Non PTSD, PTSD
Conditions
Brief summary
The overarching objectives of this study are: 1) To investigate the neurobiology of posttraumatic stress disorder (PTSD) during Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep relative to wakefulness; 2) To identify the neurobiological underpinnings of sleep treatment response to prazosin or placebo during wakefulness, REM sleep, and NREM sleep in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) ( veterans with PTSD; and 3) To explore pre-treatment brain activity patterns during wakefulness, REM sleep, and NREM sleep that predict sleep treatment response. We will also explore the stability of the Positron Emission Tomography (PET) signal by comparing pre- and post-placebo changes in brain glucose metabolism in non-responders. For non-PTSD veterans, the stability of the PET signal will be evaluated in a subsample of 6 veterans without PTSD who will repeat the PET imaging procedures 8 weeks after the initial PET series. The overarching hypothesis is that PTSD is characterized by neurobiological alterations in the amygdala, medial prefrontal cortex (mPFC), and brain centers involved in the regulation of NREM and REM sleep, and that these neurobiological changes are normalized with effective sleep treatment.
Detailed description
PTSD affects both daytime functioning and sleep. Complaints of poor sleep, objective disruption of sleep, and heightened sympathovagal tone during sleep occurring early after trauma exposure increase the risk of developing PTSD up to one year later. (1-4). Insomnia is one the most common reasons for referral to mental health services in active duty personnel (5). In military personnel returning from Iraq and Afghanistan, more than 70 percent of those with PTSD report sleep problems and fatigue, whereas more than 25% percent of those without PTSD endorse these symptoms (6). Other disruptive nocturnal behaviors and sleep disorders including sleep terrors, nocturnal anxiety attacks, simple and complex motor behaviors and vocalizations, acting out dreams, sleep apnea, and periodic leg movement disorders are also frequently reported by PTSD patients (7-12). In PTSD, sleep disturbances independently contribute to poor clinical outcomes such as increased severity of daytime PTSD symptoms (8), depression (13), suicidality (13), general psychiatric distress (14), poorer quality of life and functioning (14), poorer perceived physical health (14), and increased substance use (15;16).
Interventions
DRUGPrazosin
The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
DRUGPlacebo
The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
Sponsors
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* OIF/OEF veteran * Between the ages of 18 and 50 years old * Not taking medications known to affect sleep or wake function for 2 weeks Additional selection criteria for PTSD subjects are: * Trauma occurred three months or more before study entry * Meeting diagnostic criteria for current PTSD according to the Clinician Administered PTSD Scale (CAPS) * Participants will remain in ongoing counseling services Additional selection criterion for non-PTSD healthy subjects: * Not meet DSM-IV diagnostic criteria for current PTSD * Have a total score \< 13 on the Beck Depression Inventory * Participants who are active-duty military personnel will be required to obtain permission from their commander to participate in this study.
Exclusion criteria
* Current diagnosis of untreated, severe depression as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual- IV Edition (DSM-IV), non-patient version * Beck Depression Inventory \> 30 * History of psychotic or bipolar disorder * Current history (within 3 months) of substance or alcohol abuse * Significant or unstable acute or chronic medical conditions * Other current sleep disorders * Presence of implanted devices or metal in body such as cardiac pacemaker, aneurysm clip, ear implant, shrapnel, neurostimulators or other metal devices * Fear of closed spaces * Previous radiation exposure (past year) that exceeds recommended safety limits * Pregnancy or breast feeding * Resting blood pressure \< 90/60 at the screening physical examination * Heart rate \> 100 beats/minutes * Current use of a beta-blocker * Use of an alpha-1 antagonist agent in the previous 3 weeks * Refusal to follow the safety measures in the case of use of a phosphodiesterase 5 inhibitor (Cialis, Viagra, Levitra) * Unexpected, untreated, or serious EKG findings
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Baseline and post-intervention at 8-10 weeks | The reported Z value reflect the magnitude of the state difference (Wake vs. Non-REM or Wake vs. REM) within the prazosin group pre-to-post treatment, and after using a mask to adjust for the spurious effects of the passage of time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pittsburgh Sleep Quality Index (PSQI): | Baseline and post-treatment at 8-10 weeks | Self-report sleep quality measure. Scores range from 0 to 21, with higher scores reflecting poorer sleep quality. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prazosin Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep.
Prazosin: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking. | 20 |
| Placebo A placebo is a sugar pill, which will be used to compare with the results of the active medication
Placebo: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Prazosin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 29.7 years STANDARD_DEVIATION 6.55 | 27.2 years STANDARD_DEVIATION 6.25 | 27.7 years STANDARD_DEVIATION 5.14 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose
The reported Z value reflect the magnitude of the state difference (Wake vs. Non-REM or Wake vs. REM) within the prazosin group pre-to-post treatment, and after using a mask to adjust for the spurious effects of the passage of time.
Time frame: Baseline and post-intervention at 8-10 weeks
Population: 9 of the 20 participants who were randomized to prazosin and 13 of the participants randomized to placebo provided scans pre- and post-treatment that were of sufficiency quality to be included in the final analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Pre-to-Post Treatment (Wakefulness < REM) | 3.36 Z values |
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Pre-to-Post Treatment (Wakefulness > NREM) | 3.78 Z values |
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Pre-to-Post Treatment (Wakefulness < NREM) | 3.76 Z values |
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Pre-to-Post Treatment (Wakefulness > REM) | 3.52 Z values |
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Within-state time-dependent decrease in rCMRglc | 4.12 Z values |
| Prazosin -Placebo | Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose | Within-state time-dependent increase in rCMRglc | 3.89 Z values |
Comparison: Wakefulness \> Non-Rapid Eye Movement (NREM): Mean K-cluster voxels (Ke)=15,586: x,y,z= -36, -74, 0. Left Brodmann's Area (BA) 3, 6, 7, 10, 17, 19, 20,21,23, 38p-value: <0.001Full Factorial ANOVAs and Paired T-tests
Comparison: Wakefulness \< NREM: Ke=7,013: x,y,z= 26, 22, -40. Right BA 4, 10-14, 21, 25, 32, 38, 45;p-value: 0.039Full Factorial ANOVAs and Paired T-tests
Comparison: Wakefulness \> (Rapid Eye Movement (REM): No cluster size, coordinates, or brain regions to reportp-value: 0.701Full Factorial ANOVAs and Paired T-tests
Comparison: Wakefulness \< REM: No cluster size, coordinates, or brain regions to reportp-value: 1Full Factorial ANOVAs and Paired T-tests
Comparison: Within-state decrease in rCMRglc: Ke=6,150: x,y,z= -30, -30, 2. Left BA 40, insula, hippocampus, caudate, and putamen;p-value: 0.03Full Factorial ANOVAs and Paired T-tests
Comparison: Within-state increase in rCMRglc: Ke=7,049: x,y,z= 66, -18, 26. Right BA 1, 3, 15, 21, 22, 23, 41, 42p-value: 0.01Full Factorial ANOVAs and Paired T-tests
Secondary
Pittsburgh Sleep Quality Index (PSQI):
Self-report sleep quality measure. Scores range from 0 to 21, with higher scores reflecting poorer sleep quality.
Time frame: Baseline and post-treatment at 8-10 weeks
Population: 9 of the 20 participants who were randomized to prazosin and 13 of the participants randomized to prazosin provided scans pre- and post-treatment that were of sufficiency quality to be included in the final analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prazosin -Placebo | Pittsburgh Sleep Quality Index (PSQI): | PSQI: Baseline | 9.25 units on a scale | Standard Deviation 2.64 |
| Prazosin -Placebo | Pittsburgh Sleep Quality Index (PSQI): | PSQI: Post | 6.71 units on a scale | Standard Deviation 4.31 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI): | PSQI: Baseline | 8.08 units on a scale | Standard Deviation 2.72 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI): | PSQI: Post | 6.54 units on a scale | Standard Deviation 2.57 |