Circadian Effects of Escitalopram

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01214044
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 43
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: placebo/escitalopram	N/A

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Determination of the Circadian Resetting Effects of Escitalopram and Testing for Correlations Between Circadian Resetting and Antidepressant Effects
• Actual Study Start Date: May 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Study Drug 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; 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.; Other Names: Lexapro escitalopram

Outcome Measures

Primary Outcome Measures

1. Change in Dim Light Melatonin Onset [8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)]

   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).

Secondary Outcome Measures

1. Change in Hamilton Depression Rating Scale (HAM-D) Scores [8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)]

   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.

2. Change in Beck Depression Inventory II (BDI-II) Scores [8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)]

   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.

3. Change in Phase Angle Difference (PAD) [8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Oregon Health and Science University
• Forest Laboratories

Investigators

• Principal Investigator: Jonathan Emens, MD, Oregon Health and Science University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 3, 2008

More Information

Publications

None provided.

• Responsible Party: Jonathan Emens, Associate Professor, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT01214044
• Other Study ID Numbers: LXP-MD-132
• First Posted: Oct 4, 2010
• Last Update Posted: Aug 20, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Depression; Dexetimide; Citalopram

Study Results

Participant Flow

Arm/Group Title	Study Drug
Arm/Group Description	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 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. placebo/escitalopram: 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.
Period Title: Visit 1: Screening and Consent, Washout
STARTED	31
COMPLETED	19
NOT COMPLETED	12
Period Title: Visit 1: Screening and Consent, Washout
STARTED	19
COMPLETED	17
NOT COMPLETED	2
Period Title: Visit 1: Screening and Consent, Washout
STARTED	17
COMPLETED	14
NOT COMPLETED	3
Period Title: Visit 1: Screening and Consent, Washout
STARTED	14
COMPLETED	10
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Study Drug
Arm/Group Description	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. An initial screening visit will 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. Placebo/escitalopram: 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 weekly.
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.2 (13.6)
Sex: Female, Male (Count of Participants)
Female	5 50%
Male	5 50%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Change in Dim Light Melatonin Onset
Description	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).
Time Frame	8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)

Outcome Measure Data

Analysis Population Description

Of the 10 subjects who completed all study procedures, adequate dim light melatonin data from both study visits 3 and 11 were available for 9 subjects.

Arm/Group Title	Study Drug
Arm/Group Description	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. An initial screening visit will 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. Placebo/escitalopram: 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 weekly.
Measure Participants	9
Baseline DLMO	21.17 (1.24)
Post-escitalopram DLMO	20.77 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug
	Comments	A within subjects comparison was done to compare the time of the dim light melatonin onset before treatment with escitalopram (Study Visit 3) and after treatment with escitalopram (Study Visit 11).
	Type of Statistical Test	Other
	Comments	A paired t-test was done to see if the time of the dim light melatonin onset changed from baseline to post-treatment.
Statistical Test of Hypothesis	p-Value	0.2
	Comments	A priori threshold for significance was p = 0.05.
	Method	t-test, 2 sided
	Comments	paired t-test

2. Secondary Outcome

Title	Change in Hamilton Depression Rating Scale (HAM-D) Scores
Description	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.
Time Frame	8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)

Outcome Measure Data

Analysis Population Description

Of the 10 subjects who completed all study procedures, adequate Hamilton Depression Rating Scale data from both study visits 3 and 11 were available for 7 subjects.

Arm/Group Title	Study Drug
Arm/Group Description	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. An initial screening visit will 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. placebo/escitalopram: 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.
Measure Participants	7
Mean (Standard Deviation) [units on scale (scores)]	-2.3 (2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug
	Comments	We hypothesized that there would be a decrease in the Hamilton-21 score with escitalopram treatment. A within subjects comparison was done to compare the Hamilton-21 score before treatment with escitalopram (Study Visit 3) and after treatment with escitalopram (Study Visit 11).
	Type of Statistical Test	Other
	Comments	A paired t-test was done to see if the Hamilton-21 score decreased from baseline to post-treatment.
Statistical Test of Hypothesis	p-Value	0.01
	Comments	A priori threshold for significance was p = 0.05.
	Method	t-test, 1 sided
	Comments	paired t-test

3. Secondary Outcome

Title	Change in Beck Depression Inventory II (BDI-II) Scores
Description	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.
Time Frame	8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)

Outcome Measure Data

Analysis Population Description

Of the 10 subjects who completed all study procedures, Beck Depression Inventory-II data from both study visits 3 and 11 were available for 7 subjects.

Arm/Group Title	Study Drug
Arm/Group Description	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. An initial screening visit will 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. placebo/escitalopram: 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.
Measure Participants	7
Mean (Standard Deviation) [units on scale (scores)]	-3.3 (7.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug
	Comments	We hypothesized that there would be a decrease in the Beck Depression Inventory-II score with escitalopram treatment. A within subjects comparison was done to compare the Beck Depression Inventory-II score before treatment with escitalopram (Study Visit 3) and after treatment with escitalopram (Study Visit 11).
	Type of Statistical Test	Other
	Comments	A paired t-test was done to see if the Beck Depression Inventory-II score decreased from baseline to post-treatment.
Statistical Test of Hypothesis	p-Value	0.14
	Comments	A priori threshold for significance was p = 0.05.
	Method	t-test, 1 sided
	Comments	paired t-test

4. Secondary Outcome

Title	Change in Phase Angle Difference (PAD)
Description	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.
Time Frame	8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)

Outcome Measure Data

Analysis Population Description

Of the 10 subjects who completed all study procedures, adequate PAD data from both study visits 3 and 11 (derived from dim light melatonin onset and sleep diary) were available for 7 subjects.

Arm/Group Title	Study Drug
Arm/Group Description	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. An initial screening visit will 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. placebo/escitalopram: 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.
Measure Participants	7
Mean (Standard Deviation) [hours]	-0.6 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug
	Comments	We hypothesized that there would be a correlation between the change in phase angle difference and the decrease in the Hamilton-21 score with escitalopram treatment. The phase angle difference is the interval, in hours, between the dim light melatonin onset (a marker of biological time) and the average midpoint of sleep during the prior week.
	Type of Statistical Test	Other
	Comments	Spearman's rank-order correlation (non-parametric test) was used.
Statistical Test of Hypothesis	p-Value	0.06
	Comments	Spearman's rho (rs) = 0.66
	Method	Spearman's rank-order correlation
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Study Drug
	Comments	We hypothesized that there would be a correlation between the change in phase angle difference and the decrease in the Beck Depression Inventory-II score with escitalopram treatment. The phase angle difference is the interval, in hours, between the dim light melatonin onset (a marker of biological time) and the average midpoint of sleep during the prior week.
	Type of Statistical Test	Other
	Comments	Spearman's rank-order correlation (non-parametric test) was used.
Statistical Test of Hypothesis	p-Value	0.48
	Comments	Spearman's rho (rs) = 0.02
	Method	Spearman's rank-order correlation
	Comments

Adverse Events

Time Frame	Participants were assessed over 14 weeks (or 16 weeks in two subjects who were on fluoxetine at enrollment and therefore had a 4-week, instead of a 2-week, washout period per the protocol). Subjects had a weekly contact with study personnel throughout the 14 or 16 weeks of study except for the two week medication taper period between the last two study visits.
Arm/Group Title	Visit 1: Screening & Consent, Washout		Visit 2: End Washout & Start Placebo		Visits 3-5: Escitalopram 10 mg Daily		Visits 6-11: Escitalopram 20 mg Daily
Arm/Group Description	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. An initial screening visit will 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.		After completing the washout period, Subjects will then complete a one week, single-blind placebo lead in phase.		After the week of placebo, Subjects will then receive 10 mg/day of escitalpram for the first 2 weeks of active treatment.		After receiving 10 mg/day of escitalopram for 2 weeks, subjects will then receive escitalopram, 20 mg/day for the remaining 6 weeks of treatment.
All Cause Mortality
	Visit 1: Screening & Consent, Washout		Visit 2: End Washout & Start Placebo		Visits 3-5: Escitalopram 10 mg Daily		Visits 6-11: Escitalopram 20 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/19 (0%)		0/17 (0%)		0/14 (0%)
Serious Adverse Events
	Visit 1: Screening & Consent, Washout		Visit 2: End Washout & Start Placebo		Visits 3-5: Escitalopram 10 mg Daily		Visits 6-11: Escitalopram 20 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/19 (0%)		0/17 (0%)		1/14 (7.1%)
Psychiatric disorders
suicide attempt	0/31 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Visit 1: Screening & Consent, Washout		Visit 2: End Washout & Start Placebo		Visits 3-5: Escitalopram 10 mg Daily		Visits 6-11: Escitalopram 20 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/19 (0%)		1/17 (5.9%)		0/14 (0%)
Nervous system disorders
Headache	0/31 (0%)	0	0/19 (0%)	0	1/17 (5.9%)	1	0/14 (0%)	0

Limitations/Caveats

The sample size was small because this was a preliminary study that aimed to collect pilot data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.