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| ID | Type | Description | Link |
|---|---|---|---|
| R01MH076079 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Weill Cornell Institute of Geriatric Psychiatry | UNKNOWN |
| National Institute of Mental Health (NIMH) | NIH |
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The Department of Psychiatry at the University of Pittsburgh is conducting a research study to learn about the changes that occur in the brain when individuals suffer from and then are treated for depression. The NEMO study has two main purposes. The first is to provide medication treatment to individuals ages 60 and older who are currently depressed.
The second part of the study involves completing a series of 4 MRIs, which assess changes in brain function over the course of treatment. This research may help investigators to develop faster and more effective treatment plans in the future, as brain responses that are detected early in treatment may predict how well an individual will respond to antidepressant medication.
In this competing renewal (Year 11) of the investigators' R01 which has used functional magnetic resonance imaging (fMRI) to study late-life depression (LLD) pharmacotherapy (R01MH076079), the primary aim of this study is to characterize functional connectivity changes associated with initial medication exposure (12-hour challenge). Preliminary data suggests that these initial fMRI changes reflect monoaminergic engagement, regardless of monoaminergic class, and predict later treatment response. This study will test a neural systems level model that response in LLD is mediated by acute pharmacologically-induced changes in cognitive and affective large scale network.
Depression in older adults is frequently disabling and is often resistant to first-line treatments, requiring more prolonged treatment trials than in younger adults, mainly due to its heterogeneous pathophysiology (e.g. vascular and degenerative brain changes). Currently, there is little neurobiological data to guide changing or augmenting antidepressant medications. Thus, there has been a heightened focus on tailoring treatment to optimize outcome as described in the 2015 National Institute of Mental Health (NIMH) draft strategic plan (strategy 3.2). While antidepressant clinical response may take up to 8 weeks, recent studies suggest that physiologic changes, as measured with pharmacologic fMRI (phMRI) are seen within 12 hours of starting a new monoaminergic antidepressant (1).
For this proposal, investigators focus on three major Cognitive and Affective Networks (CAN): the Default Mode Network (DMN), the Salience Network (SN) and the Executive Control Network (ECN). The proposed model suggests that monoaminergic engagement leads to core CAN changes, changes that subsequently are related to overall clinical response as well as response in specific symptom clusters such as negative bias, somatizations/anxiety and cognitive control. The same networks that are functionally connected while individuals are at rest, are also selectively engaged during tasks. Investigators' prior work shows that pharmacotherapy - regardless of type of antidepressant used - engages these specific networks at rest and during standard cognitive and affective tasks. Given the role of cerebrovascular disease in LLD treatment response, the moderating role of vascular burden on the proposed association between CAN engagement and treatment response will also be explored.
The University of Pittsburgh will recruit 100 older adults with LLD that will be randomized to receive treatment with either a very specific serotonin reuptake inhibitor (escitalopram) or a norepinephrine reuptake inhibitor (levomilnacipran). A pair of fMRI scans one day apart will be used to measure functional connectivity (FC) associated with medication titration. Investigators will use a very early (12 hours after initiation of treatment) biomarker of treatment response, which, when validated, would decrease substantially the waiting time between medication changes. Additionally, this study will further increase knowledge of the acute neural system changes associated with monoaminergic antidepressants; this knowledge of mechanism is essential for both guiding LLD treatment research, and serving as an engagement target in LLD treatment research.
Note: The original study design involved randomization to escitalopram or placebo (instead of escitalopram and levomilnacipran). Therefore a subset of participants will complete the study according to this design.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Escitalopram Pill | Active Comparator | Participants in this arm will receive an initial dose of 5 mg. Further titrations will be decided based on clinical response and tolerability (maximum dose of 20 mg). The medication will be taken by mouth in pill form, once daily. |
|
| Placebo | Placebo Comparator | Participants will be given a sugar pill (placebo) to be taken by mouth once daily for the 6 week duration of Phase I. As this arm is also double-blinded, participants will receive an initial dose of 5 mg and further titrations (maximum dose of 20 mg) will be decided based on clinical response and tolerability. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima. |
|
| Escitalopram Pill (Phase II) | Other | Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II. Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study. |
|
| Levomilnacipran Pill |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Escitalopram Pill | Drug | Double-blinded, randomly assigned |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Montgomery Asberg Depression Rating Scale Score | Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score. | Change in Baseline MADRS score through Week 12 |
| Change in Functional Connectivity | The primary analysis will consist of linear mixed effects models with functional connectivity (for each region of interest) as the outcome measure and group (R [responder]/NR[non-responder], as defined by MADRS), time and their interaction. The results listed are the difference in Baseline to 12 hours after first dose of medication. The values derived by first preprocessing the raw data using SPM and using the AAL3 atlas to parcellate the images into anatomical brain regions. Then the mean residual time series for each region was calculated and the Pearson correlation between the time series of each region was calculated. Then the mean Pearson correlations between every other region with the region identified were calculated and these correlation values were then standardized to have a mean of 0 and a standard deviation of 1. Higher values indicate stronger and better connectivity. | Change in Functional Connectivity from Baseline to Day 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Response Styles Questionnaire- Rumination (RSQ-Rumination) | The Response Styles Questionnaire- Rumination (RSQ-Rumination) examines propensity towards negative bias during thought. To be used as covariate in functional connectivity analysis. Range of scores: 22-88. Lower the better | Baseline, Week 1, and Week 12 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Howard J Aizenstein, MD, Ph.D. | Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Associate Professor of Bioengineering and Clinical and Translational Science | Principal Investigator |
| Carmen Andreescu, MD | Assistant Professor of Psychiatry | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21536162 | Background | Andreescu C, Reynolds CF 3rd. Late-life depression: evidence-based treatment and promising new directions for research and clinical practice. Psychiatr Clin North Am. 2011 Jun;34(2):335-55, vii-iii. doi: 10.1016/j.psc.2011.02.005. | |
| Background | Delis DC, Kaplan, E., Kramer, J.H. Delis Kaplan Executive Funciton System Examiner's Manual. The Psychological Corporation; 2001. | ||
| 9845158 |
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Individual participant data (IPD) will be shared through the NIMH Data Archive.
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Data collected to date is submitted twice annually (January and July) and is shared within 4 months of submission.
NIH will provide access to scientific investigators for research purposes.
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| ID | Title | Description |
|---|---|---|
| FG000 | Escitalopram Pill | Participants in this arm will receive an initial dose of 5 mg. Further titrations will be decided based on clinical response and tolerability (maximum dose of 20 mg). The medication will be taken by mouth in pill form, once daily. Escitalopram Pill: Double-blinded, randomly assigned |
| FG001 | Placebo | Participants will be given a sugar pill (placebo) to be taken by mouth once daily for the 6 week duration of Phase I. As this arm is also double-blinded, participants will receive an initial dose of 5 mg and further titrations (maximum dose of 20 mg) will be decided based on clinical response and tolerability. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima. Placebo: Double-blinded, randomly assigned |
| FG002 | Escitalopram Pill (Phase II) | Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II. Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study. Escitalopram Pill: Double-blinded, randomly assigned |
| FG003 | Levomilnacipran Pill | Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Levomilnacipran Pill: Double-blinded, randomly assigned |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Escitalopram Pill | Participants in this arm will receive an initial dose of 5 mg. Further titrations will be decided based on clinical response and tolerability (maximum dose of 20 mg). The medication will be taken by mouth in pill form, once daily. Escitalopram Pill: Double-blinded, randomly assigned |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Montgomery Asberg Depression Rating Scale Score | Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score. | Posted | Number | persons with positive treatment response | Change in Baseline MADRS score through Week 12 |
|
12 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Escitalopram Pill | Participants in this arm will receive an initial dose of 5 mg. Further titrations will be decided based on clinical response and tolerability (maximum dose of 20 mg). The medication will be taken by mouth in pill form, once daily. Escitalopram Pill: Double-blinded, randomly assigned |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| anxiety | Psychiatric disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Rachel Berta | University of Pittsburgh | 4128607406 | goodra@upmc.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 15, 2018 | Apr 4, 2018 | Prot_SAP_000.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D003863 | Depression |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D000089983 | Escitalopram |
| D000078862 | Levomilnacipran |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D009570 | Nitriles |
| D001572 |
Not provided
Not provided
Participants will be randomly assigned to take either escitalopram or levomilnacipran throughout the 12-week trial.
The following information applies to the original study design. Enrollment according to this design was complete as of April 2018: During Phase I, participants will be randomly assigned to take escitalopram or placebo daily for 6 weeks. After 6 weeks, participants who are randomly assigned to placebo will be given the option to have an open-label of escitalopram for Phase II. Those who did not respond to escitalopram in Phase I will be referred for alternate treatment. All participants, regardless of outcome will be asked to return for follow-up procedures.
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Although this is a double-blinded study, one staff member will be unblinded regarding study randomization. Should the need ever arise, the blind can be instantly broken for the participant's safety and well-being.
Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. |
|
| Placebo | Other | Double-blinded, randomly assigned |
|
| Levomilnacipran Pill | Drug | Double-blinded, randomly assigned |
|
|
| Hamilton Anxiety Rating Scale (HARS) |
The Hamilton Anxiety Rating Scale (HARS) is a structured interview to assist in the reliable assessment of anxiety severity by standardizing the method of assessment and providing clear anchor points for the assignment of severity ratings. Examines level of anxiety and somatization. To be used as covariate in functional connectivity analysis. Range of scores: 0-56. Lower the better |
| Baseline, Week 1, and Week 12 |
| Neuropsychological Evaluations | The neuropsychological testing battery, developed by Co-I Meryl Butters, Ph.D., includes components of the Delis-Kaplan Executive Function Scale (D-KEFS), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). "dkefs_trail4_scaled_1" is a scaled score for Condition 4 (Number-Letter Switching) of the D-KEFS Trail Making Test, which measures cognitive flexibility and executive functioning. Range 1-19. Higher the better " dkefs_colorword3_scaled_1" is a score from D-KEFS Color-Word Interference. The individual is asked to inhibit an automatic reading response to name the ink color of words that spell out conflicting color names. Range 1-19. Higher the better "rbans_total_index_1" is the total index score from the RBANS, designed to assess various cognitive domains. The total index score is a composite score that provides an overall measure of cognitive functioning by combining the results from all the RBANS subtests. Range 40-155. Higher the better | Baseline and Week 12 |
| Antidepressant Treatment History Questionnaire (ATHF) | Investigators will examine prior treatment history and how this may affect treatment response in this study. Number of participants analyzed are those who have previously had a trial of at least one antidepressant. | Baseline |
| Medication Plasma Levels | Investigators will assess how blood levels of escitalopram and levomilnacipran may affect treatment response. The data was not collected because the Co-Investigator responsible for the analyses left academia and the University of Pittsburgh. No data will ever be produced and there will be no results to report. | Weeks 1-12 |
| Age of Onset | Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response. | Baseline |
| Duration of Illness | Investigators will assess how length of current episode affect treatment response. | Duration of illness at Baseline |
| Background |
| Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998 Jun;20(3):310-9. doi: 10.1076/jcen.20.3.310.823. |
| 22055976 | Background | Tomaszewski Farias S, Mungas D, Harvey DJ, Simmons A, Reed BR, Decarli C. The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales. Alzheimers Dement. 2011 Nov;7(6):593-601. doi: 10.1016/j.jalz.2011.02.007. |
| 16421116 | Background | Isella V, Villa L, Russo A, Regazzoni R, Ferrarese C, Appollonio IM. Discriminative and predictive power of an informant report in mild cognitive impairment. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):166-71. doi: 10.1136/jnnp.2005.069765. |
| Placebo |
Participants will be given a sugar pill (placebo) to be taken by mouth once daily for the 6 week duration of Phase I. As this arm is also double-blinded, participants will receive an initial dose of 5 mg and further titrations (maximum dose of 20 mg) will be decided based on clinical response and tolerability. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima. Placebo: Double-blinded, randomly assigned |
| BG002 | Escitalopram Pill (Phase II) | Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II. Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study. Escitalopram Pill: Double-blinded, randomly assigned |
| BG003 | Levomilnacipran Pill | Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Levomilnacipran Pill: Double-blinded, randomly assigned |
| BG004 | Total | Total of all reporting groups |
| age at randomzation |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Montgomery Asberg Depression Rating Scale | Measure Description: The Montgomery Asberg Depression Rating Scale measures depression severity. Scores can range from 0 to 60, with higher scores indicating higher levels of depression severity. | 8 participants were eligible after screening measures, were randomized, but were then terminated from the study before "baseline" MADRS scores were recorded. | Mean | Standard Deviation | units on a scale |
|
| OG002 | Escitalopram Pill (Phase II) | Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II. Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study. Escitalopram Pill: Double-blinded, randomly assigned |
| OG003 | Levomilnacipran Pill | Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Levomilnacipran Pill: Double-blinded, randomly assigned |
|
|
| Primary | Change in Functional Connectivity | The primary analysis will consist of linear mixed effects models with functional connectivity (for each region of interest) as the outcome measure and group (R [responder]/NR[non-responder], as defined by MADRS), time and their interaction. The results listed are the difference in Baseline to 12 hours after first dose of medication. The values derived by first preprocessing the raw data using SPM and using the AAL3 atlas to parcellate the images into anatomical brain regions. Then the mean residual time series for each region was calculated and the Pearson correlation between the time series of each region was calculated. Then the mean Pearson correlations between every other region with the region identified were calculated and these correlation values were then standardized to have a mean of 0 and a standard deviation of 1. Higher values indicate stronger and better connectivity. | Total participants with available Baseline and Day 1 scans that could be analyzed. | Posted | Mean | Standard Deviation | Z-score | Change in Functional Connectivity from Baseline to Day 1 |
|
|
|
| Secondary | Response Styles Questionnaire- Rumination (RSQ-Rumination) | The Response Styles Questionnaire- Rumination (RSQ-Rumination) examines propensity towards negative bias during thought. To be used as covariate in functional connectivity analysis. Range of scores: 22-88. Lower the better | Participants who completed all 12 weeks of the study with RSQ scores. | Posted | Mean | Standard Deviation | RSQ total score | Baseline, Week 1, and Week 12 |
|
|
|
| Secondary | Hamilton Anxiety Rating Scale (HARS) | The Hamilton Anxiety Rating Scale (HARS) is a structured interview to assist in the reliable assessment of anxiety severity by standardizing the method of assessment and providing clear anchor points for the assignment of severity ratings. Examines level of anxiety and somatization. To be used as covariate in functional connectivity analysis. Range of scores: 0-56. Lower the better | Participants who completed all 12 weeks of the study with HARS scores. | Posted | Mean | Standard Deviation | HARS total score | Baseline, Week 1, and Week 12 |
|
|
|
| Secondary | Neuropsychological Evaluations | The neuropsychological testing battery, developed by Co-I Meryl Butters, Ph.D., includes components of the Delis-Kaplan Executive Function Scale (D-KEFS), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). "dkefs_trail4_scaled_1" is a scaled score for Condition 4 (Number-Letter Switching) of the D-KEFS Trail Making Test, which measures cognitive flexibility and executive functioning. Range 1-19. Higher the better " dkefs_colorword3_scaled_1" is a score from D-KEFS Color-Word Interference. The individual is asked to inhibit an automatic reading response to name the ink color of words that spell out conflicting color names. Range 1-19. Higher the better "rbans_total_index_1" is the total index score from the RBANS, designed to assess various cognitive domains. The total index score is a composite score that provides an overall measure of cognitive functioning by combining the results from all the RBANS subtests. Range 40-155. Higher the better | Participants who had complete neuropsychological testing at both Baseline and Week 12. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Week 12 |
|
|
|
| Secondary | Antidepressant Treatment History Questionnaire (ATHF) | Investigators will examine prior treatment history and how this may affect treatment response in this study. Number of participants analyzed are those who have previously had a trial of at least one antidepressant. | The Outcome are those who were considered "responders" for this study. No participants in the Placebo group had previously taken an antidepressant. | Posted | Count of Participants | Participants | Baseline |
|
|
|
| Secondary | Medication Plasma Levels | Investigators will assess how blood levels of escitalopram and levomilnacipran may affect treatment response. The data was not collected because the Co-Investigator responsible for the analyses left academia and the University of Pittsburgh. No data will ever be produced and there will be no results to report. | Analyses will not be performed at any time in the future. | Posted | Weeks 1-12 |
|
|
| Secondary | Age of Onset | Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response. | Age of onset for current depressive episode and how it relates treatment outcome. | Posted | Count of Participants | Participants | Baseline |
|
|
|
| Secondary | Duration of Illness | Investigators will assess how length of current episode affect treatment response. | Number of participants analyzed if information was available during interviews | Posted | Count of Participants | Participants | Duration of illness at Baseline |
|
|
|
| 0 |
| 25 |
| 0 |
| 25 |
| 13 |
| 25 |
| EG001 | Levomilnacipran Pill | Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Levomilnacipran Pill: Double-blinded, randomly assigned | 0 | 22 | 0 | 22 | 6 | 22 |
| EG002 | Placebo | Participants will be given a sugar pill (placebo) to be taken by mouth once daily for the 6 week duration of Phase I. As this arm is also double-blinded, participants will receive an initial dose of 5 mg and further titrations (maximum dose of 20 mg) will be decided based on clinical response and tolerability. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima. | 0 | 4 | 0 | 4 | 0 | 4 |
| EG003 | Escitalopram Pill (Phase II) | Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II. Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily. Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study. Escitalopram Pill: Double-blinded, randomly assigned | 0 | 6 | 0 | 6 | 4 | 6 |
| blurred vision | Eye disorders | Systematic Assessment |
|
| constipation | Gastrointestinal disorders | Systematic Assessment |
|
| decreased appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| drowsiness or yawning | General disorders | Systematic Assessment |
|
| dry mouth | General disorders | Systematic Assessment |
|
| extrapyramidal symptoms | Nervous system disorders | Systematic Assessment |
|
| flatulence | Gastrointestinal disorders | Systematic Assessment |
|
| headache | General disorders | Systematic Assessment |
|
| heartburn | General disorders | Systematic Assessment |
|
| increased appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| increased body temperature/sweating | General disorders | Systematic Assessment |
|
| increased irritability | Psychiatric disorders | Systematic Assessment |
|
| increased sleep | General disorders | Systematic Assessment |
|
| insomnia or trouble sleeping | General disorders | Systematic Assessment |
|
| lightheadedness | General disorders | Systematic Assessment |
|
| nausea or vomiting | General disorders | Systematic Assessment |
|
| palpitations | Cardiac disorders | Systematic Assessment |
|
| rash/itching | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| uninary problems | Renal and urinary disorders | Systematic Assessment |
|
| vertigo | General disorders | Systematic Assessment |
|
| weight gain | General disorders | Systematic Assessment |
|
Not provided
Not provided
| D001519 |
| Behavior |
| Benzofurans |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000078764 | Milnacipran |
| D003521 | Cyclopropanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Right Middle Frontal Gyrus day 1 difference |
|
| Left Anterior Insular day 1 difference |
|
| Right Anterior Insular day 1 difference |
|
| Left Amygdala day 1 difference |
|
| Right Amygdala day 1 difference |
|
| Left prefrontal Anterior Cingulate Cortex day 1 difference |
|
| Right prefrontal Anterior Cingulate Cortex day 1 difference |
|
| Week 01 |
|
| Week 12 |
|
| Week 01 |
|
| Week 12 |
|
| dkefs_trail4_scaled_1_Week12 |
|
| dkefs_colorword3_scaled_1_Baseline |
|
| dkefs_colorword3_scaled_1_Week12 |
|
| rbans_total_index_1_Baseline |
|
| rbans_total_index_1_Week12 |
|
| Number of participants age of onset at or after age 60 |
|
| Duration of more than one year to 10 years |
|
| Duration of more than 10 years |
|