Clinical trial NCT03812588
Conditions: Major Depressive Disorder
Sponsor: New York State Psychiatric Institute
Start date: 2019-01-30; Completion date: 2021-08-01
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to develop new methods of administering antidepressant medications that will result in improved drug/placebo separation in randomized controlled trials (RCTs) for Major Depressive Disorder (MDD) and enhanced medication response in open clinical treatment. The highly intensive, weekly visit schedule followed in most antidepressant RCTs radically differs from how antidepressant medications are prescribed in standard clinical practice and is believed to be a major reason why the majority of studies submitted to the Food and Drug Administration (FDA) fail to show a significant difference between medication and placebo. Moreover, a "one size fits all" approach to psychopharmacologic management (i.e., weekly visits for all patients) does not take into account differences between patients that may predispose some individuals to respond positively to frequent follow-up visits, while others may respond negatively or not at all. Clinic visits comprise multiple components that may be therapeutic for depression, including activating patients' behavior, exposing them to medical procedures, permitting social interactions with research staff, and providing supportive meetings with clinicians. Two independent meta-analyses have associated more frequent study visits with increased antidepressant and placebo response as well as decreased separation between medication and placebo. Despite the high costs and potential disadvantages of weekly follow-up visits for patients receiving antidepressant medication, this clinical management strategy has not been studied prospectively to date. It is unknown whether weekly follow-up visits are needed to ensure treatment compliance and patient safety in clinical trials and to what degree contacts with clinicians influence medication and placebo response.

Detailed description:
This study utilizes a 2 x 2, double-blind, acute, prospective design randomizing adult

outpatients with MDD to "Research Frequency Management" (RFM, weekly study visits) vs. "Community Frequency Management" (CFM, every 4 weeks study visits) and antidepressant medication vs. placebo. Specifying visit frequency as the independent variable in this study has the distinct advantages of being easily operationalized for research purposes avoiding a priori assumptions about which components of study visits influence antidepressant and placebo response (i.e., behavioral activation vs. doctor-patient relationship vs. medical procedures). Close monitoring of all subjects will be assured by telephone evaluations of individuals randomized to CFM at intervals between monthly visits, and additional study contacts will be scheduled as necessary to maintain patient safety (all extra-protocol contacts will be recorded and included as a variable in outcome analyses). Additionally, subjects will be characterized extensively on clinical, demographic, and psychological measures to pilot the study assessment battery and search for predictor variables influencing the effects of contact frequency on medication and placebo response.

Arms: arm 1: Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits. arm 2: Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits. arm 3: Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits. arm 4: Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.
Interventions: intervention 1: Escitalopram intervention 2: Placebo
Intervention descriptions: intervention 1: Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain. intervention 2: A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient.

Protocol documents:
Prot_ICF_002.pdf: 
 
 
 
 
 
 
Contact: Developing New Clinical 
Management Strategies 
 
Protocol ID 7738 
NCT03812588 
 
 
 
Protocol Summary Form and  
Consent Form 
 
 
 
Document Version Date: 
December 17th, 2021 


Signed copy on file at IRB 
 
             v. 4/19/13 
                                          NEW YORK STATE PSYCHIATRIC INSTITUTE         
INSTITUTIONAL REVIEW BOARD 
MEMORANDUM 
 
 
 
 
 
 
 
 
 
December 13, 2021 
TO: 
 
Dr. Bret Rutherford 
 
 
 
FROM: 
Dr. Edward Nunes, Co-Chair, IRB  
Dr. Agnes Whitaker, Co-Chair, IRB 
 
 
SUBJECT: 
APPROVAL NOTICE:  CONTINUATION    
 
 
Expedited per 45CFR46.110(b)(1)(f)(8)(c) 
 
Your protocol #7738 entitled Developing New Clinical Management Strategies for 
Antidepressant Treatments (version date 12-13-2021) and Consent Forms have been approved 
by the New York State Psychiatric Institute - Columbia University Department of Psychiatry 
Institutional Review Board from December 17, 2021 to December 16, 2022.   
 
Consent requirements: 
   
  X Not applicable: (DATA BEING ANALYZED) 
    
   Signature by the person(s) obtaining consent is required to document the consent process. 
 
   Documentation of an independent assessment of the participant’s capacity to consent is also required. 
 
       
    Approved for recruitment of subjects who lack capacity to consent:   No      Yes    
 
 
    Field Monitoring Requirements:  Routine      Special:                                    
 
√   Only copies of consent documents that are currently approved and stamped by the IRB 
may be used to obtain consent for participation in this study. 
√  A progress report and application for continuing review is required 2 months prior to the  
expiration date of IRB approval. 
√  Changes to this research may be not be initiated without the review and approval of the  
IRB except when necessary to eliminate immediate hazards to participants.  
√  All serious and/or unanticipated problems involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org 
for Adverse Event Reporting Procedures and additional reporting requirements.  
 
 
 
 
 
CC: RFMH Business Office (Binational Science Fund) 
 
 
EN/AHW/Scr 


Protocol Summary Form
7738
Rutherford, Bret
Page 1 of 12
Protocol Title:
Developing New Clinical Management 
Strategies for Antidepressant Treatments
Protocol Number:
7738
First Approval:
01/09/2019
Expiration Date:
12/16/2022
Version Date:
12/13/2021
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu
Telephone: 646 774 8660
Co-Investigator(s):
Sigal Mano
Research Chief:
Bret Rutherford, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Department & Unaffiliated Personnel
Department
What Department does the PI belong to?
Neurobiology and Therapeutics of Aging
Within the department, what Center or group are you affiliated with, if any? 
Clinic for Aging, Anxiety, and Mood Disorders (CAAM)
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
Sigal Zilcha-Mano, PhD


Protocol Summary Form
7738
Rutherford, Bret
Page 2 of 12
Associate Professor and Licensed Clinical Psychology, University of Haifa
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
Subject enrollment for the Binational Science Foundation grant began on 01/22/2019. All eligible subjects 
offered participation at CAAM evaluations have agreed to participate in the study. Additionally, all subjects 
have agreed to the video consent form for taping of study visits. Overall, subjects have been complying well 
with the procedures of the clinical trial and study medication has been well tolerated. Many patients have 
expressed appreciation for the quality care that we provide and for their improvements in depressive 
symptoms.
Study recruitment was temporarily paused at the start of COVID-19 and restarted on 10/27/2020. 
Procedures were modified so study visits can be completed via telehealth video calls. To mitigate the added 
risks of contracting COVID-19, institute wide regulations and recommendations have been applied to the 
protocol for any visits that require in-person contact. Recruitment ended on 08/01/2021.
Data has been well maintained and internally monitored as we continue with analysis only.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 


Protocol Summary Form
7738
Rutherford, Bret
Page 3 of 12
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
No
Overall Progress
Approved sample size
104
Total number of participants enrolled to date
29
Number of participants who have completed the study to date 
19
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
Yes
Describe actions taken or planned to address these problems. 
Due to COVID-19 and the challenges associated with recruitment during this time, we were not able to 
enroll any patients since the last ACAR. Study recruitment has been discontinued, and we are focusing on 
data analysis only.
Comments / additional information 
Sample Demographics
Specify population
Adults 18-75 with diagnosis of Major Depressive Disorder
Total number of participants enrolled from this population to date 
29
Gender, Racial and Ethnic Breakdown 
Gender:
   Male: 38% 
   Female: 62%
 
Race:
   Black/African-American: 41%
   White: 45%
   More than one: 7%
   Don't know/Other: 7%
Ethnicity:
   Hispanic or Latino: 14%
   Not Hispanic/Latino: 79%
   Unknown: 7%


Protocol Summary Form
7738
Rutherford, Bret
Page 4 of 12
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
0
Did the investigator withdraw participants from the study? 
No
Did participants decide to discontinue study involvement? 
No
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   Use of Placebo or Sham Treatment
   Medication-Free Period or Treatment Washout
   Audio or Videotaping
   Internet-based Data Collection or Transmission
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Employees or Students
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1


Protocol Summary Form
7738
Rutherford, Bret
Page 5 of 12
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes
Select one of the following
The grant/contract is currently funded
Source of Funding
Foundation
Sponsor
Binational Science Fund
Select one of the following
Multicenter(NYSPI is the lead site)
Business Office
RFMH
Does the grant/contract involve a subcontract? 
No
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
This protocol describes research conducted by the PI at other facilities/locations
Yes
   International Sites
International Sites
Type in location(s)
Department of Psychology, University of Haifa, Israel
Uploaded Protocol Summary Form
Upload Document
Select file to upload.
PSF_Version 3.29.21.pdf
Lay Summary of Proposed Research 
Lay Summary of Proposed Research


Protocol Summary Form
7738
Rutherford, Bret
Page 6 of 12
The goal of this study is to develop new methods of administering antidepressant medications that will 
result in improved drug/placebo separation in randomized controlled trials (RCTs) for Major Depressive 
Disorder (MDD) and enhanced medication response in open clinical treatment. The highly intensive, weekly 
visit schedule followed in most antidepressant RCTs radically differs from how antidepressant medications 
are prescribed in standard clinical practice and is believed to be a major reason why the majority of studies 
submitted to the Food and Drug Administration (FDA) fail to show a significant difference between 
medication and placebo. Moreover, a “one size fits all” approach to psychopharmacologic management (i.e., 
weekly visits for all patients) does not take into account differences between patients that may predispose 
some individuals to respond positively to frequent follow-up visits, while others may respond negatively or 
not at all. Clinic visits comprise multiple components that may be therapeutic for depression, including 
activating patients’ behavior, exposing them to medical procedures, permitting social interactions with 
research staff, and providing supportive meetings with clinicians. Two independent meta-analyses have 
associated more frequent study visits with increased antidepressant and placebo response as well as 
decreased separation between medication and placebo. Despite the high costs and potential disadvantages of 
weekly follow-up visits for patients receiving antidepressant medication, this clinical management strategy 
has not been studied prospectively to date. It is unknown whether weekly follow-up visits are needed to 
ensure treatment compliance and patient safety in clinical trials and to what degree contacts with clinicians 
influence medication and placebo response.
This study utilizes a 2 x 2, double-blind, acute, prospective design randomizing adult outpatients with MDD 
to “Research Frequency Management” (RFM, weekly study visits) vs. “Community Frequency 
Management” (CFM, every 4 weeks study visits) and antidepressant medication vs. placebo. Specifying 
visit frequency as the independent variable in this study has the distinct advantages of being easily 
operationalized for research purposes avoiding a priori assumptions about which components of study visits 
influence antidepressant and placebo response (i.e., behavioral activation vs. doctor-patient relationship vs. 
medical procedures). Close monitoring of all subjects will be assured by telephone evaluations of 
individuals randomized to CFM at intervals between monthly visits, and additional study contacts will be 
scheduled as necessary to maintain patient safety (all extra-protocol contacts will be recorded and included 
as a variable in outcome analyses). Additionally, subjects will be characterized extensively on clinical, 
demographic, and psychological measures to pilot the study assessment battery and search for predictor 
variables influencing the effects of contact frequency on medication and placebo response. 
Description of Subject Population
Sample #1
Specify subject population
104
Number of completers required to accomplish study aims
70
Projected number of subjects who will be enrolled to obtain required number of completers
104


Protocol Summary Form
7738
Rutherford, Bret
Page 7 of 12
Age range of subject population
18-75
Gender, Racial and Ethnic Breakdown
We anticipate the sample will be composed of approximately 60% women and 40% men. On the basis of 
previous depression studies conducted in the Clinic for Aging, Anxiety and Mood Disorders, it is 
anticipated that the sample will be composed of approximately 75% Caucasian, 15% African American, and 
10% Hispanic subjects.
Description of subject population
104 subjects will be entered in the proposed study. Inclusion criteria are (1) men and women aged 18-75 
years, (2) diagnosis with Diagnostic and Statistical Manual (DSM) V MDD, (3) 24-item Hamilton Rating 
Scale for Depression (HRSD) score ≥ 16 and ≤ 28 and 17-item Hamilton Rating Scale for Depression 
(HRSD) score < 25, (4) capable of providing informed consent and complying with study procedures, and 
(5) using appropriate contraceptive method if woman of child-bearing age. Exclusion criteria are (1) current 
comorbid Axis I DSM V disorder other than Mild Substance Use Disorder, Adjustment Disorder, Anxiety 
Disorder or Personality Disorder, (2) diagnosis of Moderate to Severe Substance Use Disorder within the 
past 12 months, (3) present or past history of psychosis, psychotic disorder, mania, or bipolar disorder, (4) 
baseline HRSD score > 28 or HRSD suicide item > 2, (5) history of allergic or adverse reaction to 
escitalopram and duloxetine, or non-response to adequate trial of escitalopram (at least 4 weeks at dose of 
20mg) and duloxetine (at least 4 weeks at dose of 60mg) during the current episode (6) current treatment 
with psychotherapy, antidepressants, antipsychotics, or mood stabilizers, (7) Clinical Global Impressions 
(CGI)-Severity score of 6 or greater at baseline, and (8) acute, severe, or unstable medical illness.
The selection criteria for this study were designed to obtain a sample having similar characteristics to the 
patient population studied in our meta-analyses and ongoing prospective studies of patient expectancy. In 
order to ensure patient safety given the potential to be randomized to CFM, we chose to exclude subjects 
having active suicidal ideation and who are severely ill . Subjects with current substance use disorder or 
dependence are excluded, but subjects with past substance use disorder or dependence who meet DSM V 
criteria for full sustained remission (12 months without meeting abuse or dependence criteria) will be 
allowed to participate. This approach will minimize persistent neuropsychiatric sequelae of past episodes of 
abuse or dependence and decrease the risk that subjects will relapse during the study period. Participants 
will be questioned at weekly visits regarding substance use, and urine toxicology will be obtained if there is 
concern of relapse. Any use of drugs or alcohol will be recorded, but subjects will not be dropped from the 
study unless substance use rises to a level meeting DSM V abuse or dependence criteria.
Recruitment Procedures
Describe settings where recruitment will occur
Subjects will be recruited through radio, newspaper, Facebook, Craigslist, and ResearchMatch.com 
advertisements and referrals from other physicians.
How and by whom will subjects be approached and/or recruited? 
Individuals presenting to the Clinic for Aging, Anxiety and Mood Disorders are evaluated
under IRB #7284R, “Evaluation at the Adult and Late Life Depression Center.” Following this evaluation, 
one of the study psychiatrists authorized to obtain informed consent will discuss study participation with 


Protocol Summary Form
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Rutherford, Bret
Page 8 of 12
subjects.
How will the study be advertised/publicized? 
Newspaper and radio advertisements, flyers posted around CUMC and CU Morningside, physician referrals, 
the Columbia RecruitMe Website, the National Alliance on Mental Illness NYC Research Studies website, 
Facebook advertisements, Craigslist.com, and ResearchMatch.com advertisements. 
 
Digital advertisement on Facebook under the “Columbia Psychiatry” page will include a link to a contact 
information form for users to complete if they wish to be contacted by our study team. Facebook users who 
see the ad will either 1) click the Facebook ad and it will direct them to a secure and encrypted survey 
website using Qualtrics to collect name, phone number, and email address or 2) not click the ad or provide 
any contact information.
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT03812588
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
- Antidepressant Response in the Treatment of Depressive Symptoms and Frailty Characteristics in Older 
Adults - IRB #7289R
- Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) (PI Roose) - IRB 
#7409
- Mechanisms of Antidepressant Non-Response in Late-Life Depression (PI Rutherford) - IRB #6836
-Treating Hearing Loss to Improve Mood and Cognition in Older Adults (PI Rutherford) - IRB #7540
-A Study of L-DOPA for Depression and Slowing in Older Adults (PI Rutherford) - IRB #7270
- Cognitive and Neural Mechanisms of the Accelerated Aging Phenotype in PTSD - IRB #7489
- Tianeptine for Treatment-Resistant Depression - IRB# 7944
 
 
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 


Protocol Summary Form
7738
Rutherford, Bret
Page 9 of 12
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
7284R
Describe Study Consent Procedures
Prior to undergoing evaluation, participants will be consented for remote clinical or research procedures.  
The consent discussion process will include discussion and explanation of WebEx, a HIPAA-compliant 
video communication platform.  The study team will address any concerns the patient may have, such as 
access to a private space in which to take calls, or accessibility—access at home to adequate devices, cell 
signal, or wifi. Participants must first sign the CAAM evaluation consent form (IRB #7284R) and HIPAA 
consent form. A consent procedure note will include all information discussed with the participants 
regarding the remote consent process, procedures and also the risk involved in traveling for in-person visits 
during covid-19. The clinic coordinator or an CAAM research assistant will then do the 30-item Mini-
Mental State Exam to get a general idea of the patient’s global cognitive performance (this is especially 
important in older patients who may be experiencing cognitive/memory difficulties in addition to 
depression). The patient is then seen by one of the CAAM psychiatrists or a nurse practitioner (Galit 
Marcus, NP, MPH). Alternatively, the patient may be seen by medical PGY-1 psychiatry interns who come 
to our clinic for 4-week rotations and psychiatry fellows who come to our clinic for 6-month rotations 
during the Spring semester. Fellows rotate through the Statewide Geriatric Psychiatry Fellowship. All 
medical interns and fellows will have completed NYSPI-specific CITI training for human subjects research 
(specifically the Social & Behavioral Researchers & Key Personnel course or the Biomedical Researchers & 
Key Personnel course). Interns and fellows will be supervised by Steven Roose, MD, Bret Rutherford, MD, 
and Allegra Broft, MD.  Following the MD/NP evaluation, the doctor may ask for a SCID (Structured 
Clinical Interview for the DSM), a structured diagnostic interview, and HAM-D (Hamilton Rating Scale for 
Depression) to be performed by a qualified rater (Nancy Turret or trained research assistant). Based on the 
information from the MD/NP evaluation, HAM-D score, and SCID diagnosis(es), the MD/NP will decide if 
the patient is eligible for any of the CAAM research protocols.
 
The NP is licensed and board certified as a Psychiatric and Mental Health NP. She has considerable 
experience in working with a late-life population but no prior research experience in this population. That is 
why she will have an extended period of time where all her work is directly in-person supervised. The NP 
will have a lengthy orientation where she will be observing evaluations done by Drs. Roose, Rutherford, 


Protocol Summary Form
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Rutherford, Bret
Page 10 of 12
Brown and Broft. She will then do evaluations under the observation of the same MDs. Even when she is 
doing evaluations and follow-ups by herself, all cases are reviewed weekly at a clinic meeting. Even after 
orientation is over, it is the practice of the clinic that the doctors consult with and present cases to each other 
so all patients are essentially treated by the entire clinic team. 
 
Due to the COVID-19 pandemic, beginning in October 2020, CAAM will be implementing a number of 
changes to this study's operating procedures in order to ensure a safe environment while continuing to 
provide patients depression treatment through research participation. These changes include implementing 
Telehealth resources to complete visits virtually and only evaluating/enrolling 50% of our normal 
participant capacity in order to minimize the risk of contracting the virus due to physical contact. All 
measures that do not require an in-person component will be completed virtually. The evaluation procedure 
will be altered to include virtual components. Detailed descriptions of these changes are provided below. 
 
Evaluation: A two-visit evaluation procedure, one virtual and one in-person, will be implemented in order to 
reduce the risk of transmitting the virus by minimizing person-to-person contact. After an individual 
expresses interest in research participation and completes the initial phone screen process, the individual 
will be scheduled for a virtual evaluation with a research coordinator (trained study raters; BA, RN, SW) 
and a clinician. All assessments that are generally conducted during the evaluation process (Protocol 
#7284R) that can be conducted over the phone will be administered during the virtual portion. The 
individuals who may be eligible for study participation after completing the virtual evaluation will then be 
scheduled for an in-person evaluation at the clinic, in order to complete the remaining assessments that are 
necessary to determine eligibility. The virtual evaluation will be completed via WebEx or a secure 
FaceTime platform. After consenting the individual virtually and sending them a copy of the consent form 
(if they have Internet/email access; if the individual does not have these resources, a hard copy of the 
consent form will be mailed to them), the research coordinator will complete the following measures: the 
MMSE, HRSD, Logical Memory Test I and II, and the SCID. They will also gather the individual's 
pharmacy information, as well as their current physical location and emergency contact (in case of a mobile 
crisis). The research coordinator will subsequently explain how the individual can complete the self-report 
forms included in the evaluation protocol online, and will send them a link for completion (if the individual 
does not have Internet/email access, self-report forms are to be completed over the phone with the research 
coordinator). The evaluating clinician will then be notified that the individual is ready for the clinical 
interview, and send them the assessment scores collected during the first portion of the virtual evaluation. 
The evaluating clinician will then join the call, and complete the clinical interview with the research 
coordinator on mute during the duration of the interview. If the individual may still be eligible for study 
participation after the clinical interview, they will be scheduled for the in-person component of the 
evaluation. The evaluating clinician will discuss any COVID-19 risks related to travel for research purposes. 
 
On the day of the in-person evaluation, the individual will be transported to the clinic via a car service. 
Social distancing procedures will be followed in order to ensure safety, including limiting the number of 
individuals in a clinic room, implementing the use of masks, and thoroughly cleaning clinic rooms and other 
assessment instruments (ex: blood pressure cuff, grip-strength machine, etc.) after each use. The rest of the 
evaluation procedures will be completed during the in-person visit. 
If an individual is eligible after completing the in-person evaluation and consents to study participation, they 
will be scheduled for their next visit.


Protocol Summary Form
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Rutherford, Bret
Page 11 of 12
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Brewster, Katharine
Broft, Allegra, MD
Marcus, Galit
Roose, Steven, MD
Rutherford, Bret, MD
Type in the name(s) not found in the above list
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
Methods to Protect Confidentiality
Will the study be conducted under a certificate of confidentiality?
No
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Compensation Plan:
 
In order to compensate for time, participant payment in the study is approved for all in-person visits to the 
clinic. Participants will be paid for the visits completed as follows:
 
Screening: $50
Baseline/Week 0 Visit: $20


Protocol Summary Form
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Rutherford, Bret
Page 12 of 12
Acute Phase in-person Visits: $20
Continuation Phase in-person Visits: $20 
For the RFM track, compensation is up to $180 for the Acute Phase and up to $60 for the Continuation 
Phase for a total of $240. For the CFM track, compensation is up to $60 for the Acute Phase and up to $60 
for the Continuation Phase for a total of $120.
 
 Due to COVID-19, the methods for providing compensation to patients will be adjusted. Patients can choose to 
receive payments (either by an e-gift card, a physical gift card, or a check), or to receive one payment for all visits at 
the completion of the study. If the patient chooses to receive payments after each specified time point where 
compensation is provided, they will be mailed to the individual after the completion of each weekly visit.
Uploads
Upload copy(ies) of unbolded Consent Form(s)
Upload copy(ies) of bolded Consent Form(s)
Upload copy(ies) of recruitment materials/ads to be reviewed
Upload copy(ies) of the HIPAA form
Upload any additional documents that may be related to this study


Cover Page 
 
Protocol Number: 
7738  
 
     Version Date:3/29/2021 
Protocol Title: Developing New Clinical Management Strategies for Antidepressant Treatments  
Principal Investigator: Bret Rutherford, MD 
Email:bret.rutherfors@nyspi.columbia.edu; Brr8@cumc.columbia.edu 
Telephone: 
Office:        646-774-8660                                  Cell Phone:917-716-7484 
 
Lay Summary 
This section is intended to provide a basic overview of the study including a description of its purpose, methods, and subject 
population.  The summary should provide a concise overview of the study for non-scientific and scientific members of the IRB.  
Please avoid medical or technical terminology.  In general, the abstract of a grant does not provide a suitable lay summary. 
Please also paste of a copy of the Lay Summary into the PRISM PSF Form. 
 
The goal of this study is to develop new methods of administering antidepressant medications that will 
result in improved drug/placebo separation in randomized controlled trials (RCTs) for Major Depressive Disorder 
(MDD) and enhanced medication response in open clinical treatment. The highly intensive, weekly visit schedule 
followed in most antidepressant RCTs radically differs from how antidepressant medications are prescribed in 
standard clinical practice and is believed to be a major reason why the majority of studies submitted to the Food 
and Drug Administration (FDA) fail to show a significant difference between medication and placebo. Moreover, a 
“one size fits all” approach to psychopharmacologic management (i.e., weekly visits for all patients) does not take 
into account differences between patients that may predispose some individuals to respond positively to frequent 
follow‐up visits, while others may respond negatively or not at all. Clinic visits comprise multiple components that 
may be therapeutic for depression, including activating patients’ behavior, exposing them to medical procedures, 
permitting social interactions with research staff, and providing supportive meetings with clinicians. Two 
independent meta‐analyses have associated more frequent study visits with increased antidepressant and placebo 
response as well as decreased separation between medication and placebo. Despite the high costs and potential 
disadvantages of weekly follow‐up visits for patients receiving antidepressant medication, this clinical management 
strategy has not been studied prospectively to date. It is unknown whether weekly follow‐up visits are needed to 
ensure treatment compliance and patient safety in clinical trials and to what degree contacts with clinician’s 
influence medication and placebo response. 
 
This study utilizes 2 x 2, double‐blind, acute, prospective design randomizing adult outpatients with MDD to 
“Research Frequency Management” (RFM, weekly study visits) vs. “Community Frequency Management” (CFM, 
every 4 weeks study visits) and antidepressant medication vs. placebo. Specifying visit frequency as the 
independent variable in this study has the distinct advantages of being easily operationalized for research purposes 
avoiding  prior assumptions about which components of study visits influence antidepressant and placebo response 
(i.e., behavioral activation vs. doctor‐ patient relationship vs. medical procedures). Close monitoring of all subjects 
will be assured by telephone evaluations of individuals randomized to CFM at intervals between monthly visits, and 
additional study contacts will be scheduled as necessary to maintain patient safety (all extra‐protocol contacts will 


be recorded and included as a variable in outcome analyses). Additionally, subjects will be characterized extensively 
on clinical, demographic, and psychological measures to pilot the study assessment battery and search for predictor 
variables influencing the effects of contact frequency on medication and placebo response. 
Background, Significance, and Rationale 
In this section, provide a brief summary of the status quo of the relevant work field, and how the proposed study will advance 
knowledge. Specifically, identify the gaps in knowledge that your project is intended to fill. If no gaps exist that are obviously 
and directly related to your project, explain how your proposed research will contribute to the overall understanding of your 
field. Describe potential impacts of your project within your field of study and in a broader context. Provide a critical evaluation 
of existing knowledge. The literature review does not have to be exhaustive.  
Background: 
 
In randomized controlled trials (RCTs) of antidepressants for adults with Major Depressive Disorder (MDD), 
placebo response averages 31% compared to a mean medication response of 50%. Placebo response rates have 
risen at an average rate of 7% per decade over the past 30 years. High placebo response has contributed to the 
majority of clinical trials of antidepressants submitted to the Food and Drug Administration (FDA) not showing a 
significant difference between medication and placebo. Increasing numbers of failed trials have made developing 
psychiatric medications progressively more time‐ consuming (average of 13 years to develop a new medication) and 
expensive ($800 million to $3 billion per new agent). These considerations recently led several large pharmaceutical 
companies to reduce or discontinue research and development on medications for brain disorders. Moreover, 
media coverage of failed trials has been used as a platform for critiques of the pharmaceutical industry and 
questioning the efficacy of antidepressants, which may have the dangerous public health consequence of 
dissuading patients with depression from accessing treatment. To address what has been called 
“psychopharmacology in crisis,” it is imperative to develop methods of minimizing placebo response in 
antidepressant RCTs. 
 
Minimizing placebo response would facilitate the valid evaluation of new antidepressant medications, but 
there is also a pressing public health need to optimize currently available treatments. Depressive disorders are the 
most common mental health disorders, affecting 9.5% (over 18 million) of American adults in any given year. MDD 
is currently the leading cause of disability among adults aged 15‐44 and is predicted by 2020 to become the second 
overall cause of disability worldwide after heart disease. 
 
MDD is the psychiatric diagnosis most commonly associated with suicide, with the lifetime risk of suicide 
among patients with untreated depressive disorders being nearly 20%. Even with maximal treatment, many 
patients will not experience sustained remission of their depression. The cumulative percentage of patients 
achieving remission after 4 sequential antidepressant trials in the Sequenced Treatment Alternatives to Relieve 
Depression (STAR*D) study was only 51%, and 28% of patients discontinued treatment during the study. Depression 
relapse rates after 1 year of follow up increased from 40.1% among  Step 1 remitters to 71.1% among Step 4 
remitters. 
 
A feasible and effective way of addressing these public health needs may be to change the way clinicians 
manage the treatment of patients receiving antidepressant medications. Current clinical management entails 
weekly clinic visits for participants in most antidepressant RCTs, whereas depressed patients treated in standard 
clinical practice are seen at monthly intervals or less frequently. These practices are not based on experimental 
evidence, since it is unknown whether weekly follow‐up visits are needed to ensure adherence and patient safety in 
clinical trials and what visit frequency is optimal in clinical treatment. In fact, recent data show that more frequent 


study visits are associated with increased antidepressant and placebo response as well as decreased separation 
between medication and placebo, suggesting that current methods may be counterproductive in RCTs and 
insufficient in clinical practice. Additionally, more intensive follow‐ up may be beneficial for some patients while not 
for others, so determining the optimal visit frequency for different types of patients could increase antidepressant 
response, improve client satisfaction, and make RCTs more efficient. 
 
To examine the influence of visit frequency on antidepressant and placebo response, this application 
proposes a double‐ blind, acute, prospective study randomizing subjects to “Research Frequency Management” 
(RFM, weekly study visits) vs. “Community Frequency Management” (CFM, every 4 weeks study visits) and 
escitalopram or duloxetine vs. placebo (see Figure 1). Close monitoring of all subjects will be assured by telephone 
contacts with individuals randomized to CFM between monthly visits, and additional study visits will be scheduled 
as necessary to maintain patient safety. The 104 subjects (26 per cell) participating in this study will be 
systematically characterized on measures of symptomatology, personality features, treatment history, therapeutic 
alliance, and treatment preferences to identify potential predictors of response to visit frequency. In this pilot 
study, we are particularly interested in examining the feasibility of our proposed experimental design and in 
detecting a signal of effect for visit frequency that will be followed up in a larger study. Pilot data from this study 
will allow us to determine whether patients can be recruited to participate in this novel study and be retained over 
the course  of its up to 5‐month duration. We will also obtain estimates of whether participants randomized to RFM 
vs. CFM have different rates of treatment adherence and adverse events, which could affect our interpretations 
regarding the effect of visit frequency on treatment response. In addition, piloting the assessment battery used in 
this study will allow us to assess the variability between subjects on the measures we plan to utilize, whether the 
recruited subjects are generalizable to the larger population of depressed patients enrolling in antidepressant RCTs, 
and whether there are initial indications that differences between clinical, demographic, and psychological 
characteristics of included subjects influence the effect of visit frequency on treatment response. 
 
Figure 1 
  
 
 
 


Significance: 
 
Results from this study will have important significances for the pharmacologic treatment of MDD. First, the 
findings that participants in an antidepressant RCT can be safely followed and that separation between drug and 
placebo is increased using CFM (every 4 weeks with every two‐week telephone check‐ins) would have immediate 
implications for the design of Phase III clinical trials. Decreasing the number of follow‐up visits to resemble 
community care could make RCTs cheaper, more efficient, and more generalizable to clinical practice. Second, if 
increased frequency of follow‐up visits leads to increased medication response for some patients, then the 
management of these treatments could be intensified beyond the monthly or less follow‐up currently practiced in 
order to enhance response to antidepressants. Third, differentiating patients likely to respond to more frequent 
therapeutic contact regimens from those who are not on the basis of clinical, demographic, or psychological data 
collected in this study would facilitate the development cost‐effective, personalized treatment strategies tailored 
to the needs of individual patients. This information could be used to improve client satisfaction and advocate on 
behalf of patients with third party payers who currently influence treatment decisions by determining how many 
visits will be reimbursed. 
 
Rationale: 
 
Effective antidepressant medications cause salutary changes in the pathophysiology of MDD, which in turn 
lead to symptomatic improvements that are measured using rating scales for depression. These medications are 
provided within a therapeutic environment that possesses many elements of supportive psychotherapy. For 
example, patients experiencing social isolation and decreased activity levels due to their depressed state enter a 
behaviorally activating and interpersonally rich new environment. They are provided with diagnoses and psycho‐
education to explain their symptoms and regularly meet with research staff who listen to their experiences. Such 
interactions, combined with information provided during the informed consent process, instill and maintain faith in 
the potential effectiveness of the treatment. 
 
Increasing or decreasing the visit frequency in an antidepressant RCT effectively varies the “dose” patients 
receive of these therapeutic factors. These aspects of clinical trials are often referred to as “non‐specific factors,” 
but evidence suggests they have quite specific and quantifiable effects on treatment outcome. 
 
The response observed in a clinical trial for a patient assigned to receive antidepressant medication thus 
reflects the specific effects of the medication combined with the therapeutic aspects of clinic visits. Expectancy of 
improvement, behavioral activation, and a therapeutic relationship with a clinician may modulate the effects of 
antidepressant medication or else directly ameliorate a patient’s depressive illness. In the case of patients assigned 
to placebo, we hypothesize that the expectancy of improvement, behavioral activation, and interpersonal 
experiences provided during clinic visits (in combination with natural history factors and measurement error) are 
the primary causes of placebo response.  In the proposed study, we expect to find supporting evidence for this 
model by detecting a positive main effect of visit frequency on treatment response. 
 
We will also attempt to identify an interaction between visit frequency and treatment assignment, since we 
anticipate that placebo response will be more affected by differences in visit frequency than medication response. 
Additionally, our model predicts that the effect of clinic visits on treatment outcome will be influenced by 
individual patient characteristics, and we expect to find indications in moderator analyses that this is the case. 
 
Support for the therapeutic effects of meetings with clinicians comes from the report of Posternak and 
Zimmerman (2007), who investigated the influence of therapeutic contact frequency on antidepressant and placebo 


response in 41 RCTs of antidepressants for MDD. These investigators calculated the change in HRSD scores 
observed over the first 6 weeks of treatment in patients assigned to antidepressant medication and placebo, 
comparing studies having 6 weekly assessments (weeks 1‐6) to those having 5 (weeks 1‐4 and 6) and 4 (weeks 1‐2, 
4, and 6) assessments. Participants treated with placebo who returned for a week 3 visit experienced 0.86 greater 
reduction in HRSD scores between weeks 2 and 4 compared to those who did not, while participants having a week 
5 visit had 0.67 greater reduction in HRSD scores between weeks 4 and 6 compared to those who did not. A 
cumulative therapeutic effect of additional follow up visits on placebo response was found between weeks 2 and 6, 
patients with weekly visits improved 4.24 HRSD points, while those with 1 fewer visit improved 3.33 points and 
those with 2 fewer visits improved 2.49 points. Thus, the presence of additional follow up visits appeared to explain 
approximately 50% of the symptom change observed between weeks 2 and 6 among patients receiving placebo. 
Participants receiving active medication also experienced more symptomatic change with increased numbers of 
follow‐up visits, but the relative effect of this increased therapeutic contact was approximately 50% less than that 
observed in the placebo group. 
 
These results suggest that the way antidepressant medication is administered in a clinical trial has substantial 
effects on treatment outcome. Far from being “no treatment,” assignment to placebo in an antidepressant clinical 
trial represents an intensive form of clinical management that has therapeutic effects. This treatment may be 
contrasted with what patients being treated with antidepressants receive in the community. In community samples 
of patients receiving antidepressant medication, 73.6% are treated exclusively by their general medical provider as 
opposed to a psychiatrist. Less than 20% of patients have a mental health care visit in the first 4 weeks after starting 
an antidepressant, and fewer than 5% of adults beginning treatment with antidepressant medications have as many 
as 7 physician visits in their first 12 weeks on the medication. Thus, for patients who benefit from more intensive 
follow up, increasing visit frequency may be a safe and effective way of improving medication response in open 
clinical treatment.


Specific Aims and Hypotheses 
Concisely state the objectives of the study and the hypothesis or primary research question(s) being examined.  There should 
be one hypothesis for every major study procedure or intervention.  For pilot studies, it is important not to overstate the 
study's objectives.  If there are no study hypotheses, describe broad study goals/aims. 
Aim 1: The first aim of the proposed study is to examine the differential effect of visit frequency on placebo vs. medication 
response.  
Hypothesis: Visit frequency contributes to treatment outcome for both medication and placebo responses, but especially for 
the placebo response. 
 
Aim 2: Our second aim is to investigate the mechanisms underlying such an effect.  
Hypothesis: Manipulation of visit frequency on outcome is mediated by the strength of the therapeutic alliance and the 
frequent use of supportive techniques 
 
Aim 3: The third aim of the proposed study is to identify patient characteristics (clinical, demographic, and interpersonal) 
that moderate the effect of visit frequency on outcome. 
Inclusion/Exclusion Criteria 
This section details your study sample(s) and addresses the requirement for risk minimization. 
You may choose to divide your sample by population (healthy controls vs. subjects) or by procedure (subjects who will have an 
MRI) and then define different sets of criteria for each. 
For each sample, create or insert a table to describe detailed criteria for study inclusion and exclusion and the method you will 
use to ascertain each criterion. The method of ascertainment may describe tests, scales and instruments.  When relevant, 
indicate the level of training of the person who will make the assessment (e.g. clinical interview by a psychiatrist). 
Inclusion/Exclusion Criteria needs to be numbered and listed in outline form (see Table template below). 
CRITERION                                                          METHOD OF ASCERTAINMENT                
Inclusion: 
 
1. 1.Men and women aged 18-75 years 
1. Clinical interview 
2. Diagnosis with Diagnostic and 
Statistical Manual (DSM) 5 Major 
Depressive Disorder (MDD) 
2. Clinical interview, SCID 
3. 24-item Hamilton Rating Scale for 
Depression (HRSD) score ≥ 16 and ≤ 28; 
17- item Hamilton Rating Scale for 
Depression (HRSD) score < 25 
3. HRSD by trained rater 
4. Capable of providing informed consent 
and complying with study procedures 
4. Clinical interview 
5. Using appropriate contraceptive 
method if woman of child-bearing age 
and not currently pregnant 
5. Clinical interview 


Exclusion: 
 
1. Current comorbid Axis I DSM V 
disorder other than Mild Substance Use 
Disorder, Adjustment Disorder, Anxiety 
Disorder or Personality Disorder 
1. Clinical interview, SCID 
2. Diagnosis of Moderate to Severe 
Substance Use Disorder within the past 
12 months 
2. Clinical interview, SCID, Urine tox 
3. Present or past history of psychosis, 
psychotic disorder, mania, or bipolar 
disorder 
3. Clinical interview, SCID 
4. baseline HRSD 24-item score > 28 or 
HRSD suicide item > 2 or baseline HRSD 
17-item score ≥ 25 
4. HRSD by trained rater 
5. History of allergic or adverse reaction 
to escitalopram and duloxetine, or non-
response to adequate trial of 
escitalopram (at least 4 weeks at dose of 
20mg) and duloxetine (at least 4 weeks at 
dose of 60mg) during the current episode 
5. Clinical interview 
6. Current treatment with psychotherapy, 
antidepressants, antipsychotics, or mood 
stabilizers 
6. Clinical interview 
7. CGI-Severity score of 6 or greater at 
baseline 
7. CGI based on Clinical interview 
8. Acute, severe, or unstable medical 
illness 
8. Clinical interview, Physical Exam, 
Screening Labs 
 
 
Study Procedures 
Provide a clear, concise narrative of study procedures with special attention to the subjects' involvement.  Detail the overall 
study timeline and location of study procedures, list all interventions, assessments and interviews, estimate the duration of 
each procedure, provide dosing schedules, identify study personnel involved in each procedure, and provide credentials for 
relevant personnel.  For complicated study designs, we strongly encourage attaching tables, flow-charts, and study 
algorithms. 
COVID Restart: 


I attest to follow the COVID-19 Safety Guidelines for Columbia Psychiatry and NYSPI Re-Entry outlined in the NYSPI 
Director’s June 1st memo, which include but are not limited to: 
• Infection Control/PPE – Guidelines 
• Research participants will only come on-site if absolutely necessary for study procedures. 
• No volunteers/externs on-site during Stage 1. 
• Clinical research teams will screen their participants for COVID symptoms (night before and 
day of onsite visit, documenting this in the chart), and escort them in and out of the building. 
• COVID/COVID-like symptoms in participants will be reported to the IRB via PRISM as an SAE. 
 
 
Due to the COVID-19 pandemic, beginning in October 2020, CAAM will be implementing a number of 
changes to this study's operating procedures in order to ensure a safe environment while continuing to provide 
patients depression treatment through research participation. These changes include implementing Telehealth 
resources to complete visits virtually and only evaluating/enrolling 50% of our normal participant capacity in 
order to minimize the risk of contracting the virus due to physical contact. All measures that do not require an 
in-person component will be completed virtually. The evaluation procedure will be altered to include virtual 
components. Detailed descriptions of these changes are provided below. 
 
Evaluation:  
 
A two-visit evaluation procedure, one virtual and one in-person, will be implemented in order to reduce the risk of 
transmitting the virus by minimizing person-to-person contact. After an individual expresses interest in research participation 
and completes the initial phone screen process, the individual will be scheduled for a virtual evaluation with a research 
coordinator (trained study raters; BA, RN, SW) and a clinician. All assessments that are generally conducted during the 
evaluation process (Protocol #7284R) that can be conducted over the phone will be administered during the virtual portion. 
The individuals who may be eligible for study participation after completing the virtual evaluation will then be scheduled for 
an in-person evaluation at the clinic, in order to complete the remaining assessments that are necessary to determine 
eligibility. 
 
The virtual evaluation will be completed via WebEx a HIPAA compliant video conferencing platform or a secure 
FaceTime platform. After consenting the individual virtually and sending them a copy of the consent form (if they have 
Internet/email access; if the individual does not have these resources, a hard copy of the consent form will be mailed to 
them), the research coordinator will complete the following measures: the MMSE, HRSD, Logical Memory Test I and II, and 
the SCID. They will also gather the individual's pharmacy information, as well as their current physical location and emergency 
contact (in case of a mobile crisis). The research coordinator will subsequently explain how the individual can complete the 
self-report forms included in the evaluation protocol online, and will send them a link for completion (if the individual does 
not have Internet/email access, self-report forms are to be completed over the phone with the research coordinator). The 
evaluating clinician will then be notified that the individual is ready for the clinical interview, and send them the assessment 
scores collected during the first portion of the virtual evaluation. The evaluating clinician will then join the call, and complete 
the clinical interview with the research coordinator on mute during the duration of the interview. If the individual may still be 
eligible for study participation after the clinical interview, they will be scheduled for the in-person component of the 
evaluation.


 
On the day of the in-person evaluation, the individual will be transported to the clinic via a car service. Social 
distancing procedures will be followed in order to ensure safety, including limiting the number of individuals in a clinic room, 
implementing the use of masks, and thoroughly cleaning clinic rooms and other assessment instruments (ex: blood pressure 
cuff, grip-strength machine, etc.) after each use. The rest of the evaluation procedures will be completed during the in-person 
visit. These assessments include: 
Physical: vitals (height, weight, blood pressure, temperature), blood and urine collection, and EKG. RA-Administered 
Assessments: WAI-P Intake and the QIDS-SR Expectancy. 
 
If an individual is eligible after completing the in-person evaluation and consents to study participation, they 
will be scheduled for their next visit.  
 
Standard Evaluation : 
 
At the evaluation visit, subjects will first undergo an initial evaluation comprising a psychiatric interview 
(MD/NP) as well as SCID‐V‐RV and HRSD by trained raters. A psychiatrist will review the consent form with eligible 
subjects and invite them to participate. 
 
Subjects who sign the consent form will complete the remainder of the baseline evaluation, including 
further paper measures (see assessment instruments section), as well as urine tests, blood tests, and EKG (RN or 
qualified research assistant). These subjects will return the following week to review findings from these tests, 
confirm their continuing eligibility to participate (i.e., no acute or unstable medical conditions were found), and be 
randomized. This will be considered the Week 0 visit. The Week 0 visit will include the Columbia‐Suicide Severity 
Rating Scale (C‐SSRS), a questionnaire used for suicide assessment. Any score above 0 on the C‐SSRS categories 
warrants physician notification and review. If at any point in time the patient presents with suicidal ideation, the C‐
SSRS Since Last Visit will be administered for determination of suicidal risk. Prior to randomization, patients of 
childbearing potential (female patients age 18‐60) will be instructed regarding potential risks to the fetus of 
Escitalopram and/or duloxetine and the importance of using adequate birth control. Patients will be given 
instructions regarding use of effective methods of birth control, and asked to please let us know if they become 
pregnant in order to ensure safety of the mother and fetus.  After receiving instruction, the study physician will 
evaluate the participant’s willingness and reliability to practice effective birth control. Potential study participants 
who cannot agree to consistently practice effective birth control, or who the physician judges to be unreliable in 
practicing effective birth control, will not be included in the study. If a subject does become pregnant, she will be 
withdrawn from the study and evaluated on clinical grounds as to whether the medication should be continued or 
stopped. 
 
As part of the evaluation, participants will be asked to be video recorded during study visits, and video 
recorded during the initial diagnostic interview. The purpose of these recordings is to check the quality of the 
evaluations and interviews being delivered, and to improve available treatments for depression. Video recordings 
are optional, and participants do not need to agree to the recordings in order to be evaluated. Participants will be 
provided with separate Video Recording Consent Forms to document whether they agree to be recorded. 
 
Acute Phase Treatment Procedures: 


 
At the Week 0 visit, subjects will be randomized to Research Frequency Management (RFM) or Community 
Frequency Management (CFM) (see Figure 1 above). They will be apprised of the results of this randomization and 
provided with a schedule of study visits. Within each track (RFM and CFM), subjects will be randomized to 
medication, escitalopram or duloxetine (if they cannot tolerate or have had an adverse reaction to escitalopram,) or 
to placebo. Assignment to medication or placebo will be blinded by over‐encapsulating study pills such that they 
appear identical. 
 
Each clinic visit will last approximately 45 minutes and follow a set structure, regardless of group 
assignment. Patients will arrive to the Clinic on Aging Anxiety, and Mood Disorders (CAAM) and be greeted by the 
clinic coordinator (1 min). Then, the clinical research assistant will meet with the patient to measure vital signs, 
collect used pill bottles, and distribute self‐report measures (10 min). Next, the study clinician will meet with the 
patient to assess the status of their depressive symptoms, discuss side effects and other issues related to study 
medication, and fill out clinician‐rated scales (15 min). Finally, a blinded rater will complete rater‐ administered 
measures (15 min), and the clinical research assistant will collect completed self‐report measures and make a 
follow up appointment (4 min). Patient questionnaires and some assessments at Week 0 and for the duration of 
the study will be administered using Qualtrics, a HIPAA‐compliant application accessible by smart phone or 
computer, by which raters and participants can access and complete online surveys. 
 
All visits will be videotaped, and all videotaped sessions will be coded systematically under the supervision 
of the Israeli PI. Trained raters will code for aspects of the doctor‐patient relationship (alliance development) and a 
variety of techniques (clinical management techniques as well as the facilitative conditions techniques, including 
warmth, empathy, involvement, rapport, conveyed expertise, communication style, supportive encouragement) 
using software for analyzing observational data (including Observer XT), which enable coders to code behavior on‐
the‐ go, accurately and quantitatively. The Week 0, 4, and 8 visits of each patient will be coded for both 
therapeutic alliance and use of therapeutic techniques, so that three scheduled sessions will be coded for each 
patient. The three time points were chosen because they overlap the two Acute Phase track assignments. 
 
In the CFM arm of the study, telephone assessments will occur between monthly clinic visits at weeks 2 and 
6, so subjects will be evaluated with standardized measures every 2 weeks during the study. During these 
telephone assessments, the research assistant will greet the subject and assess medication adherence, a trained 
rater will administer the HRSD, and the study clinician will briefly interview the subject to discuss interval events 
and fill out clinician‐rated scales. An additional in‐person clinic visit will be scheduled as soon as possible for 
patients (1) requesting to meet with the study clinician before the next scheduled visit, (2) who have begun 
experiencing a significant new side effect, (3) who have CGI Improvement score of 6 or 7, (4) who are showing a 
24‐item HRSD score increase >30%, or (5) who have HRSD suicide item score >2. 
 
Medication Treatment  
 
Subjects assigned to receive treatment with escitalopram will begin at a daily dose of 10mg or duloxetine 
30mg. The default medication will be escitalopram.   After 4 weeks, if subjects do not meet remission criteria (HRSD 
≤ 7), escitalopram dose will be increased to 20mg for the remaining 4 weeks of the study.  Participants who have 
not responded to or tolerated escitalopram in the current depressive episode will be started on duloxetine. They 
will take 30mg for the first 4 weeks, then be increased to 60mg for the remaining 4 weeks of the study. 


 
Subjects unable to tolerate the increased dose of medication will have their dosage reduced to the maximum 
previously tolerated dose. Absence of remission was selected to trigger dosage increases, because it is a clinically 
meaningful outcome denoting the absence of significant depressive symptoms and reduction in the risk of 
depression recurrence and adverse medical outcomes. We judged 4 weeks at a stable dose of the medications 
mentioned above to be a reasonable interval in which to observe the effects of that dosage. Patients who are 
assigned to placebo will receive placebo for the duration of the study. 
 
If a patient discontinues study medication due to tolerability problems, ineffectiveness, patient preference, 
or other reasons, the patient will be dropped out of the study and enter the 3-month open treatment phase. 
Appropriate medication options will be discussed with the patient based on their symptoms and history. If the 
patient wishes, they will be provided referrals for psychotherapy or treatment options outside of our research 
clinic.  No further research measures will be conducted once a patient enters the open treatment phase. 
 
Criteria for early discontinuation are either (1) significant clinical worsening in the judgment of the study 
clinician, (2) a CGI‐Improvement rating of 6 (worse) or 7 (much worse) for 2 consecutive visits, or 3a) C‐SSRS 
category score >3 and 3b) significant suicide risk in the judgment of the study clinician. Any subjects meeting one or 
both of these criteria will be dropped from the study and treated openly. Subjects in the CFM group who meet one 
or both of these criteria will be scheduled for an in‐person clinic visit the following week to permit serial 
assessment. Furthermore, subjects may be dropped form the trial if they repeatedly miss scheduled appointments 
or clinical worsening necessitates more intensive treatment. 
 
Continuation Phase Procedures: 
 
The blind will be broken at the end of the 8‐week study period for subjects who are non‐classified 
responders and appropriate clinical options will be discussed with patients. Patients taking escitalopram or 
duloxetine, who are classified responders (HRSD decrease by at least 50% and HRSD ≤ 12) or remitters (HRSD ≤ 8) 
will likely be continued on the same medication. Placebo non‐responders will be treated openly with escitalopram 
or duloxetine, while escitalopram or duloxetine non‐responders will be treated as clinically indicated with 
augmentation or switch in class of antidepressants. 
 
In the Continuation Phase, classified responders will continue double‐blind study medication and come to clinic for 
monthly study visits for three months. All responders, regardless of Acute Phase track assignment, will continue double‐ 
blind study medication and come to the clinic for monthly study visits. There will be Q2 week phone calls in between. Study 
assessments and early discontinuation criteria will be kept the same as in the Acute Phase procedure. 
 
Study Assessment Timepoints: 
 
Study Assessment – RFM 
Track 
SCREENING 
WEEK 0 
WEEK 1 
WEEK 2 
WEEK 3 
WEEK 4 
WEEK 5 
WEEK6 
WEEK 7 
WEEK 8 
Cont. Call 1 
Cont. Month 1 
Cont. Call 2 
Cont. Month 2 
Cont. Call 3 
Cont. Month 3 
P
h
y
Electrocardiogram 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history and physical 
examination 
X 


Demographic information 
X 
Serumlaboratoryexamination 
X 
Urinalysis 
X 
Urinetoxicology 
X 
Rater-administered 
measures 
SCID 
X 
HRSD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HARS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Structured Pill Count Interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TESS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blind assessment—Clinician & 
Patient Version 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WAI – T 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
Self-report measures 
ECR 
X 
WAI – P 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WAI – P (intake) 
X 
QIDS-SR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QUIDS-SR (intake) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CES 
X 
IIP-C 
X 
CSQ – 8 
X 
LOT-R 
X 
Big Five 
X 
Cornell Treatment Preference 
Index 
X 
 
 
 
 
 
 
 




 
Criteria for Early Discontinuation 
Define criteria that will be used to exit or drop subjects from the study.  Indicate the time points when such criteria will be 
applied, and describe the rating instruments, parameters, and thresholds that will lead to a decision to terminate a subject's 
participation.  In addition, explain procedures for managing subjects who are dropped from the protocol. 
For treatment studies: To minimize risks to subjects, operationalized drop-out criteria should be defined so that subjects who 
worsen, or in some cases, fail to improve, are removed from the study and offered standard care.  The threshold for drop-out 
should consider the level of risk associated with non-improvement for the specific disorder, the availability of alternatives, and 
the typical required duration of treatment.  For example, emergence of suicidal intent, or psychosis, should prompt immediate 
clinical evaluation and withdrawal from the study. 
 
Criteria for early discontinuation are either (1) significant clinical worsening in the judgment of the study 
clinician, (2) a CGI‐ Improvement rating of 6 (worse) or 7 (much worse) for 2 consecutive visits, or 3a) C‐SSRS 
category score >3 and 3b) significant suicide risk in the judgment of the study clinician. Any subjects meeting one 
or more of these criteria will be dropped from the study and treated openly. Subjects in the CFM group who meet 
one or more of these criteria (at an in person visit or phone call) will be scheduled for an in‐person clinic visit the 
following week to permit serial assessment. If such a subject continues to have a CGI‐I of 6 or 7, he or she will be 
dropped from the study and treated openly. Any score above 0 on the C‐SSRS categories warrants physician 
notification and review. An overall score of 0‐3 on the C‐SSRS categories indicates low‐risk suicidal ideation. If at 
any point in time the patient presents with suicidal ideation, the C‐ SSRS Since Last Visit will be administered for 
determination of suicidal risk. Furthermore, subjects may be dropped form the trial  if they repeatedly miss 
scheduled appointments or clinical worsening necessitates more intensive treatment. The same discontinuation 
criteria apply regardless of Acute Phase track assignment. 
Blood and other Biological Samples 
Describe how the sample will be used and indicate, when relevant, the amount of the sample.  The IRB wants to know that the 
sample is sufficient for the purposes of the study, but that sampling is limited to what is minimally necessary.   
If you’ve indicated that you intend to store a sample for future use, indicate where the sample will be stored, how long the 
sample will be stored, and to what purposes the sample will eventually be put.  Check the IRB website at 
http://irb.nyspi.org/irbdnn/Policies/GeneticResearch/tabid/96/Default.aspx   for specific guidance and additional information 
about future use of DNA samples. 
2 tubes of blood will be drawn and sent for CBC, Chem 7, LFTs, TSH, B12, folate, total cholesterol. Urine will be sent for 
urinalysis and toxicology. 
Assessment Instruments 
List all assessment instruments, indicate who will administer them, and provide an estimate the duration of each.  The IRB 
wants to know that assessments instruments are appropriate measures for the purposes of the study and are no more 
burdensome than is necessary.  The IRB will consider the burden of assessment instruments (in terms of time, sensitivity of 
material, etc.) in the risk/benefit analysis.  Please attach copies or otherwise provide all non-standard instruments. 
Overview:  
 
The assessment schedule was designed to replicate standard practice in RCTs for RFM and open clinical 
treatment for CFM. All participating subjects will be characterized on the below measures at baseline screening, 
then return the following week (Week 0) to review test results and be randomized (see Table 1). Subjects in the 


RFM arm will be     evaluated on follow‐up measures weekly (Weeks 1‐8), while participants in the CFM arm will be 
evaluated in person monthly (Weeks 4, 8) and via telephone 
 
check‐ins between visits (Weeks 2, 6). The function of telephone ratings is to ensure close monitoring of 
patients for safety purposes rather than assessment of outcome, so ratings at Weeks 2 and 6 will be limited to CGI, 
HRSD, and measures of adherence and side effects. 
 
Clinical and demographic information: we will collect information about the number of prior depressive 
episodes, age, age  of first depressive episode onset, gender, marital status, ethnicity, employment status and 
income, years of education, and family history. Physiologic measures: Baseline assessment will include 12‐lead 
electrocardiogram, vital signs, medical history and physical examination, complete blood count (CBC), basic 
metabolic panel (BMP, including electrolytes and liver function tests), thyroid profile, urinalysis, and toxicology. 
 
Rater‐administered measures: 
Structured Clinical Interview Diagnostic for DSM‐IV TR (SCID), First, Spitzer, Gibbon, & Williams, 1996; alternatively, 
SCID‐5‐ RV may be used): semi‐structured diagnostic interview designed to assist researchers in making reliable and 
valid DSM‐IV TR psychiatric diagnoses. SCID diagnoses will allow us to determine whether patients meet selection 
criteria and document the presence of covariates such as past substance abuse and dependence, and past or 
present anxiety disorders. 
Hamilton Rating Scale for Depression (HRSD) scale for depressive symptoms administered by trained raters. The 
HRSD is the standard measure of depression severity for clinical trials of antidepressants, and was chosen as the 
primary outcome measure. 
Hamilton Anxiety Rating Scale (HARS) 14‐item scale: scale for anxiety symptoms administered by trained rater. The 
HARS is a standard measure of anxiety severity in pharmacotherapy studies that has been shown to have 
acceptable reliability and validity in studies of depressed patients. 
CGI Severity and Improvement (Spielmans & McFall, 2006): scales developed to measure the clinician’s view of 
patients’ global functioning before and after initiating study medication. The CGI correlates well with other 
standard outcome measures for depression (e.g., HRSD), is sensitive to change in antidepressant trials, and offers 
clinically understandable anchor points (Bandelow, Baldwin, Dolberg, Andersen, & Stein, 2006). 
CGI ratings will provide clinical assessment of patients at each visit, and help us maintain the safety of study 
participants by identifying significant clinical worsening that requires patients to be dropped from the study. 
Structured Pill Count Interview assessment of medication compliance, to account for each dose of prescribed study 
medication, during the study period. This standard means of determining medication compliance in a 
pharmacotherapy study will allow us to assess whether contact frequency is associated with differences in behavior 
among study patients. 
Treatment Emergent Symptom Scale (TESS): rating scale for physical symptoms reported during the study. This 
standard means of recording drug‐related adverse effects will allow us to assess whether contact frequency is 
associated with differences in side effects among study patients. 
Columbia–Suicide Severity Rating Scale (C‐SSRS): an assessment tool that evaluates suicidal ideation and behavior. 
This is the institutional standard used to assess suicidal risk. 


 
Self‐report questionnaires: 
Quick Inventory of Depressive Symptoms— Self Report (QIDS‐SR) 16 item scale: rating scale for depressive 
symptoms based on DSM criteria. A self‐report measure for depressive symptoms is valuable in this study, because 
it is less susceptible to clinician and rater bias. The QIDS‐SR has been increasingly used in antidepressant studies 
(e.g., STAR*D) due to its equivalent weightings for each symptom item, clearly understandable anchor points, and 
inclusion of all DSM criteria for depression. 
Working Alliance Inventory‐Short Revised (WAI; Tracey & Kokotovic, 1989), using the patient (WAI‐P) and therapist 
(WAI‐T) versions: rating scale for the working relationship between physician and patient. The WAI, the most widely 
used measure of the therapeutic alliance, has excellent psychometric properties (Elvins & Green, 2008) and has 
been consistently correlated with psychotherapeutic outcome (Horvath et al., 2011). Similarly, to previous ADM 
studies, we have slightly modified the scale to substitute “pharmacotherapy” for “counseling” on relevant 
questions (e.g., Zilcha‐Mano et al., 2015). The WAI total score will be used for analyses. 
Treatment Credibility and Expectancy Scale (CES; Borkovec & Nau, 1972): patients rate their impression of the 
credibility of the treatment and their estimated expectation of improvement on an 8‐item scale. Given previous 
studies on the effect of patients’ pre‐ treatment expectancy on placebo response, all analyses in the proposed 
study will be repeated controlling for the potential effect of expectancy (Rutherford et al., 2016). 
Experiences in Close Relationships Scale‐Short Form (ECR; Wei et al., 2007): scale assessing patients’ attachment 
orientation. Both ECR dimensions will be used and assessed at baseline: 6 items assess the attachment anxiety 
dimension and 6 the avoidance dimension. A self‐report questionnaire will be used for assessing attachment 
orientation because it will be easy and inexpensive to implement, enabling translation of the findings into 
personalized medicine in clinical practice. 
Inventory of Interpersonal Problems– Circumplex (IIP‐C; Alden, Wiggins, & Pincus, 1990): a 64‐item self‐report 
questionnaire assessing interpersonal difficulties and distress. 
Patients rate two types of items: interpersonal behaviors that are “hard for you to do” (e.g., “it is hard for me to let 
other people know when I am angry”) and interpersonal behaviors that “you do too much” (e.g., “I am too afraid of 
other people”). Ratings of the degree to which each problem is distressing are made on a 5‐point scale, ranging 
from 0 (not at all) to 4 (extremely). 
Client Satisfaction Questionnaire 8 (CSQ 8): self‐administered scale with items rating respondents’ satisfaction with 
mental health services they are receiving on a 4 point Likert scale. Use of the CSQ 8 will allow us to determine 
whether CFM and RFM are associated with differences in participant satisfaction. 
Cornell Treatment Preference Index: scale used in mental health studies to document the type and strength of 
patients’ treatment preferences. We will use a modified version in this study asking subjects “Based on your 
experience and how you feel right now, which of the visit frequencies in this study would be your first choice?” The 
strength of this preference will be measured on a 5‐point Likert scale. 
Revised Life Orientation Test (LOT‐R): scale developed to assess individual differences in generalized optimism 
versus pessimism. Degree of optimism on this scale has been correlated with the magnitude of placebo response 
observed in studies of placebo analgesia, and we will determine whether LOT‐R scores moderate effects of 
therapeutic contact. 


Big Five Personality Traits (BFI): this questionnaire is a widely used assessment tool for personality traits that we 
will also use to identify predictors of response to varying visit frequency. 
Blind assessment— Clinician and Patient Version: rates clinician’s and patient’s guess as to the identity of study 
condition (ADM vs placebo) and the confidence in that guess. 
This assessment is necessary to document the effectiveness of the methods of treatment allocation concealment 
for ADM and placebo. 
Coding systems: Working Alliance Inventory— Observer Form (WAI‐O; Berk, 2013): Alliance will be coded using the 
12‐item version of the Working Alliance Inventory‐ Observer form (WAI‐O) (Darchuk et al., 2000). The items and 
anchors for the WAI‐O were sampled directly from Darchuk’s measures. The WAI‐O validity and reliability have 
been documented (Berk, 2013), as was the utility of coding distinct types of treatments (Zilcha‐ Mano, Adler, & 
Shahar, 2017). 
Collaborative Study Psychotherapy Rating Scale (Hollon et al., 1988): techniques will be coded using two of the 
CSPRS observer‐rated measures of adherence: the clinical management (CM) techniques and the facilitative 
conditions (FC) techniques. The CSPRS was developed for the Treatments of the Depression Collaborative Research 
Project (TDCRP; Elkin et al., 1989). Each item on the CSPRS describes a specific intervention and is rated on a 7‐
point Likert scale as to how extensively the intervention was used during a given session. The CM subscale, based 
largely on the Fawcett et al. (1987) manual, consists of 20 items that cover medication management and generally 
supportive interventions. It includes items such as symptom inquiry, biochemical rationale, pharmacological 
rationale, medication effects expected, concerns about medication, occurrence of side effects, medication dosage, 
and adherence to regimen. The FC subscale consists of 8 items that represent relationship‐building practices 
assumed to exist across all treatments for psychiatric disorders, including supportive encouragement, warmth, 
empathy, rapport, involvement, and conveying expertise. 


 
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Research Related Delay to Treatment 
Research involving participants who are in need of treatment invariably involves delay to care, and this delay is 
associated with risk.  Scheduling of procedures must be carefully organized to minimize delay.  Other delay must involve 
only that minimally necessary to accomplish the aims of the research while respecting subject well- being and safety. 
Describe the delay, by virtue of research participation in this study, before a participant can receive treatment of known 
efficacy or standard care routinely offered in the community. 
 
Research may possibly result in a delay in treatment. Patients who present to CAAM who are not 
taking antidepressant medication will not have a delay in treatment caused by research. We recognize that 
some subjects may present for a screening visit while taking an antidepressant or having had recent treatment 
with an antidepressant medication. Subjects demonstrating a partial response on their medication regimen or 
who have not been on an adequate dose of medication for an adequate duration will not be tapered off 
medication. They will be referred back to their treating clinician with a recommendation to complete an 
adequate trial of medication. Subjects taking an antidepressant who have not responded to an adequate trial 
of the medication at the time of their screening assessment and who are interested in participating in the 
study will undergo a medication washout. Patients eligible for medication washout include patients eligible for 
study enrollment. Please see Inclusion/Exclusion Criteria for further information. Supervised by the study 
clinicians, these subjects will be tapered off of their current antidepressant medication for 1‐2 weeks and 
remain off medication for 2 weeks. Subjects undergoing a medication taper will be seen weekly for clinic visits. 
If subjects are unable to tolerate this taper or washout period as evidenced by meeting one of the criteria for 
early discontinuation, they will be treated openly with the goal of achieving remission of their depression for 
three months. Subjects will receive 3 months of free doctor/np visits in the clinic and at least 1 month of free 
medication. Every effort will be made to provide free medication for 3 months total, but we cannot guarantee 
the availability of free medication beyond 1 month. At the end of the three‐month period, patients will be 
referred out for further psychiatric follow up. 
Maximum duration of delay to standard care or treatment of known efficacy Patients assigned to placebo 
(50% of sample) will have a treatment delay of up to 5 months (Acute + Continuation Phase). 
 
Treatment to be provided at the end of the study 
 
At the end of the acute treatment protocol, appropriate treatment (medication continuation, change 
in medication, and/or follow‐up) will be provided free for 3 months. Subjects will receive 3 months of free 
doctor/np visits in the clinic and at least 1 month of free medication. Every effort will be made to provide free 
medication for 3 months total, but we cannot guarantee the availability of free medication beyond 1 month. 
At the end of the three‐month period, patients will be referred out for further psychiatric follow up. 


 
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Clinical Treatment Alternatives 
Describe what other treatment or assessment options are available to subjects who do not participate in research. 
Patients with Major Depressive Disorder do not have to participate in this study in order to receive treatment. 
They may be evaluated by a clinician in a private office, on their insurance plan, or in a low cost clinic and 
receive treatment with escitalopram and/or duloxetine for their depression. They also have the option of 
trying other antidepressant medications that a clinician recommends for their condition. 
Risks/Discomforts/Inconveniences 
"Risk" is a broad term used to convey the potential for harm, burden, and inconvenience related to research 
participation.  Use this section to provide a comprehensive description of foreseeable physical, psychological, social, 
interpersonal, and economic risks introduced by the research.  Include the source of the information.  Consider both the 
probability and magnitude of harm and its impact.  Describe the foreseeable harms associated with the research 
(untoward effects of a medication) and those related to delay to individualized treatment.  Include data from the 
literature, and local data, if available, on risk rates and subject experiences with research procedures. Describe 
procedures in place to minimize risk. In general, please create a numbered list of risks/categories of risk, and in general 
put the list in the order of significance or level of risk, the most significant risks first followed by others.  
1.  One risk to subjects in this study is the possibility of being randomized to monthly as opposed to weekly 
study visits. It is possible that a reduced visit schedule may adversely influence medication compliance, timely 
reporting of symptom changes and side effects, and motivation to continue participation in the study. 
Additionally, 52 subjects will be assigned to pill placebo for the 8‐week Acute Phase of the study. Assignment 
to placebo places subjects at risk for continued or worsening depressive symptoms when there is treatment 
available of known efficacy for depression. Subjects completing the study will receive free open clinical 
treatment for 3 months following the study, and subjects whose depressions do not remit to placebo will have 
a treatment of known efficacy started immediately upon the study’s conclusion. 
2.  Another significant risk to subjects is related to drug administration. Side effects of escitalopram include 
somnolence, diarrhea, nausea, impaired ejaculation, impotence, dry mouth, tremor, and sweating.  The most 
common side effects reported for duloxetine are insomnia, constipation or diarrhea, dry mouth, sweating, 
nausea and small increase in blood pressure.  The less common side effects of duloxetine are abnormal 
orgasm, fainting, and headache.   Escitalopram and duloxetine have a black box warning regarding an 
increased risk for suicidal thinking and behavior in adolescents and young adults (less than 24 years old) given 
the drug. Since the proposed study will enroll subjects aged 18‐75 years, participants will be apprised of this 
potential side effect and asked to tell their doctors immediately if they experience suicidal thoughts. 
3. Regarding pregnancy, escitalopram and duloxetine are Category C pregnancy risk drug, meaning there are 
no adequate studies in humans to determine the risk. Therefore, determination of the risk/benefit ratio will be 
left up to the clinician’s judgment and is dependent on the risk of depression in the mother. Female 
participants will be required to use effective methods of birth control (e.g., condom with spermicide, 
diaphragm with spermicide, or oral contraceptive pills). Patients will also be advised to please let the study 


 
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physician know if they have become pregnant. If a subject does become pregnant, she will be withdrawn from 
the study and evaluated on clinical grounds as to whether the medication should be continued or stopped. 
4.  The clinical interviews, rating scales, and questionnaires should not pose significant risk to study subjects. 
All procedures are consistent with HIPAA requirements, including the completion of online assessments using 
Qualtrics. Their major disadvantage is the time required to complete them and that some questions might be 
embarrassing or distressing to subjects. Subjects are informed that they may refuse to answer any questions 
and may ask to stop at any time. If participants become upset during the interviews and/or assessments, 
assistance will be made available for them. Another risk of this process is that it may be upsetting for the 
patient to be videotaped during the study visit. Blood drawing may cause slight discomfort at the site of 
needle entry and result in a small bruise. 
5.  Due to the COVID-19 pandemic, the additional risk of contracting the virus with any human interaction is 
present, due to the method of how the virus is transmitted. 
 
Procedures for Minimizing Risk 
 
The proposed study’s selection criteria are designed to minimize the medical and psychiatric risks to 
subjects as described above. Subjects undergo a comprehensive medical and psychiatric evaluation during the 
screening visit, including physical examination, complete blood count, chemistry profile, liver function tests, 
thyroid stimulating hormone, urinalysis, and electrocardiogram, which is designed to detect unstable medical 
illnesses. Vital signs will be obtained at each weekly clinic visit.  Subjects will be monitored for adverse effects, 
and dose adjustments will be made if indicated. 
 
The risk of being randomized to the CFM group is addressed in several ways. First, subjects with severe 
MDD (as indicated by a score of 6 or greater on the CGI—Severity scale) as well as subjects with significant 
suicidal ideation (as indicated by a HRSD item 2 score > 2) will be excluded from the study. Second, subjects in 
the CFM group will be evaluated by study personnel no less frequently than every 2 weeks. The visit schedule 
for patients randomized to the CFM group will be as follows: baseline evaluation in clinic, week 0 visit in clinic 
(1 week following evaluation visit to review evaluation data and begin study), week 2 telephone assessment, 
week 4 visit in clinic, week 6 telephone assessment, and week 8 visit in clinic. 
 
Biweekly phone assessments and monthly clinic visits apply to those eligible for the Continuation 
Phase. This schedule will permit in‐person evaluation of all patients at critical time points in the monitoring 
and management of patients receiving antidepressant medications (i.e., consideration of dosage increases at 4 
weeks). 
 
Telephone assessments will have 3 components: (1) research assistant will greet the subject and fill out 
Structured Pill Count Interview, (2) trained rater will administer the HRSD, and (3) study clinician will briefly 
interview the subject to  discuss their subjective state and interval events, fill out Treatment Emergent Side 


 
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Effect Scale (TESS), and complete Clinical Global Impressions – Severity and Improvement. This will permit 
standardized assessment of interval change in the  subject’s adherence to study medication, experience of 
side effects related to escitalopram and duloxetine, symptom severity, and clinical deterioration such as 
evolution of suicidal ideation. An additional in‐person visit will be scheduled for subjects (1) requesting to 
meet with the study clinician before the next scheduled visit, (2) who have begun experiencing a significant 
new side effect, (3) who have CGI Improvement score of 6 or 7, (4) who are showing a 24‐item HRSD score 
increase >30%, or (5) who have HRSD suicide item score >2. Third, patients will be extensively educated in the 
availability of 24‐hour coverage by a psychiatrist in addition to having an Emergency Department at CUIMC 
that is thoroughly familiar with our protocol. Participants will receive a printed card to keep on their person 
that details the procedures to reach the on‐call psychiatrist and access the CUMC emergency room. 
 
We have implemented a plan for monitoring and treating suicidal ideation developed for research 
studies by colleagues at NYSPI (Drs. Maria Oquendo and John Mann). If the patient expresses any recent 
suicidal behavior or suicidal ideation during an interview, this is indicated in the chart note and quantitatively 
measured with the suicide item of the HRSD. The HRSD score itself is not used as a clinic standard to 
determine emergency care procedures; rather, clinical interview and physician judgment use the HRSD score 
alongside other quantitative and qualitative factors in assessing patient risk. 
 
Should a research subject manifest severe suicidal ideation, arrangements for emergency care, in 
consultation with the principal investigator, will be made. The Columbia University Medical Center Emergency 
Department is located near the Clinic for Aging, Anxiety, and Mood Disorders (CAAM), and security services 
are available to assist with patient transportation to the emergency room. For subjects who may experience 
suicidal ideation between assessments, our department provides 24‐hour coverage by a psychiatrist in 
addition to having an Emergency Department that is thoroughly familiar with our protocol. As described 
above, all patients are given the pager number for the Doctor on Call, and this number is also recorded on all 
outgoing phone messages of the clinical staff. If the suicidal ideation can be managed as an outpatient, the 
subject will be given an appointment within the next two days and contact will be maintained with phone 
check ins. If the suicidal ideation is more severe, the patient will be given information to access emergency 
care and/or be escorted to the emergency room. 
 
The risk of receiving placebo or non‐response to escitalopram and/or duloxetine during the study 
period is addressed by having close clinical follow up of study subjects and stringent drop‐out criteria. These 
criteria are (1) significant clinical worsening in the judgment of the study clinician or (2) a CGI‐Improvement 
rating of 6 (worse) or 7 (much worse) for 2 consecutive visits. Any subjects meeting one or both of these 
criteria will be dropped from the study and treated openly. Subjects in the CFM group who meet one or both 
of these criteria will be scheduled for an in‐person clinic visit the following week to permit serial assessment. 
Furthermore, subjects may be dropped form the trial if they repeatedly miss scheduled appointments or 
clinical worsening necessitates more intensive treatment. Pregnant or lactating women, or those not 
practicing reliable birth control, are excluded. Subjects are instructed to inform their study physician 
immediately if they suspect they may be pregnant. 


 
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History of adverse or allergic reaction to escitalopram and duloxetine is exclusionary. Because subjects 
might potentially attempt to overdose with escitalopram and/or duloxetine, they will be provided with at 
most a 30‐day supply of medication at one time during the study. Subjects will be informed of the potential 
side effects and risks enumerated above through extensive discussions with the study physicians and research 
staff throughout the study. Subjects will be warned that risks, as yet unknown, may occur when combining 
study medication with alcohol, drugs, or other prescription medications. Subjects will give informed consent 
prior to participation in the study and are provided with the phone number of the on call doctor, who is 
available 24 hours per day. 
 
Confidentiality will be protected by storing all patient records in locked cabinets. Computer records will 
be identifiable only by a subject’s study code number. Information will be available to subjects’ physicians or 
other health services only if directly requested in writing and the subject signs a release of medical 
information form. All procedures at NYSPI are in compliance with HIPAA requirements. Subjects will be asked 
to sign a notice of privacy protection. 
 
Specifically, for in-person visits to NYSPI, individuals are at increased risk for exposure to COVID-19 
both in transit to NYSPI as well as during their time at NYSPI. Procedures are in place to minimize this risk. We 
plan to offer car transportation subject to a maximum of $50 each way, which minimizes exposure to public 
transportation for those participants. At NYSPI, personal protective equipment such as masks will be utilized at 
all times both by staff and participants, and social distancing will be adhered to when possible (exceptions 
exist for procedures such as blood draws and EKGs). Screen shields between patient and staff will be used 
during neuropsychological testing to further minimize exposure risk. 
Methods to Protect Confidentiality 
Describe the data management plan and the methods you will employ to protect subject privacy and the confidentiality 
of research data.  The section should detail how information will be collected, recorded, coded, stored, transmitted, and 
as applicable, shared with other investigators so as to minimize risks related to breach of confidentiality.  Confirm that 
identifiers are removed, to the extent possible, from research data, and explain if there are links between subject identity 
and research data, or if the data is anonymous.  Also, indicate where the data is stored, who is responsible for its 
safekeeping, and who has access to subject identity and codes, if any, which cross-link research data and subject identity.  
Confirm that identifiable data is not collected, stored, or transmitted by mail, fax, on removable drives, laptops, or via the 
internet without proper protections, e.g. encryption. 
 
All records of the participating subjects will be kept in a locked room with access provided only to staff 
members. Patients’ names will be linked with code numbers in a password protected file to which only the research 
assistant has access. Only these code numbers will appear on all pill bottles and paper measures collected during study. 
All data collected will be kept confidential and used for professional purposes only. 
  
Publications using these data will be done in a manner that protects the subjects’ anonymity. All electronically 
stored data will be accessible by password known only to the principal investigator and research assistants for the study. 


 
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There may be future analyses of all the research data conducted by the study investigators, yet unplanned, 
dealing with other aspects of illnesses of late-life. Additionally, research data may also be shared and provided to other 
investigators for the purpose of secondary analyses or distributed to another investigator for future research studies. 
The results of this study may also be published or presented at professional meetings. In each of these instances, all 
personal identifiers (such as name, birth date) will have been removed (de-identified) and replaced with a specific code 
number. The information linking this code number to subject’s identity will be kept in a separate, secure location. 
 
Patient questionnaires and some assessments at Week 0 and for the duration of the study will be administered 
using Qualtrics, a HIPAA‐compliant application accessible by smart phone or computer, by which raters and participants 
can access and complete online surveys. 
 
All study visits will be videotaped and shared for analysis via the NYSPI Office 365 Sharepoint.com platform for 
secure collaboration with pre‐approved collaborators. Via SharePoint, video data will be moving securely between NYSPI 
and Haifa University in Israel for coding analysis. This platform has been registered with NYSPI IT and is approved for 
confidential data exchange and collaboration, as advised by Chris Stanley. This is the same solution being used to 
support parts of the OPAL Center. 
 
Due to the implementation of virtual visits, additional measures to protect patient confidentiality will be 
employed. These include using only secure platforms for virtual calls (CUIMC Zoom Pro etc.), the use of headphones 
during virtual calls, and not continuing to use Qualtrics forms for data collection during week 0 and follow up calls. 
Direct Benefits to Subjects 
Describe only benefits to individual subjects that are likely to accrue during the study itself. Do not include subject 
compensation or treatment to be provided at the end of the study, as these do not figure into the IRB's risk benefit 
considerations.  Do not describe diagnostic and evaluation components unless subjects receive clinical feedback. Do not 
describe the anticipated scientific benefits of the research.  Some studies offer no direct benefit to subjects. 
As this is protocol includes a treatment medication approved for depression, the patient’s symptoms may or may not 
improve. There are no other direct benefits in this study. 
 
 
 


 
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References 
 
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recommendations. A demonstration. PloS one, 9, e83875. 


 
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of Behavior Therapy and Experimental Psychiatry, 31, 73-86. 
16.  Dolev, T., & Zilcha-Mano, S. (2016). The role of alliance in treatment: A mediation model. In preparation. 
17.  Elkin, I., Shea, M. T, Watkins, J. T, Imber, S. D., Sotsky, S. M., Collins, J. F., Glass, D. R., Pilkonis, P. A., Leber, W. R., 
 
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18.  Elvins, R., & Green, J. (2008). The conceptualization and measurement of therapeutic alliance: An empirical review. 
 
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19.  Falkenström, F., Granström, F., & Holmqvist, R. (2013). Therapeutic alliance predicts symptomatic improvement 
 
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20.  Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for 
 
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response rates in antidepressant trials: a  systematic  review of published and unpublished double-blind 
 
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24.  Hamilton, M. (1967). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56-62. 
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therapy,  interpersonal psychotherapy, and clinical management pharmacotherapy. Unpublished manuscript. 
26. Hollon, S. D., Thase, M. E., & Markowitz, J. C. (2002). Treatment and prevention of depression. 
 
Psychological Science in the Public Interest, 3, 39-77. 
 
27. Horvath, A. O., Del Re, A. C., Flückiger, C., & Symonds, D. (2011). Alliance in individual psychotherapy. Psychotherapy, 
 
48, 9-16. 
28. Hothorn, T., Hornik, K., & Zeileis, A. (2006). Unbiased Recursive Partitioning: A Conditional Inference Framework. 
 
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29.  Jensen, K., & Kelley, J. M. (2016). The therapeutic relationship in psychological and physical treatments, and their  
 
placebo controls. Psychology of Consciousness: Theory, Research, and Practice, 3(2), 132. 


 
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30.  Kessler, R. C. (2012). The costs of depression. Psychiatric Clinics of North America, 35, 1- 14. 
31.  Khan, A., Bhat, A., Kolts, R., Thase, M. E., & Brown, W. (2010). Why has the antidepressant– placebo difference in 
 
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217-226. 
32. Khan, A., & Brown, W. A. (2015). Antidepressants versus placebo in major depression: an overview. World 
 
Psychiatry, 14(3), 294-300. 
33.  Lambert, M.J. (2013). The efficacy and effectiveness of psychotherapy. In Lambert, M.J. (Ed.), Bergin and Garfield's 
 
handbook of psychotherapy and behavior change. (pp 169-218). New-York: John Wiley & Sons. 
34.  Leibovich, L., & Zilcha-Mano, S. (2016). Can supportive treatment outperform a more "active" one? In preparation. 
35.  Levy, K. N., Ellison, W. D., Scott, L. N., & Bernecker, S. L. (2011). Attachment style.  Journal of Clinical Psychology, 67, 
 
193-201. 
36.  Lorenzo-Luaces, L., DeRubeis, R. J., & Webb, C. A. (2014). Client characteristics as moderators of the relation 
 
between the therapeutic alliance and outcome in cognitive therapy for depression. Journal of Consulting and 
 
Clinical Psychology, 82, 368-373. change. New York: Guilford Press. 
37.  Morrato, E. H., Libby, A. M., Orton, H. D., deGruy III, MD, F. V., Brent, D. A., Allen, R., & Valuck, R. J. (2008). 
 
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Psychiatry, 165(1), 42-50. 
38.  Posternak, M. A., & Zimmerman, M. (2007). Therapeutic effect of follow-up assessments on antidepressant and 
 
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Journal of Psychiatry, 170, 723-733. 


 
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44.  Rutherford, B. R., Sneed, J. R., Roose, S. P. (2009). Does study design affect outcome?  the effects of placebo control 
 
and treatment duration in antidepressant trials. Psychotherapy and Psychosomatics, 78, 172-181. 
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58.  Zilcha-Mano, S., & Errázuriz, P. (2015). One size does not fit all: examining heterogeneity and identifying moderators 
 
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Consulting and Clinical Psychology. 
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New York State Psychiatric Institute
Developing New Clinical Management Strategies for Antidepressant
Treatments
OVERVIEW 
Below is a summary of the study that you are asked to participate in.  This outline is meant to be a guide 
for you to use while considering the study and reading the consent form.  It is not meant to replace the consent 
form, which you will have to sign if you decide to participate in the study. The consent form contains detailed 
information about the study and about the risks which you will need to consider before making your decision.  
Read the consent form carefully and discuss it with others before deciding to take part.  And remember that, 
even if you agree to participate, you can change your mind at any time. 
VOLUNTARY 
As with all research, this is a voluntary study, and you do not have to participate if you do not want to.  
Also, you may stop participating at any time. 
ALTERNATIVE TREATMENTS/ALTERNATIVES TO PARTICIPATION 
The alternative to participating in this study is to seek treatment outside the research project. Other 
medications in the same family as escitalopram are available (e.g., fluoxetine (Prozac), sertraline (Zoloft), etc.) 
as well as in different families of medications, such as duloxetine. In addition, psychotherapy may be helpful 
with depression, whether on its own or combined with medication. 
PROCEDURES 
x
You have a 50/50 chance (like flipping a coin) of being assigned to one of two tracks: RFM Track, 
weekly study visits or CFM, monthly study visits, both tracks being antidepressant medication vs. 
placebo and for 8 weeks in duration
x
If you still have depressive symptoms after four weeks on the pills you are given, the dose will be 
increased to two pills (either 20mg of escitalopram of 2 placebo pills, depending on the group to 
which you are assigned)
x
If you previously have not tolerated or had an adverse reaction to escitalopram, you will be started 
on 30 mg of duloxetine.  After 4 weeks, if you have not responded to the medication, you will be 
increased to 60 mg of duloxetine vs placebo.
x
If you respond, you will come monthly to our research clinic for three months after Week 8 to 
continue the double-blind study
x
At the end of the study you will be informed whether you received medication or placebo, and you 
are entitled to 3 months of free doctor visits in the clinic and at least 1 month of free medication.
RISKS AND INCONVENIENCES
This study includes some risks and discomforts (please refer to the consent form for further details 
and explanations of these risks).  These include the risk that your depression may worsen if you are assigned 
to placebo and do not receive actual medication for your condition until after the 2 to 5-month study is over. 
For the duration of the study, you may also continue taking medication which is not effective for you before 
trying another medication. The most common side effects reported for escitalopram are nausea, insomnia, 


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and inability to have an orgasm. The most common side effects reported for duloxetine are insomnia, 
constipation or diarrhea, dry mouth, sweating, nausea, and a small increase in blood pressure.
Furthermore, specifically for any potential in person visits to NYSPI, individuals are at increased risk 
for exposure to COVID-19 both in transit to NYSPI as well as during their time at NYSPI. Procedures are in 
place to minimize this risk. We plan to offer car transportation subject to a maximum of $50 each way, which 
minimizes exposure to public transportation for those participants. At NYSPI, personal protective equipment 
such as masks will be utilized at all times both by staff and participants, and social distancing will be adhered 
to when possible (exceptions exist for procedures such as blood draws and EKGs). Screen shields between 
patient and staff will be used during neuropsychological testing to further minimize exposure risk.
BENEFITS 
This research study is not meant to benefit you directly. 
QUESTIONS 
You may contact the study doctor, Bret Rutherford, MD at 646-774-8660 with any questions. 


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NEW YORK STATE PSYCHIATRIC INSTITUTE DEVELOPING NEW CLINICAL
MANAGEMENT STRATEGIES FOR ANTIDEPRESSANT TREATMENTS
The following outline is meant to serve as a guide to help you learn about this research study and decide 
whether you want to take part. It does not replace the consent form that you will be asked to read and sign. The 
consent includes much more information you’ll need to make a decision. Read the consent form carefully, ask 
questions, and take your time or speak to others if you want to before you make your choice. Remember, even 
if you agree to take part in research you can change your mind at any time. 
x
This is a research study in which you may receive treatment with escitalopram (Lexapro), duloxetine 
(Cymbalta) or placebo. Escitalopram and duloxetine are FDA approved medications indicated for the 
treatment of major depressive disorder. A placebo is a sugar pill.
x
The purpose of this study is to investigate whether individuals who have study visits with a doctor once 
per month respond to treatment differently from individuals who have study visits with a doctor once 
per week.
x
At the beginning of the study, you will be given a physical examination, an electrocardiogram (EKG), 
have your blood drawn, and fill out some psychological tests.
x
The first phase of the study lasts 8 weeks, and participants in this study will return to our clinic for visits 
either weekly or monthly.  Individuals being seen on a monthly visit schedule will speak to members of 
the research team between monthly study visits.
x
The second phase of the study lasts three months and is only for those who respond to their assigned 
medication. Individuals in the second phase will return to our clinic for monthly visits and speak with 
members of the research staff by telephone between monthly study visits.
x
The main risk of participating in this study is that your depression may worsen if you are assigned to 
placebo and do not receive actual medication for the duration of the study.
x
The most common side effects reported for escitalopram are nausea, insomnia, and inability to have an 
orgasm.
x
The most common side effects reported for duloxetine are insomnia, constipation or diarrhea, dry 
mouth, sweating, nausea, and a small increase in blood pressure.
x
You will not be charged for any procedures that are a part of this study including the study medication 
and the clinical interviews.
x
You do not have to participate in this study to receive treatment for your depression. The alternative to 
participating in this study is to seek treatment outside the research project.


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NEW YORK STATE PSYCHIATRIC INSTITUTE DEVELOPING NEW CLINICAL MANAGEMENT 
STRATEGIES FOR ANTIDEPRESSANT TREATMENTS
PURPOSE OF STUDY
The purpose of this study is to investigate whether individuals who have in-person visits with a doctor 
once per month respond to treatment differently from individuals who have in-person visits with a doctor once 
per week. If you are eligible and decide to participate in the study, you have a 50/50 chance (like flipping a 
coin) of being assigned to one of two groups. You are being asked to participate in this study because you have 
been diagnosed with Major Depressive Disorder and you are between the ages of 18 and 75. 
This research study is a medication trial. Participants in this study will be randomly assigned to either 
treatment medication or a sugar pill. Escitalopram is an FDA approved medication indicated for the treatment 
of major depressive disorder. It is the default medication for the study.  If you previously have not tolerated or 
had an adverse reaction to escitalopram, you will be treated with duloxetine. A placebo is a sugar pill. You may 
receive treatment for depression with FDA approved medications, escitalopram (Lexapro) or duloxetine 
(Cymbalta), or placebo (a sugar pill). Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) 
medication that appears to help with symptoms of depression by increasing the availability of specific 
chemicals in the brain. Duloxetine is selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that are 
thought to work by increasing the amount of mood enhancing chemicals in the brain.  Participants in this study 
will return to our clinic for visits either weekly or monthly. Individuals being seen on a monthly visit 
schedule will speak with members of the research staff by telephone between monthly study visits. 
The source of funding for this study is the Binational Science Foundation. 
VOLUNTARY
Participation in this research study is voluntary. If you decide not to participate, or if you later decide to 
stop participating, you will not lose any benefits to which you are otherwise entitled. A decision not to 
participate or withdraw your participation will not affect your current or future treatment at the New York State 
Psychiatric Institute of Columbia University Irving Medical Center.
ALTERNATIVE TREATMENT 
You do not have to participate in this study to receive treatment for your depression. The alternative to 
participating in this study is to seek treatment outside the research project. Other medications in the same 
family as escitalopram are available (e.g., fluoxetine (Prozac), sertraline (Zoloft), etc.) as well as in different 
families of medications, such as duloxetine. In addition, psychotherapy may be helpful with depression, 
whether on its own or combined with medication. 


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STUDY PROCEDURES
During COVID-19 pandemic:
In an effort to decrease direct contact and abide by social distancing guidelines, some of your 
visits may be conducted remotely using the telephone or WebEx, a HIPAA-compliant video teleconferencing. 
The consent discussion process will include discussion and explanation of WebEx, a HIPAA-compliant video 
communication platform. The study team will address any concerns you may have, such as access to a private 
space in which to take calls, or accessibility—access at home to adequate devices, cell signal, or WIFI. The 
evaluation procedures will consist of two separate visits: a virtual visit followed by an in-person visit. During 
the virtual component of the evaluation, you will be interviewed (via video conference call or phone call) by a 
doctor and a research assistant from the Clinic for Aging, Anxiety, and Mood Disorders. You will be asked to 
complete several assessments that ask about your psychological and physical health. If you may be eligible 
based on the virtual evaluation, you will then be scheduled for an in-person evaluation at the clinic in order to 
complete the remaining assessments that are necessary to determine study eligibility. During the in-person visit, 
you may be asked to complete additional measures of physical functioning, such as a physical exam, a 
cardiogram, provide a blood sample, about four tablespoons, for routine testing, and/or provide a urine sample 
for routine testing and a drug screen. If you are not eligible, you will be referred to appropriate options for 
further treatment. If you are eligible and continue to wish to participate, you will proceed with the next part of 
the study.
If you are eligible and decide to participate in the study, you have a 50/50 chance (like flipping a coin) 
of being assigned to one of two groups. This study utilizes design randomizing patients to “Research Frequency 
Management” (RFM Track, weekly study visits) vs. “Community Frequency Management” (CFM Track, every 
4 weeks study visits) and antidepressant medication vs. placebo. If you are assigned to the RFM group, you will 
return to our research clinic for weekly in-person visits (at the beginning of the study and then Weeks 1-8). If 
you are assigned to the CFM group you will return to our research clinic for in-person visits every 4 weeks (at 
the beginning of the study, Week 4, and Week 8) with every 2-week telephone check-ins in between clinic 
visits (Weeks 2 and 6). If you respond to the treatment, we will continue the double-blind study for three 
months. After Week 8, you will return to our research clinic for in-person visits every 4 weeks with 2-week 
telephone check-ins in between clinic visits. Questionnaires and assessments will be administered using 
Qualtrics, a HIPAA-compliant online application. Regardless of which study group you are assigned to, you 
will be randomly assigned to receive treatment with the antidepressant medication escitalopram (or duloxetine, 
if you previously have not tolerated or had an adverse reaction to escitalopram) or pill placebo (a sugar pill). At 
the end of the study you will be informed whether you received medication or placebo. 
If you are assigned to the study group having a monthly visit schedule, you will be asked to participate 
in a telephone check-in between clinic appointment. Each check-in will involve speaking with the doctor 
treating you as well as other members of our research staff for about 30 minutes. You may request to arrange an 
additional in-person visit to our clinic at any time during the study. We will automatically schedule an 
additional in- person visit for you if you are experiencing a significant new medication side effect or if your 
condition worsens substantially. You should also know that you will be provided with the beeper number of a 
physician who is available to speak with you 24hrs per day for emergencies. 
At the beginning of the study, you will be given a physical examination, an electrocardiogram (EKG), 
have your blood drawn, and fill out some psychological tests. The total amount of blood taken for this study is 


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about two tablespoons. You will be asked to return once a week if you are assigned to the RFM Track, or once 
a month if you are assigned to the CFM Track to see one of the study doctors and talk about how you are 
feeling. These meetings will last about 30 minutes. If you still have depressive symptoms after four weeks on 
the pills you are given, the dose will be increased to two pills (either 20mg of escitalopram or 60 mg 
duloxetine) or 2 placebo pills, depending on the group to which you are assigned). You will receive free 
medication for the duration of the study. 
During the study, if your doctor feels your condition worsens significantly, the current treatment will be 
stopped, and you will be offered different treatments for your depression. Your doctor may stop your 
participation in the study at any time without your consent if you do not comply with the study procedures or 
for other reasons. The research study will end after 8 weeks if you do not respond to treatment (either 
medication or placebo). If you respond, you will come monthly to our research clinic for three months to 
continue the double-blind study. 
Following your participation in the study, you will receive 3 months of free doctor visits in the clinic 
and at least 1 month of free medication. Every effort will be made to provide free medication for 3 months total, 
but we cannot guarantee the availability of free medication beyond 1 month. Video Recording if you agree, 
your study visits will be video recorded. The purpose of video recording the interview is to check the 
characteristics of the interview being delivered and to evaluate the reliability of our interviewers. You do not 
have to agree to be video recorded in order to be evaluated. A separate consent form will document whether 
you agree to be video recorded. 
RISKS 
The main risk of the study is that your depression may worsen if you are assigned to placebo and do not 
receive actual medication for your condition until after the 2 to 5-month study is over. If you need to be tapered 
off (dose gradually reduced to zero) of your current medication before taking the study drug or placebo, the 
amount of time during which you are not receiving actual or enough medication could be one additional month. 
You may also be assigned to the study group having monthly doctor visits, meaning that you could receive 
placebo (no medication) and have 4 weeks between in person doctor visits. For the duration of the study, you 
may also continue taking medication which is not effective for you before trying another medication. 
The most common side effects reported for escitalopram are nausea, insomnia, and inability to have an 
orgasm. Less common side effects reported for escitalopram include constipation or diarrhea, dry mouth, 
dizziness, headache, and sedation. The most common side effects reported for duloxetine are insomnia, 
constipation or diarrhea, dry mouth, sweating, nausea and small increases in blood pressure.  The less common 
side effects of duloxetine are abnormal orgasm, fainting, and headache. The Food and Drug Administration 
(FDA) has concluded that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in 
short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric 
disorders. No suicides occurred in any of these studies. It is unknown whether the suicidality risk in children 
and adolescents extends to longer-term use, i.e., beyond several months. It is also unknown whether the 
suicidality risk extends to adults, although the FDA has concluded that suicidality risk extends to individuals up 
to age 24. Please contact a study team member immediately if you are feeing worse or suicidal.


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You cannot participate in the study if you abuse alcohol or drugs. In any case, you should be careful 
about drinking alcohol, since it may have a greater effect on you in combination with medication. You must not 
take monoamine oxidase inhibitor (MAOI) drugs (tranylcypromine or Parnate, phenelzine or Nardil) during the 
study or within five weeks of ending the study (after the study). Serious reactions, including death, have been 
reported when MAOIs are co-administered with medications like escitalopram (the study drug). When your 
blood is drawn, there is a small risk you may be left with a bruise that will resolve within a few days. Blood 
taken for research purposes will remain confidential. 
The FDA has directed the manufacturers of all antidepressant medications to add a “black box” warning 
that describes the increased risk of suicidality related to antidepressant use in children and adolescents (but not 
in adults). The warning urges that adults with MDD or co-morbid (two illnesses occurring together) depression 
in the setting of other psychiatric illness being treated with antidepressants should be observed closely for 
clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at 
times of dose changes, either increases or decreases. 
The procedures of this study involving medication with escitalopram or duloxetine are low risk during 
pregnancy or breastfeeding, especially compared to the risk of depression in the mother. Still, these medications
cannot be considered safe during pregnancy or breast-feeding, because there is concern about causing 
permanent damage to a developing fetus or young infant. Therefore, you should not participate in this research 
if you are pregnant, or breast feeding a baby, or if you plan to become pregnant during the time you are in the 
study.
Should you decide to attempt to have a child or feel there is any possibility you may be pregnant, you
should notify your study physician immediately. If the pregnancy test is positive, you will not be able to 
participate in the study. It is important to understand that even if a pregnancy test is negative, you could still be 
pregnant, because these tests cannot detect very early pregnancies (that is, within the first few days). If you are 
sexually active, it is very important that you use an effective form of birth control before and throughout your 
study participation. Methods of birth control considered to be effective include double barrier methods (condom 
plus spermicide, or diaphragm plus spermicide), IUDs, and oral contraceptive pills. It is important to 
understand that even if you use an effective birth control method, there is still a chance you could become 
pregnant. Also, if you do not use the birth control method consistently (for example if you don’t use 
condom/spermicide some of the time) you may become pregnant. If you think you might be pregnant, it is 
important to let the study team know right away. The study team will conduct a pregnancy test and help you 
decide what to do next
Furthermore, specifically for any potential in person visits to NYSPI, individuals are at increased risk 
for exposure to COVID-19 both in transit to NYSPI as well as during their time at NYSPI. Procedures are in 
place to minimize this risk. We plan to offer car transportation subject to a maximum of $50 each way, which 
minimizes exposure to public transportation for those participants. At NYSPI, personal protective equipment 
such as masks will be utilized at all times both by staff and participants, and social distancing will be adhered to 
when possible (exceptions exist for procedures such as blood draws and EKGs). Screen shields between patient 
and staff will be used during neuropsychological testing to further minimize exposure risk.


IRB# 7738 
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8
BENEFITS
You may not benefit from this study, and no benefit is in any way guaranteed as a result of your 
participation. 
CONFIDENTIALITY
Your records will be stored in a locked file and will be available to research staff, and to 
Federal, State and Institutional regulatory personnel (who may review records as part of routine audits). 
Representatives of the state and institutional regulatory personnel may review your records to ensure 
compliance with study design. There are legal advocacy organizations that have the authority under State Law 
to access otherwise confidential records, though they cannot be redisclosed without your consent. All records 
will be kept confidential to the extent permitted by law. Your name and other personal identifying information 
will be stored in an electronically secure database at New York State Psychiatric Institute. Electronically stored 
data will be accessible only by password known to the study investigators and research assistants. Patient 
questionnaires and some assessments at Week 0 and for the duration of the study will be administered using 
Qualtrics, an  application accessible by smart phone or computer, by which raters and participants can access 
and complete online surveys. Qualtrics is an online application that allows patients to complete online surveys 
and assessments in a data-secure platform while maintaining compliance with existing health privacy laws.
These virtual visits will be conducted through Zoom which is a HIPAA-compliant platform or through secure 
Facetime call.
There may be future analyses of all the research data conducted by the study investigators, yet 
unplanned, dealing with other aspects of illnesses of late-life. Additionally, research data may also be shared 
and provided to other investigators for the purpose of secondary analyses or distributed to another investigator 
for future research studies. The results of this study may also be published or presented at professional 
meetings. In each of these instances, all personal identifiers (such as your name, birth date) will have been 
removed (de-identified) and replaced with a specific code number. The information linking this code number to 
your identity will be kept in a separate, secure location. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.
COMPENSATION AND ECONOMIC CONSIDERATIONS 
Due to the COVID-19 pandemic, we will not be using cash as a form of compensation until further 
notice. We will be using visa gift cards (either physical or virtual) instead, along with the option of a lump-sum 
check.
You will not be charged for any procedures that are a part of this study including the study medication 
and the clinical interviews. 
To compensate you for the time required for each weekly study visit, we offer $20 at the Week 0 visit 
and $20 for each in person visit thereafter. This money will be paid by cash at the conclusion of each of these 
visits. For the RFM track, compensation is up to $180 for the Acute Phase and up to $60 for the Continuation 
Phase for a total of $240. For the CFM track, compensation is up to $60 for the Acute Phase and up to $60 for 
the Continuation Phase for a total of $120. 


IRB# 7738 
v.3/29/2021 
9
IN CASE OF INJURY
Federal regulations require that we inform participants about our institution's policy with regard to 
compensation and payment for treatment of research-related injuries.
If you believe that you have sustained an injury as a result of participating in a research study, you may 
contact the Principal Investigator at (646) 774-8660 so that you can review the matter and identify the medical 
resources that may be available to you.
In case of injury, New York State Psychiatric Institute, Columbia University and New York 
Presbyterian Hospital will furnish that emergency medical determined to be necessary by the medical staff of 
this hospital. Please be aware that you will be responsible for the cost of such care, either personally or through 
your medical insurance or other form of medical coverage. No monetary compensation for wages lost as a 
result of injury will be paid to you by Research Foundation for Mental Hygiene, the New York State 
Psychiatric Institute, Columbia University, or by New York Presbyterian Hospital. However, you should be 
aware that by signing this consent form, you are not waiving any of your legal rights to seek compensation 
through the courts.
QUESTIONS
If you have further questions about the research procedures, or about your response to the procedures, 
research staff members are available to answer them to the best of their ability. You can reach Dr. Bret 
Rutherford at 646-774-8660 during general business hours. In an emergency, you may reach the on-call doctor 
at 917-786-6940, 24 hours per day. If you have general questions, you may contact the research coordinator at 
646-774-8677. 
We will notify you of any significant new findings that may relate to your willingness to continue to 
participate. 
If you have any questions about your rights as a research participant, want to provide feedback, or have 
a complaint, you may call the NYSPI Institutional Review Board (IRB). (An IRB is a committee that protects 
the rights of participants in research studies). You may call the IRB Office at (646)774-7155 during regular 
office hours.
You will be given a copy of this consent form to keep. 


IRB# 7738 
v.3/29/2021 
10
DOCUMENTATION OF CONSENT
I voluntarily agree to participate in the research study described above 
__________________________________________________________________________
Signature  
Date 
__________________________________________________________________________
Print Name 
I have discussed the proposed research with this participant [or patient], and, in my opinion, this participant 
[or patient] understands the benefits, risks and alternatives (including nonparticipation) and is capable of 
freely consenting to participate in this research. 
Signature of Person Obtaining Consent 
Telephone      
Date 
__________________________________________________________________________
Print Name

SAP_001.pdf: 
 
 
 
 
 
Contact: Developing New Clinical 
Management Strategies 
 
Protocol ID 7738 
NCT03812588 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
Document Version Date:  
November 21st, 2017 


Table of Contents 
Study Design .................................................................................................................................................. 2 
Sample Size Calculation ............................................................................................................................ 2 
Aims and Objectives ...................................................................................................................................... 3 
Outcomes ....................................................................................................................................................... 3 
Primary Outcome ....................................................................................................................................... 3 
Secondary Outcomes ................................................................................................................................. 3 
Other Pre-Specified Outcomes .................................................................................................................. 4 
Expected Results ............................................................................................................................................ 4 
References ...................................................................................................................................................... 6 
 
 
 


Study Design 
To examine the influence of visit frequency on antidepressant medication (ADM) and placebo response, 
we will conduct a prospective study, randomizing patients to Research Frequency Management (RFM, 
weekly study visits) vs. Community Frequency Management (CFM, monthly study visits), and double-
blind escitalopram vs. placebo. The United States Principal Investigator (US PI) will be responsible for 
clinical trial operations at the Adult and Late Life Depression Research Clinic (ALLDRC), in the New 
York State Psychiatric Institute (NYSPI). One hundred and four participating patients will be equally 
randomized to the four treatment cells, stratifying for demographic, clinical, and attachment factors: 
RFM-escitalopram (n = 26), RFM-placebo (n = 26), CFM-escitalopram (n = 26), and CFM-placebo (n = 
26). The primary experimental manipulation is visit frequency, which will be weekly in the RFM and 
monthly in the CFM group. This regime approximates practice in randomized control trials (RCTs) 
(RFM) and open clinical treatment (CFM), and it represents a balance between closely monitoring the 
patients, sufficiently differentiating the experimental groups, and generating results relevant to clinicians 
treating major depressive disorder (MDD) in the community both in Israel and the US (e.g., Stettin, Yao, 
Verbrugge, & Aubert, 2006). 
Sample Size Calculation 
The sample size was chosen to provide adequate power to test our hypotheses. The power calculation was 
based on effect sizes calculated using the meta-analyses by Posternak and Zimmerman (2007), and on 
previous studies by the applicants. First hypothesis. Based on Faul, Erdfelder, Lang, and Buchner, 
(2007), a minimum of 72 subjects is required to achieve a power of 0.8, using an error of 0.05 and an 
effect size of f = 0.15. Second hypothesis. To calculate the required sample size for the moderated 
mediation model, we used an approach based on Monte Carlo simulations, which produce more accurate 
results for power estimates than other methods when the sample size is relatively small (Zhang, 2014). 
The required sample size for significant moderated mediation was 99. Taking into account attrition 
(estimated from an RCT based on the same population, recruited from the same geographic area, 
conducted by Rutherford et al., 2013), the sample size was increased to 104. Third hypothesis. The 
required sample size was estimated using R code generated from the MLPowSim Software Package, 
applying 10,000 Monte Carlo simulations. Assuming alpha = 0.05 for pairwise interactions with the 
visit frequency, the simulations indicated a required sample size of 73 participants to ensure a power of at 
least 0.80. Subsequent exploratory analyses will include dose-effect analysis of visit frequency and the 
disentangling on the between- and within-patients effects of alliance on outcome (for more details, see 
Zilcha-Mano, 2017). 


Aims and Objectives 
The overarching objective of the present study is to explore the ingredients of the placebo effect, by 
offering and testing a theoretical model of a differential effect of visit frequency on treatment outcome in 
placebo vs. medication, mediated by the therapeutic alliance and supportive techniques. We propose to 
achieve this objective in three steps: (a) explore the differential effect of visit frequency on placebo vs. 
ADM response for patients with MDD; (b) examine the mechanisms underlying the expected effect, 
focusing on therapeutic alliance and the supportive techniques used in the sessions as potential 
mechanisms behind placebo and ADM response; and (c) identify MDD patient characteristics that 
moderate the effect of visit frequency on outcome. 
Outcomes 
On all accounts of data collection, the Israeli PI will examine all variables at all time points for 
illegitimate values, outliers, and inconsistencies. Analyses will be conducted on the intent-to-treat sample, 
with the therapist as a random effect. 
Primary Outcome 
First aim: Main outcomes. We will predict changes in HRSD as well as secondary outcomes across 
treatment as a function of visit frequency (0 = CFM, 1 = RFM) and medication (0 = placebo, 1 = 
escitalopram). Enrolled patients will be considered to have dropped out if they decide to discontinue 
participation in the study or if they miss a telephone assessment or clinic visit, and cannot be contacted 
afterwards. To fully adhere to the study visit schedule, RFM patients must attend all 9 in-person clinic 
visits, and CFM patients must attend the 3 in-person clinic visits, 6 phone interviews, and not have extra-
protocol visits. Medication adherence will be measured for each patient as the self-reported number of 
pills taken over the 8 weeks. Expected findings: we expect a significant 2-way interaction, representing 
visit effects as a function of treatment on HRSD, demonstrating that increased visit frequency results in 
better outcome for patients assigned to placebo, while patients receiving medication will be less affected. 
Based on the literature, CFM will not be inferior to RFM in drop-out rates, medication adherence, and 
adverse events. 
Secondary Outcomes 
Second aim: Moderated-mediation model. Following Preacher and Hayes (2004), we will examine 
mediation in a series of three models. The first model will test the moderation effect of treatment on the 
association between the predictor (visit frequency) and the outcome (HRSD as well as secondary 
outcomes); the second model will test the associations between the predictor and the mediator (alliance, 


evaluated by patients’ and therapists’ self-report and by trained coders, and the use of techniques, 
evaluated by trained coders on the two subscales); finally, the full mediated model will regress the 
outcome on the mediator, moderated by treatment effect and adjusted for the predictor-treatment 
interaction. We will explore whether adding another moderating path to the effect of visit frequency on 
the process mechanisms will improve the fit of the model. Expected findings: The potential mechanisms 
will partially mediate the effect of visit frequency on outcomes in placebo more than in ADM: the 
predictor will be associated with the mediator, the mediator will be significantly moderated by treatment 
(controlling for the predictor-treatment interaction), and the interaction between the predictor and 
treatment on outcome will be reduced after the interaction between the mediator and treatment is entered. 
A significant indirect effect is expected (using the Sobel test and the bootstrapping method). We predict 
that this mediation model shows a greater effect in the placebo than in the medication condition. 
Other Pre-Specified Outcomes 
Third aim: Identifying moderators. To test the potential moderators, we will examine the interactive 
influence of patients’ demographics, clinical characteristics, and attachment orientations (anxiety and 
depression) on the effect of visit frequency on outcome. Each potential moderator will be examined using 
a 2-way interaction (visit frequency × moderator). A higher-level 3-way interaction (visit frequency × 
medication vs. placebo × moderator) will not be examined because according to the literature there is no 
strong basis to argue for a differential effect between placebo and medication in this moderation model. 
Expected findings: Increased attachment security and more severe symptoms will be associated with 
increased symptom change for patients in the RFM arm. We will repeat all analyses controlling for 
potential confounders previously identified in the literature (such as treatment expectancy). 
Expected Results 
First, we anticipate that increased visit frequency will contribute more to placebo response than to 
medication response. Such a finding will support our first hypothesis that increased visit frequency results 
in better outcome for the whole cohort, but this effect is stronger for patients assigned to placebo. Second, 
we anticipate that the effect of clinic visits on treatment outcome will be mediated by the proposed 
mechanisms (alliance and supportive techniques). Third, we expect to find variability in patients' ability 
to benefit from frequent visits, and that this variability can be predicted based on patients’ pretreatment 
demographic and interpersonal characteristics. Thus, supporting the importance of optimizing 
psychopharmacologic management through personalized medicine, in which the number of visits is 
tailored to individual patient needs and characteristics. 


Risk analysis and alternative paths. First, because one of the hypotheses may not be supported, each 
hypothesis was conceptualized as statistically independent and can be tested irrespective of the others 
(e.g., a significant differential effect of visit frequency on outcome in ADM vs. PBO is not mandatory for 
the mediation analyses; Preacher, Zyphur, & Zhang, 2010). If we fail to find a general differential effect 
of visit frequency on medication vs. placebo (Hypothesis 1) or a general moderation effect of visit 
frequency on outcome (Hypothesis 2), exploring a potential higher level 3-way interaction (visit 
frequency × medication vs. placebo × moderator) will help us understand for whom such effect of visit 
frequency on treatment condition (placebo, ADM) may exist and under what circumstances (for similar 
analyses, see Zilcha-Mano & Errázuriz, 2015, 2016). Interactions of each potential moderator with the 
dummy variable of treatment condition, with visit frequency, and with the lower-level effects will be 
included in the model. Given the large number of predictors in such analysis, its exploratory nature, and 
the relatively small sample size, we will adopt rigorous systematic machine learning approaches to 
subgroup analysis, as implemented by us previously (Zilcha-Mano, Roose, Barber, & Rutherford, 2017). 
Specifically, following Zilcha-Mano, Keefe, et al. (2016), we will apply decision tree analyses with the R 
package "party" (Hothorn, Hornik, & Zeileis, 2006), using random forest variable selection (Strobl, 
Malley, & Tutz, 2009) and Monte Carlo simulation for multiple testing adjustment (Strasser & Weber, 
1999) (for the implementation of a similar procedure in ADM, see also Zilcha-Mano, Roose, Brown, & 
Rutherford, 2017). Second, it may be argued that rating supportive techniques is not feasible in clinical 
management sessions (e.g., low frequency in the use of techniques). The CSPRS, however, was 
specifically built for coding clinical management based on the exact manual used in the proposed study. 
Additionally, the adequacy of this rating system was evaluated in our research group. A pilot study (N = 
43, 20 received medication and 23 placebo) based on audio tape coding of clinical management sessions 
using the same manual (Fawcett, 1987) taken from an RCT for MDD (Barber, Barret, Gallop, Rynn, & 
Rickels, 2012) indicated that in clinical case management, clinicians use many distinct types of supportive 
interventions (coded using the clinical management and facilitative conditions techniques of the CSPRS), 
with great variability between patients. Third, because the videotapes will originate from a different 
geographic and cultural area (NYC, US) than that of the coders (Haifa, Israel), this diversity may affect 
the quality of coding. In the last two years, material taped at a psychotherapy research lab in NYC, US, 
was coded in the Israeli PI’s lab at the University of Haifa, Israel. All the coders except one (whose 
English was not adequate) produced high-quality coding, demonstrating high reliability with the group of 
NYC coders. Therefore, coders will be chosen not only based on the regular protocol but also taking into 
account their level of English and familiarity with cultural and social issues relevant to NYC. The 
experience of the last two years in the Israeli lab suggests that recruiting coders with adequate background 
is highly feasible. Fourth, as any method for studying the relationship with the therapist has strengths and 


weaknesses, the use of multiple methods in the proposed study (both patient and therapist self-report, 
behavioral observations with each session coded by two independent coders) will compensate for any 
specific methodological weakness. 
References 
Barber, J. P., Barret, M. S., Gallop, R., Rynn, M. A., & Rickels, K. (2012). Short-term dynamic 
psychotherapy versus pharmacotherapy for major depressive disorder: A randomized, 
placebo-controlled trial. Journal of Clinical Psychiatry, 73(1), 66–73. 
doi:10.4088/JCP.11m06831 
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A flexible statistical 
power analysis program for the social, behavioral, and biomedical sciences. Behavior 
Research Methods,39, 175-191. 
Fawcett, J. P. S. I. J., Epstein, P., Fiester, S. J., Elkin, I., & Autry, J. H. (1987). Clinical 
management--imipramine/placebo administration manual. NIMH Treatment of 
Depression Collaborative Research Program. Psychopharmacology Bulletin, 23, 309-324. 
Hothorn, T., Hornik, K., & Zeileis, A. (2006). Unbiased Recursive Partitioning: A Conditional 
Inference Framework. Journal of Computational and Graphical Statistics, 15(3), 651--
674. 
Posternak, M. A., & Zimmerman, M. (2007). Therapeutic effect of follow-up assessments on 
antidepressant and placebo response rates in antidepressant efficacy trials Meta-
analysis. The British Journal of Psychiatry, 190, 287-292. 
Preacher, K. J., & Hayes, A. F. (2004). SPSS and SAS procedures for estimating indirect effects 
in simple mediation models. Behavior research methods, instruments, & computers, 36, 
717-731. 
Preacher, K. J., Zyphur, M. J., & Zhang, Z. (2010). A general multilevel SEM framework for 
assessing multilevel mediation. Psychological Methods, 15, 209-233. 
Rutherford, B. R., Cooper, T. M., Persaud, A., Brown, P. J., Sneed, J. R., & Roose, S. P. (2013). 
Less is more in antidepressant clinical trials: a meta-analysis of the effect of visit 
frequency on treatment response and drop-out. The Journal of Clinical Psychiatry, 74, 
703-715. 


Stettin, G. D., Yao, J., Verbrugge, R. R., & Aubert, R. E. (2006). Frequency of follow-up care 
for adult and pediatric patients during initiation of antidepressant therapy. The American 
Journal of Managed Care, 12, 453-461. 
Strasser, H., & Weber, C. (1999). On the asymptotic theory of permutation statistics. 
Mathematical Methods of Statistics, 8, 220–250. 
Strobl, C., Malley., J., & Tutz, J. (2009). An Introduction to Recursive Partitioning: Rationale, 
Application, and Characteristics of Classification and Regression Trees, Bagging, and 
Random forests. Psychological Methods, 14(4), 323–348. 
Zhang, Z. (2014). Monte Carlo based statistical power analysis for mediation models: methods 
and software. Behavior research methods, 46(4), 1184-1198. 
Zilcha-Mano, S. (2017). Is alliance really therapeutic? A systematic answer based on recent 
methodological developments. American Psychologist.  
Zilcha-Mano, S., & Errázuriz, P. (2015). One size does not fit all: examining heterogeneity and 
identifying moderators of the alliance–outcome association. Journal of Counseling 
Psychology, 62, 579-591.  
Zilcha-Mano, S., & Errázuriz, P. (2016). Early development of mechanisms of change as a 
predictor of subsequent change and treatment outcome: The case of the working alliance. 
Accepted with minor changes, Journal of Consulting and Clinical Psychology. 
Zilcha-Mano, S., Keefe, J., Rubin, A., & Barber J. P. (2016). Dropout in treatment for 
depression: Translating research on prediction into individualized treatment 
recommendations. Journal of Clinical Psychiatry  
Zilcha-Mano, S., Roose, S. P., Barber, J. P., & Rutherford, B. R. (2015). Therapeutic alliance in 
antidepressant treatment: cause or effect of symptomatic levels?. Psychotherapy and 
Psychosomatics, 84, 177-182. 
Zilcha-Mano, S., Roose, S. P., Brown, P. J., & Rutherford, B. R. (2017). Early symptom 
trajectories as predictors of treatment outcome for citalopram versus placebo. American 
Journal of Geriatric Psychiatry.