Major Depressive DisorderPhase 4NEMONCT03128021

Neural Mechanisms of Monoaminergic Engagement in Late-life Depression Treatment Response (NEMO)

A Phase 4 study testing Escitalopram Pill and Levomilnacipran Pill in people with Major Depressive Disorder, run by Howard Aizenstein at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 60 years and older
Conditions the study is for: Major Depressive Disorder
What is being tested?: Escitalopram Pill and Levomilnacipran Pill
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 57 participants
Where: 1 siteUnited States
Study dates: 24 May 2017to 30 Aug 2023
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 60 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Show all 13Show fewer

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

Trial locations and contacts

1 site in 1 country.

United States1 site

University of Pittsburgh
Pittsburgh, Pennsylvania, 15213

Other trials in United States

About this study

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.

Read the 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.

Conditions: Major Depressive Disorder
Being tested: Escitalopram Pill, Placebo, Levomilnacipran Pill
Keywords: Depression, fMRI, Escitalopram, Lexapro, Randomized Clinical Trial, Levomilnacipran, Fetzima
Medical subject headings: Depressive Disorder, Major, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Escitalopram PillDrug
Also called Lexapro
Double-blinded, randomly assigned
PlaceboOther
Double-blinded, randomly assigned
Levomilnacipran PillDrug
Also called Fetzima
Double-blinded, randomly assigned

Study groups in NCT03128021
Study group	Role	What they receive
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. Receives: Drug: Escitalopram Pill
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. Receives: Other: Placebo
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. Receives: Drug: Escitalopram Pill
Levomilnacipran Pill	Active comparator	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. Receives: Drug: Levomilnacipran Pill

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: Change in Functional Connectivity from Baseline to Day 1

Secondary outcomes (7)

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
Measured: Baseline, Week 1, and Week 12
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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline
Duration of Illness
Investigators will assess how length of current episode affect treatment response.
Measured: Duration of illness at Baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 May 201730 Aug 2023

First posted25 Apr 2017
Study start24 May 2017
Primary completion21 Jun 2023
Study completion30 Aug 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (5)Papers the sponsor has linked to this study.
Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
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.
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 57 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03128021
Sponsor's protocol ID: STUDY19120137
Other IDs: R01MH076079
Acronym: NEMO
Status last verified: Feb 2025
First submitted: 4 Apr 2017
Last updated: 10 Mar 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Individual participant data (IPD) will be shared through the NIMH Data Archive.

Publications

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.
PubMed 21536162
Delis DC, Kaplan, E., Kramer, J.H. Delis Kaplan Executive Funciton System Examiner's Manual. The Psychological Corporation; 2001.
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.
PubMed 9845158
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.
PubMed 22055976
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.
PubMed 16421116

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 10 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Neural Mechanisms of Monoaminergic Engagement in Late-life Depression Treatment Response (NEMO)
ClinicalTrials.gov ID: NCT03128021
Acronym / sponsor ID: NEMO / STUDY19120137
Conditions: Major Depressive Disorder
Keywords: Depression, fMRI, Escitalopram, Lexapro, Randomized Clinical Trial, Levomilnacipran, Fetzima
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 57 participants (actual)
Lead sponsor: Howard AizensteinUniversity, hospital or other
Collaborators: Weill Cornell Institute of Geriatric Psychiatry, National Institute of Mental Health (NIMH)
Study start: 24 May 2017 (actual)
Primary completion: 21 Jun 2023 (actual)
Study completion: 30 Aug 2023 (actual)
First posted: 25 Apr 2017 (actual)
Results: Posted 10 Mar 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4
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.

Arm	Type	Receives
Escitalopram Pill	Active comparator	Drug: Escitalopram PillParticipants 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	Other: PlaceboParticipants 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	Drug: Escitalopram PillParticipants 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	Active comparator	Drug: Levomilnacipran PillParticipants 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.

Who may qualify

Ages: 60 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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

Key exclusion criteria (13 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Escitalopram PillAlso: LexaproDouble-blinded, randomly assigned	Drug	Escitalopram Pill, Escitalopram Pill (Phase II)
PlaceboDouble-blinded, randomly assigned	Other	Placebo
Levomilnacipran PillAlso: FetzimaDouble-blinded, randomly assigned	Drug	Levomilnacipran Pill

Primary outcome

Change in Montgomery Asberg Depression Rating Scale Score
Time frame: 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
Time frame: 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.

7 secondary outcomes

Response Styles Questionnaire- Rumination (RSQ-Rumination)
Time frame: Baseline, Week 1, and Week 12
Hamilton Anxiety Rating Scale (HARS)
Time frame: Baseline, Week 1, and Week 12
Neuropsychological Evaluations
Time frame: Baseline and Week 12
Antidepressant Treatment History Questionnaire (ATHF)
Time frame: Baseline
Medication Plasma Levels
Time frame: Weeks 1-12
Age of Onset
Time frame: Baseline
Duration of Illness
Time frame: Duration of illness at Baseline

Results and safety

Results posted to the registry on 10 Mar 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Escitalopram Pill	25	20
Placebo	4	2
Escitalopram Pill (Phase II)	6	4
Levomilnacipran Pill	22	9

Primary outcome: Change in Montgomery Asberg Depression Rating Scale Score

Time frame: Change in Baseline MADRS score through Week 12. Number. Unit: persons with positive treatment response

Measure	Escitalopram Pill n = 20	Placebo n = 2	Escitalopram Pill (Phase II) n = 4	Levomilnacipran Pill n = 9
Value	18	2	3	8

Primary outcome: Change in Functional Connectivity

Time frame: Change in Functional Connectivity from Baseline to Day 1. Mean (Standard Deviation). Unit: Z-score

Measure	Escitalopram Pill (R) n = 15	Placebo (R) n = 0	Escitalopram Pill (R) (Phase II) n = 5	Levomilnacipran Pill (R) n = 7	Escitalopram Pill (NR) n = 2	Placebo (NR) n = 0	Escitalopram Pill (NR) (Phase II) n = 1	Levomilnacipran Pill (NR) n = 0
Left Middle Frontal Gyrus day 1 difference	0.059122257 (0.970768475)	–	-0.337856865 (0.456280057)	-0.682262788 (0.394139675)	-0.005553818 (0.336358139)	–	-0.577911771	–
Right Middle Frontal Gyrus day 1 difference	0.090272305 (1.047858325)	–	0.80863611 (0.591200619)	-0.064993511 (0.942271068)	1.243841088 (0.160518864)	–	-1.315813839	–
Left Anterior Insular day 1 difference	0.007749148 (1.206679758)	–	-0.48413394 (1.3756677)	-0.224292239 (0.655920209)	-1.553051837 (0.638678017)	–	0.976927111	–
Right Anterior Insular day 1 difference	-0.227766723 (1.228475106)	–	-0.23236189 (0.616824453)	0.147147958 (0.887236616)	1.056817365 (1.504505678)	–	0.820792593	–
Left Amygdala day 1 difference	0.259715101 (0.91863688)	–	-0.592134869 (1.3814767)	0.147597427 (0.599482713)	-1.33405492 (0.601671616)	–	1.9845321	–
Right Amygdala day 1 difference	-0.443833224 (1.739580169)	–	-1.311685475 (1.328056717)	0.548047987 (1.379828096)	-0.030660361 (0.159008845)	–	0.964444893	–
Left prefrontal Anterior Cingulate Cortex day 1 difference	0.048557684 (1.079632973)	–	0.735636432 (1.010043826)	-0.003163926 (0.783815631)	-0.216753695 (0.608987758)	–	-1.215843301	–
Right prefrontal Anterior Cingulate Cortex day 1 difference	0.206183452 (1.994469683)	–	1.413900498 (1.543971432)	0.131919092 (0.80516401)	0.839416177 (2.093317463)	–	-1.637127786	–

Population analysed: Total participants with available Baseline and Day 1 scans that could be analyzed.

7 secondary outcomes are reported in the full results.

Adverse events

Time frame: 12 weeks. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Escitalopram Pill	0 of 25 (0%)	13 of 25 (52%)	0 of 25
Levomilnacipran Pill	0 of 22 (0%)	6 of 22 (27.3%)	0 of 22
Placebo	0 of 4 (0%)	0 of 4 (0%)	0 of 4
Escitalopram Pill (Phase II)	0 of 6 (0%)	4 of 6 (66.7%)	0 of 6

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 21536162Andreescu 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.
BackgroundDelis DC, Kaplan, E., Kramer, J.H. Delis Kaplan Executive Funciton System Examiner's Manual. The Psychological Corporation; 2001.
Background: PubMed 9845158Randolph 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.
Background: PubMed 22055976Tomaszewski 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.
Background: PubMed 16421116Isella 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.
Individual participant dataSharing planned: Yes. Individual participant data (IPD) will be shared through the NIMH Data Archive.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Howard J Aizenstein, MD, Ph.D. principal investigator

Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Associate Professor of Bioengineering and Clinical and Translational Science

Carmen Andreescu, MD principal investigator

Assistant Professor of Psychiatry

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Escitalopram Pill and Levomilnacipran Pill in people with Major Depressive Disorder, run by Howard Aizenstein at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Mar 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Montgomery Asberg Depression Rating Scale Score (time frame: Change in Baseline MADRS score through Week 12). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03128021, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2025.