
10.3.1 Training 
Laboratory staff members are well experienced in the collection, processing and 
analysis of all protocol-related data.  Nevertheless, as technologies and procedures 
continue to evolve, the quality assurance officer and study coordinator will ensure 
that all necessary training in the areas of data collection, processing, analysis, and 
reporting; are routinely performed via specialized training courses offered at the 
University of California, San Diego.   
10.3.2 Quality Control Committee  
In accordance with the Data and Safety Monitoring Plan, laboratory personnel 
will provide yearly study reports to the Independent Monitoring Committee (see 
section 7.6 for list of committee members) to evaluate data quality, ensure protocol 
goals are met and recommend any necessary modification to protocol. 

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10.3.3 Metrics 
The Quality Assurance Officer (QAO) will train personnel and implement data 
collection procedures and practices to ensure maximum consistency, reliability and 
validity of data acquisition, data entry and data analysis. Immediately after input to 
computer data files, the QAO will check the data file against the original data 
source(s) (e.g., paper records) and will examine means and standard deviations of 
data inputs for outliers, normality/skewness, etc.  
A key element in the data acquisition process will be the routine use of check 
lists and spread sheets which identify individual components, as well as the 
person(s) responsible for executing each component of the research protocol. The 
QAO and Clinical Coordinator will examine check lists daily to verify that strict 
compliance with procedures is achieved. 
Mood Measures: 
To establish a reliable diagnosis of PMDD, an experienced, Ph.D.-level 
clinical rater will administer and interpret mood measures over two consecutive 
menstrual cycles. In consultation with the Principal Investigator, a licensed 
psychiatrist, diagnoses of PMDD will be established based on DSM-IV criteria.  
After they are admitted for study, the clinical rater will evaluate patients according 
to the evaluation schedule outlined in section 6.1 using standard clinical rating 
instruments, including  HRSD, BDI, BAI, etc. before and after treatment (sleep + 
light). Mood improvement will be determined based on differences between 
before and after measures. Further, the exit interview will provide an opportunity 
for the patient express satisfaction with the protocol and to identify issues or 
problems in data collection, thereby providing valuable feedback for improving 
procedures. Complaints from participants regarding aspects of the protocol that 
are too burdensome will be evaluated and alterations considered.  
Urine Melatonin: 
The Clinical Coordinator will instruct each patient and demonstrate 
procedures for completing the Urine Log and collecting, transferring urine 
samples to tubes (using urine kits provided to them prior to cycle day 10 in 
months 2, 3 and 5) and freezing samples at home. The Research Associate will 
telephone patients to prompt them to collect samples when menstruation 
approaches (based on menstruation histories), will collect frozen urine kits and 
data logs within 3 days of collection (but not before completion of actigraphy 
measures), catalogue identifying information, and store samples at -700 
centigrade. On the day the patient transfers samples to the laboratory, missing 
samples or log entries will be noted and the participant will be instructed on the 
importance of providing complete samples and records. As urine collections 
(particularly during mornings) may be problematic for women in school or work, 
patients that cannot collect some morning/evening urine samples are instructed 
to record time of missed collections in order to later extrapolate 6-SMT excretion 
rates before proceeding with analysis. Patients that are completely unable to 
collect urine will not be excluded from participation in the study as they will still 
collect mood, activity, light and sleep data for analysis of treatment outcomes. 
Sleep Measures: 

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The Clinical Coordinator will instruct each patient on the proper use of the 
Actiwatch device and the completion of its accompanying log.  Actigraphy devices 
and logs will be collected by the research associate at the same time as the urine 
samples.  Data will be verified against logs to ensure completeness and accuracy, as 
well as to monitor compliance with sleep and light protocols.  Compliance with wake 
therapy will be monitored by means of half-hourly message left to a laboratory voice 
mail.  Timing of these messages must correspond to the required treatment time.  
Failure to comply with wake therapy will result in repetition of wake therapy prior to 
commencing light treatment. 
As precise timing of ovulation is essential to the protocol, Recruitment 
Officer/Clinic Coordinator will train personnel to read luteinizing hormone 
(Clearblue®) indicators. The Coordinator and another staff member will 
independently examine the Clearblue® on the day after the participant phones in 
with her putative ovulation identification. If both agree that ovulation has occurred, 
the participant will be advanced to the next phase of testing. If not, further testing will 
be postponed until clear-cut evidence of ovulation is obtained. 
10.3.4 Protocol Deviations 
Laboratory staff, particularly the study coordinator and research associate, will 
monitor and record any deviation from study protocol and immediately report to 
principal investigator to assess the necessary follow up steps to achieve a resolution. 
Deviations in study protocol also will be reported to the Independent Monitoring 
Committee, the UCSD Human Research Protection Program and the NCCAM/NIH 
Program Official for review and follow up. 
10.3.5 Monitoring 
Protocol compliance will be monitored via the annual DSMP Study Report for the 
Independent Monitoring Committee. For detailed monitoring methods, please consult 
the Data Safety Monitoring Plan.   
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Institutional Review Board (IRB) Review  
This protocol, the informed consent documents, and any subsequent 
modifications will be reviewed and approved by the UCSD Human Research 
Protection Program responsible for oversight of the study. 
11.2 
Informed Consent Forms 
Written informed consent will be obtained from each subject at entry into the 
study.  For participants who cannot consent for themselves, such as those with a 
legal guardian (e.g. person with power of attorney), this individual must sign the 
consent form. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy will be 
given to each participant or legal guardian and this fact will be documented in the 
participant’s record.  Informed consent is obtained by the following process: 
1. The subject will be asked to review the study consent form. 

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2. The PI, Study Coordinator and/or one of their associates will meet with the 
subject to review the form, to confirm and to answer any questions the 
subject might have.  The UCLA Office of Protection of Research Studies 
“Evaluation to Sign a Consent form for Research” will be administered to 
insure that all participants have understood the consent document, before 
they are asked to sign it. 
3. Once the subject demonstrates understanding of the study and agrees to 
participate in the study, the consent will be signed in the presence of the 
Study Coordinator or a Research Associate and a witness. 
 
11.3 
Participant Confidentiality  
All of the materials collected are for research purposes only, and data will be kept 
in strict confidence in accordance to the Health Insurance Portability and 
Accountability Act (HIPAA). No information will be given to anyone without 
permission from the subject. The consent form includes the informed consent 
statement required by the University of California, San Diego. All data will be 
identified with a randomly generated identification code unique to the subject. 
All study data will be secured with password protection. Electronic 
communication with outside collaborators will involve only unidentifiable information. 
Source documents including all paper and electronic records for all enrolled subjects 
(i.e., case report forms, laboratory reports, subject study binders, etc.) will be kept in 
locked cabinets within locked offices.  Data, specimens, forms, reports, and other 
records that leave the site will be identified only by a participant identification number 
(PID) to maintain confidentiality. All records will be kept in a locked file cabinet. All 
computer entry and networking programs will be done using PIDs only. Information 
will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the IMC and NCCAM. 
11.4 
Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCAM, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
12. COMMITTEES  
As described in section 7.4, this research protocol has an Independent Monitoring 
Committee that will oversee data quality and patient safety. 
13. PUBLICATION OF RESEARCH FINDINGS  
Publication of research findings will be at the discretion of the principal investigator.  
Findings will be made available to NCCAM and will also be published in ClinicalTrials.gov in 
accordance to their individual policies and procedures. 

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15. SUPPLEMENTS/APPENDICES 
 
I. 
Procedures Schedule 
 
Consult Schedule of Evaluations (see section 6.1) for specific evaluations, forms and 
ratings associated with each time point listed below. 
 
1. Screening: 
a. Telephone screening to ensure potential participants meet eligibility criteria 
and to schedule initial in-office screening visit, 
b. Screening Visit: 
i. Patient signs Screening Consent 
ii. Perform urine toxicology screening 
iii. Complete Menstrual Assessment Questionnaire 
iv. Record most recent start of menses (Cycle Day 1) 
 
2. Evaluation Month 1 
a. Evaluation week 1 
i. Provide patient with binder that includes all required study forms, 
calendars, checklists and equipment/collection instructions needed in 
Evaluation Months 1 and 2  
b. Evaluation week 2 
c. Evaluation week 3 
d. Evaluation week 4 
 
3. Evaluation Month 2 
a. Record Cycle Day 1 (patient will call Study Coordinator with date) 
b. Evaluation week 5 – (Steps i – iv below must occur before Cycle Day 10): 
i. Provide Clearblue® ovulation (luteinizing hormone surge-LHS) test kit 
ii. Provide urine collection kit 
iii. Provide Actiwatch Spectrum 
iv. Provide instructions and demonstration of proper form completion, 
sample collection and equipment use  
c. Evaluation week 6 
d. Evaluation week 7 
e. Evaluation week 8 
f. The following steps are not categorized within the previous 4 evaluation 
weeks (5-8) as varying menstrual cycle times make it difficult to determine 
exactly when each of the following events will occur: 
i.  Menstrual Cycle Day 10 – commence testing for LHS (7 days of 
testing) 
ii. Ovulation Day (LHS) – commence actigraphy recording (for 10 days) 
iii. 8-9 Days after LHS (LHS+8  LHS+9) – commence urine collection 
(30 hrs) 
iv. LHS+11 – equipment, samples and forms are returned to lab 
 
4. Treatment 1 (Month 3) 

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a. Record Cycle Day 1 (patient will call Study Coordinator with date and to 
schedule pre-intervention in-office visit)  
b. Pre-Intervention Visit – to be completed between cycle days 1 and 10: 
i. Patient signs the Study Consent 
ii. Patient is randomized to treatment 
iii. Provide ovulation test kit 
iv. Provide urine collection kit  
v. Provide Actiwatch Spectrum 
c. Menstrual Cycle Day 10 – commence testing for LHS (7 days of testing) 
d. Ovulation Day (LHS) – commence actigraphy recording (for 10 days) 
     – commence Wake Therapy (1 night) 
e. Day after LHS (LHS+1) – commence first light treatment (for 7 days) 
f. LHS+8  LHS+9 – commence urine collection (30 hrs) 
g. LHS+11 – equipment, samples and forms are returned to lab 
 
5. Washout (Month 4) 
a. Perform clinical ratings only 
 
6. Treatment 2 (Month 5) 
a. Record CD1 (patient will call Study Coordinator with date and to schedule 
pre-intervention in-office visit)  
b. Pre-Intervention Visit – to be completed between cycle days 1 and 10: 
i. Provide ovulation test kit 
ii. Provide urine collection kit  
iii. Provide Actiwatch Spectrum 
c. Menstrual Cycle Day 10 – commence testing for LHS (7 days of testing) 
d. Ovulation Day (LHS) – commence actigraphy recording (for 10 days) 
     – commence Wake Therapy (1 night) 
e. LHS+1 – commence first light treatment (for 7 days) 
f. LHS+8  LHS+9 – commence urine collection (30 hrs) 
g. LHS+11 – equipment, samples and forms are returned to lab 
 
7. Final Visit (can be performed at time of item 6.g. above) 
a. Review side effects to treatment and subjective global assessment of 
treatment effectiveness. 
 
8. Follow-up (luteal phase in the month following Treatment 2) 
a. Perform clinical ratings per telephone.