Circadian Effects of Escitalopram

Background: The human biological clock (circadian pacemaker) has long been thought to play a
role in non-seasonal depression. A connection is suggested by the demonstration of 24-hour
rhythms in mood, subjective and objective changes in sleep with depression, and reports of
changes in the timing and amplitude of biological rhythms in depression. Furthermore, it is
known that the neurotransmitter serotonin has a significant role in regulating biological
rhythms and that drugs that act on serotonin (such as some antidepressants) are able to
reset the biological clock in animals.

Objective: The aim of the study is to obtain preliminary data that will test whether the
antidepressant medication escitalopram has a resetting effect on the human biological clock
and whether the improvement in depression symptoms with escitalopram correlates with the
degree to which the timing of the biological clock is realigned with the timing of sleep.

Design: 14-16-week, fixed dose (after titration), open label trial.

Setting and Subjects: 50 individuals will be screened for participation. 15 individuals with
unipolar, non-seasonal depression will be studied over 1 year.

Intervention: Subjects will first complete a one week, single-blind placebo lead-in phase.
Subjects will then receive escitalopram for 8 weeks (10 mg/day for the first 2 weeks of
treatment and then 20mg/day for the remaining 6 weeks of treatment).

Measurements: Subjects will keep a sleep diary and wear a wrist activity monitor throughout
the study to document the timing and quality of sleep. On two occasions (end of placebo week
and end of last treatment week) blood and/or saliva will be sampled every 30 minutes for 7
hours and the resulting samples will be assayed for melatonin. The onset of melatonin
secretion (dim light melatonin onset or DLMO) will be used to mark the timing of the
biological clock (circadian phase). Circadian misalignment will be measured using the time
interval between the DLMO and the average midsleep of the prior week (phase angle difference
or PAD). Mood will be assessed throughout the study using the Hamilton Depression Rating
Scale (HAM-D) as well as the Beck Depression Inventory-II (BDI-II) and Beck Anxiety
Inventory (BAI).

Inclusion Criteria:

- 18-65 years old

- able to comply with requirements of the experimental protocol

- competent to sign informed consent

- have mild to severe major depressive disorder without psychotic features and without
a seasonal pattern

- currently be under the care of a licensed mental health care provider or primary care
physician

- Score > 7 when interviewed by a trained rater using the 21-Item Hamilton Depression
Scale (HAM-D)

- be in good physical health

- not be suicidal

- not be taking any other antidepressant medications besides escitalopram during the
study

- be free of antidepressant medications for 2-4 weeks prior to beginning the study

- not have a history of transmeridian travel or shift work in the past 2 months and
have no plans for transmeridian travel or shift work for the duration of the study

- be able to maintain a regular sleep wake schedule for the weeks one and nine of study

- women of childbearing potential must have a negative pregnancy test and practice an
acceptable method of birth control

Exclusion Criteria:

- abnormal heart, liver, or kidney function

- significant laboratory abnormalities on CBC, Complete Metabolic Set, TSH, EKG, &
urinalysis

- shift work or transmeridian travel in the last 2 months

- current use of melatonin

- evidence of a primary sleep disorder by history

- women who are pregnant or lactating

- be taking medications with known sedative or stimulating effects or that would
interfere with the production of melatonin