Combined Prolonged Exposure and Pramipexole Treatment for Patients With PTSD and Depression
Phase: PHASE3
Conditions: PTSD, MDD
Sponsor: Research Foundation for Mental Hygiene, Inc.

Cover Page for ClinicalTrials.gov 
Official Title of the Study: 
 
Combined Treatment of Prolonged Exposure and Pramipexole for Posttraumatic Stress 
Disorder and Depression 
NCT Number: 
 
NCT03765138 
Principal Investigator:  
 
Yuval Neria, PhD 
 
Yuval.Neria@nyspi.columbia.edu 
 
646-774-8041 
Date of Document: 
 
August 28, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Statistical Analysis Plan 
No statistical data will be produced due to early termination of protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

NEW YORK STATE PSYCHIATRIC INSTITUTE 
INSTITUTIONAL REVIEW BOARD 
MEMORANDUM 
 
Signed copy on file at IRB. 
EN/AHW/SCR4ALW 
December 18, 2018 
TO:   
YUVAL Y. NERIA, PHD 
 
FROM:  
Dr. Edward Nunes, Co-Chair, IRB 
 
 
Dr. Agnes Whitaker, Co-Chair, IRB 
 
SUBJECT:  
EXPEDITED APPROVAL OF PROTOCOL AMENDMENT 
 
 
The amendment to your protocol #7692 entitled: COMBINED PROLONGED EXPOSURE 
AND PRAMIPEXOLE TREATMENT FOR PATIENTS WITH PTSD AND DEPRESSION (to 
add exclusion criterion for attention allocation task only of current or past 
ADHD diagnosis; to add RecruitMe as a source of recruitment, as per the 
12/14/2018 memorandum) has been approved by the Psychiatric Institute - 
Columbia University Department of Psychiatry Institutional Review Board. 
 
Please note that this does not change the IRB's cycle of review.  A progress report 
and an application for continuing review will be required 2 months before the 
study's approval is due to expire: (9/16/2019). 
 
 
 

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Protocol Title:
Combined Prolonged Exposure and 
Pramipexole Treatment for Patients with 
PTSD and Depression
Protocol Number:
7692
First Approval:
10/04/2018
Expiration Date:
09/16/2019
Version Date:
12/18/2018
Clinic:
Anxiety Disorders Clinic
Contact Principal Investigator:
Yuval Neria, PHD
Email: ny126@columbia.edu
Telephone: 646-774-8092
Co-Investigator(s):
Raphael Campeas, MD
Franklin Schneier, MD
Xi Zhu
Amit Lazarov
Research Chief:
Helen Simpson, 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 proposing an amendment only to an existing protocol
Division & Personnel
Division
What Division/Department does the PI belong to?
Anxiety, Mood, Eating and Related Disorders
Within the division/department, what Center or group are you affiliated with, if any? 
Anxiety Disorders Clinic
Unaffiliated Personnel

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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.
There are no investigators who will be participating in this protocol who are not affiliated with the New 
York State Psychiatric Institute or Columbia University.
Amendment
Describe the change(s) being made 
We would like to add the following exclusionary criteria for the attention allocation task only: current or 
past ADHD diagnosis, Eye-tracking calibration difficulties (determined during study day). We would also 
like to add the Recruitme website as an advertising platform for the study.
Provide the rationale for the change(s) 
We would like to add the exclusionary criteria for the attention allocation computer task only as the 
described criteria (ADHD diagnosis, and calibration difficulties), as these conflict with task administration. 
Specifically, ADHD diagnosis could be a confounding variable for the results of the attention allocation task 
and calibration difficulties would disable the task from being administered as the task cannot be operated 
without calibrating the eye-tracking machine to each specific patient. We would like to add Recruitme as an 
additional recruitment source in order to reach a larger population of potential subjects for this study.
Comment on the extent to which the proposed change(s) alter or affect risks/benefits to subjects 
The proposed changes do not alter or affect risks or benefits to subjects.
Comment on if the proposed change(s) require a modification to the Consent Form (CF)
The proposed changes do not require a modification to the consent form.
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Collection of Biological Specimens
   Medication Trial
   Psychotherapy Trial
   MRI
   Audio or Videotaping
Population

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Indicate which of the following populations will be included in this research
   Adults
Research Support/Funding
Will an existing internal account be used to support the project?
Yes
Describe internal account
Gift Money through the RFMH business office.
Is the project externally funded or is external funding planned?
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
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
Approximately half of the individuals with posttraumatic stress disorder (PTSD) present with major 
depressive disorder (MDD). Compared to PTSD alone, patients with comorbid PTSD-MDD demonstrate 
greater distress and poorer treatment outcome. Functional magnetic resonance imaging (fMRI) show that 
relative to PTSD alone, PTSD-MDD is associated with decreased resting state functional connectivity (rs-
FC) in both fear- and reward-processing circuits. In addition, our data suggest that Prolonged Exposure 
(PE), first-line PTSD treatment, may successfully target impairments in the fear circuits, but not in the 
reward circuits, which may explain the treatment-refractory quality of PTSD-MDD. 
The goal of this pilot study is to collect preliminary data for future NIMH application, by testing the 
feasibility, safety and initial efficacy of an integrated therapeutic approach targeting both fear and reward 
impairments in PTSD-MDD patients. Specifically, we will examine a combination treatment with PE, 
shown to effectively address fear circuitry deficits, and Pramipexole, a dopamine agonist, shown to increase 
reward circuit function and to have promise in treating depression but not previously studied in PTSD. The 
central hypothesis is that combined PE/Pramipexole will a) improve PTSD and depressive symptoms in 
PTSD-MDD patients, and b) increase functional connectivity of fear and reward pathways as measured by 
fMRI rs-FC. In this pilot study, 15 adults aged 18-60 years with PTSD-MDD will receive combined 10-
week of PE and Pramipexole up to the maximum dose of 4mg a day. They will clinically assessed at 
baseline, week 5, post treatment and at 3-month follow up, behaviorally assed on a probabilistic reward task 
(PRT) and attention allocation tasks, and fMRI scanned for resting state functional connectivity (rs-FC), at 

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baseline, and posttreatment.
Background, Significance and Rationale
Background, Significance and Rationale
Comorbid PTSD-MDD is common and is associated with greater severity and worse outcome than PTSD 
alone. Up to 50% of the PTSD cases, across multiple samples, have been shown to meet criteria for MDD 
(1, 2). Compared to PTSD alone, patients with PTSD-MDD exhibit greater distress (3), higher risk of 
suicide (4, 5), poorer treatment outcome (6), and impaired neurocognitive functioning (14). Despite these 
findings, no study to date has developed and examined novel treatments for patients with PTSD-MDD. 
There is a need for novel treatments for patients with PTSD-MDD. While cognitive behavioral therapy 
(CBT) approaches for PTSD have been generally shown to be effective, many patients do not benefit from 
these treatments. For PE, the gold standard CBT treatment for PTSD, non-response rates range from 25 to 
60%, with dropout rates reaching 50% (15, 16). Few medications have been found to ameliorate PTSD, with 
only small effect sizes (17). One factor that was previously linked to treatment outcome in PTSD is 
emotional engagement (18, 19). However, since depression is frequently associated with emotion 
dysregulation, amotivation, and flattening of affect, it has been suggested that comorbid depressive 
symptoms in patients with PTSD may decrease emotional engagement, consequently hindering treatment 
efficacy (20). In sum, patients with PTSD-MDD may have poorer response to current treatments due to 
reduced emotional engagement and numbing symptoms. 
SSRIs treatment has shown limited efficacy in PTSD. Previous reviews and meta-analyses of 
pharmacological treatments for PTSD have been mixed. Some reviews rated SSRIs as equivalent to trauma-
focused psychological treatments (35, 36), including a Cochrane review (37). Several major reports, 
however, concluded poor efficacy of medication treatment for PTSD (38, 39, 40, 17). These findings 
suggest that a better understanding of the neurobiological processes underlying motivational symptoms and 
reward processing deficits in PTSD-MDD can potentially improve treatment development and ultimately 
personalized medicine.
 
PE alone may not target reward processing deficits in PTSD-MDD. The empirical evidence of decreased 
efficacy of PE in PTSD-MDD cited above is consistent with PE's hypothesized mechanism involving 
extinction processes (8, 41, 42) and not reward processing deficits.
Combining Pramipexole with PE may address limitations of PE alone by targeting reward processing and 
improving depressive symptoms. Agents enhancing dopamine neurotransmission with documented efficacy 
for depression (11, 43, 44) may be particularly useful for PTSD patients with comorbid MDD. Pramipexole 
is a dopamine agonist (D3) with strong evidence for anti-depressant efficacy (9, 10, 45-49) but that is yet to 
be studied in PTSD. There is a compelling theoretical rationale supporting the therapeutic utility of a 
dopamine agonist in this patient population, as PTSD-MDD is associated with anhedonia (30) and reward 
processing deficits (7). A wide array of findings, including studies of reward processing (50, 51), suggest 
that reward and motivation deficits are related to decreased dopaminergic function in reward circuitry. 
Relative to placebo, pramipexole treatment was associated with changes in a variety of reward-related brain 
regions. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant 
action that is distinct from that previously reported for serotonin reuptake inhibitor treatment and support a 
range of evidence that the central dopaminergic system plays a role in the pathophysiology of depression 

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(53-55). 
Pramipexole was originally noted to improve mood in Parkinson’s disease -- a meta-analysis of 14 RCTs of 
pramipexole for Parkinson’s found that mood symptoms improved in 65% on pramipexole vs. 43% on 
placebo, and motivational symptoms improved 63% on pramipexole vs. 45% on placebo (56). Importantly, 
10 studies (including controlled and open trials, and retrospective studies) of pramipexole support its 
efficacy for depression in patients without Parkinson’s disease. A pooled analysis of three RCTs of 
pramipexole in psychiatric populations reported large effect sizes (0.6 - 1.1) in treating depression, based on 
the Hamilton Rating Scale for Depression (HRSD) (47). Tolerability of pramipexole in depressed patients 
has been comparable to that of approved antidepressant medications, with discontinuation rate of 9% based 
on pooled data from 253 patients in 8 studies. In our preliminary data in an open trial in MDD, pramipexole 
was highly efficacious and well-tolerated. Taken together, pramipexole has never been studied in PTSD, but 
it has shown promise in improving reward processing, altering reward network, and treating depression, 
providing a strong foundation for our plan to develop novel treatment for patients with PTSD-MDD. 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
We hypothesize that combined treatment with PE/Pramipexole will improve PTSD and depressive 
symptoms and increase functional connectivity of fear and reward pathways as measured by fMRI. 
Description of Subject Population
Sample #1
Specify subject population
PTSD-MDD
Number of completers required to accomplish study aims
15
Projected number of subjects who will be enrolled to obtain required number of completers
20
Age range of subject population
18-60
Gender, Racial and Ethnic Breakdown
45% White
30% Black
15% Hispanic
10% Asian/Hawaiian/Pacific Islander
 
60%  Females
40% Males 

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Description of subject population
All participants will have a diagnosis of PTSD-MDD based on SCID-V, CAPS-5 ≥ 25, and 17-item HRSD 
≥ 17. 
Recruitment Procedures
Describe settings where recruitment will occur
Anxiety Disorders Clinic
How and by whom will subjects be approached and/or recruited? 
Patients will respond to an advertisement (see below "study advertised/ publicized") or be contacted by an 
RA after receiving a signed Permission to Contact form. Patient will call the clinic and after verbal is 
obtained consent the research assistant (RA) will conduct a preliminary phone screen that is part of a 
preexisting screening protocol (IRB #7094R). If the patient will be eligible for the study the RA will invite 
the patient for further screening at the clinic.
How will the study be advertised/publicized? 
Patients will be informed of the study through: (a) word-of-mouth referrals from former patients, (b) referral 
from area medical and mental health professionals, (c) publicity about the study, including articles in local 
newspapers and magazines, our IRB approved website (http://columbiapsychiatry.org/trauma), Recruitme 
Website, IRB approved flyers, appearances on local radio and television shows, etc., leading to self-referral 
of prospective patients, (d) advertisements placed in local media and on the Internet
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
03765138
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Participants who are assessed for the following NYSPI IRB approved studies # 7136, #7489, #7469, and # 
7464 will be offered to participate in the current study. 
Inclusion/Exclusion Criteria

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Name the subject group/sub sample
PTSD-MDD
Create or insert table to describe the inclusion criteria and methods to ascertain them
 Inclusion Criteria:
 Method of 
Ascertainment:
 1.Males or Females by the age of 18 and 60
 History
2. Current DSM-V diagnosis of PTSD comorbid 
with MDD
 SCID-V
3. CAPS-5 ≥ 25, and 17-item HRSD ≥ 17
CAPS-V, PCL-5, HRSD-
17
4. Able to give consent, fluent in English
 Clinical Interview
 5. Not currently taking psychotropic medication
 Clinical Interview and 
history
Create or insert table to describe the exclusion criteria and methods to ascertain them
 Exclusion Criterion:
Method of 
Ascertainment: 
1. Prior or current diagnosis with traumatic brain injury, 
bipolar disorder, psychotic disorder, gambling or impulse 
control disorders, or dementia
 SCID-V and 
clinical 
interview
2. History of psychosis, psychotic disorder, mania or 
bipolar disorder
 SCID-V and 
clinical 
interview
3. Severe substance use disorder excluding nicotine (i.e., 
nicotine use disorder and mild-moderate alcohol/cannabis 
use disorder are accepted)
SCID-V and 
clinical 
interview 
4. Individuals at risk for suicide based on history and 
current mental state. BDI-II suicide item > 2 or CGI-
Severity baseline score of 7.
 HRSD-17, CGI, 
clinical 
interview 
5. Treatment with antidepressants or other psychotropic 
medication in the past 4 weeks (or 6 weeks for fluoxetine; 
an exception will be made for zolpidem used 
intermittently for sleep).
 Clinical 
interview and 
history
6. Pregnancy or plans to become pregnant during the 
period of the study.
 Urine β-HCG, 
clinical 
interview
 7. Current psychotherapy
 Clinical 
interview
 8. Current unstable or untreated medical illness
 Clinical 
interview, 

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physical exam, 
blood chemistry
 9. Any condition that would exclude clinical MRI exam 
(e.g. pacemaker, paramagnetic metallic prosthesis, surgical 
clips, shrapnel, necessity for constant medicinal patch, 
some tattoos, severe obesity, claustrophobia)
 Clinical 
interview, 
physical exam, 
MRI screening 
questionnaire
 10. History of untoward reaction to pramipexole
 Clinical 
interview, 
history
 11. Prior or current diagnosis of OCD, Panic Disorder or 
Social Phobia
 SCID-V and 
Clinical 
Interview
 12. Medical diagnosis of Parkinson's disease
 Clinical 
Interview, 
physical exam, 
blood chemistry
 13. Eye tracking calibration difficulties as determined 
on day of study (Attention Allocation Task participants 
only)
 Calibration 
procedures
 14. Current or past ADHD diagnosis (Attention 
Allocation Task participants only)
 SCID-V and 
Clinical 
Interview
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 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures

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Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
7094R
Describe Study Consent Procedures
Research assistant will obtain verbal consent from patient in order to conduct a preliminary phonescreen. 
Phonescreening will be conducted as part of the Anxiety Disorders Clinic's preexisting screening protocol 
(IRB #7094R). If the patient will be eligible for the study the RA will invite him for further screening at the 
clinic. 
 
At the clinic, patient will meet face to face with a person that is authorized to discuss and document consent 
(see “person designed to discuss and document consent”). After patient reads the consent the clinician will 
go over the consent with the patient and answer all the patient’s questions. After answering all the patient’s 
questions by the clinician patient will sign the study consent. The highest educational degree needed for the 
consenting clinician is a Doctor of Medicine degree (M.D.). Throughout this process, the patient will be told 
that they are free to refuse to participate in the research and that participation or non participation in 
research has no effect on their ability to continue to receive clinical care or services. 
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
Campeas, Raphael, MD
Markowitz, John, MD
Sanchez-Lacay, jose, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
The study consists of the following procedures: 1) screening and diagnostic assessments including: 
psychiatric interview and medical history, SCID interview, labs and urine drug screen, informed screening 
consent (3 hrs.); 2) informed study consent, baseline fMRI, behavioral task (2 hours); 3) Ten treatment visits 
and self-report forms, including CGI (1.5 hours); 4) Midpoint clinical assessment after treatment visit 5 and 
self-report forms (1 hour) ; 5) Follow up clinical assessment, follow up fMRI and behavioral task (2.5 
hours); and 6) 3 month follow up clinical assessment and self-report forms. 
4.A1. Preliminary Screening: Potential subjects will be screened by telephone by a research assistant after 
obtaining oral consent as a part of the Anxiety Disorders Clinic's preexisting screening protocol (IRB 
#7094R). Patients on prohibited psychoactive medication will be excluded and will not be tapered off such 

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medication for the purpose of entering this study. Psychiatric Diagnostic Evaluation: Patients deemed study 
eligible following preliminary screening will sign the Anxiety Disorders Clinic informed written consent for 
the psychiatric screening evaluation (IRB # 7094R). An experienced psychiatrist will evaluate presenting 
symptoms, psychiatric history, treatment history, medical history, trauma history, social and family history, 
and current medical status. Additional screening measures include: 1) collection of blood samples (20 cc) 
for chemistry profile, thyroid function tests, and CBC; 2) a urine sample for urinalysis and toxicology (and 
pregnancy for females); 3) structured interview (the SCID), CAPS-V, HRSD-17, CGI, CVC Suicide Risk 
Assessment and Screener and TBI performed by trained research team member; 4) a physical exam; 5) self-
report forms: PCL-5, LEC-5, BDI-II and SHAPS
After obtaining informed consent and determining eligibility based on the above screening and laboratory 
testing, study visits will be scheduled.
4.A.2. fMRI Scan: Patients will undergo two fMRI sessions. MRI scans will be performed in the NYSPI 
3.0T GE scanner and the 3T Siemens Prisma scanner at Zuckerman Institute MR Center. The scanning 
session will last approximately 30 minutes, with an additional 30 minutes total for set-up. Thus, the fMRI 
session lasts about 1 hour. Female subjects will have a urine pregnancy test on the day of the MRI scan, 
before being scanned. Structural MRI scan will be performed to quantify regional brain volumes and 
cortical thickness as well as provide a clinical reading by a neuroradiologist to forward results from the scan 
to the participant. Resting state fMRI will measure functional connectivity.
MRI Results
The results of the structural MRI will be shared with the subject and/or a physician of their choice, as
detailed below. Because the structural MRI scan is being performed for research purposes only it may not
show problems that would normally be found in a typical clinical MRI scan ordered by a doctor for a
specific medical problem. The MRI scans obtained in this study may provide information that is clinically
relevant. The quality of clinical information available from these images can vary widely, based on
resolution, degree of motion artifact, and numerous aspects of the pulse sequences used to acquire them. All
scans will be read by a clinical neuroradiologist (see “Personnel and Responsibilities”). As with any
imaging procedure, if the radiologist determines that the quality of the scan does not lend itself to a clinical
reading, he or she will provide written documentation to this effect. Only the radiologist may make this
determination. The MRI will receive a clinical reading by a neuroradiologist within 4 weeks of the scan, and
a confirmatory report will be written within 6 weeks of the scan as the following details. When the readings
yield findings that are of urgent clinical concern, the radiologist (see “Personnel and Responsibilities”) will
immediately provide an oral report followed by a handwritten or typed note to the PI, Yuval Neria, PhD, 
and the Director of the MRI Center. A final written transcript of the clinical reading will be
provided within two weeks of the oral report. The radiologist will provide routine written reports to Dr.
Neria within one month of image acquisition. Because T1 images are acquired in this study, all subjects
will receive feedback about their scans in accordance with IRB policy. All results will be shared with
research subjects in a manner that is consistent with the acuity and certainty of the finding, and will be
communicated by an appropriately qualified member of the research team in the form of a letter that is
approved by the IRB and will also be contacted by telephone if there is evidence of a clinically-significant
abnormality. Results will be shared with the subject and/or a physician designated by the subject.
Probabilistic Reward Task (PRT): Subjects sit at a PC monitor and they are instructed to press a button to 
indicate whether a short (11.5 mm) or a long (13 mm) mouth was presented on a previously mouthless 

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cartoon face. The task includes three blocks of 100 trials. The difference between mouth sizes presented as 
well as the duration of stimulus exposure (100ms) is small, providing a setting in which a response bias may 
develop in response to asymmetric reinforcement: either the short or long mouth is rewarded (“Correct!! 
You won 20 Cents”) three times more frequently (“rich stimulus”) than correct identification of the other 
mouth (“lean stimulus”). In each block, only 40 correct trials (30 rich, 10 lean) are rewarded, so each subject 
is exposed to the same reward ratio. Subjects are informed that the purpose of this task is to win as much 
money as possible. Moreover, they are instructed that not all correct response will receive a reward feedback 
but they will be unaware that one of the stimuli will be disproportionately rewarded. Performance will be 
analyzed with respect to response bias, discriminability, and reaction time (RT), following prior procedures. 
This task will take approximately 25 minutes.
Attention Allocation Task: In each trial subjects will be shown a stimuli matrix containing 16 images, 6 
negative and 6 neutral, for 6 seconds. The task is comprised of two 30 trial blocks. Participants will be asked 
to view the different image matrices freely with no specific instructions while being recorded by an eye-
tracking apparatus collecting eye-movement data. Eye-tracking recording does not pose any danger or harm 
for participants. The task will take approximately 20 minutes.
4.A.3. Treatment: Prolonged Exposure (PE) Therapy. PE is a cognitive behavioral treatment, considered a 
“gold standard” treatment for PTSD, regardless of whether patients have comorbid depression or not. It will 
consist of 10 sessions of 90-minute duration, normally conducted once a week (note—make up for missed 
sessions are allowed within 10-12 week time frame). Therapists will follow the PE manual developed by 
Foa and colleagues and used in the Anxiety Disorders Clinic for more than a decade. Elements of PE 
include imaginal and in vivo exposure to trauma reminders; breathing retraining; cognitive restructuring; 
and PTSD psychoeducation. In each session, the patient recounts a trauma narrative, which is recorded on 
audiotape or electronically for daily home listening. The therapist helps the patient cognitively restructure 
his/her experience of the traumatic event. Each week the narrative is elaborated, becoming more detailed 
and exhaustive, until the patient habituates to it, extinguishing the anxiety it aroused. Each session the 
patient will also complete a BDI-II to track progress. Patients will see the same clinician for each of their 
treatment visits.
Pramipexole. In addition to receiving PE as described above, patients will have Pramipexole treatment 
administered by our team’s psychiatrists who have expertise in PTSD pharmacotherapy and
clinical trials. Initial dosing will follow the methods of Schneier (Preliminary Studies 3.3.B.6) and Goldberg 
(13): Daily dose will be started at 0.25 mg/day and increased by 0.25 mg/day every 3-4 days to a target of 
2.5mg day by week 5. Beginning week 6 daily dose will be increased weekly by 0.5 mg/day to a maximum 
dose of 4mg. Adverse events will be systemically queried at each visit and vital signs will be checked. 
Compliance will be assessed by weekly pill count. Dose will be increased as tolerated unless the patient has 
achieved remission and will be decreased in the event of intolerable adverse events. Patients will check in 
with their treating psychiatrist for 15 minutes after every PE treatment session, for a total of 10 visits, 
normally conducted once a week (note—make up for missed sessions are allowed within 10-12 week time 
frame).Patients will see the same psychiatrist for each of their treatment visits. Staff psychiatrists carry 
beepers or cell phones and are available 24 hours per day for clinical emergencies. Patients will receive 
written information on how to contact staff by telephone or pager in the event of an emergency. 
4.A.4. Midpoint Assessment (week 5): Patients will meet with a clinician and complete CAPS-V, HRSD-17, 

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CGI, CVC Suicide Risk Assessment and Screener and TBI performed by trained research team member and 
self-report forms: PCL-5, BDI-II and SHAPS. 
4.A.5. Follow up visit: Patients will repeat fMRI scanning session and behavioral tasks. Procedures are 
identical to the first fMRI session. Follow up medical examinations, including physical exam, blood work, 
urinalysis will not be done routinely, but will be performed at any time during the study if clinically 
indicated by occurrence of a specific
adverse effect. In addition, patients will complete a follow up assessment with a CAPS-V, HRSD-17, CVC 
Suicide Risk Assessment and Screener and CGI performed by trained research team member; and self-
report forms: PCL-5, BDI-II and SHAPS. 
4.A.6. 3 Month follow up visit: Patients will meet with a clinician and complete CAPS-V, HRSD-17, 
CGI and TBI performed by trained research team member and self-report forms: PCL-5, BDI-II and 
SHAPS.
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
At least weekly, the PI and study psychiatrist will review participants awaiting study procedures and will 
withdraw a person from the study if the participant:
1. Requests to be withdrawn from the study.
2. Reports significant suicidal ideation, as assessed by the clinician and/or by the BDI-II suicide item > 2 
3. Symptomatic worsening, as measured by a score of 6 (much worse) or 7 (very much worse) on the CGl at 
any visit, or as per the treating psychiatrist’s judgment
4. Is non-compliant with protocol requirements. 
5. Manifests a new or inter-current illness that prevents the patient from complying with the protocol
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
20 cc of blood will be drawn for chemistry, CBC, and thyroid function tests. 
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Structured Clinical Interview for DSM-V (SCID) (60 minutes at screening)
Clinician Administered PTSD Scale (CAPS-5) (30 Minutes) 
Hamilton Rating Scale for Depression (HRSD-17) (10 minutes)
Posttraumatic Stress Disorder Checklist (PCL-5) (5 minutes)
Structured Pill Count Interview (5 minutes)

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Treatment Emergent Side Effect Scale (10 minutes)
Life Events Checklist (LEC) (5 minutes)
Clinical Global Impression Severity and Improvement (CGI) (5 minutes) 
Snaith-Hamilton Pleasure Scale (SHAPS) (5 minutes)
Traumatic Brain Injury Identification Method (TBI) (5 minutes)
CVC Suicide Risk Assessment and Screener (10 minutes)
Please attach copies, unless standard instruments are used
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
   Drug
Select the number of drugs used in this study
1
Drug #1
Name of the drug 
Pramipexole
Manufacturer and other information
Generic brands will be used and therefore will be made by multiple companies. 
Approval Status
No IND is required
Choose one of the following options
FDA has determined that IND is not required
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
The maximum delay to study treatment is two weeks. As a safety measure, weekly clinical check-ins by 
phone or in-person will occur. The patient will have immediate access to the psychiatrist who did the 
psychiatric intake evaluation, if he or she presents with an emergent clinical issue.
Maximum duration of delay to standard care or treatment of known efficacy
Prolonged Exposure (PE) is an active, first line treatment of PTSD (with or without concurrent MDD), with 
established efficacy. The maximum delay to PE is two weeks.
Treatment to be provided at the end of the study
Participants will be referred for further treatment as needed.

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Clinical Treatment Alternatives
Clinical treatment alternatives
Other treatments used to treat PTSD and depression are SSRIs, such as paroxetine (Paxil) and setraline 
(Zoloft), which are the only medications approved, separately, for both PTSD and depression, as well as 
other psychotherapies include cognitive-behavioral therapy and approved medications, are available to 
participants outside of this research study and patients can discuss with their healthcare provider. 
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
MRI Scan: MRI scanning is not associated with any known medical risks, except for persons who have a 
heart pacemaker or have metal in their body (e.g. shrapnel or surgical prostheses) which may be affected by 
the magnet. Subjects will be screened by interview and questionnaire to determine the presence or absence 
of metallic objects, and informed that they cannot participate in the study if their body contains any 
paramagnetic metal other than standard dental work. Some people have reported sensations during MRI 
scans with the 3T magnet, such as “tingling” or “twitching” (or, very rarely, a painful sensation), which are 
caused by changes in the magnetic field. The MRI scanner also produces a loud noise; earplugs will be 
provided to reduce this discomfort. Some subjects become anxious and feel claustrophobic in the MRI 
scanner. If this is the case, staff will be available for help and support and, if the subject requests, the scan 
will be stopped. Women of child-bearing age will be required to have a pregnancy blood test at the time of 
medical screening and a pregnancy urine test on the day of the MRI scan. For women of child-bearing age, 
it will also be asked and it will be documented that they responded negatively (or procedure will not occur) 
to questioning on the MRI day (before the procedure is initiated) whether it is possible they may have 
become pregnant in the prior two-week period.
Prolonged Exposure treatment: Time-limited psychotherapies carry limited iatrogenic risks.
Patients may become distressed by the discussion of sensitive or painful material or by the experience of 
strong emotions during treatment. Some patients may find psychotherapy embarrassing or anxiety 
provoking, whether or not the treatment presses them to confront reminders of past traumas. A risk of any 
treatment is that it may be ineffective and that patients may not improve. Every effort will be made to insure 
patients’ comfort during treatment, and patients will be withdrawn if needed. Non-improvement and/or 
worsening. There is the risk that some patients will not improve clinically or will experience worsening of 
their symptoms during treatment.
Pramipexole: The most common adverse events reported for pramipexole in prior trials for depression in 
patients without Parkinson’s disease are nausea, sedation, and headache (2). In studies of restless legs 
syndrome, the following side effects were present in >2% and more common than in the placebo group: 
Nausea, constipation, diarrhea, dry mouth, fatigue, influenza, headache and somnolence. In studies of early 
Parkinson’s Disease, in which dosage tend to be higher than that proposed in this study, the following 
additional side effects were present in >1% and more common than in the placebo group asthenia, edema, 
malaise, fever, anorexia, dysphagia, weight loss, dizziness, insomnia, hallucinations (positively related to 
age), confusion, amnesia, hyperesthesia, dystonia, akathisia, thinking abnormalities, decreased libido, 

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myoclonus, vision abnormalities, impotence. Compulsive gambling has been reported as an adverse effect 
of pramipexole in persons with Parkinson’s disease, but this has been reported rarely in persons treated for 
restless legs syndrome, and it has not been reported in persons treated for depression. Sleep attacks have 
also been reported in persons taking dopamine agonists for Parkinson’s disease, but have not been reported 
for persons with restless legs or depression.
Interviews/assessments: Some subjects may find the interviews and assessment to be anxiety provoking or 
upsetting. Subjects will be informed that they may choose not to answer specific questions, and may stop 
the interview at any time if they are feeling uncomfortable. Every effort will be made to insure patients’ 
comfort. 
Blood-drawing: Drawing blood for tests may cause bruising around the needle site that may last days. Some 
may experience brief pain or discomfort at the needle entry site. There is also a rare risk of infection at the 
needle entry site. Some participants may feel dizzy; and bloods will be drawn with the participant in a 
supine position if there is a history of vasovagal syncopy in reaction to blood drawing. Proper sterile 
techniques will minimize the rare risk of infection.
Audiotaping: Some patients may feel uncomfortable about the evaluation sessions being audiotaped. The 
purpose of the audiotaping will be explained, confidentiality will be respected, and tapes will be erased after 
the spot checks or following supervision. Informed consent for taping will be obtained.
 
Describe procedures for minimizing risks
Minimizing risks of pramipexole: 
a) Pramipexole will be initiated conservatively following procedures of Schneier and Goldberg (3) prior 
studies of depressed patients that resulted in low levels of adverse events. Daily dose will be started at 0.25 
mg/day and increased by 0.25 mg/day every 3-4 days to a target of 2.5mg day by week 5. Beginning week 6 
daily dose will be increased weekly by 0.5 mg/day to a maximum dose of 4mg. Dosage will be lowered or 
medication stopped if needed for adverse reactions. Patients will be carefully monitored for signs of daytime 
drowsiness and warned not to drive while drowsy if this occurs. Adverse events will be inquired about 
systematically through use of a checklist of side effects previously associated with pramipexole treatment, 
and vital signs will be assessed at each treatment visit. 
b) Patients will be educated about potential adverse interactions with other medications they may wish to 
take and advised to contact study physicians before starting new medications.
c) Careful monitoring of patients weekly during study treatment by experienced clinicians. Patients will see 
the same clinician for each of their treatment visits. Staff psychiatrists carry beepers or cell phones and are 
available 24 hours per day for clinical emergencies. Patients will receive written information on how to 
contact staff by telephone or pager in the event of an emergency. In the event of clinically significant 
suicidal ideation or a medical or psychiatric emergency in the clinic, patients will be escorted to the 
emergency room of New York Presbyterian Medical Center, which is adjacent to New York State 
Psychiatric Institute.
d) Patients will be instructed to contact study personnel during treatment in the event of worsening of 
symptoms or significant adverse events. Patients who experience clinically significant worsening (CGI 
change score > 5) will have study treatment discontinued and will be given appropriate clinical care until 
stabilized. All patients leaving study treatment will be offered 6 months of free open treatment, after which 
time they will be referred to appropriate clinical treatment.

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e) Patients will be consented prior to the start of study treatment, and they will be informed that they may 
withdraw from study treatment at any time. 
f) At the conclusion of study treatment patients discontinuing pramipexole will have it discontinued 
gradually under supervision. 
g) At the termination of PE/pramipexole treatment, patients will be offered six months of open treatment, 
including the option to continue PE and/or pramipexole, or to receive other therapy or medication 
treatments, if clinically indicated.
 
MRI Scan: Subjects will be screened by interview and questionnaire to determine the presence or absence of 
metallic objects, and informed that they cannot participate in the study if their body contains any 
paramagnetic metal other than standard dental work. Earplugs will be provided to reduce discomfort. Staff 
will be available for help and support and, if the subject requests, the scan will be stopped. Women of child-
bearing age will be required to have a pregnancy blood test at the time of medical screening and a 
pregnancy urine test on the day of the MRI scan. For women of child-bearing age, it will also be asked and 
it will be documented that they responded negatively (or procedure will not occur) to questioning on the 
MRI day (before the procedure is initiated) whether it is possible they may have become pregnant in the 
prior two-week period.
Prolonged Exposure treatment: Every effort will be made to insure patients’ comfort during treatment, and 
patients will be withdrawn if needed. 
Interviews/assessments: Subjects will be informed that they may choose not to answer specific questions, 
and may stop the interview at any time if they are feeling uncomfortable. Every effort will be made to insure 
patients’ comfort. 
 
All patients will be assessed using the Columbia Veterans Center Suicide Risk Assessment and Screener 
instrument at intake, midpoint, and termination. Patients will also be continuously assessed by treating 
clinicians and by means of the BDI-II.
 
In the case of clinical deterioration or evidence of suicide risk, the on-call psychiatrist will be involved and 
available to see the patient right away and supervise the patient's management in the event of a serious 
problem such as worsening of suicidal ideation. In the occurrence of active suicidal ideation, the participant 
will be removed from research and be treated as clinically indicated. 
For those deemed to be at greater than minimal risk at any time, the following steps will be taken:
• Provision of contact information for emergency services (911, Anxiety Disorders Clinic pager, NYC 
Mobile Crisis Team)
• Scheduling with ADC MD as soon as possible
• Completion of Safety Plan, copy of which is kept by patient
• Discussion of removal of means, including firearms
• Increased frequency of visits
• Phone check ins between sessions and upon missed appointment
For those at high risk, the following will be considered based on clinical judgment:
• Referral to high risk treatment program, such as DBT

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• Emergency room (voluntary)
• Emergency room (involuntary)
For those who present with elevated risk at termination, we will offer:
• Referral to alternate or high risk treatment programs, as indicated
Blood-drawing: Proper sterile techniques will minimize the rare risk of infection.
Audiotaping: The purpose of the audiotaping will be explained, confidentiality will be respected, and tapes 
will be erased after the spot checks or following supervision. Informed consent for taping will be obtained.
 
Other Procedures for Minimizing Risk:
1) Careful medical and psychiatric screening to identify patients for whom risk for potential adverse
effects are elevated. Such patients will be excluded from the study. As an example, an actively
suicidal patient would be excluded from study participation and appropriate clinical treatment
provided.
2) Patients with any of the following will be removed from research and treated openly or as
clinically indicated: a) the occurrence of assaultive or illegal behavior; b) the occurrence of active
suicidal ideation at any point during the trial as assessed by clinical interview; c) behaviors while
intoxicated that are a danger to him/herself or others.
3) Inclusion of psychoeducation about PTSD, the treatment process and memory triggers within the
therapeutic framework.
4) Careful monitoring of patients during pretreatment and study participation by experienced
clinicians. Patients will see the same clinicians for each of their treatment visits. 
5) Ability to remove any patient from the study who evidences significant clinical deterioration
during acute treatment. Provisions will be made for appropriate clinical care of such patients.
6) Patients failing to benefit from the study treatment will be exited from the study and provided with
appropriate clinical care based on weekly review with termination criteria (see section 4A.7).
7) All data will be coded and stored in locked files to insure confidentiality.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
All data collected will be kept confidential and used for research purposes only. Patient charts will be kept 
in locked file cabinets identified by number. Access to research records is restricted to research staff and 
Federal, State, and Institutional regulatory authorities. Electronic data will be protected by password access. 
No subject’s identifying data will be published.
 
MRI: The results of the structural MRI will be shared with the subject and/or a physician of their choice, as 
detailed below. Because the structural MRI scan is being performed for research purposes only it may not 
show problems that would normally be found in a typical clinical MRI scan ordered by a doctor for a 
specific medical problem. The MRI scans obtained in this study may provide information that is clinically 

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relevant. The quality of clinical information available from these images can vary widely, based on 
resolution, degree of motion artifact, and numerous aspects of the pulse sequences used to acquire them. All 
scans will be read by a clinical neuroradiologist (see “Personnel and Responsibilities”). As with any 
imaging procedure, if the radiologist determines that the quality of the scan does not lend itself to a clinical 
reading, he or she will provide written documentation to this effect. Only the radiologist may make this 
determination. 
The MRI will receive a clinical reading by a neuroradiologist within 4 weeks of the scan, and a 
confirmatory report will be written within 6 weeks of the scan as the following details. When the readings 
yield findings that are of urgent clinical concern, the radiologist (see “Personnel and Responsibilities”) will 
immediately provide an oral report followed by a handwritten or typed note to the co-investigator, Franklin 
Schneier, MD, and the Director of the MRI Center. A final written transcript of the clinical reading will be 
provided within two weeks of the oral report. The radiologist will provide routine written reports to Dr. 
Yuval Neria, PhD, within one month of image acquisition. Because T1 images are acquired in this study, all 
subjects will receive feedback about their scans in accordance with IRB policy. All results will be shared 
with research subjects in a manner that is consistent with the acuity and certainty of the finding, and will be 
communicated by an appropriately qualified member of the research team in the form of a letter that is 
approved by the IRB and will also be contacted by telephone if there is evidence of a clinically-significant 
abnormality. Results will be shared with the subject and/or a physician designated by the subject. 
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
All participants will receive a complete psychiatric evaluation and medical evaluation, results of which will 
be communicated to the participant’s and their physician, at the participant’s request. PTSD and MDD 
symptoms may improve as a result of the PE and pramipexole treatment, but patients will receive no direct 
benefit from fMRI or other study procedures. A potential benefit to society of this research is that the 
knowledge gained may provide future benefits for individuals with PTSD-MDD in terms of improved 
understanding of brain function in PTSD-MDD, which may improve future treatments.
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.
Study participants will receive $100.00 for the completing the first MRI visit ($16.20 for completion of the 
Probabilistic Reward Task, $20 for completion of the self-report tasks and $63.80 for completion of the 
MRI), $100 for completing the second MRI visit ($16.20 for the Probabilistic Reward Task $20 for 
completion of the self-report tasks and $63.80 for completion for the MRI).  Participants will receive 30$ 

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for completion of the midpoint evaluation (clinician assessment and self-report forms). Participants will also 
receive an additional $50 for completing the 3-month follow up (clinician assessment and self-report forms). 
Study patients will receive up to a total of $280 for their participation in the study. Compensation will be 
pro-rated if the subject does not complete all the study procedures. Payments to subjects will be in the form 
of a check payable by RFMH mailed to the participant within 4-6 weeks of the end of the subject’s study 
participation.
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7692 Recruitme Ad.pdf
7692 Recruitme Ad2.pdf
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Upload any additional documents that may be related to this study

7692 Recruitme Ad 
Approximately half of the individuals with Posttraumatic Stress Disorder (PTSD) present with major 
depressive disorder (MDD). Compared to PTSD alone, patients with comorbid PTSD-MDD demonstrate 
greater distress and poorer treatment outcome. Functional magnetic resonance imaging (fMRI) show 
that relative to PTSD alone, PTSD-MDD is associated with decreased resting state functional connectivity 
(rs-FC) in both fear-and reward-processing circuits. In addition, our data suggest that Prolonged 
Exposure (PE), first-line PTSD treatment, may successfully target impairments in the fear circuits, but 
less so in the reward circuits, which may explain the treatment-refractory quality of PTSD-MDD. The goal 
of this pilot study is to collect preliminary data on the feasibility, safety, and initial efficacy of an 
integrated therapeutic approach targeting both fear and reward impairments in PTSD-MDD patients. 
Specifically, we are examining a combination treatment with PE, shown to effectively address fear 
circuitry deficits, and Pramipexole, a dopamine agonist, shown to increase reward circuit function and to 
have promise in treating depression but not previously studied in PTSD. The central hypothesis is that 
combined PE/Pramipexole will a) improve PTSD and depressive symptoms in PTSD-MDD patients and b) 
increase functional connectivity of fear and reward pathways as measured by fMRI rs-FC. 
Currently Recruiting Participants- Call Shay Arnon at 646-774-8106 for more information. 
Recruitme Screening Questions: 
1. Are you between the ages of 18 and 60? 
2. Are you not currently on psychotropic medications (i.e. antidepressants)? 
3. Have you ever experienced a traumatic event (such as a sexual or physical assault, natural 
disaster, combat)? 
4. Do you experience nightmares or thinking about the traumatic event when you don’t want to? 
5. Do you feel constantly on guard, watchful, or easily startled? 
6. Do you experience feeling guilty or down on yourself? 
7. Do you experience feeling very restless or slowed down? 

7692 Recruitme Ad 
Approximately half of the individuals with Posttraumatic Stress Disorder (PTSD) present with major 
depressive disorder (MDD). Compared to PTSD alone, patients with comorbid PTSD-MDD demonstrate 
greater distress and poorer treatment outcome. The goal of this pilot study is to collect preliminary data 
on the feasibility, safety, and initial efficacy of an integrated therapeutic approach of a combination 
treatment with PE and Pramipexole, a dopamine agonist, in treating patients suffering with PTSD and 
Depression. This study includes pre and post treatment research MRI Scans. 
Currently Recruiting Participants- Call Shay Arnon at 646-774-8106 for more information. 
Recruitme Screening Questions: 
1. Are you between the ages of 18 and 60? 
2. Are you not currently on psychotropic medications (i.e. antidepressants)? 
3. Have you ever experienced a traumatic event (such as a sexual or physical assault, natural 
disaster, combat)? 
4. Do you experience nightmares or thinking about the traumatic event when you don’t want to? 
5. Do you feel constantly on guard, watchful, or easily startled? 
6. Do you experience feeling guilty or down on yourself? 
7. Do you experience feeling very restless or slowed down?