Extinction of Fear Memories With Glucocorticoids in Veterans With PTSD

Posttraumatic Stress Disorder Clinical Trial

— VA CORT  

Official title:

Extinction of Fear Memories With Glucocorticoids in Veterans With PTSD

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01090180
• Other study ID #: D6902-R
• Secondary ID: 09-052
• Status: Active, not recruiting
• Phase: N/A
• First received: March 15, 2010
• Last updated: June 23, 2014
• Start date: April 2010
• Est. completion date: December 2014

Study information

• Verified date: June 2014
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to examine the effects of glucocorticoid administration following traumatic memory reactivation on psychiatric symptoms in veterans with combat-related PTSD, in addition to examining the effects of glucocorticoid administration following traumatic memory reactivation on physiological responses to veteran's personal combat memories. The following hypotheses will be tested:

1. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate fewer PTSD and depression symptoms one week later, compared to those who receive a placebo after traumatic memory reactivation.

2. The glucocorticoid reduction effects will be cumulative; that is, reduction will persist, and further post-reactivation glucocorticoid administration will further reduce symptoms

3. Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for subjects receiving an exogenous glucocorticoid compared to those subjects receiving placebo

4. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate decreased physiological responses one week later, compared to those who receive a placebo after traumatic memory reactivation.

5. As with the psychological measures, suppression of the physiological measures will demonstrate both persistence over time and accumulation with subsequent post-reactivation glucocorticoid administration.

Description:

Background information and related research:

Post-traumatic stress disorder (PTSD) is characterized, among other things, by intrusive memories in the form of unwanted images, nightmares, and flashbacks. These memories are associated with intense distress and involve excessive physiological and psychological responses to fear associated stimuli. Prevalence rates of combat-related PTSD are increasing due to Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments, with the estimated risk for PTSD from service in the Iraq War at 18%, and 11% for Afghanistan.

According to the Pentagon's own mental health taskforce, 38% of soldiers, 31% of marines, 49% of National Guard members, and 43% of marine reservists have shown symptoms of post-traumatic stress disorder or other psychological problems within three months of returning from active duty. Estimates from the National Center on PTSD suggest that 40% of OEF/OIF troops may have or will acquire PTSD. The Department of Defense (DoD) reports that 22% of OEF/OIF troops have been flagged for PTSD and referred for follow-up care, and records indicate that over 39,000 OEF/OIF vets had been treated for PTSD as of December, 2006.

Current research efforts are exploring the underlying neurochemical changes associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to trauma by administration of medication to affect the underlying neurochemical processes. For example, preliminary evidence suggests that interference with consolidation of trauma-related memories using the beta-antagonist, propranalol, may prevent PTSD in humans with recent traumas. However, given that as much as 90% of the US population is exposed to at least one traumatic event during their lifetime, the utility of this treatment is limited by the logistical problems of treating everyone at risk for developing PTSD after a trauma. To date, there are very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established.

The trauma experience is initially stored in short-term memory, then consolidated into long-term memory. However, the long-term stability conferred by the consolidation process undergoes a period of labiality as follows. Each time a consolidated memory is activated, the memory trace becomes newly labile and must be consolidated again to remain in long-term memory. This process is called reconsolidation. Reconsolidation therefore offers a biologic window during which long-term memories can be disrupted. Preclinical studies have begun to unravel the biological changes that underlie these processes. Both pharmacological agents, including glucocorticoids, and protein synthesis inhibitors can interfere with memory consolidation and reconsolidation. Endogenously produced stress-hormones, or glucocorticoids, enhance consolidation for emotionally-arousing experiences, but these effects are dependent on dose, aversiveness of task, and timing of hormone administration. Conversely, glucocorticoids appear to impair the retrieval of memories of aversive experiences.10 Recent data also suggest that glucocorticoids enhance extinction of traumatic memories.

Preclinical work in our laboratory at the UT Southwestern Medical Center has established that corticosterone can dose-dependently reduce an established fear memory in rodents. In this study, mice were trained to associate foot-shock with a specific training context to induce fear memory. When this fear memory was reactivated by the contextual stimulus and then followed by glucocorticoid administration, subsequent reactivation of the fear memory produced significantly less fear responses relative to mice administered saline after memory reactivation. After only one pairing of reactivation and glucocorticoid, this effect was reversible with a subthreshold reminder shock and was transient, indicating that the effect of glucocorticoids was on the extinction process. These results strongly suggested glucocorticoid treatment paired with therapeutic traumatic memory reactivation as a specific therapy for PTSD in humans and directly informed our pilot studies in PTSD patients.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 102
• Est. completion date: December 2014
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• male veterans enrolled to receive care through the VA North Texas Healthcare System

• diagnosis of combat-related PTSD

Exclusion Criteria:

• Hypersensitivity to dexamethasone

• Current use of steroids

• Current psychosis

• Organic Brain Damage

• Current major depressive disorder with melancholic features

• Substance dependence in the last 3 months

• Prominent suicidal or homicidal features

• Medical conditions: diabetes, uncontrolled hypertension, severe congestive heart failure, hepatic failure, or any other contraindicated medical condition (such as HPA Axis disease, Addison's Disease or Cushing's Disease).

• Veterans taking medication with established drug interactions with dexamethasone

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Posttraumatic Stress Disorder
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

Drug:
• Dexamethasone
anti-inflammatory adrenocortical steroid The following dose schedule will be given: 0.15mg/kg (based on body weight) every 7 days for 4 consecutive weeks
• Placebo (sugar pill)
inactive

Locations

Country	Name	City	State
United States	VA North Texas Health Care System, Dallas	Dallas	Texas

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Psychophysiological Measures (Skin Conductance, Heart rate, electromyograph of frontalis muscle, electromyograph of corrugator muscle. We expect to see a decrease in all these psychophysiological measures from week to week after each memory activation.		7 days after the first administration of study medication, and then 60 minutes after receiving study medication for 3 consecutive weeks	No
Secondary	Clinician Administered PTSD Scale (CAPS). This will be used to measure PTSD symptoms in the past month. It is recognized as the gold standard of PTSD assessment in the field.		This measure will be administered at the baseline assessment session (before treatment), as well as 1 month, 3 months and 6 months after treatment concludes.	No
Secondary	Quick Inventory of Depressive Symptomatology- Self Report (QUIDS-SR). Because depression can be comorbid with PTSD (70% comorbidity found in pilot sample), this assessment will be used to measure depressive symptoms over a 1 week timeframe		This measure will be administered at all study visits: Baseline, Treatment sessions 1-4, 1 month, 3 months, and 6 months follow up.	No
Secondary	PTSD Checklist (PCL). A self-report, face valid measure of PTSD symptoms over a 1 week time period		This measure will be administered at all study visits: Baseline, Treatment sessions 1-4, 1 month, 3 months, and 6 months follow up.	No