Major Depressive Disorder
Conditions
Keywords
Depression, fMRI, Escitalopram, Lexapro, Randomized Clinical Trial, Levomilnacipran, Fetzima
Brief summary
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.
Detailed description
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.
Interventions
Double-blinded, randomly assigned
OTHERPlacebo
Double-blinded, randomly assigned
DRUGLevomilnacipran Pill
Double-blinded, randomly assigned
Sponsors
Weill Cornell Institute of Geriatric Psychiatry
National Institute of Mental Health (NIMH)
Howard Aizenstein
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to 60 years old * Current Major Depressive Episode or Current Depressive Disorder Not Otherwise Specified or Dysthymic Disorder * Montgomery-Asberg Depression Rating Scale (MADRS) greater than or equal to 12 * Modified Mini-Mental State (3MS) score greater than or equal to 84 * MoCA-BLIND greater than or equal to 13
Exclusion criteria
* History of Mania or Psychosis * Current suicidal ideation that cannot be safely managed within the confines of a clinical trial * Alcohol or Substance Abuse (current or past 3 months) endorsed via phone screening interview or diagnosed by Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (SCID) * Dementia of any etiology endorsed via phone screening interview or diagnosed by SCID * Medical conditions with known significant effects on mood (e.g., stroke, current hypothyroid state) as well as unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, hyperlipidemia, or cardiovascular risk factors that are not under medical management Unwilling or clinically determined to be unable to taper from high doses of benzodiazepines (equivalent to \> 2 mg lorazepam/day) or other anti-depressant/anti-anxiety medications at time of screening. However, for participants who are prescribed low dose psychotropics for pain, sleep disturbances, and/or medical conditions (e.g. amitriptyline for peripheral neuropathy, low dose trazodone as a sleep aid), these will be allowed in most circumstances. We will include participants on certain dosages of the most commonly prescribed antidepressants (for medical reasons) as follows: amitriptyline up to 50 mg/d, doxepin up to 50 mg/d, trazodone up to 100 mg/d, and imipramine up to 50 mg/d. Participants will also be able to continue taking buspirone, an antianxiety medication. As per the examples above, the PI will decide if the participants are eligible for the study and if they may continue the current medication. Justification regarding all decisions will be documented in the research record. * Inability to complete required assessments including brain MRI and blood draw * Hearing/vision impairment precluding neuropsychological testing * Difficulty conversing in English * Clinical contraindication to use of escitalopram or levomilnacipran or history of treatment resistance to escitalopram or levomilnacipran * Unable or unwilling to provide a secondary/emergency contact person * History of stroke with residual symptoms, current epilepsy, or current post-concussive symptoms * Clinically relevant hyponatremia (below 130 mEq/L) * Significant renal impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montgomery Asberg Depression Rating Scale Score | Change in Baseline MADRS score through Week 12 | Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score. |
| Change in Functional Connectivity | Change in Functional Connectivity from Baseline to Day 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological Evaluations | Baseline and Week 12 | 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 |
| Antidepressant Treatment History Questionnaire (ATHF) | Baseline | 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. |
| Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline, Week 1, and Week 12 | 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 |
| Age of Onset | Baseline | Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response. |
| Duration of Illness | Duration of illness at Baseline | Investigators will assess how length of current episode affect treatment response. |
| Medication Plasma Levels | Weeks 1-12 | 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. |
| Hamilton Anxiety Rating Scale (HARS) | Baseline, Week 1, and Week 12 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 25 |
| 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 | 4 |
| 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 | 6 |
| 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 | 22 |
| Total | 57 |
Baseline characteristics
| Characteristic | Escitalopram Pill | Placebo | Escitalopram Pill (Phase II) | Levomilnacipran Pill | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.13 age at randomzation STANDARD_DEVIATION 6.29 | 63.74 age at randomzation STANDARD_DEVIATION 3.02 | 64.47 age at randomzation STANDARD_DEVIATION 2.17 | 68.43 age at randomzation STANDARD_DEVIATION 7.72 | 67.55 age at randomzation STANDARD_DEVIATION 6.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 4 Participants | 6 Participants | 22 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Montgomery Asberg Depression Rating Scale | 19.43 units on a scale STANDARD_DEVIATION 6.68 | 25.33 units on a scale STANDARD_DEVIATION 5.51 | 23.83 units on a scale STANDARD_DEVIATION 5.19 | 21.94 units on a scale STANDARD_DEVIATION 6.35 | 21.20 units on a scale STANDARD_DEVIATION 6.45 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 2 Participants | 3 Participants | 18 Participants | 45 Participants |
| Region of Enrollment United States | 25 participants | 4 participants | 6 participants | 22 participants | 57 participants |
| Sex: Female, Male Female | 13 Participants | 3 Participants | 5 Participants | 10 Participants | 31 Participants |
| Sex: Female, Male Male | 12 Participants | 1 Participants | 1 Participants | 12 Participants | 26 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 / 25 | 0 / 22 | 0 / 4 | 0 / 6 |
| other Total, other adverse events | 13 / 25 | 6 / 22 | 0 / 4 | 4 / 6 |
| serious Total, serious adverse events | 0 / 25 | 0 / 22 | 0 / 4 | 0 / 6 |
Outcome results
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.
Time frame: Change in Functional Connectivity from Baseline to Day 1
Population: Total participants with available Baseline and Day 1 scans that could be analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram Pill | Change in Functional Connectivity | Left Middle Frontal Gyrus day 1 difference | 0.059122257 Z-score | Standard Deviation 0.970768475 |
| Escitalopram Pill | Change in Functional Connectivity | Left Amygdala day 1 difference | 0.259715101 Z-score | Standard Deviation 0.91863688 |
| Escitalopram Pill | Change in Functional Connectivity | Left prefrontal Anterior Cingulate Cortex day 1 difference | 0.048557684 Z-score | Standard Deviation 1.079632973 |
| Escitalopram Pill | Change in Functional Connectivity | Right Anterior Insular day 1 difference | -0.227766723 Z-score | Standard Deviation 1.228475106 |
| Escitalopram Pill | Change in Functional Connectivity | Left Anterior Insular day 1 difference | 0.007749148 Z-score | Standard Deviation 1.206679758 |
| Escitalopram Pill | Change in Functional Connectivity | Right Middle Frontal Gyrus day 1 difference | 0.090272305 Z-score | Standard Deviation 1.047858325 |
| Escitalopram Pill | Change in Functional Connectivity | Right prefrontal Anterior Cingulate Cortex day 1 difference | 0.206183452 Z-score | Standard Deviation 1.994469683 |
| Escitalopram Pill | Change in Functional Connectivity | Right Amygdala day 1 difference | -0.443833224 Z-score | Standard Deviation 1.739580169 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Left Middle Frontal Gyrus day 1 difference | -0.337856865 Z-score | Standard Deviation 0.456280057 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Right Amygdala day 1 difference | -1.311685475 Z-score | Standard Deviation 1.328056717 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Right Middle Frontal Gyrus day 1 difference | 0.80863611 Z-score | Standard Deviation 0.591200619 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Left prefrontal Anterior Cingulate Cortex day 1 difference | 0.735636432 Z-score | Standard Deviation 1.010043826 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Right prefrontal Anterior Cingulate Cortex day 1 difference | 1.413900498 Z-score | Standard Deviation 1.543971432 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Left Anterior Insular day 1 difference | -0.48413394 Z-score | Standard Deviation 1.3756677 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Right Anterior Insular day 1 difference | -0.23236189 Z-score | Standard Deviation 0.616824453 |
| Escitalopram Pill (Phase II) | Change in Functional Connectivity | Left Amygdala day 1 difference | -0.592134869 Z-score | Standard Deviation 1.3814767 |
| Levomilnacipran Pill | Change in Functional Connectivity | Right Middle Frontal Gyrus day 1 difference | -0.064993511 Z-score | Standard Deviation 0.942271068 |
| Levomilnacipran Pill | Change in Functional Connectivity | Left prefrontal Anterior Cingulate Cortex day 1 difference | -0.003163926 Z-score | Standard Deviation 0.783815631 |
| Levomilnacipran Pill | Change in Functional Connectivity | Right prefrontal Anterior Cingulate Cortex day 1 difference | 0.131919092 Z-score | Standard Deviation 0.80516401 |
| Levomilnacipran Pill | Change in Functional Connectivity | Left Middle Frontal Gyrus day 1 difference | -0.682262788 Z-score | Standard Deviation 0.394139675 |
| Levomilnacipran Pill | Change in Functional Connectivity | Left Anterior Insular day 1 difference | -0.224292239 Z-score | Standard Deviation 0.655920209 |
| Levomilnacipran Pill | Change in Functional Connectivity | Left Amygdala day 1 difference | 0.147597427 Z-score | Standard Deviation 0.599482713 |
| Levomilnacipran Pill | Change in Functional Connectivity | Right Anterior Insular day 1 difference | 0.147147958 Z-score | Standard Deviation 0.887236616 |
| Levomilnacipran Pill | Change in Functional Connectivity | Right Amygdala day 1 difference | 0.548047987 Z-score | Standard Deviation 1.379828096 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Right prefrontal Anterior Cingulate Cortex day 1 difference | 0.839416177 Z-score | Standard Deviation 2.093317463 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Left Amygdala day 1 difference | -1.33405492 Z-score | Standard Deviation 0.601671616 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Right Middle Frontal Gyrus day 1 difference | 1.243841088 Z-score | Standard Deviation 0.160518864 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Left Anterior Insular day 1 difference | -1.553051837 Z-score | Standard Deviation 0.638678017 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Right Amygdala day 1 difference | -0.030660361 Z-score | Standard Deviation 0.159008845 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Left prefrontal Anterior Cingulate Cortex day 1 difference | -0.216753695 Z-score | Standard Deviation 0.608987758 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Left Middle Frontal Gyrus day 1 difference | -0.005553818 Z-score | Standard Deviation 0.336358139 |
| Escitalopram Pill (NR) | Change in Functional Connectivity | Right Anterior Insular day 1 difference | 1.056817365 Z-score | Standard Deviation 1.504505678 |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Right Amygdala day 1 difference | 0.964444893 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Right prefrontal Anterior Cingulate Cortex day 1 difference | -1.637127786 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Right Anterior Insular day 1 difference | 0.820792593 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Left prefrontal Anterior Cingulate Cortex day 1 difference | -1.215843301 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Right Middle Frontal Gyrus day 1 difference | -1.315813839 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Left Amygdala day 1 difference | 1.9845321 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Left Anterior Insular day 1 difference | 0.976927111 Z-score | — |
| Escitalopram Pill (NR) (Phase II) | Change in Functional Connectivity | Left Middle Frontal Gyrus day 1 difference | -0.577911771 Z-score | — |
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.
Time frame: Change in Baseline MADRS score through Week 12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram Pill | Change in Montgomery Asberg Depression Rating Scale Score | 18 persons with positive treatment response |
| Placebo | Change in Montgomery Asberg Depression Rating Scale Score | 2 persons with positive treatment response |
| Escitalopram Pill (Phase II) | Change in Montgomery Asberg Depression Rating Scale Score | 3 persons with positive treatment response |
| Levomilnacipran Pill | Change in Montgomery Asberg Depression Rating Scale Score | 8 persons with positive treatment response |
Secondary
Age of Onset
Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response.
Time frame: Baseline
Population: Age of onset for current depressive episode and how it relates treatment outcome.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Escitalopram Pill | Age of Onset | Number of participants age of onset before age 60 | 6 Participants |
| Escitalopram Pill | Age of Onset | Number of participants age of onset at or after age 60 | 10 Participants |
| Placebo | Age of Onset | Number of participants age of onset before age 60 | 2 Participants |
| Placebo | Age of Onset | Number of participants age of onset at or after age 60 | 0 Participants |
| Escitalopram Pill (Phase II) | Age of Onset | Number of participants age of onset before age 60 | 2 Participants |
| Escitalopram Pill (Phase II) | Age of Onset | Number of participants age of onset at or after age 60 | 1 Participants |
| Levomilnacipran Pill | Age of Onset | Number of participants age of onset before age 60 | 2 Participants |
| Levomilnacipran Pill | Age of Onset | Number of participants age of onset at or after age 60 | 4 Participants |
| Escitalopram Pill (NR) | Age of Onset | Number of participants age of onset before age 60 | 2 Participants |
| Escitalopram Pill (NR) | Age of Onset | Number of participants age of onset at or after age 60 | 0 Participants |
| Placebo (NR) | Age of Onset | Number of participants age of onset before age 60 | 0 Participants |
| Placebo (NR) | Age of Onset | Number of participants age of onset at or after age 60 | 0 Participants |
| Escitalopram Pill (NR) (Phase II) | Age of Onset | Number of participants age of onset at or after age 60 | 0 Participants |
| Escitalopram Pill (NR) (Phase II) | Age of Onset | Number of participants age of onset before age 60 | 0 Participants |
| Levomilnacipran Pill (NR) | Age of Onset | Number of participants age of onset before age 60 | 1 Participants |
| Levomilnacipran Pill (NR) | Age of Onset | Number of participants age of onset at or after age 60 | 0 Participants |
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.
Time frame: Baseline
Population: The Outcome are those who were considered responders for this study. No participants in the Placebo group had previously taken an antidepressant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Escitalopram Pill | Antidepressant Treatment History Questionnaire (ATHF) | 7 Participants |
| Placebo | Antidepressant Treatment History Questionnaire (ATHF) | 0 Participants |
| Escitalopram Pill (Phase II) | Antidepressant Treatment History Questionnaire (ATHF) | 1 Participants |
| Levomilnacipran Pill | Antidepressant Treatment History Questionnaire (ATHF) | 2 Participants |
Secondary
Duration of Illness
Investigators will assess how length of current episode affect treatment response.
Time frame: Duration of illness at Baseline
Population: Number of participants analyzed if information was available during interviews
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Escitalopram Pill | Duration of Illness | Duration of one year or less | 6 Participants |
| Escitalopram Pill | Duration of Illness | Duration of more than one year to 10 years | 5 Participants |
| Escitalopram Pill | Duration of Illness | Duration of more than 10 years | 5 Participants |
| Placebo | Duration of Illness | Duration of more than 10 years | 2 Participants |
| Placebo | Duration of Illness | Duration of one year or less | 0 Participants |
| Placebo | Duration of Illness | Duration of more than one year to 10 years | 0 Participants |
| Escitalopram Pill (Phase II) | Duration of Illness | Duration of more than 10 years | 2 Participants |
| Escitalopram Pill (Phase II) | Duration of Illness | Duration of one year or less | 1 Participants |
| Escitalopram Pill (Phase II) | Duration of Illness | Duration of more than one year to 10 years | 0 Participants |
| Levomilnacipran Pill | Duration of Illness | Duration of one year or less | 3 Participants |
| Levomilnacipran Pill | Duration of Illness | Duration of more than one year to 10 years | 2 Participants |
| Levomilnacipran Pill | Duration of Illness | Duration of more than 10 years | 1 Participants |
| Escitalopram Pill (NR) | Duration of Illness | Duration of more than 10 years | 0 Participants |
| Escitalopram Pill (NR) | Duration of Illness | Duration of one year or less | 0 Participants |
| Escitalopram Pill (NR) | Duration of Illness | Duration of more than one year to 10 years | 2 Participants |
| Placebo (NR) | Duration of Illness | Duration of more than 10 years | 0 Participants |
| Placebo (NR) | Duration of Illness | Duration of one year or less | 0 Participants |
| Placebo (NR) | Duration of Illness | Duration of more than one year to 10 years | 0 Participants |
| Escitalopram Pill (NR) (Phase II) | Duration of Illness | Duration of more than one year to 10 years | 0 Participants |
| Escitalopram Pill (NR) (Phase II) | Duration of Illness | Duration of one year or less | 0 Participants |
| Escitalopram Pill (NR) (Phase II) | Duration of Illness | Duration of more than 10 years | 0 Participants |
| Levomilnacipran Pill (NR) | Duration of Illness | Duration of more than one year to 10 years | 0 Participants |
| Levomilnacipran Pill (NR) | Duration of Illness | Duration of one year or less | 1 Participants |
| Levomilnacipran Pill (NR) | Duration of Illness | Duration of more than 10 years | 0 Participants |
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
Time frame: Baseline, Week 1, and Week 12
Population: Participants who completed all 12 weeks of the study with HARS scores.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram Pill | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 12.3 HARS total score | Standard Deviation 6.4 |
| Escitalopram Pill | Hamilton Anxiety Rating Scale (HARS) | Baseline | 19.3 HARS total score | Standard Deviation 6.66 |
| Escitalopram Pill | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 7.5 HARS total score | Standard Deviation 5.44 |
| Placebo | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 7 HARS total score | Standard Deviation 5.66 |
| Placebo | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 19.5 HARS total score | Standard Deviation 7.78 |
| Placebo | Hamilton Anxiety Rating Scale (HARS) | Baseline | 22.5 HARS total score | Standard Deviation 9.19 |
| Escitalopram Pill (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Baseline | 26.6 HARS total score | Standard Deviation 3.05 |
| Escitalopram Pill (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 18.3 HARS total score | Standard Deviation 7.64 |
| Escitalopram Pill (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 19.7 HARS total score | Standard Deviation 1.53 |
| Levomilnacipran Pill | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 16.4 HARS total score | Standard Deviation 4.53 |
| Levomilnacipran Pill | Hamilton Anxiety Rating Scale (HARS) | Baseline | 21.5 HARS total score | Standard Deviation 5.26 |
| Levomilnacipran Pill | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 10.6 HARS total score | Standard Deviation 8.33 |
| Escitalopram Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 21.5 HARS total score | Standard Deviation 3.54 |
| Escitalopram Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Baseline | 25.5 HARS total score | Standard Deviation 2.12 |
| Escitalopram Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 18.5 HARS total score | Standard Deviation 4.95 |
| Escitalopram Pill (NR) (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Baseline | 24 HARS total score | — |
| Escitalopram Pill (NR) (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 20 HARS total score | — |
| Escitalopram Pill (NR) (Phase II) | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 17 HARS total score | — |
| Levomilnacipran Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Week 12 | 32 HARS total score | — |
| Levomilnacipran Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Week 01 | 24 HARS total score | — |
| Levomilnacipran Pill (NR) | Hamilton Anxiety Rating Scale (HARS) | Baseline | 23 HARS total score | — |
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.
Time frame: Weeks 1-12
Population: Analyses will not be performed at any time in the future.
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
Time frame: Baseline and Week 12
Population: Participants who had complete neuropsychological testing at both Baseline and Week 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram Pill | Neuropsychological Evaluations | rbans_total_index_1_Baseline | 97.4 score on a scale | Standard Deviation 9.21 |
| Escitalopram Pill | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Week12 | 10.8 score on a scale | Standard Deviation 3.65 |
| Escitalopram Pill | Neuropsychological Evaluations | rbans_total_index_1_Week12 | 102.9 score on a scale | Standard Deviation 12.04 |
| Escitalopram Pill | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Baseline | 11 score on a scale | Standard Deviation 3.26 |
| Escitalopram Pill | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Week12 | 11.6 score on a scale | Standard Deviation 2.5 |
| Escitalopram Pill | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Baseline | 11 score on a scale | Standard Deviation 3.71 |
| Placebo | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Baseline | 9 score on a scale | — |
| Placebo | Neuropsychological Evaluations | rbans_total_index_1_Baseline | 110 score on a scale | — |
| Placebo | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Week12 | 9 score on a scale | — |
| Placebo | Neuropsychological Evaluations | rbans_total_index_1_Week12 | 107 score on a scale | — |
| Placebo | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Baseline | 11 score on a scale | — |
| Placebo | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Week12 | 11 score on a scale | — |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | rbans_total_index_1_Baseline | 94 score on a scale | Standard Deviation 1.41 |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Week12 | 9 score on a scale | Standard Deviation 4.24 |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Week12 | 10.5 score on a scale | Standard Deviation 0.71 |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Baseline | 9 score on a scale | Standard Deviation 0 |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Baseline | 8 score on a scale | Standard Deviation 5.66 |
| Escitalopram Pill (Phase II) | Neuropsychological Evaluations | rbans_total_index_1_Week12 | 102.5 score on a scale | Standard Deviation 2.12 |
| Levomilnacipran Pill | Neuropsychological Evaluations | rbans_total_index_1_Week12 | 102.6 score on a scale | Standard Deviation 20.41 |
| Levomilnacipran Pill | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Baseline | 10.6 score on a scale | Standard Deviation 3.21 |
| Levomilnacipran Pill | Neuropsychological Evaluations | dkefs_trail4_scaled_1_Week12 | 12.25 score on a scale | Standard Deviation 1.26 |
| Levomilnacipran Pill | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Baseline | 11 score on a scale | Standard Deviation 2 |
| Levomilnacipran Pill | Neuropsychological Evaluations | dkefs_colorword3_scaled_1_Week12 | 10.6 score on a scale | Standard Deviation 3.58 |
| Levomilnacipran Pill | Neuropsychological Evaluations | rbans_total_index_1_Baseline | 103.2 score on a scale | Standard Deviation 17.92 |
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
Time frame: Baseline, Week 1, and Week 12
Population: Participants who completed all 12 weeks of the study with RSQ scores.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 33.7 RSQ total score | Standard Deviation 10.39 |
| Escitalopram Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 39 RSQ total score | Standard Deviation 11.08 |
| Escitalopram Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 45.1 RSQ total score | Standard Deviation 11.01 |
| Placebo | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 40.5 RSQ total score | Standard Deviation 2.12 |
| Placebo | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 39.5 RSQ total score | Standard Deviation 3.54 |
| Placebo | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 28.5 RSQ total score | Standard Deviation 3.54 |
| Escitalopram Pill (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 42.7 RSQ total score | Standard Deviation 8.96 |
| Escitalopram Pill (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 60.7 RSQ total score | Standard Deviation 11.15 |
| Escitalopram Pill (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 52.3 RSQ total score | Standard Deviation 16.74 |
| Levomilnacipran Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 40.5 RSQ total score | Standard Deviation 7.23 |
| Levomilnacipran Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 49.7 RSQ total score | Standard Deviation 8.73 |
| Levomilnacipran Pill | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 40.4 RSQ total score | Standard Deviation 9.87 |
| Escitalopram Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 61 RSQ total score | Standard Deviation 9.9 |
| Escitalopram Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 67.5 RSQ total score | Standard Deviation 0.071 |
| Escitalopram Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 60 RSQ total score | Standard Deviation 1.41 |
| Escitalopram Pill (NR) (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 49 RSQ total score | — |
| Escitalopram Pill (NR) (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 30 RSQ total score | — |
| Escitalopram Pill (NR) (Phase II) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 46 RSQ total score | — |
| Levomilnacipran Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 12 | 67 RSQ total score | — |
| Levomilnacipran Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Week 01 | 51 RSQ total score | — |
| Levomilnacipran Pill (NR) | Response Styles Questionnaire- Rumination (RSQ-Rumination) | Baseline | 50 RSQ total score | — |