Clinical trial NCT01728194
Conditions: Depression
Keywords: Depression Depressive Disorder Behavioral Symptoms Mood Disorders Mental Disorders Escitalopram Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Physiological Effects of Drugs Muscarinic Antagonists Antidepressive Agents Psychotropic Drugs Serotonin Uptake Inhibitors Neurotransmitter Uptake Inhibitors Serotonin Agents Magnetic Resonance Imaging, Functional fMRI Magnetic Resonance Imaging
Sponsor: Weill Medical College of Cornell University
Start date: 2012-07-01; Completion date: 2019-07-31
Enrollment: 121 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study may help identify how abnormalities in brain systems that control the ability to ignore irrelevant information may contribute to the development of depression in older adults.

Detailed description:
Approximately half of those who develop depression in late life never had depression before. The classic view is that changes taking place in our brains as we age contribute to the development of late-onset depression. This view is supported by the relative absence of family history for those with late onset depression. This research study will recruit 70 older adults with late life depression and 70 older adults without depression. All participants will receive a sub-clinical, non-contrast (magnetic resonance imaging (MRI) scan at the beginning of the study and then again 12 weeks later at the completion of the study. The depressed older participants will also receive a Food and Drug Administration (FDA)-approved antidepressant, escitalopram (Lexapro), as treatment for their depressive symptoms over 12 weeks. This MRI study may help the researchers identify how abnormalities in brain systems that control our ability to ignore distractions, control our emotions, and anticipate reward may contribute to the development of depression in older adults. The investigators hope that the findings promote the development of tests that may improve the detection of older adults at risk for poor treatment outcomes and eventually guide the development of novel treatments for depression.

Arms: arm 1: Target dose 20mg for 12 weeks arm 2: Non-psychiatric comparison participants.
Interventions: intervention 1: Escitalopram intervention 2: Magnetic Resonance Imaging
Intervention descriptions: intervention 1: 20 mg target dose for 12 weeks intervention 2: Structural and functional MRI of the brain for research purposes.

Protocol documents:
Prot_001.pdf: 
White Matter and Emotional and Cognitive Control in Late-Onset Depression 
 
NCT01728194 
 
03/24/15 
 
 


OVERVIEW & RESEARCH QUESTION 
 
The primary aim of this project is to use sub-clinical, non-contrast functional magnetic 
resonance imaging (fMRI) and diffusion tensor imaging (DTI) in LOD to examine whether 
dysfunction of the emotional and cognitive control systems are mechanisms by which aging- 
related structural and functional abnormalities contribute to the development of LOD and to the 
persistence of its symptoms. 
 
For our primary hypotheses we will focus on the role of microstructural white matter 
abnormalities and activation of control structures in the development of LOD. 
 
For our secondary hypotheses, we will focus on the role of microstructural abnormalities, 
activation of control structures and the persistence of LOD despite treatment with a FDA- 
approved SSRI antidepressant medication (escitalopram). In addition, we will examine the role 
of microstructural abnormalities, and activation of reward systems in the presence and 
persistence of LOD despite treatment with escitalopram. 
 
The aims will be pursued in 70 normal and 70 older adults with LOD. The LOD group will 
undergo a one-week psychotropic washout phase during which they will complete an MRI 
session that includes fMRI and diffusion tensor imaging. LOD patients will then receive 12 
weeks of escitalopram treatment at the target daily dose of 20 mg. 
 
In addition to testing our hypotheses, the study enables exploratory analyses of the: 
1) Role of white matter integrity in the development and persistence of LOD; 
2) Relationships of control network and reward system activation after 12 weeks of SSRI 


treatment to baseline activation and white matter integrity and persistence of 
depression at 12 weeks. 
 
We expect this MRI study of LOD to offer novel information about the neural circuitry 
mechanisms of depression. In addition, the identification of structural and functional 
impairments of LOD can aid the development of clinical instruments and targeted interventions. 
 
EXPERIMENTAL DESIGN 
 
Participants 
 
The subjects will be divided into two groups each with 70 participants: 
• 
Older adults (aged 60-85 years) with late-onset (>60 years), unipolar, non-psychotic, 
major depression and without cognitive impairment; 
• 
Normal controls (aged 60-85 years) without psychiatric illness and without cognitive 
impairment. 
We anticipate that approximately 15% of depressed patients will improve and fail to meet the 
depression severity eligibility criterion after the washout phase and approximately 12% of 
subjects will have unusable fMRI scans (e.g., excessive motion, claustrophobia, clinically 
significant abnormalities on MRI). Thus, we anticipate the need to recruit 94 patients and 80 
controls to meet our requirements. 
 
Medication: Depressed Subjects 
 
This section pertains only to subjects with depression. Depressed patients will undergo a 
psychotropic washout phase of one week duration (at the end of which they will have an MRI) 
followed by 12 weeks of escitalopram treatment at the target daily dose of 20 mg. The washout 
phase is intended to reduce the impact of prior treatment on brain activation. While a longer 
psychotropic-free period may be advantageous, concerns about worsening of depression made 
us limit the washout phase. (Patients on fluoxetine and MAOIs will be excluded from the study 
because they would require a longer drug-free period.) 
 
Subjects will only be asked to discontinue psychiatric medications (e.g. antidepressants, select 
sleep agents, and anxiolytics. See exclusion criteria for full description) after it has been 
ascertained that, in spite of the medication, the subject still has significant depressive symptoms 
of at least moderate severity, i.e. they meet the diagnostic criteria for a current episode of MDD 
and are suffering at least a moderate level of depressive symptoms (24-HDRS score > 19). 
Under the supervision of the study psychiatrist, subjects will be asked to gradually withdraw 
other psychotropic medications. (Zolpidem for insomnia will be permitted; see exclusion criteria 
for full description). 
 
In most cases, the washout phase will last one week (7 days). If subjects continue to meet 
depression severity criteria at the end of this one week period, they will be started on 
medication. 
 
The washout phase may extend beyond 7 days for the following reasons: 
1. If the study psychiatrists believe that it is clinically indicated to lengthen the washout 
period in order to reduce side effects of removing psychotropic medications. The 
maximum washout period will be two weeks. 
2. On rare occasions when subjects miss their scheduled appointment (due to bad 
weather, illness, etc.) during which they will begin active medication, every effort will be 


made to reschedule this study visit within two-three days, thus extending the washout 
phase until they come in for the visit; 
3. The washout phase may extend beyond 7 days if a subject no longer meets the 
depression severity cut-off for study inclusion, and the study physician judges that such 
improvement is transient and based on instability of symptoms during the washout 
phase, or that symptoms are not covered by the HDRS and are likely to return, the study 
physician may extend the washout for a maximum of seven additional days. If after that 
extension the subject meets criteria s/he will be entered into the 12-week active 
treatment phase of the study. If the subject no longer meets entry criteria the study 
physician will discuss the subject’s symptom improvement and will refer him/her for 
further evaluation or treatment as clinically indicated. 
In some instances the washout phase may be less than one week. The one-week washout 
phase may be truncated or eliminated if, in the opinion of the study physician and PI, the 
patient's symptom severity is such that they would not be able to tolerate the full washout 
phase. 
 
The SSRI escitalopram was selected because it combines an easy to achieve therapeutic 
dosage with limited drug-drug interactions, safety in overdose, few CNS activation side effects 
(e.g., restlessness, insomnia, tremor) and a mild withdrawal syndrome. Our research Institute 
has studied this drug in over 220 depressed elders. Thus, data will be available for secondary 
analyses of response characteristics. We target 20 mg daily to avoid under-treatment. 
 
Following the drug washout, escitalopram will be started at 10 mg each morning, increased to 
15 mg in 1 week, and to 20 mg 1 week later. As its average elimination half-life is 32 hours, 
steady state kinetics are expected to be achieved before each dose increment so that dose- 
dependent side effects can be adequately assessed before a higher dose is given. In subjects 
unable to tolerate 20 mg escitalopram, the dosage will be reduced to 15 or 10 mg. However, 
subjects unable to tolerate 10 mg/day will be excluded from this protocol, as lower dosages may 
be of limited efficacy.  Based on the Institute’s experience, we expect to terminate less than 
10% of subjects from the study because of intolerance of escitalopram. In all such cases, 
Institute clinicians will provide treatment until a referral for community based care can be 
established. 
 
Depressed subjects will be seen by a study psychiatrist on week 0, 1, 2, 3, 4, 5, 7, 9, 11, 13 and 
given a 12-week course of treatment with escitalopram. During their visits (15-20 minutes), 
subjects will meet with a research psychiatrist, who will follow a medication management format 
(review psychiatric symptoms, medical state, side effects, suicidal ideation, and adherence to 
treatment). To reduce burden, psychiatrist visits will be scheduled immediately after research 
assessment sessions, so that information obtained by the research assistant can be shared with 
the psychiatrist. The “comprehensive assessment” will be completed before termination. 
 
At the completion of the treatment phase of the research study subjects will be referred for 
continued treatment, if needed, to our clinical services or to a qualified clinician of the subject’s 
choice. If the treating research-study psychiatrist determines it is indicated that a subject 
remain on escitalopram at termination, we will provide up to 4-weeks of escitalopram, at the 
study MD’s discretion, at no cost to the subject to assist in transitioning to treatment outside of 
the research study. 
 
Medical Evaluations & Research Assessments: Depressed Subjects 


The objective of the initial research assessment is to screen for study eligibility by establishing a 
diagnosis, gathering basic demographic data and screening for the presence of any significant 
past or present psychiatric disorders, acute or severe medical problems, or cognitive limitations. 
Subjects will undergo a physical and neurological examination at our clinic.  The examination 
will be performed and recorded by study psychiatrists. With the subject’s consent, the study MD 
will request results from recent blood tests (SMAC, CBC, TSH). If such test from the previous 
three months, or more recently in some cases based on clinical judgment of the study MD, the 
subject will be asked to obtain the tests, either in our laboratory or at their own doctor’s office. 
Patients will be responsible for charges not covered by their insurance for these tests. 
 
Research Assistants (RAs) will administer all study questionnaires in order to minimize 
misunderstanding and incomplete ratings.  All RAs have a minimum of an undergraduate 
degree and are trained by staff psychologists or psychiatrists proficient in the use of the study 
instruments. Training involves didactics, reading and discussion of measure administration 
manuals and study procedure manuals, observation of in-person subject interviews, and 
credentialing after conduct of in-person subject interviews with a supervisor. Ongoing inter-rater 
reliability auditing will monitor instrument administration. 
 
Three comprehensive assessments will be conducted at Baseline, week 7, and week 13. 
Additional brief assessments will be performed at weeks 0, 2, 3, 4, 5, 9 and 11 of treatment 
principally for monitoring depressive symptoms and antidepressant side effects and adherence. 
Subjects who exit the study prior to completion, will be invited to have a “comprehensive 
assessment” before termination. 
 
Study Schedule: Depressed Subjects 
 
 
 
Week 
0 
Week 
1* 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
7 
Week 
9 
Week 
11 
Week 
13 
Entry 
X 
 
 
 
 
 
 
 
 
 
MD Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
<------------------------------------- Medication ----------------------------------- > 
Brief 
Assessment 
X 
 
X 
X 
X 
X 
 
X 
X 
Long 
Assessment 
X 
 
 
 
 
X 
 
 
X 
MRI 
 
X 
 
 
 
 
 
 
 
Optional 
*Note: Week 1 is the medication start-date, and is considered the primary baseline assessment. . 
 
Baseline Comprehensive Assessment (~3 hours): 
• 
Demographic data (5 min): Data on age, gender, race, religion, living conditions, 
marital status, occupation, and education will be collected. 
• 
Medical Evaluation (30 min): Physical examination will be performed by psychiatrists. 
Blood tests (SMAC, CBC, TSH) and ECG will be obtained. A psychiatrist will quantify 
medical burden with the Cumulative Illness Rating Scale, modified for geriatrics (CIRS- 
G). Additionally, a research assistant will administer the Charlson Comorbidity Index 
(CCI) (Charlson et al., 1987). Information obtained from the CCI will be used to quantify 
medical co-morbidity. This approach reduces patient burden and bias towards illness 
under-reporting. 
• 
Diagnosis (~60 min): A study psychiatrist will interview each subject. In addition, the 
SCID-R, as rated by a trained research assistant, will be used for diagnosis. DSM-IV 


diagnoses will be assigned during the research team’s daily morning meeting by 
consensus of two geriatric psychiatrists after reviewing the SCID-R and Baseline 
Assessment data and examining the psychiatrist’s report. 
• 
History of Treatment (15 min): Patients with any exposure to citalopram or 
escitalopram during the current depressive episode will be excluded because 
retrospective assessment of treatment adequacy, adherence, tolerability, and response 
is difficult. This decision intends to protect our subjects who have been exposed to a 
potentially ineffective or not tolerated treatment. We will record the dosage and duration 
of treatment with each psychotropic used during the index episode, and in subjects with 
recurrent depression, during the last inter-episode interval. We will classify the intensity 
of antidepressant treatment according to the criteria of the Longitudinal Interval Follow- 
Up Evaluation. We will also use the Treatment Intensity Index modified by the Institute of 
Geriatric Psychiatry for depressed elderly patients. Thus we will be able to study the 
impact of prior psychotropic use on control systems. 
• 
Substance Abuse (5 min.): The CAGE questionnaire will be administered to screen for 
alcohol dependence, and records will be reviewed for tranquilizer and analgesic use. 
Subjects with addiction disorders by SCID-R/DSM-IV will be excluded. 
• 
Severity of Depression (15 min.): We will use the Montgomery Asberg Depression 
Rating Scale (MADRS) as the primary depression outcome because it is influenced little 
by physical symptoms and is sensitive to change. We will use the Scale of Suicidal 
Ideation (SSI) and a suicidality severity subscale (GRIM) to assess suicide risk. 
• 
Side Effects (5 min): We will use the UKU, which includes SSRI side effects. 
• 
Functional Status (20 min): The World Health Organization Assessment Schedule II 
(WHODAS II), 36-item will be used. This instrument is compatible with the international 
classification system, is cross-culturally applicable, and has high test-retest reliability. 
The ADL and IADL scales (~5 min) of the Philadelphia Multiphasic Assessment 
Inventory (Lawton, Moss et al. 1982) will be used as most of our disability studies were 
based on this instrument. 
• 
Clinical Features of Depression (15 min): In order to explore how brain activity and 
white matter integrity are related to clinical features of the illness we will administer a 
brief battery of self-report measures. Anhedonia: We will use the Snaith-Hamilton 
Pleasure Scale (SHAPS), a brief measure of hedonic capacity and anhedonia. 
Anhedonic symptoms, as measured by the SHAPS, are associated with activation in 
frontolimbic circuitry in major depression(108). Apathy:  We will use the Apathy 
Evaluation Scale (AES). Anxiety: We will use the Clinical Anxiety Scale (CAS)(111), 
which is derived from the Hamilton Anxiety Scale. Rumination: We will use the 
Response Style Questionnaire (RSQ)(Nolen-Hoeksema et al.) to measure rumination. 
This scale yields two subscales, brooding and pondering. Behavior Disturbances: We 
will use the Frontal Systems Behavior Scale (FrSBe) (Stout et al. 2003) to assess 
behavior disturbances associated with damage to the frontal-subcortical brain circuits. 
Negativity Bias: We will use the Brain Resource Inventory of Social Cognition (BRISC), a 
self-report measure that assesses the attributional bias toward perceiving and expecting 
negative events and outcomes, to examine negativity bias. 
1. Clinical Neuropsychological Battery (75 min.): This battery is not comprehensive as it 
was designed to minimize burden while enabling us to generate hypotheses about 
control networks and cognitive functions. The Wechsler Test of Adult Reading (WTAR) 
will be used to estimate an individual's level of intellectual functioning before the onset of 
injury or illness (in our case, major depression). Overall cognitive dysfunction: Mattis 
Dementia Rating Scale (DRS). Simple auditory attention will be evaluated with the 


Digits Forward portion of the Digit Span from the Wechsler Adult Intelligence Test 
(WAIS-IV). Working memory will be evaluated with Digits Backward from the WAIS-IV. 
Verbal memory will be evaluated with the Hopkins Verbal Learning Test -Revised, which 
has alternative forms and norms for geriatric patients. Processing speed will be 
assessed with the Stroop Word and Trails A. Language functions will be assessed with 
the Controlled Oral Word Association test (COWAT). The Controlled Oral Word 
Association Test (COWAT) evaluates the spontaneous production of words under 
restricted search conditions (verbal association and fluency). Executive functions will be 
assessed with the Stroop Color/Word, Iowa Gambling Task, Wisconsin Card Sort 
(WCST) and Trails B. We will explore the relationship of control networks to executive 
functions and use attention/working memory, verbal memory, and processing speed to 
examine specificity. The Trait Task is a computerized task involves the presentation of 
normed (positive and negative) trait descriptors on the computer screen one at a time. 
The subjects are instructed to as quickly as possible select a response that indicates 
whether or not each descriptor describes themselves. The endorsement of more 
negative words as being self- descriptive may reflect a “negativity bias” and is expected 
to be associated with poorer antidepressant response. 
When MCI is suspected we will use an expanded test battery during screening. 
• 
Social Support (5 min.): Among the various existing social support measures, the Duke 
Social Support Index was selected because major depression is associated with low 
subjective social support in elderly medical patients (Krishnan, Hays et al. 1997). The 
Index yields scores on 5 categories: subjective social support, social interaction, 
instrumental social support, social networks, and satisfaction with relationships. 
 
Brief Follow-up Assessments (60 min; weeks: 0, 2, 3, 4, 5, 9, 11): 
The purpose of these assessments is to evaluate the severity of depression, functional status, 
the presence of side effects, adherence to escitalopram, and pulse and blood pressure. We will 
rely on both patient and caregiver reports, pill counts, and plasma levels, as each offers varying 
degrees of reliability. The HDRS, MDRS, GDS, along with UKU items related to SSRI side 
effects, a fall questionnaire, and the 12-item WHODAS II, (described above, in Comprehensive 
Assessment) will be administered. At each visit, changes in medical condition, and the use of all 
non-study medications (prescription, over the counter, and alternative), will be recorded on a 
rating form. 
 
We will provide logs so that patients and caregivers can record daily medication use. We will 
draw blood on week 7 and 13 and escitalopram plasma levels will be assayed. Nonlinear-mixed 
effects modeling will be used to determine concentration ranges consistent with acceptable 
adherence. Subjects with acceptable drug logs and pill counts but plasma concentrations 


outside the range associated with adherence will be re-interviewed and excluded from the main 
analyses if non-adherence is established. 
 
Comprehensive Follow-up Assessments (week 7: ~1.5 hr and week 13: ~2.5 hrs): 
The purpose of these assessments is to provide information on the outcomes of interest after a 
month and a half of treatment (at Week 7 when patients are expected to show signs of 
improvement) and at the end of the study. The instruments used in the Baseline Comprehensive 
Assessment will be used to assess: depression severity, suicidal ideation, adherence to 
escitalopram, side effects, and functional status. To minimize practice effects, cognitive tests will 
not be performed at the Week 7 assessment. Subjects exiting early will be invited to have a 
comprehensive assessment at exit. 
 
Please note that all study measure are validated and published. We will seek IRB approval 
before use of any new, co-investigator developed measures. 
 
Medical Evaluations & Research Assessments: Control Subjects 
 
As with depressed subjects, the objective of the initial research assessment for control subjects 
is to screen for study eligibility by establishing a diagnosis, gathering basic demographic data 
and screening for the presence of any significant past or present psychiatric disorders, acute or 
severe medical problems, or cognitive limitations. A neuropsychologist will supervise the 
interview. After the clinical and cognitive screening, it may be determined that the subject is 
ineligible for participation. If this occurs, the study neuropsychologist will inform the subject of 
his/her exclusion and provide a referral for follow-up care if indicated. 
 
Study Schedule: Control Subjects 
 
 
 
Week 
0 
Week 
1* 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
7 
Week 
8 
Week 
11 
Week 
13 
Entry 
X 
 
 
 
 
 
 
 
 
Ph.D. Visit 
X 
 
 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
 
 
Brief Assessment 
 
 
 
 
 
 
 
 
 
Long Assessment  
X 
 
 
 
X 
 
 
X 
MRI 
 
X 
 
 
 
 
 
 
Optional 
*Note: For controls, Week 1 is considered the primary baseline assessment. 
Control subjects who are eligible for participation after the baseline visit will be asked to return 
for two additional follow-up assessments at 7 weeks and then again 13 weeks after the baseline 
visit. These two follow-up visits are intended to collect clinical and cognitive follow-up data, and 
will be compared to LOD subject data after a month and a half of medication treatment (when 
the LOD subjects are expected to show signs of improvement), and at the end of the study. In 
order to minimize practice effects, the neuropsychological assessments will be performed at the 
baseline and week 13 assessment only. The week 7 assessment should last approximately 1.5 
hours while the week 13 assessment will last approximately 2.5 hours. We will not draw blood 
from Control subjects as part of this protocol. 
 
MRI Scanning Sessions 
 
Overview: Sub-clinical, non-contrast fMRI will be performed at the Nathan Kline Institute (NKI) in 
Orangeburg, NY at the end of the placebo phase for depressed subjects or after enrollment for 


non-depressed controls. Each trip to the NKI will last approximately 2.5 hours which includes 
consent, preparation for the scan, a brief practice session, and the scan itself. The MRI is 
limited to a scan of the head. The scanning procedure itself lasts approximately 60 to 90 
minutes during which time the subject’s head and upper body will be immobile and rest in the 
scanning apparatus. Travel arrangements will be made by the Cornell research team and, 
when needed, the subjects will be escorted to NKI by a research assistant and/or the study PI. 
 
MRI Acquisition: MRI will be performed at the Center of Advanced Brain Imaging (CABI) at NKI. 
Scanning will be done on a 3T Siemens Tim Trio (Erlangen, Germany) housed at the CABI of 
NKI. First, a sagittal localizer will be used to orient the 3D volume scan. A FLAIR sequence will 
be acquired to quantify WMH and to screen for structural abnormalities. High resolution images 
will be acquired using a 3D T1-weighted rapid gradient echo for co-registration with the fMRI 
and DTI. Prior to fMRI acquisition, the operator will electronically shim the field to minimize 
inhomogeneities. BOLD images will be acquired in a single-shot multi-slice EPI with a TR of 
2000, a TE of 30 ms, and flip-angle of 80 degrees. Each of the volumes will consist of 34 slices, 
which allows for whole brain coverage. Each of 4 BOLD acquisitions runs (2 
Cognitive/Emotional Conflict runs and 3 Probabilistic Reversal Learning runs) will last 7 minutes. 
A field-mapping scan will be acquired that consists of 34 slices to be used for 
examination/correction for susceptibility induced geometric distortions in our EPI data. Diffusion 
tensor scans will be acquired in an axial plane parallel to the AC-PC plane with a pulsed 
gradient, double spin echo EPI method. Diffusion will be measured along 64 noncollinear 
directions. A field map will be acquired to match the parameters of the DTI and will be used to 
correct susceptibility induced distortions using FSL’s Prelude and Fugue programs. 
 
MRI Tasks: Subjects will practice each task outside of the scanner. Head motion will be 
minimized using the Siemens head-holder. Visual stimuli will be presented via a back-projection 
zoom to a LCD screen mounted at the rear of the bore. Responses to tasks will be collected 
using a 2-button response pad. Participants’ vision will be corrected by non-magnetic glasses. 
 
Each subject will participate in two sets of MRI tasks: 
• 
During the Emotional/Cognitive Control Task, face stimuli are paired with the 
superimposed words "HAPPY" or "SAD" to produce emotionally congruent and 
incongruent stimuli, and subjects are instructed to categorize the facial expressions as 
happy or sad while ignoring task-irrelevant word stimuli (e.g. Word “HAPPY” on a sad 
face). 
• 
During the Probabilistic Reversal Learning Task, subjects will choose between two 
colored triangles and receive feedback on their choices. They will be instructed to 
choose the color that is correct the majority of the time, to stick with it even when it is 
occasionally wrong, and to only switch to the other color when they are sure that the rule 
has changed. 
 
Responses consist of manual button presses on a key pad using the middle and the index finger 
of the right hand. The order of tasks is counterbalanced across subjects. For the 
Emotional/Cognitive Control Task, subjects are instructed to respond to each face as quickly 
and accurately as possible. The Emotional/Cognitive Control Tasks is presented in an event- 
related design. Each trial consists of a face on a black background, depicting either a happy or 
a sad face (10 male, 10 female). The Emotional/Cognitive Control Task consists of two runs of 
80 trials. Stimuli are presented for 1250 ms, with a varying interstimulus interval (ISI) of 2750 – 
4750 ms (mean ISI = 3750 ms), during which a white central fixation cross is displayed. Stimuli 
are counterbalanced, with equal numbers of congruent–congruent, congruent–incongruent, 
incongruent–congruent, and incongruent–incongruent stimulus sequences. Gender and facial 


expression are counterbalanced across responses and trials. For the Probabilistic Reversal 
Learning Task, each trial consists of a blue and a yellow triangle against a black background. 
Subjects are instructed to choose the “correct” color and given positive feedback in the form of a 
green smiley face when they are correct, and given negative feedback in the form a red sad 
face when they are incorrect. Twelve times per block, the “correct” color reverses. The number 
of trials between reversals varies between 8 and 15 (mean reversals = 12). Stimuli are 
presented for a maximum of 2500ms. The feedback is presented for 500ms, and the ISI is 
3000ms. 
 
Sub-clinical Examination: The MRI scan that is part of this research study is not a clinical MRI 
examination and is not intended to provide any benefit to study participants in diagnosing brain 
abnormalities. 
 
Since NKI is conducting all of this study’s MRI scans, we will follow NKI over-read policy on sub- 
clinical research scans. A radiologist will review all of the MRIs performed at Nathan Kline 
Institute. If the radiologist detects an abnormality, it is then the responsibility of the Principal 
Investigator (PI) to directly contact the research participant and provide appropriately sensitive 
notification of a possible clinically significant finding and to recommend that the patient follow up 
with their private physician. Under the patient confidentiality guidelines, no personal information 
will be given to the specialist. If the specialist recommends a follow-up, he/she will contact the 
Principal Investigator identifying the subject by using the unique, study-assigned ID. The study 
PI or designate will then contact the research participant. The initial contact may be verbal 
(telephone or in-person) followed by a notification letter describing the nature of the finding and 
the kind of follow-up that is recommended. If requested, a copy of the images (on a CD) can be 
mailed to the participant or picked up in-person. The decision as to whether to proceed with 
further examination lies with the participant. 
 
Transfer of MRI Scanning Results: After the NKI technician completes the MRI scan, he/she 
will burn the reading onto a CD identified with the subject’s unique study ID number. The CD 
will not have any other identifying information. The study co-investigator who is present during 
the scan will bring the CD back to our research institute in White Plains and place it in a locked 
file cabinet in the PI’s locked office. For analysis, data from the reading will be uploaded to our 
ITS-maintained secure, password protected server with access available only to study co- 
investigators. 

SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White Matter and Emotional and Cognitive Control in Late-Onset Depression 
 
NCT01728194 
 
07/15/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Analyses for Primary Hypotheses:  
Hypothesis 1. Microstructural WM abnormalities in the emotional control system will distinguish 
LOD subjects from normal elders, especially in the presence of increased activation in 
emotional control structures (rostral ACC, amygdala) in response to an emotional control 
challenge.  Logistic regression analyses will test main effects and the interaction of FA and 
activation of emotional control structures. Depression status (depressed, controls) will be 
the outcome variable.  
Hypothesis 2. Microstructural WM abnormalities in the cognitive control system will distinguish 
LOD subjects from normal elders, especially in the presence of hypoactivation in cognitive 
control structures (dorsal ACC, DLPFC).  Similar to H1, logistic regression analyses will 
examine main effects and the interaction of FA and activation of the cognitive control structures 
with depression status as the outcome.  
For H1 and H2 a significant main effect or interaction would provide empirical support for our 
hypothesis. A Likelihood ratio (LR) test comparing nested models with and without this 
interaction will examine the incremental contribution of the interaction term.   
Analyses for Secondary Hypotheses: SH1. In LOD subjects, microstructural WM 
abnormalities in the control system will be associated with slower decline of depressive 
symptoms (MADRS) during escitalopram treatment (target dose: 20 mg for 12 weeks), 
especially in the presence of hyperactivation in emotional control structures (rostral ACC, 
amydgala) in response to a control challenge. 
These analyses will include the depressed subjects. A mixed-effects linear regression model will 
include up to 7 repeated MADRS assessments over the open-label trial (baseline and weeks 2, 
4, 6, 8, 10, 12) as the dependent variable. The model will include a random subject-specific 
intercept, a random slope, and fixed effects for baseline activation of emotional control 
structures and FA.  
An LR test will examine the incremental contribution of 2 interactions using nested regression 
models: activation by time and FA by time. Analyses will be based on the principle of intention to 
treat - that is, all individuals with baseline visit data will be included.  
SH2. In LOD subjects, microstructural WM abnormalities in the cognitive control system will be 
associated with slower decline of depressive symptoms (MADRS) during escitalopram 
treatment especially in the presence of hypoactivation in control structures  SH2 and SH3 will be 
tested with mixed-effects linear model as described in SH1.  
The sample size was determined based on statistical power analyses for the primary 
hypotheses H1 and H2. Our preliminary study demonstrated the feasibility of the proposed 
design. However, the pilot data sample size renders estimates too imprecise for power analyses 
Thus, a simulation study (with 1000 data sets per specification) examined statistical power of 
analyses proposed for H1 and H2 using SAS PROC LOGISTIC.  Odds ratios for the interaction 
term varied (1.4, 1.5); the correlation between independent 
variables ranged (-0.2 to 0.2). Simulation results (Table 1), 
indicate that the proposed N (70 depressed vs. 70 controls) 
provides sufficient power (>80%) to detect meaningful 
relationships among white matter integrity, activation, and 
diagnostic group.  
C2.16. Attrition: H1 and H2 use cross-sectional data and 
thus attrition should not pose a problem.  In contrast, SH1 
and SH2 involve longitudinal data. Several steps have been 
taken to minimize the impact of attrition.  First, in the spirit of 
ITT, every effort will be made to continue assessments for 
the entire course of treatment, even among those who 
Table 1. Power for H1and H2 for N=140 
Odds 
Ratio 
Correlation 
between 
predictors 
Power 
(Interaction) 
1.4 
-0.2 
0.87 
-0.1 
0.84 
0 
0.81 
0.1 
0.84 
0.2 
0.87 
1.5 
-0.2 
0.91 
-0.1 
0.87 
0 
0.84 
0.1 
0.87 
0.2 
0.90 


discontinue escitalopram. Second, mixed-effects models yield valid inferences assuming 
ignorable attrition.