Rapamycin as a Means of Interference With Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory

This study has been completed.
Sponsor:
Collaborator:
North Texas Veterans Healthcare System
Information provided by (Responsible Party):
Alina Suris, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01449955
First received: September 16, 2011
Last updated: March 1, 2014
Last verified: March 2014
  Purpose

The purpose of the proposed study is to determine if pairing reactivation of a traumatic memory with a single administration of Rapamycin (e.g., Sirolimus) in men with combat-related Posttraumatic Stress Disorder leads to a reduction of the emotional strength of that particular traumatic memory.

The following hypotheses will be tested:

  1. Traumatic memory reactivation paired with a single dose of Rapamycin will decrease objective measures of stress and self-report of stress during replay of the traumatic memory, relative to, subjects receiving placebo.
  2. Pairing administration of Rapamycin with traumatic memory reactivation will decrease symptoms of Posttraumatic Stress Disorder one month and three months later, relative to patients receiving placebo.

Condition Intervention
Posttraumatic Stress Disorder
Drug: Rapamycin
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: mTOR Kinase as a Therapeutic Target in Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) [ Time Frame: Baseline and 1 month posttreatment ] [ Designated as safety issue: No ]
    Clinician administered interview which assesses the symptoms of Posttraumatic Stress disorder at baseline, and then again 1 month posttreatment. The CAPS is a 25 item semi-structured interview that assesses the 17 DSM-IV PTSD criteria as well as social and occupational impairment. For each item the participant can respond with a rating of 0-8 (with 0 indicating no symptom severity and frequency and 8 indicating extreme symptom severity and frequency). The range of total scores on a CAPS is from 0-136, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items. Additionally, the CAPS assesses for a positive PTSD diagnosis by assessing for the three DSM-IV criteria of B, C, and D. In order to meet a positive screen for each criteria, a person must screen positive for symptoms by reporting a score of 3 or more on the specific symptom criterion.

  • Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) [ Time Frame: change in CAPS score from baseline to 3 months posttreatment ] [ Designated as safety issue: No ]
    The CAPS is administered to assess the frequency and intensity of PTSD symptoms at baseline, and then again 3 months posttreatment.


Secondary Outcome Measures:
  • PTSD Checklist (PCL) [ Time Frame: change in PCL score from baseline to 1 month posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of the intensity of PTSD symptoms

  • PTSD Checklist (PCL) [ Time Frame: change in PCL score from baseline to 3 months posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of the intensity of PTSD symptoms

  • Quick Inventory of Depressive Symptomatology (QIDS) [ Time Frame: change in QIDS score from baseline to 1 month posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of depressive symptoms

  • Quick Inventory of Depressive Symptomatology (QIDS) [ Time Frame: change in QIDS score from baseline to 3 months posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of depressive symptoms

  • Quick Inventory of Depressive Symptomatology (QIDS) [ Time Frame: change in QIDS score from baseline to 1 week posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of depressive symptoms

  • Psychophysiology Measurements: Heart Rate [ Time Frame: one week after medication ] [ Designated as safety issue: No ]
    The participant's heart rate is monitored during a script-driven imagery procedure. This procedure involves listening to 4 scripts: 2 neutral, 2 combat-related.

  • Psychophysiology Measurements: Skin Conductance [ Time Frame: one week after medication ] [ Designated as safety issue: No ]
    The participant's skin conductance response is monitored during a script-driven imagery procedure. This procedure involves listening to 4 scripts: 2 neutral, 2 combat-related

  • Psychophysiological Measurements: Electromyogram [ Time Frame: one week after medication ] [ Designated as safety issue: No ]
    The participant's left lateral frontalis and left corrugator muscle activity is monitored during a script-driven imagery procedure. This procedure involves listening to 4 scripts: 2 neutral, 2 combat-related

  • PTSD Checklist (PCL) [ Time Frame: change in PCL score from baseline to one week posttreatment ] [ Designated as safety issue: No ]
    Self-report measure of the intensity of PTSD symptoms


Enrollment: 54
Study Start Date: August 2008
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo (e.g., sugar pill)
15 mg Placebo will be administered once, in pill form.
Drug: Placebo
Inactive
Other Name: sugar pill
Active Comparator: Rapamycin
15 mg of Rapamycin will be administered once, in pill form.
Drug: Rapamycin

Sirolimus is an FDA approved immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. It is non-toxic to kidneys, unlike other immunosuppressants. In this study, the medication will be administered once to see if it interferes with emotional memory reconsolidation. This is based on the fact that it inhibits the mammalian target of Rapamycin (mTOR) through directly binding the mTOR Complex1 (mTORC1). mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription.

a single dosage of 15mg will be administered during this study.

Other Names:
  • Rapamycin
  • Sirolimus
  • X-Rapamune

Detailed Description:

Post-traumatic stress disorder (PTSD) is characterized by intrusive memories in the form of unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic event . Current research efforts have begun to explore the underlying neurochemical changes associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to trauma. For example, preliminary evidence suggests that interference with consolidation of trauma-related memories using the beta-antagonist, propranolol, 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 lifetimes, the utility of this treatment is limited by the logistical problems of treating everyone at risk. To date, there have been 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 memory5. 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. In preclinical studies, the global protein synthesis inhibitor anisomycin can block reconsolidation, leading to a reduction in strength of traumatic memories. Unfortunately, the toxicity of anisomycin is prohibitive for therapeutic use. Thus, rather than using a global protein synthesis inhibitor, a more effective and selective means of reducing consolidation of an established traumatic memory is to target only a subset of protein translation important for synaptic plasticity. The protein kinase mTOR (mammalian target of rapamycin) is just such a regulator of a subset of protein synthesis critical for synaptic plasticity.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male Veterans
  • Diagnosis of Posttraumatic Stress Disorder related to combat

Exclusion Criteria:

  • Hypersensitivity to Rapamycin
  • Organic brain damage (including unresolved Traumatic Brain Injury sequela)
  • Substance dependence in the last three months
  • On any immunosuppressant therapy
  • Prominent suicidal or homicidal features
  • Medical conditions: systemic infections, congestive heart failure, renal failure, hepatic failure
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01449955

Locations
United States, Texas
VA North Texas Healthcare System
Dallas, Texas, United States, 75216
Sponsors and Collaborators
University of Texas Southwestern Medical Center
North Texas Veterans Healthcare System
Investigators
Principal Investigator: Alina M Suris, Ph.D. UT Southwestern Medical Center; VA North Texas Healthcare System
Study Chair: Carol North, M.D. UT Southwestern Medical Center; VA North Texas Healthcare System
  More Information

Publications:
Responsible Party: Alina Suris, Assistant Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01449955     History of Changes
Other Study ID Numbers: 08-049
Study First Received: September 16, 2011
Results First Received: June 18, 2013
Last Updated: March 1, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Texas Southwestern Medical Center:
PTSD

Additional relevant MeSH terms:
Disease
Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Anxiety Disorders
Mental Disorders
Pathologic Processes
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014