Sleep Disorders, Stress Disorders, Post-Traumatic
Conditions
Keywords
Prazosin, Paroxetine, Stress Disorders, Post-Traumatic, Sleep Disorders
Brief summary
The purposes of this study are: * to evaluate the efficacy and tolerability of the drug prazosin compared to placebo for combat stress-related nightmares, sleep disturbance and overall function in recently combat-exposed returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). * to evaluate the effects of the selective serotonin reuptake inhibitor (SSRI) paroxetine on behavioral symptoms and overall function in this population.
Detailed description
Trauma-related nightmares and sleep disruption that follow combat exposure are distressing and frequently treatment resistant symptoms that impair quality of life and overall function. These symptoms closely resemble core nighttime symptoms of posttraumatic stress disorder (PTSD), and are increasingly recognized in returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Prazosin, a generically available brain active alpha-1 adrenergic receptor antagonist, markedly reduced or eliminated combat trauma-related nightmares and sleep disruption in 23 of 25 combat-exposed returnees from OIF at Madigan Army Medical Center (MAMC). The use of prazosin in OIF returnees was based on clinical efficacy of prazosin for trauma-related nightmares, sleep disturbance, and overall function in Vietnam combat veterans with chronic PTSD. The only drugs FDA approved for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. However, SSRI effectiveness in combat trauma PTSD, especially for nighttime symptoms, remains questionable. This is a placebo-controlled clinical trial of prazosin vs. the SSRI paroxetine for combat trauma-related nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) clinical severity in OIF/OEF returnees. Both neurobiologic considerations and our preliminary clinical treatment data provide support for the proposed trial. Preclinical and clinical studies suggest a role for increased central nervous system (CNS) adrenergic outflow and/or responsiveness in PTSD pathophysiology. Possible mechanisms include alpha-1 adrenergic receptor-mediated effects on sleep physiology, corticotropin releasing hormone secretion, and disruption of cognitive processing. Here we propose a double-blind, placebo-controlled parallel group 12 week clinical trial of prazosin vs. paroxetine to test the following hypotheses: Hypothesis 1. Prazosin will be more effective than paroxetine or placebo for reducing frequency and intensity of combat trauma-related nightmares (as measured by the distressing dreams item of the Clinician Administered PTSD Scale \[CAPS\]). Hypothesis 2. Prazosin will be more effective than paroxetine or placebo for improving sleep quality (as measured by the Pittsburgh Sleep Quality Index \[PSQI\]). Hypothesis 3. Prazosin will be more effective than paroxetine or placebo for improving overall clinical status (as measured by the Clinical Global Impression of Change \[CGIC\]). Hypothesis 4. Prazosin will be better tolerated than paroxetine as measured by days retained in the study and frequency of adverse events. Primary outcome measures will assess trauma-related nightmares, sleep disturbance and change in global clinical status: these will include the CAPS \[59\] Recurrent Distressing Dreams item, the PSQI (60) and the CGIC (58) score. Secondary outcome measures will include total CAPS score, the CAPS subscale scores (Reexperiencing/ Intrusions, Avoidance/Numbing, and Hyperarousal), the Nightmare Frequency Questionnaire (NFQ), Insomnia Severity Index, and measures of depressive signs and symptoms, quality of life, and number of study days completed.
Interventions
DRUGprazosin
taken by mouth, twice daily, titrated up to efficacy or a maximum of 5 mg at 10a and 25 mg at bedtime for duration of study
DRUGparoxetine
20 mg taken at 10a for duration of the study
DRUGPlacebo
Placebo
Sponsors
United States Department of Defense
VA Puget Sound Health Care System
Seattle Institute for Biomedical and Clinical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Hazardous duty in Iraq or Afghanistan with the US Armed Forces during Operations Iraqi Freedom and Operation Enduring Freedom * Exposure to at least a moderate level of combat (\>5 on Revised Combat Exposure Scale) * Good general medical health * Stable dose of non-excluded medications for at least 4 weeks prior to randomization * \>5 on CAPS recurrent distressing dreams item * \>5 on CAPS difficulty falling or staying asleep item
Exclusion criteria
* Acute or significant chronic medical illness, preexisting hypotension or orthostatic hypotension, pancreatitis, gout, Ménière's disease, benign positional vertigo, narcolepsy, or any other unstable medical condition. * Women of childbearing potential with either positive pregnancy test or refusal to use effective birth control method will be excluded. * Lifetime schizophrenia, schizoaffective disorder, bipolar disorder, psychotic disorder or any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) cognitive disorder, current delirium, substance dependence disorder within 3 months of the study, severe psychiatric instability or severe situational life crises, including evidence of being actively suicidal or homicidal, or any behavior which poses an immediate danger to patient or others. * Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist or paroxetine or any other SSRI, no concurrent use of another alpha-1 antagonist agent, no concurrent use of an antidepressant (other than trazodone prescribed for sleep).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12 | Baseline and Week 12 | Item B-2 recurrent distressing dreams of the event is a single item from the Clinician Administered PTSD Scale. The rating consists of two parts: Frequency and Intensity. Symptom frequency rated 0 to 4. Symptom intensity rated 0 to 4. Frequency plus Intensity ratings equal the total score. A higher score is worse; a lower score is better. This outcome measure evaluates the change in score from Baseline to Week 12. Minimum = 0 Maximum = 8 |
| Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12 | Baseline to Week 12 | Pittsburgh Sleep Quality Index is a self-report questionnaire assessing sleep quality and disturbances over a 1-month time interval. A global score is obtained by summing the seven component subscales (total score range: 0-21). A score of 5 or less indicates good sleep quality. A score of more than 5 indicates poor sleep quality. Change is measured from Baseline to Week 12. |
| Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12 | Baseline to Week 12 | The Clinical Global Impression of Change is a 7-point scale that rates global change compared to baseline (1=markedly improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=moderately worse, 7=markedly worse). The CGIC is used to determine the impact of treatment effects on meaningful and distinct change in overall sense of well-being and functioning. This outcome measure evaluates change from baseline to Week 12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prazosin Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms. | 18 |
| Paroxetine Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A. | 20 |
| Placebo Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials. | 21 |
| Total | 59 |
Baseline characteristics
| Characteristic | Paroxetine | Placebo | Prazosin | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 21 Participants | 18 Participants | 59 Participants |
| Age, Continuous | 28 years STANDARD_DEVIATION 5 | 32 years STANDARD_DEVIATION 9 | 29 years STANDARD_DEVIATION 7 | 30 years STANDARD_DEVIATION 7 |
| Region of Enrollment United States | 20 participants | 21 participants | 18 participants | 59 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 19 Participants | 20 Participants | 17 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 18 | 3 / 20 | 1 / 21 |
| serious Total, serious adverse events | 0 / 18 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12
Item B-2 recurrent distressing dreams of the event is a single item from the Clinician Administered PTSD Scale. The rating consists of two parts: Frequency and Intensity. Symptom frequency rated 0 to 4. Symptom intensity rated 0 to 4. Frequency plus Intensity ratings equal the total score. A higher score is worse; a lower score is better. This outcome measure evaluates the change in score from Baseline to Week 12. Minimum = 0 Maximum = 8
Time frame: Baseline and Week 12
Population: Number of subjects analyzed equals the number of subjects who were able to complete this assessment at week 12 (e.g., completed the study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prazosin | Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12 | -1.29 scale points | Standard Deviation 1.11 |
| Paroxetine | Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12 | -3.11 scale points | Standard Deviation 2.52 |
| Placebo | Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12 | -2.67 scale points | Standard Deviation 3 |
Primary
Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12
The Clinical Global Impression of Change is a 7-point scale that rates global change compared to baseline (1=markedly improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=moderately worse, 7=markedly worse). The CGIC is used to determine the impact of treatment effects on meaningful and distinct change in overall sense of well-being and functioning. This outcome measure evaluates change from baseline to Week 12.
Time frame: Baseline to Week 12
Population: Number of subjects analyzed equals the number of subjects who were able to complete this assessment at week 12 (e.g., completed the study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prazosin | Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12 | 3.14 scale points | Standard Deviation 1.86 |
| Paroxetine | Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12 | 2.11 scale points | Standard Deviation 1.05 |
| Placebo | Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12 | 2.33 scale points | Standard Deviation 1.22 |
Primary
Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12
Pittsburgh Sleep Quality Index is a self-report questionnaire assessing sleep quality and disturbances over a 1-month time interval. A global score is obtained by summing the seven component subscales (total score range: 0-21). A score of 5 or less indicates good sleep quality. A score of more than 5 indicates poor sleep quality. Change is measured from Baseline to Week 12.
Time frame: Baseline to Week 12
Population: Number of subjects analyzed equals the number of subjects who were able to complete this assessment at Week 12 (e.g., completed the study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prazosin | Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12 | -2.33 scale points | Standard Deviation 2.94 |
| Paroxetine | Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12 | -6.44 scale points | Standard Deviation 3.91 |
| Placebo | Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12 | -3.33 scale points | Standard Deviation 5.45 |