Posttraumatic Stress Disorder
Conditions
Keywords
PTSD
Brief summary
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.
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.
Interventions
DRUGRapamycin
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.
DRUGPlacebo
Inactive
Sponsors
North Texas Veterans Healthcare System
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | Baseline and 1 month posttreatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PTSD Checklist (PCL) | change in PCL score from baseline to 1 month posttreatment | Self-report instrument which assesses the intensity of Posttraumatic Stress Disorder symptoms. The PCL measures the 17 DSM-IV PTSD criteria in 17 items. For each item the participant can respond with a rating of 1-5 (with 1 indicating not at all bothered 5 indicating extremely bothered by the symptom) The range of total scores on the PCL is from 17-85, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items. |
| Quick Inventory of Depressive Symptomatology (QIDS) | change in QIDS score from baseline to 1 month posttreatment | The QIDS is a 16-item self-report measure that assesses how much a participant endorses each of the DSM-IV-TR symptoms of depression, with each item scored from 0 (no endorsement of symptom) to 3 (endorsement of severe symptomatology). Scores on the QIDS range from 0-27, with higher scores indicating higher depressive symptom severity. |
Countries
United States
Participant flow
Recruitment details
Recruited by flyers, clinician referral and letters mailed to male VA North Texas patients with PTSD.
Pre-assignment details
excluded if did not meet PTSD criteria according to the CAPS
Participants by arm
| Arm | Count |
|---|---|
| Rapamycin 15mg Rapamycin administered once in pill form | 28 |
| Placebo 15mg Placebo administered once in pill form | 26 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Rapamycin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 27 Participants | 53 Participants |
| Age, Continuous | 42.15 years STANDARD_DEVIATION 15.46 | 42.64 years STANDARD_DEVIATION 14.39 | 42.21 years STANDARD_DEVIATION 14.77 |
| Region of Enrollment United States | 26 participants | 28 participants | 54 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 26 Participants | 28 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 28 | 0 / 26 |
| serious Total, serious adverse events | 0 / 28 | 0 / 26 |
Outcome results
Primary
Clinician Administered Posttraumatic Stress Disorder Scale (CAPS)
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.
Time frame: Baseline and 1 month posttreatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | Baseline | 72.13 scores on a scale | Standard Deviation 15.27 |
| Rapamycin (e.g., Sirolimus) | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 1 month posttreatment | 58.27 scores on a scale | Standard Deviation 22.96 |
| Placebo | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | Baseline | 70.63 scores on a scale | Standard Deviation 16.37 |
| Placebo | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 1 month posttreatment | 64.54 scores on a scale | Standard Deviation 17.88 |
Comparison: ANOVA comparing the results of change over time (e.g., comparing baseline to 1 month posttreatment) as well as comparing differences between condition (e.g., placebo compared to rapamycin).p-value: >0.05ANOVA
Primary
Clinician Administered Posttraumatic Stress Disorder Scale (CAPS)
The CAPS is administered to assess the frequency and intensity of PTSD symptoms at baseline, and then again 3 months 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.
Time frame: change in CAPS score from baseline to 3 months posttreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 72.13 units on a scale | Standard Deviation 15.27 |
| Placebo | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 70.63 units on a scale | Standard Deviation 16.37 |
| Rapamycin (e.g., Sirolimus) at 3 Months Posttreatment | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 55.26 units on a scale | Standard Deviation 22.62 |
| Placebo at 3 Months Posttreatment | Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) | 62.63 units on a scale | Standard Deviation 17.6 |
p-value: >0.5ANOVA
Secondary
PTSD Checklist (PCL)
Self-report instrument which assesses the intensity of Posttraumatic Stress Disorder symptoms. The PCL measures the 17 DSM-IV PTSD criteria in 17 items. For each item the participant can respond with a rating of 1-5 (with 1 indicating not at all bothered 5 indicating extremely bothered by the symptom) The range of total scores on the PCL is from 17-85, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items.
Time frame: change in PCL score from baseline to 1 month posttreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | PTSD Checklist (PCL) | 57.19 units on a scale | Standard Deviation 10.61 |
| Placebo | PTSD Checklist (PCL) | 60.83 units on a scale | Standard Deviation 10.26 |
| Rapamycin (e.g., Sirolimus) at 3 Months Posttreatment | PTSD Checklist (PCL) | 49.62 units on a scale | Standard Deviation 13.14 |
| Placebo at 3 Months Posttreatment | PTSD Checklist (PCL) | 55.00 units on a scale | Standard Deviation 11.85 |
p-value: >0.05ANOVA
Secondary
PTSD Checklist (PCL)
Self-report instrument which assesses the intensity of Posttraumatic Stress Disorder symptoms. The PCL measures the 17 DSM-IV PTSD criteria in 17 items. For each item the participant can respond with a rating of 1-5 (with 1 indicating not at all bothered 5 indicating extremely bothered by the symptom) The range of total scores on the PCL is from 17-85, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items.
Time frame: change in PCL score from baseline to 3 months posttreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | PTSD Checklist (PCL) | 57.19 units on a scale | Standard Deviation 10.61 |
| Placebo | PTSD Checklist (PCL) | 60.83 units on a scale | Standard Deviation 10.26 |
| Rapamycin (e.g., Sirolimus) at 3 Months Posttreatment | PTSD Checklist (PCL) | 51.07 units on a scale | Standard Deviation 13.81 |
| Placebo at 3 Months Posttreatment | PTSD Checklist (PCL) | 54.13 units on a scale | Standard Deviation 11.23 |
p-value: >0.05ANOVA
Secondary
Quick Inventory of Depressive Symptomatology (QIDS)
The QIDS is a 16-item self-report measure that assesses how much a participant endorses each of the DSM-IV-TR symptoms of depression, with each item scored from 0 (no endorsement of symptom) to 3 (endorsement of severe symptomatology). Scores on the QIDS range from 0-27, with higher scores indicating higher depressive symptom severity.
Time frame: change in QIDS score from baseline to 1 month posttreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | Quick Inventory of Depressive Symptomatology (QIDS) | 14.48 units on a scale | Standard Deviation 3.97 |
| Placebo | Quick Inventory of Depressive Symptomatology (QIDS) | 13.79 units on a scale | Standard Deviation 4.45 |
| Rapamycin (e.g., Sirolimus) at 3 Months Posttreatment | Quick Inventory of Depressive Symptomatology (QIDS) | 11.27 units on a scale | Standard Deviation 5.03 |
| Placebo at 3 Months Posttreatment | Quick Inventory of Depressive Symptomatology (QIDS) | 11.75 units on a scale | Standard Deviation 3.75 |
p-value: <0.05ANOVA
Secondary
Quick Inventory of Depressive Symptomatology (QIDS)
The QIDS is a 16-item self-report measure that assesses how much a participant endorses each of the DSM-IV-TR symptoms of depression, with each item scored from 0 (no endorsement of symptom) to 3 (endorsement of severe symptomatology). Scores on the QIDS range from 0-27, with higher scores indicating higher depressive symptom severity.
Time frame: change in QIDS score from baseline to 3 months posttreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapamycin (e.g., Sirolimus) | Quick Inventory of Depressive Symptomatology (QIDS) | 14.48 units on a scale | Standard Deviation 3.97 |
| Placebo | Quick Inventory of Depressive Symptomatology (QIDS) | 13.79 units on a scale | Standard Deviation 4.45 |
| Rapamycin (e.g., Sirolimus) at 3 Months Posttreatment | Quick Inventory of Depressive Symptomatology (QIDS) | 11.56 units on a scale | Standard Deviation 5.13 |
| Placebo at 3 Months Posttreatment | Quick Inventory of Depressive Symptomatology (QIDS) | 11.29 units on a scale | Standard Deviation 4.32 |
p-value: >0.05ANOVA