Depression
Conditions
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.
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).
Interventions
DRUGplacebo/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.
Sponsors
Forest Laboratories
Oregon Health and Science University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. 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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Visit 1: Screening and Consent, Washout | Ineligible | 3 |
| Visit 1: Screening and Consent, Washout | Lost to Follow-up | 4 |
| Visit 1: Screening and Consent, Washout | Withdrawal by Subject | 5 |
| Visits 3-5: Escitalopram 10 mg Daily | Withdrawal by Subject | 3 |
| Visits 6-11: Escitalopram 20 mg Daily | Adverse Event | 1 |
| Visits 6-11: Escitalopram 20 mg Daily | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Study Drug |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 50.2 years STANDARD_DEVIATION 13.6 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 19 | 0 / 17 | 0 / 14 |
| other Total, other adverse events | 0 / 31 | 0 / 19 | 1 / 17 | 0 / 14 |
| serious Total, serious adverse events | 0 / 31 | 0 / 19 | 0 / 17 | 1 / 14 |
Outcome results
Primary
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).
Time frame: 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Drug | Change in Dim Light Melatonin Onset | Baseline DLMO | 21.17 decimal military time (hours) | Standard Deviation 1.24 |
| Study Drug | Change in Dim Light Melatonin Onset | Post-escitalopram DLMO | 20.77 decimal military time (hours) | Standard Deviation 1.17 |
Comparison: 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).p-value: 0.2t-test, 2 sided
Secondary
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.
Time frame: 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Drug | Change in Beck Depression Inventory II (BDI-II) Scores | -3.3 units on scale (scores) | Standard Deviation 7.4 |
Comparison: 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).p-value: 0.14t-test, 1 sided
Secondary
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.
Time frame: 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Drug | Change in Hamilton Depression Rating Scale (HAM-D) Scores | -2.3 units on scale (scores) | Standard Deviation 2 |
Comparison: 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).p-value: 0.01t-test, 1 sided
Secondary
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.
Time frame: 8 Weeks: Study Visit 3 (after 1 week of placebo) to study Visit 11 (after 8 weeks of escitalopram)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Drug | Change in Phase Angle Difference (PAD) | -0.6 hours | Standard Deviation 0.8 |
Comparison: 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.p-value: 0.06Spearman's rank-order correlation
Comparison: 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.p-value: 0.48Spearman's rank-order correlation