Conditions: PTSD
Keywords: Dexamethasone Virtual Reality Military PTSD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
Evidence from preliminary studies suggests that people with PTSD have heightened fear responses and that cortisol suppression reduces this heightened fear. Research has shown the drug dexamethasone (DEX), a cortisol suppressor, reduces the startle response in civilians with PTSD. This current research proposal represents a blinded, randomized, placebo-controlled efficacy study with the goal of determining whether a drug that suppresses the stress hormone cortisol will increase the efficacy of exposure therapy. Specifically, it is proposed that a dose of DEX, given the night before (approximately 10 hours before) each of 5 to 11 individual virtual reality exposure (VRE) therapy sessions, will significantly enhance the rate of response and possibly the efficacy of treatment. Participants will be treated until they have experienced at least a 70% reduction in PTSD symptoms from baseline or up to 12 sessions or until they and their therapist agree treatment should be terminated, a minimum of 6 sessions to a maximum of 12 sessions. Comprehensive multi-modal outcomes will be assessed by independent assessors blind to subject condition on interviews, self-report measures, and psychophysiological measures. Participants will be assessed pre- and post-treatment and at a follow-up of 3, 6 and 12 months to assess long term effects.

Detailed description:

Arms:
arm 1: 0.5 mg DEX + virtual reality exposure therapy arm 2: Placebo + virtual reality exposure therapy

Interventions: intervention 1: Virtual reality exposure therapy intervention 2: 0.5 mg DEX
Intervention descriptions: intervention 1: Virtual reality exposure (VRE) therapy is a form of exposure therapy in which participants are helped to confront their traumatic memories in a therapeutic manner. They describe the events out loud and their therapist attempts to match what they are describing in the virtual reality. This is done repeatedly, allowing distress associated with these memories to decrease. Material that emerges during the VRE exposure is processed, or discussed, after the exposure, allowing participants to think about themselves and the event differently. intervention 2: A dose of DEX will be given the night before (approximately 10 hours before) each of 5 to 11 individual virtual reality exposure (VRE) therapy sessions.

Protocol document:
Prot_SAP_000.pdf: 
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9-23-2015 
Identifiers: NCT01965366   Unique Protocol ID: IRB00068205 
Title:  A pilot study of the effects of dexamethasone administration on virtual reality 
exposure therapy for PTSD 
Principal Investigator:   
Barbara Rothbaum, PhD  
Date: 09/23/2015 
 
 


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Title:  A pilot study of the effects of dexamethasone administration on virtual reality 
exposure therapy for PTSD 
 
Principal Investigator:   
Barbara Rothbaum, PhD  
 
Co-Principal Investigator: Tanja Jovanovic, PhD 
 
Co-Investigators:  
 
Kerry Ressler, MD, PhD 
Sheila Rauch, PhD  
Boadie Dunlop, MD 
 
 
Corresponding: 
 
Department of Psychiatry and Behavioral Sciences 
Emory University School of Medicine 
12 Executive Park Drive, NE 
3rd Floor, Suite 300 
Atlanta, GA 30329 
404-712-8866 
brothba@emory.edu 
 
 
 
 
Summary:  Evidence from preliminary studies suggests that subjects with PTSD have 
exaggerated expression of fear responses to danger and safety cues after fear acquisition, and 
that cortisol suppression reduces this pathological fear. Further pilot research has shown the 
drug dexamethasone (DEX), a cortisol suppressor, to reduce startle response in civilians with 
PTSD. This current research proposal represents a blinded, randomized, placebo-controlled 
efficacy study with the goal of determining whether a drug that suppresses the stress-hormone 
cortisol and an exaggerate startle response will increase the efficacy of exposure therapy. 
Specifically, it is proposed that a single dose of DEX, given the night before (approximately 10 
hours before) each of 5 to 10 individual virtual reality exposure (VRE) therapy sessions, will 
significantly enhance the rate of response and possibly the efficacy of treatment. 
Comprehensive multi-modal outcomes will be assessed by independent assessors blind to 
subject condition on interviews, self-report measures, psychophysiological measures, and a 
behavioral avoidance test. Participants will be assessed pre- and post-treatment and at a follow-
up of 3, 6 and 12 months to assess long term effects.  
 
This type of combined treatment -- specific pharmacotherapeutic augmentation of 
psychotherapy -- would be novel and would potentially be generalizable to many different forms 
of psychotherapy for a wide range of disorders. If this translational research is successful, the 
ability of a relatively benign agent administered acutely before a psychotherapy session to 
facilitate the psychotherapeutic process could have important clinical, humanitarian, and 
economic advantages. 
 
1.  Preliminary Studies 
 
Exaggerated Fear Responses in PTSD  
Overgeneralization of trauma-related stimuli or situations can lead to hyper-vigilance and 
exaggerated physiological responses that are part of the PTSD clinical presentation. 
Neuroimaging studies have shown that the brain structures that are activated in response to 


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fearful stimuli, such as the amygdala, show hyperactivation in PTSD subjects compared to 
controls (Liberzon & Martis, 2006; Shin, Rauch, & Pitman, 2006). These patients show 
overgeneralization of fear and in tandem an inability to inhibit fear responses in the presence of 
safety; impaired fear inhibition may be a specific biomarker of PTSD (Jovanovic, Norrholm, 
Blanding, Davis, et al., 2010). Early studies with Vietnam and Gulf War veterans found 
enhanced fear conditioning in PTSD (Grillon & Morgan, 1999; Grillon, Morgan, Davis, & 
Southwick, 1998; Orr et al., 2000). A recent meta-analysis of 15 studies using fear conditioning 
found that patients with anxiety disorders showed greater levels of fear responses compared to 
healthy controls (Lissek et al., 2005). Fear conditioning is based on a simple Pavlovian 
conditioning model in which a neutral conditioned stimulus (CS, for example, a light) is paired 
with an aversive unconditioned stimulus (US, for example, electric shock). After a number of 
pairings, the association is formed so that the CS alone elicits the conditioned response (CR, for 
example, a fear response). This basic model is used in animal as well as human research to 
investigate mechanisms of fear acquisition. The amygdala, part of the limbic system located in 
the temporal lobe of the brain, is an integral part of the fear circuitry (Davis, Falls, Campeau, & 
Kim, 1993; LeDoux, 2000).  Since the amygdala is one of the neural structures that has been 
found to be hyperactive in PTSD (Shin, et al., 2006), fear conditioning methods provide good 
laboratory tools for testing exaggerated fear symptoms of PTSD. In humans, the acoustic startle 
response provides an ideal translational tool to investigate fear conditioning, since the amygdala 
is directly connected with the startle circuit (Davis, 1992; Grillon & Morgan, 1999). Fear-
potentiated startle (FPS) is the relative increase in the startle magnitude elicited in the presence 
of a conditioned stimulus (CS+) that was previously paired with a US; this psychophysiological 
measure can be used to index both the increase in fear during conditioning, as well as the 
reduction of fear during extinction, which is the repeated presentation of the CS without the US. 
Extinction provides a laboratory analog of exposure therapy; thus developing methods that 
enhance extinction may also facilitate exposure-based therapies for PTSD. 
In addition to FPS, the skin conductance response (SCR), an index of sympathetic 
nervous system activity, is frequently used in measuring fear acquisition and extinction in 
tandem with brain imaging studies (Bremner et al., 2005; Knight, 2005; LaBar, Gatenby, Gore, 
LeDoux, & Phelps, 1998; Milad et al., 2007; Phelps, Delgado, Nearing, & LeDoux, 2004). 
Studies using both FPS and SCR have found fear extinction deficits in subjects with PTSD 
(Guthrie & Bryant, 2006; Milad et al., 2008). We have recently developed a startle paradigm that 
measures fear potentiation and inhibition of fear. Using this paradigm, we found that PTSD 
subjects with higher current symptoms showed impaired inhibition of fear in the presence of 
safety cues (Jovanovic et al., 2009). We have also found that traumatized individuals with PTSD 
show exaggerated FPS compared to trauma controls (Jovanovic, Norrholm, Blanding, Phifer, et 
al., 2010) during fear conditioning as well as during fear extinction (Norrholm et al., 2011). 
Finally, we found that individual variability in hyper-arousal symptoms of PTSD were associated 
with impaired fear inhibition (Jovanovic, Norrholm, Blanding, Davis, et al., 2010), while 
individuals with the highest re-experiencing symptoms showed the most exaggerated fear 
during conditioning and extinction (Norrholm, et al., 2011). Heightened “fear load” can hinder 
effective therapy; thus developing strategies for reducing fear expression may significantly 
increase treatment efficacy. A potential pharmacological target for reducing fear is the 
glucocorticoid system, given that elevated cortisol releasing hormone (CRH) levels are 
associated with increased fear responses (Kalin & Takahashi, 1990) and anxiety (Sutton, Koob, 
Le Moal, Rivier, & Vale, 1982), including the startle response (Keen-Rhinehart et al., 2008; Lee 
& Davis, 1997; Liang et al., 1992) and enhanced fear conditioning (Roozendaal, Brunson, 
Holloway, McGaugh, & Baram, 2002; Swerdlow, Britton, & Koob, 1989).  
 
 


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Glucocorticoid Receptor Sensitivity in PTSD  
Recently, genetic markers have been discovered that interact with early childhood abuse 
to increase risk for PTSD; specifically, polymorphisms of the FKBP5 gene have been associated 
with PTSD symptoms (Binder et al., 2008; Xie et al., 2010). This gene is involved in regulating 
cortisol feedback function (Binder, 2009; Binder, et al., 2008), the stress hormone mechanism 
that is one of the most frequently reported neurobiological alterations in PTSD (Baker et al., 
1999; de Kloet et al., 2007; Yehuda, 2009; Yehuda, Giller, Southwick, Lowy, & et al., 1991). 
Heightened cortisol reactivity in response to psychosocial stress has been observed in victims 
of physical and sexual childhood abuse ( Heim et al., 2000). On the other hand, exaggerated 
suppression of hypothalamic-pituitary-adrenal (HPA) axis activity following administration of 
dexamethasone, a cortisol analogue, has been a consistent finding in PTSD (Yehuda, Golier, 
Halligan, Meaney, & Bierer, 2004; Yehuda, Halligan, Golier, Grossman, & Bierer, 2004; Yehuda, 
Halligan, Grossman, Golier, & Wong, 2002), although recent studies indicate that this effect is 
strongest in individuals with higher genetic risk, i.e., carriers of the FKBP5 risk allele (Binder, et 
al., 2008). Taken together, these studies suggest that HPA dysregulations are long-term 
sequelae of trauma ( Heim, Newport, Mletzko, Miller, & Nemeroff, 2008; Yehuda, et al., 2002) 
that are associated with genetic risk for PTSD. Another component of the HPA axis is 
glucocorticoid receptor (GR) hypersensitivity (Yehuda, 2009), which is evident from exaggerated 
negative feedback (Yehuda, et al., 2002), and may be due to increased numbers of GR 
receptors in PTSD (Yehuda, Lowry, Southwick, Mason, & Giller, 1991) or altered receptor 
binding properties. GR alterations may be related to early environment, epigenetic effects 
(McGowan et al., 2009), or genetic risk factors (Binder, et al., 2008). While peripheral levels of 
cortisol, which is the end product of the HPA axis, have not been consistently associated with 
PTSD, the current status of the literature has been to focus on glucocorticoid receptor 
sensitivity, rather than hormone levels (Yehuda, 2009). The proposed study will use 
dexamethasone suppression of cortisol, which specifically targets GR hypersensitivity as a 
mechanism, rather than absolute values of baseline or suppressed cortisol levels.    
Cortisol Suppression and Fear Expression in PTSD  
As described above, the amygdala is part of 
the fear neurocircuitry that is dysregulated in 
PTSD. In addition, the amygdala has outputs to 
hypothalamus (Figure 1), which is the target of 
negative feedback by cortisol via GR. A study 
using fear-potentiated startle in healthy 
subjects found that high cortisol to 
dehydroepiandrosterone-sulfate (DHEA-S) 
ratios after fear conditioning were associated 
with increased startle potentiation (Grillon et 
al., 2006). Our data using dexamethasone 
suppression of cortisol with fear-potentiated 
startle in PTSD patients suggest that GR sensitivity to cortisol may interact with amygdala 
activation to enhance fear responses in PTSD (Jovanovic et al., 2011). Given the neuroimaging 
findings of amygdala hyperactivity in PTSD (Shin, et al., 2006), and the well-known association 
between glucocorticoids and the amygdala in nonhuman studies (Roozendaal, Barsegyan, Lee, 
E. Ronald De Kloet, & Eric, 2007), this understudied area of research is of paramount 
importance to progress in the field of PTSD neurobiology. Virtual Reality Exposure Therapy:  
Exposure therapy was chosen for its direct translation from extinction paradigms in 
animals and the efficacy of exposure therapy in the treatment of chronic PTSD. Virtual reality 
was chosen as the medium for exposure therapy based on its efficacy to date and primarily for 
the experimental control it affords. An obvious anxiety disorder to target is posttraumatic stress 
Figure 1. Diagram 
of the proposed 
relationship 
between prefrontal 
cortex (PFC), 
amygdala (AMY), 
and hypothalamus 
(HYP), showing 
enhanced negative 
feedback from 
cortisol 
 
PFC 
HYP 
AMY 
CORTISOL 
LEGEND: 
             HYPOACTIVE 
              HYPERACTIVE 


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9-23-2015 
disorder (PTSD), as it has been conceptualized as resulting from a failure of extinction 
(Rothbaum & Davis, 2003).  Results from our current trial of VRE with the  virtual Iraq and virtual 
Afghanistan augmented with various medications, ongoing but closed to enrollment, has shown 
VRE to be safe, acceptable, and effective across augmentation groups with statistically 
significant improvement in PTSD symptoms from baseline assessment to post-treatment 
assessment as well as 3, 6, and 12 month follow-ups. These veterans are younger and 
“cleaner” with fewer concomitant medications and comorbid disorders than the Vietnam 
veterans.  
Virtual reality offers a human-computer interaction paradigm in which users are no 
longer simply external observers of images on a computer screen but are active participants 
within a computer-generated three-dimensional virtual world. Virtual environments differ from 
traditional displays in that computer graphics and various display and input technologies are 
integrated to give the user a sense of presence or immersion in the virtual environment. The 
most common approach to the creation of a virtual environment is to outfit the user in a head-
mounted display. Head-mounted displays consist of separate display screens for each eye, 
along with some type of display optics, stereo earphones, and a head-tracking device. The user 
is presented with a computer-generated view of a virtual world that changes in a natural way 
with head and body motion. For some environments, users may also hold a second position 
sensor in their hand that allows them to manipulate their environment.  
The Virtual Environments (VE) to be used in the proposed study were developed with 
input from veterans returning from Iraq and Afghanistan  The VE includes not only a series of 
diverse scenario settings (i.e. city) but also the creation of options for providing the user with 
different first person user perspective options. These options, when combined with real time 
clinician input via the clinical interface, are envisioned to allow for the creation of a user 
experience that is specifically customized to the varied needs of patients who participate in 
treatment. This is an essential component for giving the therapist the capacity to modulate client 
anxiety as is required for an exposure therapy approach. Such customization and real time 
stimulus delivery flexibility are key elements for these types of VR exposure applications. The 
software has been designed such that clients can be exposed to specific scenario settings 
based on a determination as to which environments most closely match the client’s needs, 
relevant to their individual combat related experiences. All scenario settings are adjustable for 
time of day or night, weather conditions and lighting illumination.  
 1. City Scenario –This setting has the appearance of a typical urban environment including 
various desolate, low populated streets as well as old buildings, apartments, and mosques.  The 
city scenario also includes more highly populated areas with more traffic activity, marketplace 
scenes, and monuments. Some of the City Scenario buildings (i.e. the mosque) have interiors 
modeled that will allow the participant to navigate through them.  2. Desert Road Humvee – 
This scenario consists of a single Humvee travelling on a paved desert highway; views from the 
vehicle include desert scenery and the occasional highway overpass.  Stimuli within this 
environment include battle wreckage, debris, human figures by the side of the road, insurgents, 
explosions, and IED blasts.  Subjects may be seated in the driver position, passenger position 
or the gunner position of the vehicle.   3.  Desert Road Humvee Convoy - This scenario is the 
same as described above (single Humvee). However, added stimuli include a convoy of 
vehicles. 
 
The VR system is designed such that once the scenario setting is selected, it is possible 
to select from a variety of user perspective and navigation options in order to provide flexibility in 
how the interaction in the scenario settings can be customized to suit the client’s needs. The 
current VE also includes trigger stimuli based on reports on relevancy by returning soldiers and 
military subject matter experts. These include: 1. Auditory (i.e., weapon fire, explosions, vehicle 
noise, wind, human voices), 2. Static Visual (i.e. wounded civilians and combatants, wrecked 
vehicles), 3. Dynamic Visual (i.e., distant views of human and vehicle movement), 4. Dynamic 


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Audiovisual (i.e., nearby human and vehicle movement).  A variety of auditory trigger stimuli 
(i.e., incoming mortars, weapon fire, voices, wind, helicopter flyovers above the user’s position 
etc.) that can be actuated by the clinician via mouse clicks on a clinical interface.  
 
The VE allows for the addition of two additional types of stimuli, olfactory and tactile. 
Scents may be employed as direct stimuli (e.g., scent of burning rubber) or as cues to help 
immerse persons in the world (e.g., ethnic food cooking). This allows for the simultaneous 
delivery of these stimuli with visual and audio events to create a multi-modal experience.  The 
amount of scent to be released is specified in seconds. The scents are concentrated and gelled 
much like an air freshener cartridge and enclosed within the Scent Palette in an airtight chamber 
that fills with compressed air. When activated, the scent is released into an air stream provided 
by 4 electric fans so that it moves past the user and then dissipates into the volume of the room.  
The scents that have been selected for this application thus far include burning rubber, cordite, 
garbage, body odor, smoke, diesel fuel, Iraqi spices and gunpowder. Scent has been shown to 
be related to emotional responding and will allow clinicians greater range of options when 
applying VR in clinical settings.  Similarly, tactile input in the form of vibration adds another 
sensory modality to the virtual environment, again to enhance presence. Vibration is obtained 
through sound transducers located beneath the client’s floor platform driven by an audio 
amplifier. The sound files embedded in the software are customized to provide vibration 
consistent with relevant visual and audio stimuli in the scenario. For example, explosions and 
gunfire can be accompanied by this additive sensation and the vibration can also be varied as 
when a virtual vehicle moves across seemingly uneven ground.   
Clinical Interface.  The clinical interface allows the clinician to customize the therapy 
experience to the client’s individual needs via the systematic real-time delivery and control of 
“trigger” stimuli in the environment. The clinician uses a separate computer monitor/mouse or 
tablet laptop to display and control the clinical interface. The clinician can adjust the time of day, 
weather options, ambient sounds, scent and vibration configurations and user perspective. 
Once these options are selected, the client can experience this customized environment setting 
while the clinician then may focus on the judicious delivery of trigger stimuli.  These interface 
options have been designed, with the aid of feedback from clinicians, with the goal to provide a 
usable and flexible control system for conducting thoughtfully administered exposure therapy 
that can be readily customized to suit the needs of the client. 
 
1. Significance of the Proposed Research 
This type of combined treatment -- specific pharmacotherapeutic augmentation of 
psychotherapy -- would be novel and would potentially be generalizable to many different forms 
of psychotherapy for a wide range of disorders. If this translational research is successful, the 
ability of a relatively benign agent administered before a psychotherapy session to facilitate the 
psychotherapeutic process could have important clinical, humanitarian, and economic 
advantages. Although exposure therapy is highly effective in treating PTSD in those patients 
who complete the full regiment, it is sometimes difficult for patients to overcome the initially 
aversive component of imaginal or virtual exposure. In addition to enhancing the therapeutic 
effect of exposure therapy, we expect that reducing fear prior to the onset of the therapy session 
will make recalling traumatic memories more tolerable for the patients, resulting in fewer drop-
outs and better compliance with therapy. This could have profound effects on improving 
patients’ long-term outcomes. 
Understanding the neurobiological underpinnings of PTSD is crucial to improving both 
psychotherapy and pharmacotherapy for these patients. Discovering brain-based phenotypic 
biomarkers of the disorder will optimize diagnosis and treatment strategy resulting in better and 
faster treatment response. These new strategies will be invaluable as the number of patients 
increases. There is no question that PTSD is a serious and urgent public health problem and 
that the biological mechanisms of vulnerability to developing psychopathology after trauma must 


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be investigated very closely. A promising candidate neurobiological mechanism involves the 
neurocircuitry of fear, which, according to several lines of evidence, appears to be dysregulated 
in PTSD (Jovanovic, et al., 2009; Liberzon & Martis, 2006; Milad et al., 2009; Norrholm, et al., 
2011; Shin, et al., 2006). 
 
2.  Objectives  
Specific Aims and Research Hypotheses 
The proposed study is designed to achieve the following specific aims:  
Aim 1. To explore whether dexamethasone (DEX), a cortisol analogue, administered 10+ hours 
prior to the virtual reality exposure (VRE) therapy session, enhances exposure therapy in 
humans with PTSD as compared to pill placebo;  
Aim 2. To explore whether any enhancement in exposure therapy produced by DEX in VRE 
evidenced within session and immediately post-treatment results in long-term gains in treatment 
response as compared to pill placebo. 
 
The following hypotheses will be tested: 
1) DEX will facilitate fear extinction in humans. It is predicted that the patients who receive 
VRE combined with 0.5 mg DEX + 10hr will evidence more improvement on symptom 
measures, and on reduced psychophysiological arousal measured via startle, skin 
conductance, and heart-rate responses during exposure to Iraq or Afghanistan military 
scenes, than the placebo group. Furthermore, DEX + VRE will result in faster 
improvement in symptoms (fewer sessions to reach 70% reduction in symptoms), and 
fewer drop-outs (i.e., better tolerance of exposure therapy). 
2) Facilitation of therapeutic response aided by DEX will result in long-term gains. It is 
predicted that the group of patients who receive VRE combined with 0.5 mg of DEX will 
evidence more improvement on a follow-up assessment gathered 3, 6, and 12 months 
post-treatment as compared to baseline on symptom measures and reduced startle, skin 
conductance, and heart-rate responses during exposure to Iraq or Afghanistan military 
scenes than the group who receives placebo. 
 
Exploratory analyses of genetic markers will examine predictors of treatment response. The 
long-term goals include furthering translational research and directly applying paradigms shown 
successful in animals to humans. For this specific paradigm, we plan to establish whether DEX 
can facilitate exposure therapy and apply this knowledge to other disorders. Random 
assignment of participants to placebo or active conditions, standardized treatment delivery, 
homogeneous DSM inclusion criteria, and blind independent assessment will assure a 
methodologically rigorous study. 
 
 
3.0 
Participant Selection  
 
3.1 
Eligibility Criteria 
 
 Participant Inclusion Criteria: 
(a) Participants will be 100 males and females between ages of 21 and 65. 
(b) Participants must meet DSM-V criteria for PTSD due to exposure to a trauma while 
serving in Operation Iraqi Freedom and/or Operation Enduring Freedom-Afghanistan 
and Operation New Dawn.   


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(c) Patients must be literate in English.  
(d) Patients must be medically healthy or medically stable such that the stress of VR and DEX 
are not contraindicated. (e) Participants must comprehend his or her role in the study and the 
risks involved in order to be entered. 
 
 
Gender and Minority Participants’ Inclusion Plan. Males and females of all races and 
ethnic groups will be entered. The racial composition of Atlanta is 71% white, 26% black, and 
3% other (based on the 1990 US Census). Approximately 1% of these persons are of Hispanic 
origins. The gender composition of Atlanta is 51% female. This study will provide free treatment 
and will be advertised in the popular press, thus ensuring equal opportunities for all to learn 
about and participate in this study. The treatment setting is located in a racially diverse county 
(DeKalb County), is easily accessible by public transportation and is wheelchair accessible. It is 
therefore expected that the study sample will closely approximate the demographic composition 
of Atlanta, except that only 15% of the military is currently female. Based on our current study of 
VRE, we expect that the current sample will be approximately 40% Caucasian, 60% non-
caucasian, and 5% female. Persons between18-21 will not be included, as there are specific 
treatments for children and younger people with PTSD and the effects of dexamethasone are 
unknown in children.  
 
3.2 
Ineligibility Criteria 
 
Participant Exclusion Criteria:  
(a) Patients with a history of mania, schizophrenia, or other psychoses;  
(b) Patients with prominent suicidal ideation;  
(c) Patients with current alcohol or drug dependence; 
(d) Patients unable to tolerate wearing the VR helmet;  
(e) Patients unwilling to take study medication; 
(f) Patients on psychotropic medication(s) must have been on a stable dose for at least                 
2 weeks prior to beginning the study and must agree not to change their current 
medication regimen throughout the course of the study. The concomitant use of 
psychotropic medications will be recorded and examined in data analyses. 
(g) Patients with special medical conditions such as pregnancy, renal insufficiency, or a 
history of significant head injury 
(h) Active medical disorders contributing to psychiatric sx e.g. hypo or hyperthyroidism, 
SLE, advanced cirrhosis, etc. (per clinical judgment of study physician) 
(i) Patients stabilized on potentially data-obscuring medications (glucocorticoids). 
 
3.3 
Any current unstable medical illness or medical illness that represents a contraindication 
to taking low-dose dexamethasone, such as osteoporosis, diabetes, narrow-angle 
glaucoma, immunosuppressed state (e.g. HIV infection), current infection, as assessed 
by one of the study physicians, Dr. Boadie Dunlop or Dr. Jeffrey Rakofsky. 
3.4 
Issues related to medication stabilization  
(a) we currently request no less than a two week period of time between the last change 
in a daily chronic psychotropic medication (such as SSRI or mood stabilizer) before 
the initiation of the first study drug administration 
(b) for long-acting benzodiazepines, such as clonazepam and valium, this stabilization 
period off of benzodiazepines should be 1 month. 
(c) For short-acting, and PRN benzodiazepines (e.g. ambien or xanax) 2 weeks 
stabilization should be sufficient. 


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9-23-2015 
(d) For other non-benzo PRN medications with short half-life (trazadone for sleep, pain 
medication, etc.) we request that these are not used for 24 hours prior to the 
medication – therapy combination. 
 
4.0 
Pretreatment Evaluation 
See Data Collection below. 
 
5.0 
Registration/Randomization 
Participants will be self-referred or referred by professionals; phone screening will be 
conducted by a member of the study team to determine appropriateness of this study for each 
participant and to inform the participant of study procedures. Patients may be referred from both 
VA personnel and non-VA sources. At this time, basic inclusion and exclusion criteria, including 
medical history, chronic medical issues, suicidality, and alcohol/substance abuse/dependence 
will be briefly reviewed according to a structured telephone screening interview.  The 
investigators are requesting an IRB waiver of consent for the various pre-randomization 
screening activities, including any review of relevant records and the telephone screening 
process. If an individual is potentially eligible and interested in participating, an initial evaluation 
will be scheduled. All assessments will be conducted by independent assessors who will be 
blinded to treatment condition once randomization occurs, individually and in person.  All 
assessment interviews will be videotaped for use in assessing inter-rater reliability. 
Study staff will not recommend that a potential participant discontinue current 
medications, nor assess response to those current medications. If a potential participant 
indicates interest in being evaluated for participation in the study but is currently on exclusionary 
medications, they will be told that study staff will not render an opinion on whether someone 
should discontinue current medications and that this decision should be made between the 
individual and their treating physician. Study staff will note that there are risks associated with 
discontinuing medications, and that there is no guarantee that they would be eligible for entry 
into the study even if they do discontinue their current medications. 
 
 
6.0 
Therapy  
 
 Treatment will commence following the pre-treatment assessment and all participants 
will be then randomized and seen for an introductory session and then treated once or twice per 
week for 6-11 therapy sessions, including one information gathering and preparation for VRE 
sessions. Patients will be randomized to receive dexamethasone or pill placebo before the VRE 
sessions. VRE will be limited to a minimum of 6 sessions and a maximum of 11 sessions, based 
upon reaching criterion of 70 % symptom improvement as indicated on the PTSD Symptom 
Scale or an agreement between clinician and participant that maximum treatment response has 
been achieved. All sessions will be individual and weekly or twice weekly. The first session will 
last approximately 90 minutes and will be spent in information gathering, treatment planning, 
and explaining the treatment rationale to the patient. Information gathering will review the history 
of PTSD and their military service and will include a brief psychosocial history, including review 
of prior treatment. The VRE sessions will last 90-minutes each. During VRE sessions patients 
will wear a head-mounted display with stereo earphones that will provide visual and audio cues 
consistent with Iraqi or Afghan military scenarios. The therapist will make appropriate comments 
and encourage continued exposure until anxiety has habituated. During exposure, information 
will be gathered on the participant’s anxiety level through the use of a 0-100 SUDs scale. All 
therapists will have been trained in Prolonged Imaginal Exposure therapy (PE) followed by 
training in VRE by Drs. Rothbaum and Rauch. Drs. Rothbaum and Rauch will supervise all 
therapy. 
 


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Medication 
As described above, we will compare pill placebo to dexamethasone in a double-blind 
manner. Patients will be instructed to take the single pill the night before each VRE session and 
will be given a reminder call the night before the VRE session to reinforce medication 
compliance.  
Patient Compliance 
Individual patient compliance with treatment will be evaluated based on attendance at 
therapy sessions, pill count, completion of assessments and cortisol levels present at onset of 
each therapy session. 
 
 
 
7.0 
Pathology 
Participants must meet DSM--V criteria for Posttraumatic Stress Disorder due to military 
service in Iraq or Afghanistan. 
 
 
8.0 
Patient Assessment 
Pre-Treatment Assessment 
 
Potential subjects will be asked to provide a copy of their DD214 to verify combat 
exposure. Once a potential participant has met all screening inclusion and exclusion criteria and 
consented to participate, the CAPS will be administered to determine current PTSD status.  
 
The Clinician Administered PTSD Scale (CAPS-5; Blake et al., 1995; updated for DSM 
V) is an interviewer-administered diagnostic instrument that measures PTSD. The CAPS 
provides a diagnostic measure of PTSD and a continuous measure of the severity, frequency, 
and intensity of the three symptom clusters (intrusion, avoidance, and arousal) and overall 
PTSD. If positive for current PTSD on the CAPS, and all other eligibility criteria are fulfilled, the 
rest of the pre-treatment measures will be administered. 
The Columbia–Suicide Severity Rating Scale. (Columbia; Posner et al., 2011). The 
Columbia–Suicide Severity Rating Scale was initially designed to assess suicidal ideation and 
behavior in clinical trials. It assesses occurrences, types, and severity of suicidal ideation and all 
types of behavior. 
Neurobehavioral Symptom Inventory (NBI; Mererko et al., 2012). This is a 22 item 
measure designed to assess postconcussive symptoms following deployment-related mild 
traumatic brain injury among veterans. 
Patient-Reported Outcomes Measurement Information System 8a and 4a -Satisfaction 
with Social Roles and Activities (PROMIS 4a, PROMIS8a, (Cella et al., 2010). The PROMIS 
item bank assesses satisfaction with performing one’s usual social roles and activities. 
The Patient Health Questionnaire (PHQ-9; Kroenke, Spitzer, & Williams 2001). The 
PHQ-9 is assesses each of the 9 DSM-IV criteria for depression as “0” (not at all) to “3” (nearly 
every day). 
 
The Alcohol Use Disorders Identification Test—Consumption (AUDIT-C; Frank, Danielle 
et al. 2008). The AUDIT-C is a brief validated self-report screen for risky drinking and alcohol 
abuse and dependence (alcohol misuse). It has three questions that ask the frequency and 
amount of alcohol consumed. 
 
Life Events Checklist for DSM-V (LEC-5; Weathers, et al., 2013). This is a self-report 
measure designed to screen for potentially traumatic events in a respondent’s lifetime.  It is 
useful in more specifically identifying the Criterion A stressor queried during the CAPS  
interview. 
 
The Demographics Questionnaire  covers demographics; family composition; personal 
psychiatric history; and income and education to obtain a Hollingshead Four Factor Scale of 
Socioeconomic Status.  


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The Childhood Trauma Questionnaire (CTQ; Bernstein, 1995) is a self-report measure 
which assesses history of childhood trauma employing a Likert-scale format with 5 responses 
per item. 
 
PTSD Symptom Scale-Interview for DSM-5 (PSS-I-5; Foa & Capaldi, 2013) assesses 
current symptom frequency and intensity for the past month. 
 
The MINI International Neuropsychiatric Interview (M.I.N.I. .; Sheehan, D. V. et al., 1998) 
will be administered to screen axis 1 disorders and to establish co-morbid diagnosis.  
 
The Beck Depression Inventory-II (BDI; Beck, Steer, & Brown, 1996) is a 21-item 
measure of cognitive and vegetative symptoms of depression is widely used in a variety of 
populations, including trauma victims and is sensitive to treatment effects on depression.   
 
State Trait Inventory (STAI; Spielberger et al., 1983). The STAI-State is a 20-item self-
report scale employing a Likert scale format with 4 responses per item (1-4). Ten of the STAI 
items measure feelings of stress and anxiety, while the remaining ten items measure feelings of 
relaxation.  
 
Deployment Risk and Resiliency Inventory (DRRI; King et al., National Center for PTSD, 
2003) is a self-report measure of pre-deployment, deployment and post-deployment 
experiences and trauma specific to the veteran population. The scale employs yes-no and Likert 
scale format responses ranging from 1-5. 
 
           The Quality of Life Inventory (QOLI; Frisch et al., 1992) The QOLI consists of 16 items 
selected to include all areas of life that have been empirically associated with life satisfaction.  
Respondents rate how important each of the 16 domains is to their overall satisfaction and 
happiness; they then rate how satisfied they are in the area.  The total score reflects one’s 
satisfaction in areas that one considers important to them.  The QOLI’s sensitivity to treatment-
related change has been demonstrated with clinical samples of depressed, socially 
anxious/phobic, and chemically-dependent patients.     
 
Clinical Global Impressions Scale, Severity of Illness (CGI-Severity; Guy & Bonato, 
1970).  This is a study personnel rated measure of severity of illness ranging from 0 (not 
assessed) to 7 (among the most extremely ill patients).     
 
Mini-Mental State Examination (MMSE; Folstein et al., 1975).  The MMSE is an 11-
question, personnel rated measure that covers patient orientation, registration, 
attention/calculation, recall, and language skills.   
 
Psychophysiological Patient Report:  This is a brief self-report administered following 
each psychophysiological assessment.  Using a likert scale (Not at all to Very/Severe) 
participants rate the assessment VE as to 1. How closely the video matched their experience 
and 2. How distressing they found the video.   
 
Intent to Attend (Leon et al., 2007) is a short, two question survey asking participants 
how likely they are to complete all of the study and how likely they are to attend the next 
session. 
 
Psychophysiological Reactivity Assessment: Acoustic startle response, skin 
conductance, and heart rate will be assessed during a viewing of three VR scenes. The VR 
scenes will be presented through a head-mount display for a duration of 15 minutes. 
Psychophysiological data collection is described below. 
 
Cortisol Reactivity Assessment: Saliva cortisol will be sampled at four intervals relative 
to the 15-min viewing of VR scenes: prior to, immediately after, 15 min, and 45 min after VR.  
Cortisol sampling methods are described below.   
 
The Emory Treatment Resistance Interview for PTSD (E-TRIP) is a structured interview 
that assesses prior trials of pharmacology and psychotherapy PTSD treatments and provides a 
quantitative indicator of PTSD treatment resistance. 
 
Posttraumatic Stress Disorder Checklist (PCL): The PCL is a 17-item self-report 
checklist of PTSD symptoms based closely on the DSM-IV criteria. Respondents rate each item 


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from 1 ("not at all") to 5 ("extremely") to indicate the degree to which they have been bothered 
by that particular symptom over the past month. 
 
 
Measures at each Therapy Session 
 
Expectancy of Therapeutic Outcome Questionnaire (ETOQ) assesses how logical the 
treatment appears, and the expectancy of success for the patient and for others. This measure 
is administered after session 1 only.  
 
Clinical Global Impressions Scale, Severity of Illness (CGI-Severity; Guy & Bonato, 1970).  
This is a study personnel rated measure of severity of illness ranging from 0 (not assessed) to 7 
(among the most extremely ill patients).  This measure is administered after sessions 1–6.   
 
Clinical Global Impression – Improvement (CGI-Improvement; Guy & Bonato, 1970).  
This is a study personnel rated measure of patient’s improvement since start of study ranging 
from 1 (very much improved) to 7 (very much worse).  This measure is administered after 
sessions 2-6.   
 
Clinical Global Improvement Scale, Patient Report (CGI - Self Report; Guy & Bonato, 
1970).  This is a self-reported global measure of change in severity of symptoms, ranging from 1 
(very much improved) to 4 (unchanged) to 7 (very much worse).  This measure is administered 
after sessions 1-6.   
 
The PTSD Symptom Scale is a 17-item interview used to aid in the detection and 
diagnosis of PTSD (described above), administered before sessions 2-6.  
Subjective Units of Discomfort (SUDs) will be gathered during each exposure session 
(sessions 2-6). Participants will be asked to rate their level of discomfort on a scale of 0 (no 
anxiety) to 100 (panic levels of anxiety) every 5 minutes during the VR exposure. 
 
Intent to Attend (Leon et al., 2007) is a short, two question survey asking participants 
how likely they are to complete all of the study and how likely they are to attend the next 
session. 
 
Blinded Medication Check is a one-question measure to asses which medication the 
participant believes they took. 
 
Cortisol Sampling will be obtained from saliva in order to measure post-dexamethasone 
cortisol levels and detect the presence of dexamethasone in saliva. Cortisol sampling methods 
are described below. 
 
 
Post treatment and 3, 6 and 12-month Follow-up Assessments  
 
The Clinician Administered PTSD Scale (CAPS) (see above).  
 
The Beck Depression Inventory (BDI) as above. 
 
The PTSD Symptom Scale as above. 
 
The Clinical Global Improvement Scale (Severity, Improvement, and Patient Report) as 
described  above. 
 
The Quality of Life Inventory as above. 
 
The State Trait Inventory as above. 
 
Patient Update Interview: This a brief study personnel-interview administered to obtain 
general patient follow-up data, i.e. between-assessment treatment, medication changes, 
substance use status/changes, and patient report on relationship/employment/health changes. 
 
Psychophysiological Patient Report as above. 
 
Psychophysiological and Cortisol Reactivity (as described above) to the VR scenes will 
be assessed at each follow-up point. 
 
Posttraumatic Stress Disorder Checklist (PCL) as above. 
 
 


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Psychophysiological Data Collection: 
Psychophysiological data will be acquired at a sampling rate of 1kHz, amplified and digitized 
using the EMG module of the Biopac MP150 for Windows (Biopac Systems, Inc., Aero Camino, 
CA). 
1. The acoustic startle response (eyeblink component) will be measured via electromyographic 
(EMG) recordings of the right orbicularis oculi muscle. Two 5 mm Ag/AgCl pre-gelled disposable 
electrodes will be positioned approximately 1 cm under the pupil and 1 cm below the lateral 
canthus. The startle probe (noise burst) will be a 108-dB (A) SPL, 40-ms burst of broadband 
noise with a near instantaneous rise time.  
2. Skin conductance level and skin conductance response will be acquired at a sampling rate of 
1 kHz using the GSR module of the Biopac system.  Two 5 mm Ag/AgCl disposable electrodes 
filled with isotonic paste will be attached to middle phalanges of the second and fourth finger of 
the non-dominant hand.  
 3.  Heart-rate and heart-rate variability (HRV) will be measured using the ECG module of the 
Biopac system at a sampling rate of 1 kHz. One 5mm Ag/AgCl electrode will be placed on the 
chest above the right clavicle, another electrode will be placed on the chest under the left side of 
the ribcage. 
 
 
Collection of Salivary Samples:  
Salivary samples will be collected in prior to the beginning of the VR assessment, immediately 
after viewing VR scenes and 15 and 45 min after VR scenes using saliva collection tubes. The 
saliva samples will be assayed for cortisol levels on assessment days. On intervention days, 
saliva samples will be collected in the morning when the patient arrives for the session and will 
be assayed for cortisol and presence of dexamethasone to confirm compliance. Assays will be 
completed in the Yerkes Endocrinology Core Laboratory at Emory using commercial 
radioimmunoassay kits (DiaSorin, Stillwater, Minn.).  The inter- and intra-assay coefficients of 
variation will be determined and is expected to be between 4-7%.  Radioimmunoassay kits from 
IgG Corporation (Nashville, Tenn.) will be used to determine dexamethasone concentrations to 
confirm that subjects have detectable dexamethasone levels for the post-dex cortisol sample. 
Interventions: 
VRE. The VRE treatment program will consist of 90-minute individual treatment sessions. 
Procedures include education about common reactions to trauma, breathing retraining, 
prolonged (repeated) virtual exposure to trauma, and discussion of thoughts and feelings 
related to exposure exercises.  The discussion addresses unrealistic beliefs about the self and 
the world, attempting to “process” material that came up during the exposure and make new 
associations explicit (e.g., “You see, by staying with the image long enough, your anxiety 
decreases.”)  Session 1 is devoted to information gathering, education about common reactions 
to trauma, elaboration of the index trauma, breathing retraining, and fostering a therapeutic 
alliance.  The remaining 5-10 sessions consist of VRE interventions and discussion of these 
experiences.    
 
The patient will be encouraged to expose him or herself to traumatic memories triggered 
by the virtual environments, following guidelines for standard exposure therapy. As the number 
of sessions is limited, we are limiting exposure to the identified index trauma, and in some 
cases, a second traumatic event.  The therapist asks the patient to give a SUDs (Subjective 
Units of Discomfort, 0= no anxiety and 100=maximum anxiety) rating approximately every five 


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minutes during all exposures as an indication of his level of anxiety. The therapist makes 
appropriate comments and encourages continued exposure until anxiety has decreased. The 
therapist simultaneously views on a video monitor all of the virtual environments in which 
patients are interacting and therefore is able to comment appropriately and is attempting to 
match stimuli that the patient is describing to the virtual stimuli, as much as possible, for 
example by landing the helicopter at the appropriate time in the memory, or by having gunfire, 
bombs, fog, or night time to match the memory.  The 90-minute session will consist of 15 
minutes of checking in with the patient about their functioning and anxiety since the last session, 
up to 45 minutes of exposure to their traumatic memories and the virtual stimuli,  followed by 
processing and discussion about the material from the exposure. Information is gathered each 
session on any other exposure the patient may have conducted, although no homework will be 
assigned, as patients will only be on study medication for office visits.  
 
Medication. Beginning with session 2 (the first session where VRE is used), the patients will 
take either the dexamethasone medication (0.5 mg) or placebo 8-10 hours prior to the VRE 
session. A study staff member will call the patient to remind them to take their medication at the 
appropriate time.  As the study will be double-blind, neither the patients, the study staff nor 
clinicians will know which pill the patient took.  However, as a check for compliance, saliva 
samples will be tested for the presence of dexamethasone. These results will be available to 
investigators once the study is completed and unblinded. This approach has been used in our 
previous IRB protocols (IRB #51911, PI: Jovanovic), with high compliance rates. 
 
8.1 Procedure  
 
Study staff will conduct extensive phone screening to determine appropriateness of this 
project for each patient and will provide information on project design and procedures. Upon  
medical history review and a physical exam performed by the study physician, a pre-
assessment visit will be scheduled at which time patients will be thoroughly evaluated as to 
inclusion and exclusion criteria (detailed above) and explained the procedures of the project in 
detail. Informed consent will be obtained at this pre-assessment visit. The consent form, CAPS 
and M.I.N.I. will be completed prior to official study entry.  If eligible and willing to participate, 
individuals will officially be enrolled in the study and will complete the pre-treatment assessment 
questionnaires.   During the pre-assessment visit we will collect a one-time saliva sample to be 
used for the purpose of DNA extraction.  DNA extraction is optional and will be presented to 
participants under a separate consent.  Following consent, initial diagnostic interviews, self-
reports, and DNA extraction (if consented), psychophysiological data will be collected 
(described above), including 3 cortisol samples at each assessment, and the first of the therapy 
visits will be scheduled.   Following randomization, the participant will receive a pill and be 
instructed to take it at 11pm before every VRE therapy session.  During any visit after taking 
dexamethasone, the participants will be assessed for adverse effects of the drug by the study 
staff. Significant adverse effects will be reviewed by the study physician; if the study physician 
determines that the study puts the participant at undue risk, their participation will be stopped. 
All treatment will be free of charge to the participant and no funding is available to 
compensate for these visits (treatment sessions 1-6 or 11).   Post treatment and follow-up visits, 
however, (post, 3, 6, and 12-month follow-up) will be compensated $20 for time and travel.   
 
If the treating therapist makes a clinical judgment at the conclusion of treatment sessions 
that a participant requires additional follow-up treatment sessions for stabilization, these may be 
offered as compassionate care.  The participant will also continue with scheduled post-
treatment assessments as per the study protocol.    
 
 
 
Independent Assessor Reliability Monitoring. All MINI and CAPS interviews will be 
videotaped and rated for reliability. Ten percent of the baseline MINI and CAPS interviews will 


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be randomly selected in an ongoing way in order to monitor the reliability of the interview 
process. 
 8.2. Risks to participation: 
 
As a guard against risk of breach of confidentiality, all information will be stored in locked 
files in a locked research area that can only be accessed by research personnel.  No 
names or identifying information will be used in publications that result from this 
research.  Under no circumstances will identifying information be released to any outside 
party (beyond those immediately connected with the study) without written consent from 
the subject.  In cases where data are stored on computers, no data containing identifiers 
or PHI will be stored on hard drives—only on removable media, which will be removed 
from the computer when not in use. All databases will be password protected.   
 
With regard to risk of distress associated with interviews, the participants will be told that 
they can stop the process at any point if they become overwhelmed or fatigued. 
Following their participation in the research, participants will be debriefed and have an 
opportunity to discuss their participation in the research and ask any questions they may 
have for the interviewer.  If the patients are currently in psychiatric treatment, they will be 
encouraged to discuss any distress with their clinician (and with their permission we will 
provide feedback on the assessment to the treating clinician). If they are no longer in 
treatment, or if they request it, a list of resources (local mental health services) will be 
provided to them after participation.  All subjects completing interviews and 
questionnaires will be provided with phone numbers so that they can have any questions 
answered that they feel have not been satisfactorily addressed. The investigative team 
has extensive experience, and they will determine if there is a need for clinical 
intervention; if necessary, arrangements for appropriate clinical services will be made.   
 
With regard to risks associated with the acoustic startle response, electrodermal activity, 
and electrocardiogram recording, if skin cleansing becomes uncomfortable for a given 
subject, the researcher will end the skin preparation at that point and apply the 
electrodes without further cleansing.  The decibel levels and duration of the auditory 
stimuli are not sufficient to cause any damage to the ear.  If a subject finds the noises 
too uncomfortable, the researcher will stop the experimental session immediately.  
 
With regard to risk of dexamethasone administration, no significant side effects have 
been observed in response to intermittent administration of dexamethasone (Decadron; 
Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com).  Decadron can 
cause anaphylactic shock in allergic patients and there are a wide range of side effects 
associated with prolonged administration. Participants will be carefully prescreened for 
allergies, pregnancy and other medical problems such as osteoporosis, diabetes, 
narrow-angle glaucoma, immunosuppressed state (e.g. HIV infection), and current 
infection that this medicine might affect before drug administration and a review of 
medical history and a physical exam will be performed by the study physician prior to 
study randomization 
8.3  Benefits of Therapy: 
 
The benefit of this project to individual subjects is the potential for clinical improvement, 
which far outweighs the risks. This project's potential to contribute knowledge regarding this 
application and the ability of acute dosing with DEX to facilitate treatment of PTSD are 
considered significant benefits with no foreseen global risks. Participants have the opportunity to 
complete the entire, full package of PE, (12 sessions), thereby increasing the odds that each 
patient should benefit from participating in this study. 
 
 


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9.0  Data Collection: 
 
The sources of research material collected from patients will include paper and pencil 
self-report questionnaires, information from structured interviews, psychophysiological 
measures (including heart rate, skin conductance, salivary cortisol, and startle), and clinician 
ratings of symptomatology. Assessment and treatment sessions will be videotaped to calculate 
inter-rater reliability of assessments and treatment compliance. All of the above will become part 
of each patient's research file. This data will be collected specifically for this research program. 
Data will be entered and stored electronically using REDCap, a secure, online database capture 
application (Harris et al., 2009). All information about individual participants, including the 
questionnaires, videotapes, assessment results, and therapy notes will be kept private, to the 
extent allowed by law. All information about participants (including videotapes) will be stored in 
locked file cabinets in locked offices. Videotapes will only be shared with other study staff to 
make sure treatment is being conducted correctly. Videotapes will contain initials rather than full 
names. Videotapes will be erased or destroyed 3 years after completion of the study. 
10.0 
Statistical Considerations 
10.1 Preliminary Analyses 
Premature Termination. Patients will be considered dropouts (a) if they miss two or more 
sessions or (b) if serious adverse reactions or clinical complications (e.g., suicidal intention) 
develop. Initial data analyses will be conducted on treatment completers. This will address 
relative efficacy among treatment completers. A second analysis will be conducted including all 
patients who initiate treatment using an intent-to-treat analysis. This will address relative 
efficacy in the population intended for treatment, thus incorporating issues related to potential 
differential dropouts in the treatment groups. Finally, analyses will be conducted to see if 
treatment completers differ from drop-outs on demographic variables and pre-treatment 
measures. 
 
Group Equivalence:  We will evaluate the effectiveness of random assignment to two 
treatment groups by comparing the groups on demographics, baseline measures of key 
outcome variables, and other important theoretical covariates.  We will characterize differences 
between study dropouts and completers, and between dropouts from the VRE+DEX and 
VRE+placebo groups.  We will compare dropouts to completers on the same set of baseline 
variables that will be used to examine initial group equivalence. Differences between conditions 
will be assessed using one way ANOVA for continuous variables and chi-square analyses for 
categorical variables (Fleiss et al., 2013). Any observed differences that approach statistical 
significance (P< 0.15), and which are theoretically or empirically identified as potential 
confounders will be included as covariates in subsequent cross sectional and longitudinal 
analyses. 
10.2 Statistical Analyses 
Power and Sample Size  
 Power calculations are based on Cohen (1992). We set the Type I Error rate at 0.05 
(two-tailed) for all computations. We first calculated the number of participants needed to test 
the effect of VRE augmentation with DEX at immediate post-treatment assessment (Hypothesis 
1 above). Then, knowing how many participants would be needed at the end of this phase, we 
worked backward to calculate how many participants would need to be enrolled initially. We will 
continue to collect data from all participants, including those who drop out of treatment or are 
discontinued. Thus, loss to the study represents a failure to participate in measurement, and not 
merely dropout from treatment. We assumed that: (1) 10% of participants will be lost to the 


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study by the end of treatment; an additional 15% of participants will drop out of treatment, 
resulting in 25% of participants randomized to placebo or 0.5mg DEX groups that would not 
complete treatment. We anticipate that 10% of completers will be lost to the study prior to the 3 
month follow-up visits.  
The effect size measure used, d, represents the standardized difference between 
sample means.  Cohen (1988) has proposed that d = .30, .50, and .80 be categorized as 
“small,” “medium,” and “large,” respectively.  We assume that a medium effect size—half a 
standard deviation—is the smallest clinically meaningful difference between DEX-augmented 
VRE vs. placebo-augmented VRE at the end of treatment. 
For a two-group study design, 100 participants (n=50 in each group) would be needed to 
achieve a minimum desired power of 85% to detect an effect size of .65 with a 2-sided test at a 
significance level of 0.05.  
 
Hypothesis 1: Patients who receive VRE+DEX will evidence more improvement on 
within-session measures (SUDs), on immediate post-treatment symptoms measures and on 
startle, SCR and HR, than the group who receives placebo.  
To analyze pre-treatment and immediate post-treatment differences, the first analysis 
will compare the VRE+DEX condition to the VRE+placebo condition on the following outcome 
measures: 1) symptom measures (continuous variables); 2) psychophysiological measures 
(startle responses, cortisol levels, heart-rate, skin conductance) (continuous variables). It is 
expected that VRE+DEX participants will show significant improvement on all outcome 
measures immediately post-treatment compared to VRE+ placebo participants.   
Continuous variables will be analyzed using multivariate repeated measures ANCOVA 
with treatment condition being the between subjects factor, the pre-treatment vs. post-treatment 
condition being the within subjects factor, and the scale scores as the multiple measures 
accounting for appropriate covariates as determined through preliminary analyses discussed 
above. Adjusted means and mean differences as well as interaction terms will be obtained and 
evaluated. Categorical variables will be analyzed using logistic regression and controlling for 
appropriate covariates resulting in adjusted odd ratios. 
An additional approach to testing this hypothesis will involve using two categorical 
measures of clinically significant improvement: 1) a 30% decrease in the CAPs, and 2) a rating 
of "much improved" or "very much improved" by the therapist and participant on the CGI 
inventory at the end of active treatment. These data will be analyzed using logistic regression 
with the inclusion of appropriate terms for the covariates and treatment-by-covariate 
interactions.  
Furthermore, we will look at the number of sessions required to reach 70% improvement 
or maximum treatment response and the number of dropouts, predicting fewer sessions to 
reach 70% improvement or maximum treatment response and fewer dropouts in the VRE + 
DEX group. 
Within-subject measures will also be obtained to assess improvement within sessions.  
SUDS and psychophysiological measures (heart rate and skin conductance) will be used to 
measure within session anxiety levels.  Average and peak values of these continuous variables 
will also be analyzed using a repeated measures ANCOVA.   
Hypothesis 2: Patients who receive VRE+DEX will evidence more improvement on 
follow-up assessments (symptom measures and psychophysiological responses) gathered 3, 6 
and 12 months post-treatment compared to the patients who receive the placebo. 
Interval specific analyses: First, the effectiveness of the VRE+DEX treatment will be 
analyzed for the two interval periods separately: from immediately post-treatment to the 3, 6 and 
12 -month assessment.  To test these time interval specific treatment effects, logistic regression 
will be used to compute adjusted odd ratios for dichotomous outcomes and multivariate 


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repeated measures ANCOVA will be used to obtain adjusted means, mean differences and 
interaction terms for continuous outcomes. For each of these analyses, the baseline measure 
for each specific outcome will be included as a covariate in the analysis.   
GEE Modeling for analysis of entire 12-month assessment period: Additionally, to 
evaluate treatment effects for the entire 12-month follow up period, logistic and linear 
generalized estimating equation (GEE) regression models will be used for dichotomous and 
continuous variables respectively. GEE modeling is an appropriate analytic tool for longitudinal, 
repeated measures data as it is designed to adjust for within-subject correlations over time 
(Liang & Zeger, 1986; Kleinbaum et al., 1998; Hardin & Hilbe, 2003). By using the GEE method, 
the relationship between outcome variables obtained at different assessment time points and 
predictor variables are analyzed simultaneously. GEE models are comprised of a time 
independent variable (i.e. treatment condition) and a time-dependent variable (i.e. key outcomes 
variables and covariates). The estimated coefficients reflect the relationship between the time-
independent and time-dependent using all available longitudinal data. Since repeated 
observations within one subject are not independent of each other, a correction must be 
implemented to account for within-subject correlations. This correction is achieved by assuming 
an a priori correlation structure for the repeated measurements of the outcome variables. It is 
proposed that the autoregressive correlation structure will be utilized. The assumption behind 
the autoregressive correlation structure is that the correlation between responses is dependent 
on the interval of time between responses. The resulting GEE parameters can be interpreted as 
the odds or the mean difference for logistic and linear regression models respectively, over the 
entire 12-month period for an average participant. GEE analyses will be performed using  
STATA, version 8.0 (Stata Press, College Station, Texas) using the xtgee command with 
corr(ar1). 
Security.  A participant will be identified throughout the central database by his or her 
unique subject identification number (SID).  Information which could identify a subject, such as 
name, address or social security number, will either not be stored electronically or will be kept in 
files on a separate machine and network from the database files containing study data.  All 
subject paper files will be stored in locked cabinets at all times. All computer systems and 
programs will be password protected.  All network-based communications of study and other 
confidential information will be encrypted.  Good computer security practice (shutting down of 
computer after work hours, restricting physical access to machines, prohibition of password 
sharing) will be required of all study personnel. Virus protection software will be installed on 
each study machine.  The virus detection tools will be used, maintained, audited and, if 
necessary, updated on all computers and pathways into the system.  Redundant backups will 
allow for quick restoration of data in the unlikely event that a hardware failure or security breach 
should occur.  Periodically, database files will be archived onto compact discs and stored offsite. 
 
Archiving.  All study raw data, forms, documents, software programs, software applications and 
computer data files will be indexed and archived routinely.  Strict version control of documents 
and software applications will be instituted.  At the completion of the study, primary study 
documentation will be consolidated and retained in filing cabinets in an organized fashion, with a 
clear index to organization. 
 
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