Prolonged Exposure for Post Traumatic Stress Disorder (PTSD) With/Without Yohimbine

The proposed study has three distinct but related research objectives. The first research
goal is to measure psychophysiological correlates of treatment gains associated with
Prolonged Exposure (PE) therapy for PTSD in veterans of Operations Enduring Freedom and Iraqi
Freedom (OEF/OIF). Specifically, heart rate, heart rate variability, skin conductance, and
facial electromyography, will be recorded before and after treatment during a three minute
anxiety probe specific to the patient's index trauma. These measures will be compared to
patient's self reported subjective accounts of symptom improvement on traditional measures of
PTSD pathology (Subjective Units of Distress (SUDs), PTSD Checklist-Military Version (PCL),
Clinician Administered PTSD Scale (CAPS), and the Beck Depression Inventory (BDI)). This goal
is significant for veterans because currently no widely used objective criteria exist to
measure treatment progress in PTSD. While the preponderance of existing evidence suggests
that no one objective psychophysiological measurement will be a valid correlate for all
individuals, even establishing a measurement paradigm that can show mean differences between
groups will provide researchers with an objective tool to measure outcomes on clinical
trials.

The second goal of the study is to investigate if the administration of yohimbine, a drug
found to promote the extinction of conditioned fear in animal models, and more recently, in
humans with claustrophobia, improves the facilitation of fear extinction in PE. Yohimbine is
a safe drug that is already extensively used in human populations. Specifically, this goal
will be investigated using a double blind placebo controlled randomized trial design. The
hypothesis is that one 21mg oral dose of yohimbine given concurrently with a 40 minute
imaginal exposure exercise in PE will lead to a greater reduction in cue-induced anxiety
during the following weekly PE session than placebo. This goal is significant because current
projections of PTSD in OEF/OIF veterans indicate that the need for psychological services
will likely outpace the supply of such services. Accordingly, assisting treatments to be more
efficient will likely translate into more veterans receiving much needed mental health
services.

The 3rd goal is to investigate if ability to habituate to loud, 95db, audio tones correlates
to baseline PTSD pathology and treatment outcomes for PE. This goal represents an important
step forward in understanding characteristics of trait habituation, fear extinction, and
learning in humans, which are all factors related to the successful treatment of PTSD. It is
also significant because such research may lead to the development of individual responder
policies that will assist veterans by individualizing treatment plans based on personal
characteristics.

Inclusion Criteria:

- Subjects must be competent to provide informed consent for research participation.

- Subjects must be male veterans and post deployed active duty male personnel of
OEF/OIF.

- Subjects must be between the ages of 18 and 45.

- Subjects must meet DSM-IV diagnostic criteria for PTSD on the CAPS.

- For subjects taking SSRI's, subjects must be stabilized on the current prescribed dose
for a period of at least 14 days prior to the trial and remain at that dose for the
remainder of the study. Subjects who change their SSRI status or dosage during the
study will continue to receive services via the study resources but data generated
will not be used in analyses. Subjects will be eligible for the study if they are
willing to titrate off potentially confounding agents prior to yohimbine
administration (for a period of five half-lives), given that such titration is also
clinically appropriate and deemed to be in the patient's best interests.

Exclusion Criteria:

- Subjects with a recent (< 2 month) history of psychiatric hospitalization or suicide
attempt. Recent work with veterans with severe mental illness suggests that a 2-month
period of stabilization is sufficient to minimize risk and possible relapse (Frueh,
2005). Subjects with an existing diagnosis of schizophrenia or other Axis I serious
mental illnesses (SMI, besides PTSD) will be excluded. SMI will include any severe and
persistent mental illness.

- Subjects with a current diagnosis of drug dependence, due to potential interactions
with study measurements and treatments. Alcohol use disorders will be allowed given
that subjects can pass exclusion criterion 12 without withdrawal symptoms.

- Subjects with any acute illness or fever. Individuals who otherwise meet study
criteria will be rescheduled for evaluation for participation.

- Subjects with evidence of or a history of clinically significant hematological,
endocrine, cardiovascular, hepatic, pulmonary, renal, gastrointestinal, or
neurological disease including diabetes, as these conditions may affect
physiological/subjective responses.

- Subjects with SCID-diagnosed panic disorder, as yohimbine may precipitate panic
attacks.

- Subjects with an abnormal ECG.

- Subjects with a blood pressure of 140/90 or higher, as yohimbine has been shown to
elevate blood pressure.

- Subjects taking Beta blockers, alpha-adrenergic agents, Beta-agonist inhalers, opiates
or opiate antagonists and any psychotropic medications other than SSRI's because these
may affect test response.

- Subjects who are unwilling or unable to maintain abstinence for three days prior to
yohimbine administration from over-the-counter drugs with sympathomimetic properties,
e.g., asthma medications, cold medicines with ephedrine, dietary supplements with
ephedrine alkaloids, and illegal drugs, e.g., amphetamines, methamphetamine, cocaine,
and MNDA as well as alcohol because these may exacerbate the action of yohimbine.

- Subjects taking alpha-adrenergic antagonists, e.g. prazosin for hypertension; and
beta-adrenergic antagonists, e.g. propranolol. Because they may attenuate effects of
yohimbine. Subjects will be eligible for the study if they are willing to titrate off
potentially confounding agents prior to yohimbine administration (for a period of five
half-lives), given that such titration is also clinically appropriate and deemed to be
in the patient's best interests.

- Asthmatic subjects and subjects on medications for hypertension, due to criteria 9 and
10.

These inclusion/exclusion criteria will allow the majority of veterans treated in the PCT
to be study eligible. Accordingly, the sample will be likely generalizable to the
population of interest.