Conditions: Posttraumatic Stress Disorder
Keywords: Traumatic Event Trauma Survivor Exposure Therapy PTSD DCS Telemedicine Telepsychiatry Telemental health
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This study proposes to evaluate the effects of D-cycloserine (DCS) combined with cognitive-behavioral treatment with exposure therapy in a sample of patients who developed posttraumatic stress disorder (PTSD) as a consequence of various traumas (e.g., motor vehicle and accidents, burns and other injuries, combat, World Trade Center attack, etc.). In addition, this study hopes to determine whether a common human genetic single nucleotide polymorphism (SNP) in a growth factor, brain derived neurotrophic factor, BDNF SNP (Val66Met), predicts treatment response to PTSD.

Patients living in areas that are not geographically proximal to the Weill-Cornell Medical Center New York City campus will receive cognitive behavioral therapy using telemedicine (videoconferencing technology).

Overall, this study aims 1) to determine if subjects administered DCS show a significantly larger decrease in symptoms of PTSD as compared to those administered a placebo, 2) to determine if subjects administered DCS show a decrease in PTSD symptomatology significantly earlier (as measured by weeks) than those administered a placebo, 3) to determine if differences in symptomatology are evident at a 6-month follow-up and indicate long-term differences between groups, 4) to determine if the BDNF SNP predicts treatment response, 5)to determine if it is feasible and acceptable to provide imaginal exposure (IE) therapy for PTSD using videoconferencing technology.

Detailed description:
Following an initial assessment evaluating eligibility for the study, eligible participants will be randomly assigned to one of two treatment groups: imaginal exposure (IE) plus DCS (100mg) or IE plus placebo (sugar pill). DCS is a broad spectrum antibiotic that has recently been implicated as a cognitive enhancer and may enhance the treatment that occurs. The participant, assessor and treating clinicians will be blinded to which pill the participant is receiving. The dose of medication will need to be taken only on the days of therapy sessions during which the exposure occurs (approximately 9 times). Both groups will be treated with a standardized cognitive-behavioral exposure therapy protocol utilizing gold-standard treatment, consisting of 12-14 weekly individual (one-on-one) sessions with a highly qualified clinical psychologist. Treatment interventions include imaginal exposure, graduated in vivo exposure, psycho-education, relaxation training, behavioral activation, and cognitive restructuring. Assessments will occur prior to treatment, following sessions 3, 6 and 10, following completion of treatment, and 6 months after the conclusion of treatment. In addition, all participants will be genotyped once for the BDNF SNP (Val66Met) using a non-invasive saliva sample.

Arms:
arm 1: 100 mg on days of therapy session arm 2: Sugar pill

Interventions: intervention 1: DCS intervention 2: Placebo
Intervention descriptions: intervention 1: 1\. Cognitive behavioral treatment with exposure therapy plus D-Cycloserine (100 mg on days of therapy session (approximately 9 times) intervention 2: 2\. Cognitive behavioral treatment with exposure therapy plus a placebo(sugar pill) (Placebo given on days of therapy session (9 times)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
                                                                                                                IRB Protocol Number: 0802009646 
                                                                                                               Clinicaltrials.gov ID: NCT00875342 
 
 
Title: D-cycloserine Enhanced Imaginal Exposure Therapy for Posttraumatic Stress Disorder (PTSD) 
 
Coordinating Center: Weill Cornell Medical College, Department of Psychiatry 
 
 
 
 
IRB Protocol Version and Date:  
Version dated December 11, 2009 
No substantial amendments since December 11, 2009 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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SUMMARY 
 
Posttraumatic stress disorder (PTSD) is a serious mental health condition that can develop after exposure 
to a traumatic event, such as an accident. Research has found that cognitive-behavioral treatment with 
exposure therapy, and also antidepressant medications, are effective treatments for PTSD. Cognitive-
behavioral therapy involves learning more adaptive ways to interpret trauma-related memories and 
engaging in activities that help recovery from trauma, i.e. relaxation. Imaginal exposure therapy involves 
subjects repeatedly recounting memories of their trauma, within a controlled, supportive environment. 
However, research also shows that these treatments are not effective in as many as half of all subjects. 
The goal of this study is to develop more effective PTSD treatments. The study tests whether adding an 
antibiotic drug, D-Cycloserine (DCS), to cognitive-behavioral treatment with exposure therapy will make 
the treatment more effective. Pilot research studies suggest that DCS enhances the therapeutic effects of 
exposure therapy for subjects who have a fear of heights and for those with social anxiety. This study 
compares cognitive-behavioral treatment with exposure therapy plus DCS, versus cognitive-behavioral 
treatment with exposure therapy plus a placebo (sugar pill), to test whether subjects given the DCS will 
show a faster and larger improvement in their PTSD symptoms. Patients living in areas that are not 
geographically proximal to the Weill-Cornell Medical Center New York City campus will receive 
cognitive behavioral therapy using telemedicine (videoconferencing technology) as a way to investigate 
the feasibility and acceptability of using this technology to increase access to care for patients with PTSD. 
 
 RESEARCH DESIGN AND METHODS  
 
The proposed study is a double blind placebo controlled evaluation of whether adding D-Cycloserine 
(DCS; Seromycin) to cognitive-behavioral exposure therapy improves treatment of posttraumatic stress 
disorder (PTSD) in survivors of trauma. Expert treatment guidelines for PTSD were published for the first 
time in 1999, recommending that cognitive-behavioral treatment (CBT) with exposure therapy should be 
the first-line therapy for PTSD4. Although there are unique aspects to each type of trauma exposure, CBT 
plus exposure therapy has been shown to be the most efficacious form of treatment for PTSD, with 
equally beneficial outcomes for survivors of a variety of traumatic events, including combat, motor 
vehicle and other accidents, burn injuries, physical and sexual assaults, and history of childhood abuse4, 5. 
Cognitive therapy involves identifying and challenging negative trauma-related thoughts that evoke 
anxiety, depression, and anger. Behavioral therapy involves re-engaging in pleasurable activities and re-
connecting with loved ones so as to alleviate the PTSD symptoms of emotional numbness, anhedonia 
(loss of the ability to enjoy things), and social estrangement. Imaginal exposure and in vivo exposure are 
also types of behavioral therapy. For in vivo exposure, the clinician and subject construct a hierarchy of 
situations that the subject avoids because they are associated with the traumatic event. The subject then 
progressively works his/her way up the hierarchy, gradually confronting each situation until there is no 
more behavioral avoidance5. During imaginal exposure, subjects repeatedly recount memories of their 
traumatic event, within a controlled, supportive environment5. As they recount memories, subjects also 
rate their anxiety level every few minutes, so that the clinician can monitor this. Subjects recount the 
memories until their distress level declines, which usually takes 20-40 minutes, depending upon the initial 
level of distress. Exposure has been hypothesized to involve extinction of the aversive, symptomatic 
associations to the memory (or, in the case of in vivo exposure, to situations and environmental stimuli). 
Extinction itself is believed to involve active learning of a new set of associations and responses to the 
traumatic memory and trauma-related stimuli and situations.  
 
The proposed study tests whether D-Cycloserine (DCS) can enhance the effects of exposure therapy for 
PTSD. DCS is a broad-spectrum antibiotic used in clinical trials over the last decade as a cognitive 
enhancer 6-9. DCS is a partial agonist at the N-methyl-D-aspartate (NMDA) glutamatergic receptor, which 
has an essential role in learning and memory. DCS has been shown to enhance learning, including the 


 
 
 
 
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extinction of conditioned fear responses 10-11. The proposed study will test the hypothesis that DCS will 
enhance the effects of imaginal exposure to alleviate PTSD symptoms. This hypothesis is supported by 
preliminary data from three sources. First, Ressler et al.2 demonstrated that DCS combined with virtual 
reality (VR) exposure therapy for fear of heights significantly reduced the number of sessions needed to 
treat the phobia from six to only two sessions. Hoffman and colleagues3 also found that DCS combined 
with imaginal exposure was an effective treatment for social anxiety. Lastly, we are currently conducting 
a double blind placebo controlled pilot study (IRB-approved Protocol #0411007625), in which we are 
comparing VR treatment plus DCS to VR treatment plus placebo for the treatment of PTSD in survivors 
of the World Trade Center attack. Preliminary results from the four subjects randomized thus far show a 
large effect size (d = 2.11) for the VR plus DCS intervention. 
 
To evaluate the feasibility and acceptability of using existing telemedicine systems to deliver this 
treatment, ten patients will have their treatment delivered via the University of Vermont Medical Center’s 
telemedicine technology (videoconferencing). Patients will go to the University of Vermont’s Burlington 
Campus, where the telemedicince equipment is located, and be connected via videoconferencing with 
their therapist in NYC. The safety and well-being of the patient will be monitored by Dr. Rabinowitz, 
Medical Director of Telemedicine at University of Vermont Medical Center in Burlington. To increase 
recruitment potential and increase generalizability for the telemedicine portion of this study, we will 
include 20 additional participants with PTSD resulting from varied traumas, including OIF/OEF veterans, 
as well as individuals from occupations-at-risk for PTSD, such as law enforcement and disaster workers. 
We will also expand our potential recruitment locations to include residents in New York State, New 
Jersey, Connecticut, and Pennsylvania.  
For patients outside of the Burlington area, we will use other Internet-based videoconferencing (e.g. 
Skype, Adobe Connect) to connect participants with the therapist, when Polycom equipment is not 
available. Multiple HIPAA-compliant Internet-based videoconferencing systems (e.g., Polycom, Skype, 
or Adobe Connect) will be used to connect the patient with the therapist, depending on what technology is 
avaialable and is most appropriate to each subject’s situation. In this way, we hope to increase flexibility 
and accessibility and decrease cost.  
 
After providing written informed consent, consecutively referred survivors of a variety of traumas will be 
assessed to determine initial eligibility for the study. See Section A6 for inclusion/exclusion criteria. An 
independent evaluator (unaware of treatment condition) will assess symptoms of PTSD and other 
psychopathology using structured clinical interviews and self-report measures with well-established 
psychometric properties at pre-treatment, during treatment, immediately post-treatment, and at six-month 
follow-up. Subjects who are diagnosed with a psychiatric disorder but who do not meet the inclusion 
criteria will be offered a referral for treatment to an appropriate provider. Prior to treatment subjects will 
also meet in person (or by video for telemedicine participants) with one of the two study physicians, 
Margaret Altemus, M.D. and Francis Lee, M.D., for medical clearance to participate. The physician will 
review each subject’s medical history to ensure they have no contraindications to DCS treatment.  
 
The treatment sample will be 144 subjects with PTSD as a consequence of any trauma (e.g., motor 
vehicle and accidents, burns and other injuries, combat, World Trade Center attack, etc.) (n=114), as well 
as telemedicine subjects with PTSD who live in Vermont, New York State, New Jersey, Connecticut, and 
Pennsylvania (n=30). Subjects will be randomly assigned to one of two treatment groups: imaginal 
exposure (IE) plus DCS (n=72) or IE plus placebo (n=72). Both experimental treatment groups will 
complete a standardized exposure therapy protocol similar to the IRB-approved protocol of the PI’s 
current DCS VR exposure therapy study. The therapy is 12-14 weekly sessions that include well-
validated and widely used cognitive-behavioral treatment (CBT) interventions: imaginal exposure, 
graduated in vivo exposure, psycho-education, relaxation training, engaging in pleasurable events, and 
cognitive reframing. Subjects will be instructed to take the pill they are provided (i.e., DCS or placebo) 90 


 
 
 
 
4 
minutes prior to all sessions that include exposure (sessions 3 on) and compliance will be assessed 
weekly. To assess emotional engagement and habituation during imaginal exposure, in 5-minute intervals, 
the subject rates his/her Subjective Units of Distress (SUDS) level, with 0 indicating no distress and 100 
indicating the maximum. (Treatment is described under Section A.7 and a treatment manual is attached in 
Appendix A.) During treatment, subjects will be assessed by an independent evaluator after sessions 3, 6, 
and 10, to determine at what point, if any, differences between groups begin to emerge. Subjects will 
complete a limited battery of self-report questionnaires on a weekly basis prior to the treatment session 
and will be assessed for potential side effects at each session in which medication is taken.  
 
The study instrumentation will be identical to that previously approved by the IRB for use in our current 
DCS study. During the evaluations subjects will be assessed with the following standardized instruments 
widely used in PTSD and clinical research: the Clinician Administered PTSD Scale (CAPS)12, the 
Trauma History Questionnaire13, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-
1)14, the Posttraumatic Stress Disorder Checklist15, the Peri-traumatic Dissociative Experiences 
Questionnaire (PDEQ) 16, the Beck Depression Inventory17, the State-Trait Anger Expression Inventory18, 
the Brief Symptom Inventory19, the Pittsburgh Sleep Quality Index20, the WHO-Disability Assessment 
Scale21, the Michigan Alcohol Screening Test22, the UCLA Social Support Inventory23, the Life Events 
Scale (LES) 24, and the Dyadic Adjustment Scale25. The Treatment Fidelity Rating Scale26 will be used to 
assess clinicians’ adherence to treatment by an independent protocol monitor.  
Study-specific instruments include (1) the Patient Information Profile, a questionnaire assessing 
demographic information; (2) Expectancy of Therapeutic Outcome, a 3-item scale that evaluates the 
credibility of the treatment program used in the PI’s other exposure therapy protocols; the (3) Usefulness 
of Treatment Inventory27 which assesses preferences and usefulness of the specific skills and 
interventions, and is also used in the PI’s other treatment studies; the Working Alliance Inventory Short 
Form52, which measures therapeutic alliance; the Client Satisfaction Questionnaire53, a treatment 
satisfaction measure; (4) Medication Side-effect Checklist, created by our research group to assess the 18 
symptoms that have been named as potential side effects of DCS. The participant is asked to rate how 
much they experienced each symptom on the day the medication was taken on a 5-point Likert scale 
ranging from ―not at all to ―extremely. Any medical problems and medication taken since the last 
session (including dosage and frequency) will also be recorded. Study –specific instruments are attached 
in Appendix B. Telemedicine patients will complete these measures online as well as an online version of 
Telemedicine Satisfaction and Acceptance Scale54, which assesses satisfaction with the videoconferencing 
technology used, and submit electronically using a secure site Internet site so that the clinician at WCMC 
will have access to this data before each session begins. Homework will be completed on hard copy and 
then scanned in to a computer and transmitted electronically (by fax or e-mail) to the clinician at WCMC.  
In addition to these instruments, all subjects will be genotyped for the BDNF SNP (Val66Met) by 
standard PCR methods from saliva samples. At the beginning of the first meeting, subjects will be asked 
to rinse their mouths with water and then salivate into a cup. Samples will be collected using the universal 
identifier for that subject, and transferred to the laboratory of Dr. Lee located in the Lasdon building, in 
batches for processing. (Telemedicine patients will receive assistance from local site staff and/or study 
assessor with the collection of saliva samples and mailing to Dr. Lee’s laboratory at WCMC). Collection 
of saliva samples is non-invasive, reducing risks to both subjects and staff. Saliva samples will be 
collected using the Oragene system (DNA Genotek), which provides a number of benefits for a study 
with the proposed design. Primarily, samples can be stored at room temperature for extended periods of 
time. 
 
Telemedicine patients in the Burlington area using Polycom will complete telemedicine sessions using 
equipment currently installed at Fletcher Allen Health Care (FAHC) or University Health Center (UHC), 
the teaching hospital and outpatient clinic respectively of the University of Vermont College of Medicine. 
Dr. Terry Rabinowitz or his designee will activate the videoconferencing connection with Weill Cornell 


 
 
 
 
5 
Medical Center and ensure that the videoconferencing systems between WCMC and UVMC are fully 
operational and connected. Current instrumentation used at UVMC and WCMC is state-of-the-art 
Polycom (www.polycom.com/home/) videoconferencing equipment and large-screen Liquid Crystal 
Display (LCD) or Cathode Ray Tube (CRT) monitors. These systems provide remote camera control and 
pan-tilt-zoom (PTZ) functionality as well as dynamic management of available bandwidth with an 
extremely low call failure rate. All instrumentation, whether ―clinician-side‖ or ―subject-side,‖ has the 
capability to control the other site’s camera. That is, each has the ability to perform PTZ operations of the 
distant camera. In addition, all instruments have picture-in-picture (PIP) functionality—the ability to view 
oneself as one appears to the distant site (a small inserted real-time video image) while at the same time 
viewing the patient and others (the larger, full-screen video image on the same monitor) at the distant site. 
For this study, the distant sites’ PIP and remote PTZ functionality will be turned off. We have found this 
helps to minimize patient distraction or confusion. Except for these modifications, all videoconferencing 
consultations will be fully interactive. Specifically, both clinicians and subjects will have real-time audio 
and video functionality. Transmission is via three Basic Rate Interface (BRI) Integrated Services Digital 
Network (ISDN) lines transmitting at a bandwidth of 384 kbps. Each facility will designate a room for 
imaginal exposure sessions that is comfortable, private, quiet, well-lighted, and uncluttered, in order to 
avoid distraction.  
Dr. Rabinowitz or a designated associate will remain on the UVMC hospital grounds during all sessions, 
in case of medical emergency, and will be accessible by text-pager.  
Other Vermont, New York State, New Jersey, Connecticut, and Pennsylvania participants will similarly 
utilize Polycom equipment with a minimum bandwidth of 384 kbps in a private room or will utilize other 
Internet-based videoconferencing equipment that is HIPAA compliant to connect with the therapist. 
When the Polycom equipment is used, a designated onsite staff person will activate the local 
videoconferencing connections, ensure that the connection is fully operational and connected to WCMC 
as well as be available during all sessions in case of any emergency.  
The addition of a telemedicine component to the study does not constitute a new type of treatment, rather, 
it is implementing a technical addition designed to increase access to the already approved imaginal 
exposure treatment that has been in place at WCMC, using established telemedicine technologies. The 
aim of this pilot arm of the project is to evaluate the feasibility and acceptability of using telemedicine to 
deliver the imaginal exposure protocol as a way to increase access to evidence-based PTSD treatment.  
 
A6. Inclusion criteria: (1) English-speaking; (2) between the ages of 18 and 70; (3) survivors of a variety 
of traumas (e.g., motor vehicle and accidents, burns and other injuries, combat, World Trade Center 
attack, etc.); (4) diagnosed with PTSD; and (5) in good health. For persons with chronic injuries/ 
conditions related to their accidents, ―good health‖ is defined as the injury being in a state of 
stabilization and able to attend weekly outpatient sessions. Exclusion criteria: (1) current organic mental 
disorder (2) schizophrenia or symptoms of psychosis/delusions; (3) bipolar disorder (4) current substance 
abuse or dependence (5) active suicidal/homicidal ideation, intent, or plan (6) use of pacemaker (7) 
significant health impairment including renal disease (8) taking oral anticoagulant medication, 
ethionamide, isoniazid, or anti-depressant medication (9) hypersensitivity to cycloserine (10) history of 
seizures; (11) pregnant or currently trying to conceive or breastfeeding.  
 
A7. Treatment Plan:  
Medication Administration: Subjects in the present study will take a standard dose of 100mg of DCS or a 
placebo capsule orally one time per week 90 minutes prior to each IE therapy session. The dosing 
regimen is based on the Ressler et al2 study and our current protocol, #0411007625, which show that 
there was no difference in efficacy between the 50 and 500 mg dose, and on the Hoffman study3 showing 
that 50mg was an effective dosing for social anxiety disorder. Thus, we are proposing to use a dose that 
will minimize the likelihood of side effects, and which is also consistent with our ongoing pilot study 
which includes a 100 mg dose. There were no reports of significant side effects in the Ressler study2, the 


 
 
 
 
6 
Hoffman study3, or the studies of human memory14-15 at doses of up to 500mg, and we have not 
observed any in our pilot study thus far. Thus, DCS appears to be well tolerated when delivered as 
proposed for this project. The study physicians, Margaret Altemus, M.D., and Francis Lee, M.D., will be 
available to evaluate subjects who experience any side effects in response to the medication.  
We will use weekly dosing, occurring 90 minutes before the exposure sessions, because this dosing 
regimen was effective in the animal and human fear extinction studies2, 37-38 and because there is evidence 
that daily, longer-term dosing can reduce the cognitive enhancing effects of DCS39, possibly due to 
desensitization of the NMDA receptor over time with daily dosing40. The chosen dosing regimen will 
allow sufficient time for the medication to be absorbed into the bloodstream, and will allow the exposure 
session to be completed while circulating levels of the medication are still robust. Subjects will be 
instructed to take the dose of DCS 90 minutes prior to the start of the exposure session, because previous 
work in humans has shown that peak cerebral spinal fluid concentrations occur at 2 hours following a 
single oral dose of 250mg DCS41 and that peak blood levels occur within 3-4 hours after dosing. DCS has 
a half-life of 10 hours42-43. In the Resslar et al. study2, DCS was given 2-4 hours prior to exposure 
sessions, and in the Hofmann et al study3 1 hour prior to each exposure session. Similarly, the weekly 
dosing strategy used in the 2-week acrophobia and 5-week social anxiety treatment trials, and our own 
10-week study, support the use of a weekly dosing strategy.  
Following the procedures employed in our current DCS study, matching drug and placebo capsules will 
be prepared by the Research Pharmacy at the University of California, San Francisco. The pharmacy will 
pulverize 250mg capsules of DCS and 100mg of powder will be packed into a capsule. Lactose powder 
will be used for the placebo capsules. Randomization and drug dispensing will be performed by the 
Research Pharmacy of New York Presbyterian Hospital. Medication will be mailed to participants 
receiving treatment via telemedicine in New York State, New Jersey, Connecticut, Pennsylvania, and 
Vermont.  
 
Therapy Protocol: The manual is attached in Appendix B. The protocol is 12-14 weekly 75-min. sessions. 
The number, frequency and length of IE sessions was chosen to be consistent with our DCS study and the 
DCS phobia treatment study by Ressler and colleagues2 and closely follows the procedures adapted from 
the PI’s DCS and other PTSD treatment projects 44-45. During ET, the subject recounts a detailed 
description of the traumatic event until anxiety is sufficiently reduced (ideally, 50%), while the therapist 
monitor the subject’s self-reported distress every five minutes. As described, treatment also includes 
empirically-supported, widely used CBT components5: (1) psycho-education for the subjects and 
significant other; (2) relaxation training; (3) in vivo exposure, in which the subject creates a hierarchy for 
avoided situations and confronts these outside of session; (4) behavioral activation (participation in 
pleasurable events); and (5) cognitive techniques (e.g., reframing, adaptive self talk, etc.). 
 


 
 
 
 
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Statistical considerations (e.g. justification for sample size or “n”): 
Sample size estimates were based on the formula outlined by Diggle et al.46 for longitudinal studies. 
Although our pilot data and the published DCS phobia treatment studies suggest large effect sizes for a 
combined DCS treatment, we followed the recommendations by Kraemer et al.47 who suggested that the 
critical effect size at which the power is computed to be 80% should be the threshold below which 
clinicians are unlikely to be interested in the effect. Adopting the procedures used in a large-scale study of 
Vietnam Veterans with PTSD48, we designated a decline of 10 points on the CAPS (based on ½ a 
standard deviation) as the minimum clinically meaningful effect, which corresponds to a conservative 
(small-moderate) estimated effect size of d = .5. The calculations were based on the assumption of a 
strong correlation within subjects over time, rho = .6, and also assume alpha = .05. The number of 
assessments for the primary outcome measure (CAPS scores) was 5 (baseline, 3 clinical assessments 
during treatment, and post). A sample size of 34 per group was found to be sufficient at 80% power to 
detect the effect. Estimating an attrition rate of 30%, we plan to enroll 114 (57 per group) to ensure that 
an adequate sample remains by post-treatment and follow up. In addition, pilot subject data (n=10) will be 
collected to investigate the feasibility and acceptability of telemedicine to provide imaginal exposure (IE) 
therapy for PTSD. 
 
 
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