Circadian Effects of Escitalopram

Study Overview
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Brief Summary
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The goal of the study is to obtain preliminary data that will test whether the antidepressant medication escitalopram resets the body clock: a collection of nerve cells in the brain that control the timing of many body processes. The study will also test whether the improvement in depression symptoms with escitalopram correlates with the degree to which the timing of the body clock is properly aligned with the timing of sleep.

Detailed Description
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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).

Official Title
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Determination of the Circadian Resetting Effects of Escitalopram and Testing for Correlations Between Circadian Resetting and Antidepressant Effects

Conditions
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Depression

Intervention / Treatment
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* Drug: placebo/escitalopram


Participation Criteria
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Eligibility Criteria
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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 Complete Blood Count, Complete Metabolic Set, Thyroid Stimulating Hormone, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Drug<br>Subjects will have a total of 12 visits to Oregon Clinical & Translational Research Institute at Oregon Health & Science University over the 14-16 weeks of study. Subjects will first undergo an initial screening visit to determine eligibility. Subjects who meet criteria and agree to participate will then stop taking their current antidepressant medication (if applicable), during which time the study doctor and staff will conduct weekly mood assessments to ensure safety. Subjects will then have a study initiation/materials visit followed by 9 visits during treatment with placebo or escitalopram. A final post-study follow-up safety visit will be scheduled at the end of treatment. | Drug: placebo/escitalopram<br>* Subjects will first complete a one week, single-blind placebo lead in phase. Subjects will then receive escitalopram for 8 weeks. Subjects will receive 10 mg/day for the first 2 weeks of active treatment, and then 20 mg/day for the remaining 6 weeks of treatment. Medication will be dispensed on a weekly basis.<br>* Other names: escitalopram;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Dim Light Melatonin Onset | The Dim Light Melatonin Onset (DLMO) is the time of the onset of melatonin secretion under dim light conditions using the equivalent thresholds of 10 pg/ml in plasma and 3 pg/ml in saliva. It is a marker of biological time. Data are provided in decimal and military time (e.g., 9:30 pm equals 21.50). This measure is used to determine if there was a change in the time of the dim light melatonin onset (DLMO) before treatment with escitalopram (at Study Visit 3) and after treatment with escitalopram (at Study Visit 11). | 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Depression Rating Scale (HAM-D) Scores | The HAM-D is the total score on the 21-question Hamilton Depression Rating Scale. Scores range from 0 to 53 with higher scores indicating worse symptoms of depression. | 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram) | 
| Change in Beck Depression Inventory II (BDI-II) Scores | The BDI-II is the total score on the 21-question Beck Depression Inventory II questionnaire. Scores range from 0 to 63 with higher scores indicating worse symptoms of depression. | 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram) | 
| Change in Phase Angle Difference (PAD) | The PAD is the time interval (number of hours) between the Dim Light Melatonin Onset (DLMO) and the average midpoint of sleep during the prior week. Larger PADs indicate a longer time interval between the DLMO and midpoint of sleep. A negative change in PAD value indicates a shortening of the time interval from Study Visit 3 to Study Visit 11. | 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram) |