Melatonin Treatment for Induced Transient Insomnia

This study uses a randomized, double-blind, placebo-controlled, parallel groups design. The
independent variable will be melatonin treatment group (0.3 mg melatonin, 3.0 mg melatonin,
or placebo). Day of treatment will be an independent variable in analysis of sleep,
cortisol, performance and alertness data. The primary outcome variables will be sleep
efficiency and the peak of the plasma cortisol rhythm. Subjective and objective measures of
alertness and performance during wake time will also be assessed as part of an exploratory
analysis. Safety of short-term melatonin treatment will be assessed. The experimental
protocol is divided into 5 segments, the ambulatory baseline segment, the laboratory
adaptation segment, the initial constant posture (CP, to assess circadian phase), the
melatonin/placebo intervention before advanced scheduled sleep, and second CP to assess
final circadian phase.

The experimental protocol is divided into 5 segments, the ambulatory baseline segment, the
laboratory adaptation segment, the initial constant posture (CP) for circadian phase
assessment, the melatonin/placebo intervention, and a final post-treatment CP for assessment
of circadian phase.

The Ambulatory Baseline consists of at least 21 days, outside the laboratory. During this
segment, wrist activity and light levels will be recorded using an ambulatory recording
device (Actiwatch-L) while the subject goes about his/her normal routine. During this
segment, the subject will maintain a regular, self-selected sleep-wake/light-dark schedule
(8h in bed, 16h awake), and a sleep diary. The subject will also call in to our time-stamped
sleep-wake call-in telephone system just prior to each bedtime and immediately after each
wake time.

The Laboratory Adaptation begins upon admission to the laboratory (Day 1 on protocol
schematic in Figure 13) and continues until Day 3. The subject will be scheduled to sleep
and wake at his/her regular times (determined during the ambulatory baseline). This segment
of the study is designed to allow the subject to adapt to the laboratory environment and to
allow all subjects to experience a standardized lighting regime prior to initial circadian
phase assessment. We believe another reason the baseline days are essential is because prior
to study individual subjects will experience varying light exposure patterns and levels. The
standardized lighting conditions during baseline days allow stabilization of the subjects'
circadian phase and phase of entrainment, and also control immediate lighting history prior
to the study interventions. Ambient lighting during waking on the baseline days will be
provided by ceiling panels and will be of ordinary indoor level, and all lights will be
turned off (darkness) during the scheduled sleep episodes (black boxes on double raster plot
of protocol). For all scheduled sleep episodes, polysomnographic recording of sleep will be
taken. Due to the nature of the study, the exact timing of the beginning and ending of each
study will be based on the individual subject's habitual sleep-wake schedule. Beginning on
Day 1 of the study, saliva samples will be taken hourly during waking, and blood samples
will be collected twice hourly for baseline melatonin and cortisol phase/amplitude
estimation. Subjective alertness assessments will be collected twice per waking hour, and
neurobehavioral performance testing will be conducted every 2 waking hours.

The initial Constant Posture (CP) circadian phase estimation begins eight hours before
habitual sleep time on Day 3 and continues for 22 h (shown in the cross-hatched bars in
Figure 13). Throughout the CP, the subject will be restricted to a semi-recumbent position
in bed in very dim indoor light (see Lighting Conditions section below for description) and
will be fed equivalent hourly snacks. This segment of the study is designed to allow
assessment of circadian phase by either eliminating factors known or suspected to obscure or
mask circadian rhythms (changes in posture, activity, food intake, light level) or by
distributing such factors across all circadian phases. The subject will be attended by a
trained staff member to ensure wakefulness throughout the CP. Collection of plasma melatonin
and cortisol, subjective alertness and neurobehavioral performance data will continue as in
the Laboratory Adaptation Segment. After the CP is complete, the subject will be allowed to
be ambulatory for another 6 hours before an 8-hour sleep episode. We chose to use CPs rather
than a Constant Routine in order to avoid sleep deprivation, the recovery from which would
obscure the results of the treatment conditions.

The melatonin/placebo intervention days follow the initial CP. On experimental Day 4-5,
scheduled sleep will occur 5 hours before habitual bedtime. Melatonin or placebo will be
administered 30 minutes before lights-out. Twelve hours after waking the following day (Day
5), the CP to asses final circadian phase will begin and continue for 22 hours. The final
sleep episode will be scheduled from 18:00 to 02:00 h to ensure that post-treatment phase
estimates are in no way compromised by change of sleep time. Subjects will be informed that
they are likely to experience sleep disruption, impaired alertness and other symptoms of
jetlag for up to several days after they are discharged from the laboratory. Four hours
after the CP on Day 7, the subject will be discharged home.

Inclusion Criteria:

- Non-smoking for at least 6 months;

- Healthy (no medical, psychiatric or sleep disorders);

- No clinically significant deviations from normal in medical history, vital signs,
physical examination, blood chemistry and hematology, and ECG;

- Women of childbearing potential must agree to use an acceptable method of birth
control, and must have a negative serum pregnancy test;

- Body mass index of > 18 or < 30 kg/m2;

- No drugs or medication likely to affect sleep or alertness, as determined by the
investigators;

Exclusion Criteria:

- History of alcohol or substance abuse;

- Positive result on drugs of abuse screening;

- Current or past history of sleep disorders, including but not limited to obstructive
sleep apnea, or any significant sleep complaint;

- Psychiatric disorder, including a history of depression or dysthymia (characterized
by depressed mood on the majority of days for at least two years);

- Recent acute or chronic medical disorder, including but not limited to hepatic
impairment and severe chronic obstructive pulmonary disease;

- History of intolerance or hypersensitivity to melatonin or melatonin agonists;

- Pregnancy or lactation;

- Shift work in the last 3 years;

- Transmeridian travel (2 or more time zones) in past 3 months;

- Any other scientific or medical reason, as determined by the PI, such as
non-compliance with protocol or intolerance to inpatient study conditions.