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

Primary Purpose

Post-Traumatic Stress Disorder

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Yohimbine
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Post-Traumatic Stress Disorder focused on measuring PTSD, Prolonged Exposure, extinction, habituation, psychophysiology

Eligibility Criteria

18 Years - 45 Years (Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Ralph H. Johnson VA Medical Center, Charleston, SC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Yohimbime Group

Placebo Group

Arm Description

Patients will take one 21.6 mg. dose of yohimbine one hour before first imaginal exposure in PE.

Patients will take a placebo one hour before first imaginal exposure in PE.

Outcomes

Primary Outcome Measures

Trauma-Cued Heart Rate Reactivity
The primary outcome was trauma-cued heart rate reactivity a week after the drug visit as measured by the PTSD Brief Reactivity (PBR) task. For each patient, a 3-minute trauma script was constructed containing vivid details of the target trauma and used in tandem with a standard neutral script for baseline measurement. Heart rate reactivity for each time point was the beats per minute (BPM) difference between the neutral and trauma scripts represented as a slope.

Secondary Outcome Measures

Change in Clinician Administered PTSD Scale (CAPS) Score
The CAPS is a structured interview for diagnosis of PTSD and is widely considered the gold-standard assessment. The CAPS produces a total score ranging from 0-136, with higher scores indicating more severe PTSD symptom severity. A 15-point decrease is considered clinically significant.
Change in Post Traumatic Stress Disorder Checklist (PCL) Score
The PCL is a 17-item self-report measure of PTSD symptom severity based on the DSM-IV and has adequate psychometric properties. The PCL produces a score range between 17-85, with higher scores indicating more distress related to PTSD symptoms. A 10-point decrease on the PCL is considered clinically significant.
Change in Becks Depression Inventory (BDI-II) Score
The BDI-II is a 21-item self-report measure that assesses depressive behavioral symptoms. It has demonstrated adequate psychometric validity, and external validity and is used widely as the dependent variable in treatment outcomes research. The BDI-II produces score ranges from 0-63, with higher scores indicating more severe depression symptom severity. A 5-point decrease on the BDI-II is considered clinically significant.

Full Information

First Posted
December 4, 2009
Last Updated
January 10, 2018
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT01031979
Brief Title
Prolonged Exposure for Post Traumatic Stress Disorder (PTSD) With/Without Yohimbine
Official Title
Psychophysiology of Prolonged Exposure for PTSD With/Without Yohimbine
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
December 1, 2010 (Actual)
Primary Completion Date
April 1, 2015 (Actual)
Study Completion Date
July 7, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
The proposed study has three distinct but related research objectives. The first goal is to measure physiological correlates of successful treatment with Prolonged Exposure (PE) therapy for posttraumatic stress disorder (PTSD) in veterans of the Iraq and Afghanistan wars. Individuals with PTSD often experience elevated heart rates and other objectively measurable signs of anxiety when confronted with safe situations that remind them of past dangerous situations. We will measure physiological responses and compare the outcomes to patient's self reported subjective accounts of symptom improvement on traditional measures of PTSD. Developing a way to measure objective gains in symptoms improvement may help researchers who are studying ways to improve PTSD treatment. The second goal of the study is to investigate if yohimbine, a drug found to promote a specific type of learning, will improve treatment outcomes for veterans in PTSD treatment. The third goal is to investigate if ability to get used to loud startling audio tones correlates to baseline PTSD pathology and treatment outcomes for PE. This goal represents an important step forward in understanding characteristics of heritable traits that are related PTSD. It is significant because such research may one day lead to the development of individual responder policies that will assist patients by individualizing treatment plans based on personal characteristics.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Post-Traumatic Stress Disorder
Keywords
PTSD, Prolonged Exposure, extinction, habituation, psychophysiology

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Yohimbime Group
Arm Type
Experimental
Arm Description
Patients will take one 21.6 mg. dose of yohimbine one hour before first imaginal exposure in PE.
Arm Title
Placebo Group
Arm Type
Placebo Comparator
Arm Description
Patients will take a placebo one hour before first imaginal exposure in PE.
Intervention Type
Drug
Intervention Name(s)
Yohimbine
Intervention Description
alpha-2 adrenergic receptor antagonist
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Trauma-Cued Heart Rate Reactivity
Description
The primary outcome was trauma-cued heart rate reactivity a week after the drug visit as measured by the PTSD Brief Reactivity (PBR) task. For each patient, a 3-minute trauma script was constructed containing vivid details of the target trauma and used in tandem with a standard neutral script for baseline measurement. Heart rate reactivity for each time point was the beats per minute (BPM) difference between the neutral and trauma scripts represented as a slope.
Time Frame
One week after drug visit
Secondary Outcome Measure Information:
Title
Change in Clinician Administered PTSD Scale (CAPS) Score
Description
The CAPS is a structured interview for diagnosis of PTSD and is widely considered the gold-standard assessment. The CAPS produces a total score ranging from 0-136, with higher scores indicating more severe PTSD symptom severity. A 15-point decrease is considered clinically significant.
Time Frame
0 Weeks, 15 weeks
Title
Change in Post Traumatic Stress Disorder Checklist (PCL) Score
Description
The PCL is a 17-item self-report measure of PTSD symptom severity based on the DSM-IV and has adequate psychometric properties. The PCL produces a score range between 17-85, with higher scores indicating more distress related to PTSD symptoms. A 10-point decrease on the PCL is considered clinically significant.
Time Frame
0 weeks, 15 weeks
Title
Change in Becks Depression Inventory (BDI-II) Score
Description
The BDI-II is a 21-item self-report measure that assesses depressive behavioral symptoms. It has demonstrated adequate psychometric validity, and external validity and is used widely as the dependent variable in treatment outcomes research. The BDI-II produces score ranges from 0-63, with higher scores indicating more severe depression symptom severity. A 5-point decrease on the BDI-II is considered clinically significant.
Time Frame
0 weeks, 15 weeks

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
Males only.
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter W. Tuerk, PhD MA BA
Organizational Affiliation
Ralph H. Johnson VA Medical Center, Charleston, SC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ralph H. Johnson VA Medical Center, Charleston, SC
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29401-5799
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26654474
Citation
Keller SM, Tuerk PW. Evidence-based psychotherapy (EBP) non-initiation among veterans offered an EBP for posttraumatic stress disorder. Psychol Serv. 2016 Feb;13(1):42-8. doi: 10.1037/ser0000064. Epub 2015 Dec 14.
Results Reference
derived
PubMed Identifier
25809565
Citation
Yuen EK, Gros DF, Price M, Zeigler S, Tuerk PW, Foa EB, Acierno R. Randomized Controlled Trial of Home-Based Telehealth Versus In-Person Prolonged Exposure for Combat-Related PTSD in Veterans: Preliminary Results. J Clin Psychol. 2015 Jun;71(6):500-12. doi: 10.1002/jclp.22168. Epub 2015 Mar 25.
Results Reference
derived

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

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