Clinical trial NCT02199652
Conditions: Post Traumatic Stress Disorder Suicidal Ideation Nightmares
Sponsor: Augusta University
Start date: 2014-03-01; Completion date: 2017-12-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with PTSD, and frequent nightmares, and mild-moderate suicidal ideation, who are already taking a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Norepinephrine Reuptake Inhibitor (SNRI) will be randomized to either prazosin or placebo. The investigators hypothesize that patients receiving prazosin will have a greater reduction in suicidal ideation.

Detailed description:

Arms: arm 1: placebo pill arm 2: prazosin pill
Interventions: intervention 1: Prazosin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
  
Reducing Suicidal Ideation through Treatment of Nightmares-PTSD 
(REST-ON-PTSD) 
 
 
 
Clinical Protocol 
 
Version 1.2 
April 6, 2015 
 
 
 
 
 
Principal Investigator: 
W. VAUGHN MCCALL, M.D., MS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version Date: April 6, 2015 
 
 
2 
 
Project Summary 
Numerous (>40) epidemiologic reports have linked insomnia and nightmares to suicidal ideation and suicide 
death. We are presently engaged in a project which tests the hypothesis that treatment of insomnia in 
depressed patients with hypnotic medications will reduce the intensity of suicidal ideation. This ongoing project 
is called Reducing Suicidal Ideation Through Insomnia Treatment (REST-IT). 
 
We have now acquired and analyzed new data since the inception of the present project that reveals that 
nightmares and disturbing dreams are more strongly related to the intensity of suicidal ideation than is 
insomnia itself.  We therefore propose to target treatment of nightmares in suicidal patients experiencing 
nightmares as part of post-traumatic stress disorder (PTSD). This new effort is named Reducing Suicidal 
Ideation Through Treatment of Nightmares in PTSD (REST-ON-PTSD).  REST-ON-PTSD will offer treatment 
with open label selective serotonin reuptake inhibitors (SSRIs) for PTSD, or open label treatment for bipolar 
disorder, combined with randomization to prazosin versus placebo. SSRIs are the only medications approved 
by the FDA for treatment of PTSD, while prazosin is the best-practice pharmacologic treatment for 
nightmares.{Aurora, 2010 1365 /id}  REST-ON-PTSD is designed to be a small, randomized controlled clinical 
trial intended to generate pilot data to estimate effect sizes for prazosin treatment in reducing suicidal ideation 
in suicidal PTSD outpatients who have nightmares and disturbing dreams, with the following Specific Aims: 
 
Primary Aim:  We will estimate the effect size of prazosin on the intensity of suicidal ideation in PTSD 
outpatients with nightmares and disturbing dreams.  
Hypothesis 1.  Prazosin, combined with an SSRI or open label treatment for bipolar disorder, will reduce 
suicidal ideation in suicidal PTSD outpatients who have nightmares and disturbing dreams. 
 
Secondary Aim: We will estimate the effect size of prazosin in reducing the intensity of nightmares and 
disturbing dreams in suicidal PTSD outpatients with nightmares and disturbing dreams.  
Hypothesis 2.  Prazosin, combined with a SSRI or open label treatment for bipolar disorder, will reduce the 
intensity of nightmares and disturbing dreams in suicidal PTSD outpatients with nightmares and disturbing 
dreams 
 
Tertiary Aims: We will assess the safety of prazosin in the treatment of suicidal PTSD outpatients with 
nightmares and disturbing dreams. We will assess the impact of prazosin in salivary amylase, which is a test of 
systemic adrenergic tone. 
 
Impact on the Field This application has the potential to change providers’ practice in the approach to treating 
PTSD patients with mild-moderate suicidal ideation. Physicians have limited options in pharmacologic 
approaches to reduce suicide risk. The success of prazosin in reducing suicidal ideation in PTSD patients 
would be a novel strategy for a serious public health problem with few known solutions.  


 
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3. RESEARCH STRATEGY 
3.a. Significance 
Suicide is a leading cause of death across all ages and occurs at a rate of 10-11 cases per 100,000 persons 
per year in the USA.{Mann, 2005 819 /id}  It is the third-leading cause of death in the USA in those under 30 
years of age.{Mann, 2005 819 /id} Across the world, the rank order of suicide in global mortality has risen 
between 1990 to 2010 from the 14th to 13th place in cause of death. An estimated 883,000 persons died by 
suicide around the world in 2010. {Lozano, 2012 1364 /id} Most suicides occur in the context of an active 
psychiatric disorder.{Mann, 2005 819 /id}  
 
Suicide rates in the US military have drawn recent scrutiny as it has been revealed that more American service 
men died of suicide in 2012 than died of battle wounds in Afghanistan. Recent expert reports indicate that 
suicide death is indeed higher in US war-veterans as compared with non-military age-matched controls, that 
young men have the highest age-adjusted disproportionate risk, and that Iraq deployment indicates  an 
especially high risk.{Krysinka, 2010 1373 /id;Rozanov, 2012 1376 /id} The standard mortality ratio (SMR) for 
the entire US Army was actually lower than expected until 2008, at which time the SMR exceeded 100, and in 
2009 the SMR was estimated at 115.3 (95% CI 113.5-117.1).{Behavioral and Social Health Outcomes 
Program, 2012 1378 /id} 
 
At least some of this elevated risk among returning war veterans is believed to be explained by post-traumatic 
stress disorder (PTSD), a mental disorder distinguished by reliving traumatic experiences, heightened 
physiologic arousal, and emotional numbing. Again, there is some debate as to whether PTSD is linked to 
excess suicide death, but there is a consensus that it is linked to elevated suicidal ideation and suicide 
attempts, and {Krysinka, 2010 1373 /id;Rozanov, 2012 1376 /id} during Vietnam PTSD represented a 4-fold 
increased risk for suicide.{Rozanov, 2012 1376 /id}  Although >50% of persons with PTSD also meet criteria 
for MDD,{Post, 2011 1372 /id} and while the risk of suicide is further amplified by the presence of major 
depressive disorder (MDD), PTSD is still an independent risk factor for suicide.{Krysinka, 2010 1373 
/id;Rozanov, 2012 1376 /id}  
 
Risk factors for suicide include both unmodifiable and some potentially modifiable factors.{Maris, 2002 1011 
/id;Coryell, 2005 674 /id;Brown, 2000 314 /id}  Examples of unmodifiable factors are advancing age, male 
gender, and Caucasian ethnicity. Potentially modifiable risk factors include symptoms of depression, 
hopelessness, social isolation, active alcohol/substance use, and severe sleep disturbance.  As a predictor, 
insomnia is stronger than a specific suicide plan in predicting near-lethal suicide attempts,{Hall, 1999 801 /id} 
yet sleep disorder is often overlooked in reviews of risk factors for suicide and suicide prevention.{Oquendo, 
1997 1019 /id}  The need to broaden the search for modifiable risk factors is epitomized by this recent 
statement: “nowhere is the lack of proven therapeutic methods greater than in the prevention of suicidal 
behavior.”{Oquendo, 2003 1018 /id} 
 
As we have reviewed elsewhere,{McCall W Vaughn, 2011 1253 /id;McCall, 2010 1193 /id;McCall WV, 2013 
1475 /id} >60 research studies link insomnia to suicidal ideation, suicidal behavior, or suicide death, including 
>40 studies in adults. {Barraclough, 1975 926 /id;Agargun, 1997 805 /id;Agargun, 1997 8 /id;Agargun, 1998 
804 /id;Smith, 2004 799 /id;Bernert, 2005 798 /id;Chellappa, 2007 892 /id;Bernert, 2009 1044 /id;Agargun, 
2007 891 /id;Sjostrom, 2007 752 /id;Goodwin, 2008 1013 /id;Fawcett, 1990 76 /id;Tanskanen, 2001 797 
/id;Fujino, 2005 809 /id;Turvey, 2002 397 /id;Li, 2010 1196 /id;Tishler, 1981 929 /id;Bailly, 2004 933 
/id;Choquet, 1989 808 /id;Choquet, 1993 807 /id;Liu, 2004 928 /id;Vignau, 1997 806 /id;Roberts, 2001 803 
/id;Cukrowicz, 2006 927 /id;Barbe, 2005 931 /id;Goldstein, 2008 930 /id;Nadorff, 2011 1197 /id;Bjerkeset, 2011 
1246 /id;Brower, 2011 1247 /id;Krakow, 2011 1248 /id;Carli, 2011 1249 /id;Fitzgerald, 2011 1254 /id;Agargun, 
2003 828 /id;McCall, 2010 1193 /id}  Insomnia and nightmares were the most common sleep disturbances 
associated with suicide, even after adjusting for severity of depression. Five studies were prospective and 
showed that insomnia was a risk for suicide death. {Fawcett, 1990 76 /id;Tanskanen, 2001 797 /id;Fujino, 2005 809 


 
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/id;Turvey, 2002 397 /id;Bjerkeset, 2011 1246 /id}  The clinical association of insomnia, nightmares, and suicidal 
ideation is paralleled by the physiologic finding that, among depressed outpatients, there is an inverse 
relationship between REM sleep latency and intensity of suicidal ideation.{Agargun, 2003 828 /id} A higher rate 
of depressed patients report unpleasant dreams (39%) as compared with persons who are not depressed 
(14%), even when both the depressed and nondepressed persons share similar life circumstances.{Cartwright, 
1996 1371 /id} Whether the depressing dreams of depressed patients are conceptually the same as the 
nightmares of PTSD is unclear, although it is clear that bad dreams are a risk factor for suicidal ideation, 
independent of a PTSD diagnosis.{Nadorff, 2011 1197 /id}  
 
Selective serotonin reuptake inhibitors (SSRIs) are a mainstay treatment for PTSD, and two of these, sertraline 
and paroxetine, are FDA approved for PTSD.  However, SSRIs do not address all PTSD-symptoms equally 
well. For example, SSRIs are beneficial for symptoms like irritability, and but do less for sleep 
disturbance.{Baker, 2009 1375 /id} Abnormal, elevated activity within the brain’s noradrenergic system is 
believed to play a role in the symptoms of hyper-arousal, such as nightmares, and SSRIs do not directly impact 
the noradrenergic system.{Krystal, 2009 1374 /id} In contrast, FDA-approved, foundational treatments for 
bipolar disorder include lithium, valproic acid, lamotrigine, quetiapine, asenapine, olanzapine, ziprasidone, 
lurasidone ,and the olanzapine-fluoxetine combination.54    
 
Given these facts, we propose that dampening the hyperarousal of PTSD with a blocker of noradrenergic 
receptors, would lead to less problematic nightmares, and culminate in lesser intensity of suicidality thinking.  
 
The American Academy of Sleep Medicine states that the best-practice pharmacologic treatment for 
nightmares is prazosin.{Aurora, 2010 1365 /id} Prazosin is an α1 adrenergic receptor blocker approved for use 
as an antihypertensive. The cardiovascular effects of the drug were fully characterized more than 30 years 
ago.{Colucci, 1982 1369 /id} The drug is slowly titrated starting with 1-mg capsules in order to minimize the risk 
of hypotension, with an average dose of 6-15 mg per day for antihypertensive effects. It generally has no effect 
on heart rate. The most common side effects at these doses are: dizziness 10.3%, headache 7.8%, 
drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%, palpitations 5.3%, and nausea 4.9%.  
 
A number of randomized controlled comparisons of prazosin have proven that prazosin is superior to placebo 
in reducing nightmares. These studies have been primarily in the study of PTSD-related nightmares, with some 
preliminary information suggesting that prazosin may also reduce non-nightmare awakenings in PTSD 
patients.{Thompson, 2008 1367 /id} The most recent large study of prazosin for PTSD-related nightmares in 
American soldiers found that a mean bedtime dose of 15.6 + 6.0 mg in men, and 7.0 + 3.5 mg in women, 
reached over a period of 5-6 weeks, was highly effective, with blood pressure changes, as compared with 
placebo. The most common side effects in this study were lightheadedness (25% versus 20% for placebo) and 
nasal congestion (22% versus 11% for placebo).{Raskind, 2013 1474 /id} 
 
3.b. The theoretical model 
One of the favored models for the etiology of insomnia posits that hyperarousal leads to sleep loss. In other 
words, it is not the sleep machinery that is broken in insomnia, but rather an awake system that is in overdrive 
and is inhibiting the expression of sleep, via an overactive sympathetic nervous system.{Bonnet, 2010 1366 
/id} The hyperarousal model of primary insomnia resonates with hypervigilence and hyperstartle reactions as 
core symptoms of PTSD, and is congruent with the finding that these sympathetic-autonomic symptoms are 
relieved by prazosin, an α1 adrenergic receptor blocker.  Sympathetic-autonomic hyperarousal may be a 
common pathway for insomnia, nightmares, and suicide risk. Therefore, our theoretical model (Figure 1, below) 
is that treatment of nightmares and disturbing dreams with an α1 adrenergic receptor blocker leads to reduced 
intensity of suicidal ideation.     
     
 


 
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Figure 1 
Theoretical Model of Mediation of the Effect of Nightmares on Suicidal Ideation 
Construct 
        Nightmares  
      Reduce the hyperadrenergic state 
Reduce Suicidal Ideation  
Metric/           Disturbing Dream & Nightmare    Prazosin 
Intervention 
Severity Index 
         
 
 
 
                             Scale for Suicide Ideation 
 
 
 
 
 
 
   
The expert workshop on suicide prevention concluded that “randomized controlled trials of 
psychopharmacology are needed in suicide prevention studies.”{Mann, 2005 819 /id} Targeted treatment of 
nightmares may represent one such avenue. We show in our Preliminary Studies that (1) the relationship 
between sleep disturbance and suicidal ideation holds true within the context of depression clinical trials, (2) 
nightmares and disturbing dreams about sleep mediate risk for suicidal ideation in insomniacs.  
 
 
 
3.c. Innovation 
We reported the first clinical trial examining insomnia and suicide risk.{McCall, 2010 1193 /id}  While all 
pharmacologic interventions targeting suicide risk are innovative and important, targeting nightmares as a 
modifiable risk factor for suicidal ideation is especially innovative. Despite dozens of reports of association 
between sleep insomnia and suicide, there are no completed psychopharmacology trials targeting nightmares 
for suicide risk reduction.  Our ongoing study, REST-IT, is the first multi-site intervention for insomnia as a 
means to reduce suicidal ideation in depressed, suicidal, insomniacs. The present proposal, REST-ON-PTSD, 
will target treatment for nightmares and disturbing dreams as a second avenue for reducing suicidal ideation. 
We will test the impact of prazosin on suicidal thinking, and as part of our innovation, we will test whether 
improvement is mediated via reduction in nightmares and disturbing dreams.   
 
3.d. How this project will improve knowledge and practice 
This project is consistent with the August 2010 Report of the National Advisory Mental Health Council’s 
Workgroup, “From Discovery to Cure”, which emphasized the importance of advancing ‘personalized 
treatment’ and ‘preemptive treatment’ (page 3).{Leon, 1999 1256 /id} The emphasis of this Report is evident in 
our proposal as we identify nightmares as a symptom of particular relevance in some, but not all suicidal 
patients, and deserving of targeted intervention, leading to a preemptive reduction in nightmares and disturbing 
dreams, and presumably, suicidal ideation. In Recommendation 2.4.1, the Report also calls for support for 
clinical trials which show that (a) “the adaptation [i.e., intervention] changes a factor [nightmares] that has been 
associated with ….partial response [suicidal ideation], and (b) clear explication of the mechanism by which the 
moderator variable [nightmares] functions to disadvantage… a subgroup [suicidal PTSD outpatients with 
nightmares].  This project meets the needs expressed in the Report. 
 
3.e. Approach 
 
3.e.1  Preliminary Studies 
Relationship between insomnia and suicidal ideation during a 10-week clinical trial   
We consented 60 depressed insomniacs to participate in a study examining the value of adding a hypnotic 
medication to a SSRI.{McCall, 2010 1149 /id}  After a week of baseline assessment, patients received one 
week of open-label fluoxetine (FLX) monotherapy, starting at 20 mg in the morning. Patients still reported 
insomnia after one week of FLX and continued on with 8 more weeks of open label FLX, and were also 
randomized to also receive either the hypnotic eszopiclone (ESZ) 3 mg or placebo given on a double-blind 


 
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basis at bedtime. Patients who still had a 24-item Hamilton Rating Scale for Depression (HRSD24) {Hamilton, 
1960 371 /id} >15 at the end of 4 weeks of randomized treatment could choose to take 40 mg FLX for the next 
4 weeks. Study endpoints included measures of sleep, mood, and suicidal ideation. Insomnia severity was 
graded by the Insomnia Severity Index (ISI).{Bastien, 2001 639 /id} Suicidal ideation was measured with the 
Scale for Suicide Ideation (SSI). {Beck, 1979 18 /id;Beck, 1997 19 /id;Beck, 1999 20 /id} 
 
Participants were 18-70 years old, with either (a) sleep latency > 30 minutes and sleep efficiency < 85% at 
least 4 nights per week. {Edinger, 2004 553 /id}  All participants met a DSM-IV diagnosis of unipolar MDE per 
Structured Clinical Interview for DSM-IV (SCID), {American Psychiatric Association, 1994 286 /id} and a 
HRSD24 score > 20. {Hamilton, 1960 371 /id}  All participants completed one night of baseline polysomnogram 
(PSG) which showed no clinically significant sleep apnea (Apnea/Hypopneas index >15) or Periodic Limb 
Movement Disorder (PLM arousal index >15), following standard measurement procedures described 
elsewhere. {McCall, 2009 1052 /id}    
 
The average age of the randomized sample was 41.5 + 12.5 years, and 66% were women, with 23.2% 
minorities. At baseline, the average HRSD24 score was 27.1 + 3.9, and the average ISI score was 20.7 + 4.0.  
Scale for Suicide Ideation (SSI) scores were analyzed using generalized linear mixed models for repeated 
measures with predictor variables being insomnia (ISI scores), the mood item, and the anhedonia item from 
the HRSD24. Baseline SSI was 3.7 + 5.2, with 55% having a SSI score >1, and 37% of patients having a SSI 
score > 3.  
 
The model with ISI as the predictor for SSI was significant with the regression coefficient corresponding to ISI 
being positive (β=0.055, SE=0.02, p<0.01). Other univariate models found that the depressed mood item was 
also a significant predictor of suicidal ideation (p<0.005), but anhedonia was not a predictor of suicidal ideation 
(p=0.9). A multivariate model simultaneously including both the insomnia and the depressed mood items found 
that both were independent predictors of suicidal ideation (both p<0.05). Our findings confirm that the intensity 
of insomnia predicts intensity of suicidal ideas during a clinical trial of MDE, even after adjusting for depressed 
mood and anhedonia.{McCall, 2010 1193 /id}  
 
Suicidal ideation is mediated by nightmares 
In a new study we have recently reported that the relationship between insomnia and suicide is mediated 
through nightmares and disturbing dreams.{McCall, 2013 1348 /id} We collected cross-sectional data on 50 
adults (mean 55 y.o.) in various stages of active depression or recovery, including 16 psychiatric inpatients and 
23 outpatients and 11 emergency psychiatry patients. Bad dreams were measured with the Disturbing Dreams 
and Nightmare Severity Scale (DDNSI), while the intensity of suicidal ideation was measured with Scale for 
Suicide Ideation (SSI).{Beck, 1979 18 /id;Beck, 1997 19 /id;Beck, 1999 20 /id} DDNSI was significantly related 
to SSI (r=0.60, p<0.001), and in a mediation analysis we found that the relationship between insomnia and 
suicidal ideation was in fact mediated in part by disturbing dreams and nightmares. These results support the 
premise that nightmares mediate insomnia as a risk factor for suicidal ideation in depressed patients. Using a 
receiver operating curve, we also found that emergency psychiatry patients are best discriminated from 
outpatients by a Scale for Suicide Ideation score of 16, and while the outpatients and emergency patients were 
best separated by a Disturbing Dreams and Nightmare Severity Scale score of 6 (p<0.001). 
 
METHODS OF THE PRESENT PROPOSAL 
 
3.e.2. OVERVIEW 
This pilot study will enroll 20 participants with PTSD who have prominent problem with nightmares and a mild-
to-moderate degree of suicidality. Participants will have been on a stable dose of an SSRI or open label 
treatment for bipolar disorder, at a therapeutic dose, for at least one month before baseline assessment. 
Patients with bipolar disorder will have been on a stable dose of FDA-approved treatment for bipolar disorder 


 
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(lithium, valproic acid, lamotrigine, quetiapine, asenapine, olanzapine, ziprasidone, lurasidone or the 
olanzapine-fluoxetine combination). Patients who meet all qualifying requirements at baseline will then be 
randomized in a 1:1 proportion to either prazosin 1 mg at bedtime or placebo. Over the course of 6 weeks, the 
dose of prazosin will be increased as tolerated, while the dose of the SSRI or medication for bipolar disorder is 
held constant.  Participants will be re-assessed weekly for 8 weeks  post-randomization, and only enough 
prazosin will be provided to last until the next visit.  
 
3.e.3.  Participants 
Inclusion criteria:  Participants are 18-65 years of age, including both men and women.  The local project 
manager confirms a DSM-IV-TR diagnosis of PTSD by SCID and by the Clinician Administered PTSD Scale 
(CAPS).{Weathers, 2001 1377 /id} The participant must have a least a moderate degree of nightmare severity, 
as indicated by a Disturbing Dreams and Nightmares Scale score of > 10.{Krakow, 2002 1368 /id}   
Participants must provide their own written, informed consent.  Participants will have a mild-moderate level of 
suicidal ideation defined as a SSI score > 3 but  will not have imminent  intent to commit suicide consistent with 
a Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation level of < 4.{Oquendo, 2003 1018 /id} All 
participants will have been on a stable dose of a SSRI for at least 4 weeks before baseline assessment, at a 
dose equivalent to fluoxetine 20 mg (i.e., sertraline 50 mg, paroxetine 20 mg, etc.), or if the patient has a 
diagnosis of bipolar disorder, they must be on a stable dose of an FDA-approved bipolar medication for at least 
4 weeks (lithium > 300mg daily, valproic acid > 500mg daily, lamotrigine > 50mg daily, quetiapine > 100mg 
daily, asenapine >10mg daily, olanzapine > 5 mg, ziprasidone > 20 mg, lurasidone > 40 mg or the olanzapine-
fluoxetine combination)Other psychotropics, including additional antidepressants, mood stabilizers, 
benzodiazepines, and antipsychotics are permitted as long as no dosage changes are anticipated during the 
randomized treatment with prazosin. A co-morbid diagnosis of major depression is permitted, as well as 
diagnoses of generalized anxiety, panic disorder, social phobia, and obsessive compulsive disorder. 
Participants sexual orientation and gender will be assessed with the following form: 
 
 
1. Do you consider yourself to be:  
 Heterosexual/straight 
 Gay/lesbian/homosexual 
 Bisexual 
 Not sure 
 Decline to state 
  
2. What is your gender? (check all that apply) 
□ Male  
□ Female  
□ Transgender, Male-to-Female (MTF)  
□ Transgender, Female-to-Male (FTM)  
□ Transgender, do not identify as male or female  
□ Not sure 
□ Decline to state 
 
Exclusion criteria: Participants are excluded if they have an active diagnosis of alcohol or substance abuse 
within the last 90 days, active episode of bipolar mania or hypomania, or lifetime diagnosis of schizophrenia 
per the SCID.  Patients with a clinical diagnosis of major neurocognitive disorder or a MMSE < 24, will be 
excluded.  
Additional exclusion criteria  
 
History of sensitivity or allergy to prazosin or quinazolines 


 
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 
History of fainting or syncopal episodes in the last 6 months 
 
History of hypotension 
 
Automatic Blood Pressure readings with systolic BP <90, or diastolic <50, either sitting or standing.  
 
Planned use of sildenafil, tadalafil, or similar erectile dysfunction medications 
 
3.e.4. Treatment 
 
Dose finding during randomized care  
Participants who pass all screening and baseline-week assessments immediately begin one capsule of 
prazosin 1 mg capsule or a placebo. Study drug will be taken at bedtime. Participants will be called by study-
staff after two nights, and if participants do not appreciate an improvement in their disturbing dreams and 
nightmares after 2 nights, then they are allowed to increase their bedtime study drug to two capsules, following 
the design of Raskind et al (Table 1).{Raskind, 2013 1474 /id}  
REST-ON participants return to the clinic each week for routine follow up and assessment of treatment 
response, BP, and adverse events. If the patient and research physician judge the benefit of study drug to be 
inadequate for sleep continuity or nightmares, then the dose may be increased according to the titration 
schedule below. At any point during the medication titration, upward dosages will not be permitted if: systolic 
BP <90, or diastolic <50, either sitting or standing, or if the patient has felt faint or near-syncopal, or has had a 
syncopal attack.  The final research visit will be at the end of the eighth week of randomized treatment, and 
decisions will be finalized at that time of transition to care as usual.  
 
 
 
 
 
 
 
 
Table1 Prazosin dose titration schedule 
 
Week/Day 
Men’s 
Dose 
Women’s 
Dose 
Days 1-2 
1 
1 
Days 3-7 
2 
2 
Week 2 
4 
2 
Week 3 
6 
4 
Week 4 
10 
6 
Week 5 
15 
10 
Week 6 
20 
10 
 
Calculating the number of study-drug capsules dispensed at each visit 
At the time of the first medication dispensation, enough medication will be given to last until the next scheduled 
visit one-week later, plus three more days in case the visit has to be rescheduled. Thus, at the time of the first 
dispensation, participants will receive 2 capsules for the first two nights, then 10 capsules for the next 5 nights 
(in the even that there is inadequate effect from one capsule), then 6 more capsules for three more nights in 
the event that the one-week follow up must be rescheduled. This means that participants will receive 18 
capsules at the time of the first dispensation. 
 
Participants will be asked to bring all remaining study drug to the next visit to estimate adherence and 
medication usage rates. At the time of the second dispensation at the end of week-one of randomized care, 
participants will be eligible to increase the dose according to the titration schedule, with additional capsules  


 
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available in the event that the second follow up visit is later rescheduled up to three days past the one-week 
timeframe. Of course, the number of capsules will be less in the event that (1) a lower dosage was found to be 
effective in treating nightmares in the first week, or (2) there are side effects or hypotension at lower doses.  
 
Randomization and blinding 
Randomization of the 20 participants will be accomplished with blocked randomization: 5 blocks of two patients 
each. Blinding will be single blind, as the placebo we will use will be a generic lactose-filled capsule, and we 
will not attempt to create a matching placebo for the purposes of this pilot study. Our reasons for not making a 
matching placebo are as follows: (1) prazosin is generic and the physical appearance of the prazosin capsules 
may be subject to change, (2) the vast majority of participants will not know what generic prazosin looks like 
and hence will remain blind even if the placebo does not look like generic prazosin, (3) our most important 
outcome measures are self-report measures and hence not subject to investigator bias, (4) from prior 
experience, we have learned that creation of matching placebos would incur a minimum expense of about 
$1000 -  an expenses that is unnecessary for our purposes.  
 
Post-randomization care 
Participants are referred for standard outpatient management at the end of 8 weeks of randomized care. The 
blind will be broken by a psychiatrist who is not involved in the patient’s care during the study, and depending 
upon randomized assignment and the response to treatment under randomized assignment, the patient will 
then have the option of receiving a prazosin prescription at the end of the trial until they re-enter usual care. 
While study drug and doctor’s visits were provided to the participants at no cost during randomization, the cost 
of medications and doctor’s visits will be borne by the participant or their insurance company after they leave 
randomized care. Weekly phone calls will be made after the last visit until the patient has connected with their 
care provider.   
  
 
   
3.e.5. Measurement of Suicidal Ideation and Behavior 
The Scale for Suicide Ideation (SSI) consists of 19 items that evaluate active suicidal desire, specific 
plans for suicide, and passive suicidal desire.{Beck, 1979 18 /id;Beck, 1997 19 /id;Beck, 1999 20 /id} Each 
item is rated by the patient on a 3-point scale from 0 to 2 for a maximum score of 38; a lower score indicates 
less severe suicidal ideation.   The SSI will be collected at baseline and at weeks 1, 2, and 4 of randomized 
treatment, and once by telephone one month after completing randomized treatment.  An SSI score >2 
predicts increased risk for suicide death over a period of years.{Brown, 2000 314 /id} The SSI will be collected 
at the start of each visit, before the participant is seen by the study psychiatrist.  
The Columbia-Suicide Severity Rating Scale (C-SSRS){Oquendo, 2003 1195 /id} is based upon the 
Columbia Classification Algorithm of Suicide Assessment(C-CASA).{Posner, 2007 932 /id} This C-SSRS is 
used by the FDA in clinical trials to assess suicide risk, and includes a structured assessment of past or recent 
suicidal behavior.  It will be administered at each visit by a study psychiatrist blinded to treatment assignment. 
C-CASA has excellent inter-rater reliability in classifying suicide attempts, with an overall intra-class correlation 
coefficient of 0.89. 
 
3.e.6. Measurement of PTSD symptom severity 
The severity of PTSD symptoms will be measured with the PTSD-checklist-specific version (PCL-S). The PCL-
S has been shown to have excellent test-retest, internal consistency, convergent and discriminant validity 
(versus depression), and good sensitivity to change.{Wilkins, 2011 1382 /id} Each participant will complete this 
self-report scale. 
 
3.e.7. Measurement of Depression 
Depression severity will be tracked by the observer-rated 24-item HRSD. {Hamilton, 1960 371 /id;Beck, 1988 


 
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10 
 
337 /id}  The HRSD24 will be administered by same project manager, blind to treatment assignment, at 
baseline and thereafter at weeks 1, 2, and 4 of randomized treatment.  Research staff will demonstrate inter-
rater reliability > 0.85 against a criterion-set of clinical videotapes.   The HRSD24 has three sleep items and 
one suicide item. The HRSD will be recorded as the total score (HRSD24), and will also be analyzed without 
the three sleep items or the suicide item (HRSD20).  The three insomnia items and the suicide item will be 
separately examined. 
 
3.e.8. Measurement of nightmares: The Disturbing Dreams and Nightmare Severity Scale 
The frequency and intensity of disturbing dreams and nightmares will be measured with the Disturbing Dreams 
and Nightmare Severity Scale (DDNSI). This scale is derivative of a simpler Nightmare Frequency 
Questionnaire that had a test-retest weighted kappa>0.85.{Krakow, 2002 813 /id} The revised DDNSI has 
good internal consistency with a Cohen’s alpha >0.80.{Bernert, 2005 798 /id;Bernert, 2009 1044 /id} A DDNSI 
score >10 indicates a clinical nightmare disorder. {Krakow, 2002 1368 /id} Each participant will complete this 
self-report scale.  
 
3.e.9. Measurement of insomnia: The Insomnia Severity Index 
The Insomnia Severity Index (ISI) is a 7-item self-report measure that examines the intensity of distress 
associated with night-time and daytime symptoms of insomnia. It is well validated and we have used it 
extensively in our own research. We have no a prior hypotheses regarding the ISI scale, but include it primarily 
to provide a complete description of sleep symptoms. {Bastien, 2001 639 /id} 
 
3.e.10 Qualitative assessment of nightmares 
The VAS scales are designed to tease out any important differences between depressing dreams as reported 
in depressed patients as opposed to classic PTSD-type nightmares. The VAS scales will be 100 mm long, and 
will be anchored to the left end with the word ‘never’, and anchored on the right end with the word ‘always’. The 
participant will be asked to make a single mark on each of several VAS lines relevant to each of the following 
dimensions of their dreams: 
 
Repetitive sameness of the dream plot from night-to-night 
 
Dream content is related to prior real-life traumatic event 
 
Likelihood of awakening from the dream 
 
Feeling sad during or after the dream 
 
Feeling scared during or after the dream 
 
Feeling angry during or after the dream 
 
3.e.11 Blood pressure measurement 
Blood pressure will be measured at each REST-ON visit after 5 minutes of quiet sitting, followed by 2 minutes 
of standing. BP will be measured with an approved automated BP machine.  
 
3.e.12 Clinical Global Impression – Severity (CGI-S) and Clinical Global  Impression-Improvement (CGI-I) 
The participants’ overall clinical status and response to treatment will be assessed with the CGI-S and CGI-I. 
Both scales will be rated along a 7-point dimension. The CGI-S and CGI-I will be completed by a study 
psychiatrist. The CGI-S will be scored from “Normal” to “Among the most severely ill”, while the CGI-S will be 
scored from “Very much improved” to “very much worse” The CGI-S will be completed at baseline and at all 
randomized treatment visits, while the CGI-I will be completed only during post-randomization treatment visits.  
 
3.e.13. Salivary amylase 
In humans, α-amylase levels are highest in pancreatic and salivary secretions. Increased salivary amylase 
activity is a marker for increased sympathetic  nervous system activity.{Nater, 2009 1466 /id}  We will collect 
samples of saliva at baseline and each follow up visit. The tubes containing the samples will be vortexed, 
centrifuged at 2000xg at 4 C for 10 minutes, and the saliva will be aliquoted and frozen at -80C for future 


 
Version Date: April 6, 2015 
 
 
11 
 
analysis. On the day of the assay, the samples will be thawed and will be centrifuged once more to assure that 
solids are removed from suspension. Salivary amylase activity will be determined using the Amylase Activity 
Assay kit (Sigma). In this kit, amylase activity is determined using a coupled enzymatic assay, which results in 
a colorimetric 
(405nm) 
product, 
proportional to 
the amount of 
substrate, 
ethylidene-pNP-
G7, cleaved by 
the amylase. 
One unit is the 
amount of 
amylase needed 
to generate 1.0 
umole of p-
nitrophenol per 
minute at 25 ₒC.  
 
 
Table 2 – Order 
of Assessments 
for REST-ON-
PTSD 
 
Baseline of REST-
ON 
Follow up Visits in REST-ON 
Evaluation to sign consent 
1 
 
Consent 
2 
 
Registration 
3 
 
Demographics 
                 4 
 
 
Visual Analogue scales for nightmare descriptors 
                 5 
 
Vitals with orthostatic BP 
                 6 
1 
PCL-S 
7 
2 
SCID and CAPS 
8 
 
Hamilton Rating Scale for Depression (HRSD) 
9 
7 
Beck Suicide Severity Index (SSI) 
10 
3 
Columbia-Suicide Severity Rating Scale  
11 
4 
Disturbing Dreams and Nightmare Severity Index 
12 
5 
Insomnia Severity Index 
13 
6 
Concomitant Medications 
14 
8 
CGI-S  
15 
9 
CGI-I 
16 
                        10 
Adverse events  
 
11 
Encounter Disposition Form- Baseline/Baseline Follow-up 
17 
12 
Study Medication Accountability  
 
13 
Salivary amylase 
18 
14 
 
Baseline of REST-
ON 
Follow up Visits in REST-ON 
Evaluation to sign consent 
1 
 
Consent 
2 
 
Registration 
3 
 
Demographics 
                 4 
 
 
Visual Analogue scales for nightmare descriptors 
                 5 
 
Vitals with orthostatic BP 
                 6 
1 
PCL-S 
7 
2 
SCID and CAPS 
8 
 
Hamilton Rating Scale for Depression (HRSD) 
9 
7 


 
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12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.e.14 Adverse events 
The study psychiatrist will elicit spontaneous reports of adverse events (AEs) and serious adverse events 
(SAEs) at each treatment visit. In the unexpected event of potentially self-injurious behavior, the behavior will 
be coded as a suicide attempt according to the Columbia-Suicide Severity Rating Scale (C-SSRS){Oquendo, 
2003 1195 /id}, which in turn is based upon the Columbia Classification Algorithm of Suicide Assessment(C-
CASA) {Posner, 2007 932 /id}. The C-CASA will be completed by the study psychiatrist and has excellent inter-
rater reliability in classifying suicide attempts, with an overall intra-class correlation coefficient of 0.89. 
 
 
 
STATISTICAL CONSIDERATIONS 
 
3.f. Statistical Analyses 
Outcome measures will be collected at baseline and weekly for the 8 weeks of participation.   Repeated 
measures models will be used to assess the changes over time in suicidal ideation and intensity of nightmares 
Beck Suicide Severity Index (SSI) 
10 
3 
Columbia-Suicide Severity Rating Scale  
11 
4 
Disturbing Dreams and Nightmare Severity Index 
12 
5 
Insomnia Severity Index 
13 
6 
Concomitant Medications 
14 
8 
CGI-S  
15 
9 
CGI-I 
16 
                        10 
Adverse events  
 
11 
Encounter Disposition Form- Baseline/Baseline Follow-up 
17 
12 
Study Medication Accountability  
 
13 
Salivary amylase 
18 
14 


 
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13 
 
and disturbing dreams.  These models will be used to obtain estimates of the treatment effects (the changes in 
the outcome measure from baseline to end of randomization), estimates of the variability of the outcome 
measures at each time adjusted for baseline measures, and estimates of the within patient correlations over 
time.  These estimates will be used in the design of a subsequent adequately-powered randomized clinical 
trial.  Regression diagnostics, residual plots, and exploratory analyses will be done to find appropriate 
transformations to satisfy the 1) linearity, 2) homogeneity of variances, and 3) normality assumptions.  While 
we assume compound symmetry for the correlation among repeated measures, we will also consider other 
covariance patterns. We will also assess the correlation amongst all the measures collected over time. While 
our sample size is small, we will also use a mediation analysis to determine the degree to which nightmares 
are responsible for (or mediate) the changes in suicidal ideation.{Baron, 1986 1126 /id}-{MacKinnon, 2004 
1260 /id;Efron, 1979 1261 /id}    
 
3.g. Potential Pitfalls and Alternative Solutions 
 
 
Alternatives to Prazosin: Clonidine has been reported to have some effect in reducing nightmares but is 
generally described as less effective than prazosin. In contrast, prazosin is the best-practice pharmacologic 
treatment for nightmares is prazosin.{Aurora, 2010 1365 /id} Some psychotherapies that hold promise for 
the treatment of nightmares, notably imagery rehearsal therapy.{Hansen, 2013 1370 /id} However, this 
approach is unlikely to be adopted by most physicians managing PTSD. This approach may well prove to 
be useful but deserves its own separate line of inquiry. 
 
Conclusions and Future Directions 
Results from this project will provide a first clue as to whether a SSRI-prazosin combination treatment is a 
candidate treatment for reducing the intensity of suicidal ideation in PTSD patients. If so, it opens the possibility 
that other forms of nightmare treatment (i.e., imagery rehearsal therapy) may also have benefit. This project 
will also provide support for hypothetical mechanisms explaining the association between nightmares and 
suicidal ideation. 


 
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14 
 
6. PROTECTION OF HUMAN SUBJECTS 
 
6.a 
Subject selection procedures 
 
The subject selection features of REST-ON-PTSD are intended to:  (1) yield a sample with PTSD associated 
with suicidality, and (2) exclude patients who might be harmed by exposure to psychotropics, including 
pregnant women. Three procedures are used to assure participant safety at the baseline assessment: the Mini 
Mental State Exam (MMSE),{Folstein, 1975 78 /id} a pregnancy test for women of conception age, and a 
baseline Columbia- Suicide Severity Rating Scale (C-SSRS) score. 
 
 A MMSE score < 24 is statistically abnormal at any age and is consistent with global cognitive deficits such as 
seen in dementia.{Crum, 1993 313 /id}   
 
All women of child bearing age will complete a urine pregnancy test at the first face to face visit. Persons 
excluded because of overly intense suicidal ideation (C-SSRS suicidal ideation score >3) will be evaluated for 
safety and perhaps the need for psychiatric hospitalization. 
 
The additional subject exclusion factors are: 
 
History of sensitivity or allergy to prazosin or quinazolines 
 
History of fainting or syncopal episodes in the last 6 months 
 
History of hypotension 
 
Automatic Blood Pressure readings with systolic BP <90, or diastolic <50, either sitting or standing.  
 
Planned use of sildenafil, tadalafil, or similar erectile dysfunction medication 
 
 
6.b.  
Recruitment and Consent Procedures  
 
 
6.b.1. Recruitment     
 
6.b.2.  Consent procedures  The Project Manager will describe the overall study design, and will detail the 
time commitment required from the participant. The project manager provides a copy of the consent form, 
allowing enough time for the participant to read the consent form and ask questions, and sign the consent 
form. We will assure the capacity of each patient to understand the risks and benefits of participation by 
assessing each participant with the Evaluation to Sign Consent (ESC). The ESC was developed by Love in 
1988 (unpublished; as cited in Deronzo, Conley, & Love, 1998).{Deronzo, 1998 1446 /id}  The ESC assesses 
the factual understanding of subjects, is composed of five items, and can be adapted to any research design.  
 
6.c. 
Potential risks 
The risks of participating in this project are related to prazosin. The primary risk from prazosin is orthostatic 
hypotension. Prazosin is an α1 adrenergic receptor blocker approved for use as an antihypertensive. The 
cardiovascular effects of the drug were fully characterized more than 30 years ago.{Colucci, 1982 1369 /id} It 
generally has no effect on heart rate. The most common side effects as these doses in hypertensive patients 
are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%, palpitations 
5.3%, and nausea 4.9%. The most common side effects (>5%) when given to patients with PTSD are:  
lightheadedness 25%, nasal congestion 22%, and palpitations (6%).{Raskind, 2013 1474 /id} We will manage 
the risk of hypotension by excluding participants with a history of fainting or syncopal episodes in the last 6 
months, history of hypotension, or automatic Blood Pressure readings with systolic BP <90, or diastolic <50, 
either sitting or standing. The risk of side effects might be severe if the patient took an intentional overdose, 


 
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15 
 
although limited reports of overdose suggest a low acute toxicity.{Lip, 1995 1447 /id} 
 
 
6.d. 
Safeguards 
 
 
The Star*D trial was among the first NIH-sponsored trials to follow the 2001 NIH guidelines for studies which 
included patients at risk of suicide. http://www.nimh.nih.gov/health/topics/suicide-prevention/issues-to-
consider-in-intervention-research-with-persons-at-high-risk-for-suicidality.shtml  {Nierenberg, 2004 924 /id}  
The guidelines have several stipulations, and we have responded accordingly: 
1) “Provide specific inclusion criteria and their measurement with regards to suicidality” 
 
Response: Patients included in the study will have a Scale for Suicidal Ideation (SSI) scores >3 but with C-
SSRS suicidal ideation scores of <3. This range defines patients with mild and moderate suicidal 
ideation, but with no intent to commit suicide. This inclusion range for suicidal ideation is consistent with 
prior clinical trials of suicidal patients.  {Brown, 2005 1468 /id;Grunebaum, 2012 1470 /id} 
“Specify the criteria for withdrawal from the treatment trial with regard to increased suicidality, increased 
related symptoms, lack of treatment response, and treatment side effects, and what alternative treatment 
or referral will be offered.” 
 
Response: The decision to withdraw the participant from research treatment will be based upon either the 
participant’s view or the research psychiatrist’s opinion that the patient is experiencing severe suffering, is 
at imminent risk for suicide, or is functionally decompensating.  The clinician’s opinion will be informed on 
the basis of the DDNSI, the PCL-S, and the C-SSRS, but the decision to withdraw a participant will be 
based upon a combination of psychometrics along with global clinical judgment.  If a participant is 
withdrawn from the study, then he or she will be offered care-as-usual, or hospitalization if necessary.   
 
2) “Consider and establish criteria for hospitalization, where the hospitalization will take place, and the 
procedures within the hospital that provide additional safety” 
 
Response: Hospitalization will be offered if the patient is judged at imminent risk of suicide, is functionally 
decompensated, or needs specialized treatment outside of the protocol (such as ECT), according to the 
global clinical judgment of the study psychiatrist. Hospitalization would take place in the inpatient units of 
Georgia Regents Medical Center, or East Central Regional Hospital, or similar regional facility. 
 
 
3) “Describe procedures in the protocol for managing increases in suicidality, and how research staff is 
trained and available to provide clinical management” 
 
Response: Managing increases in suicidality is predicated upon detection of such increases. Although we 
proposed to examine participants weekly, we recognize that suicidal ideation may emerge suddenly and 
unpredictably. Therefore, research staff will make at least one mid-week phone call to each participant for 
the first 2 weeks to check on their well-being and assure them that the study staff is available. At each 
scheduled study visit, the protocol will quantify suicidality 2 ways. First, the participant will complete the  


 
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16 
 
Scale for Suicide Ideation. This information flows from the research staff to study psychiatrists at the time 
of the visit. Second, the research psychiatrist will administer the Columbia Suicide Severity Rating Scale 
(C-SSRS), allowing for a thorough review for the presence of any self-injurious behavior since the last visit 
or the development of any preparatory suicidal planning, as categorized by the C-SSRS.{Oquendo, 2003 
1195 /id}   Patients judged by the study psychiatrist to be at increased risk of suicide will have an increased 
frequency of research visits, have smaller supplies of research medication, or may be withdrawn from the 
study and possibly hospitalized. 
 
4) “Have a procedure for emergency coverage that is clearly understood by the clinical research staff, study 
participants, and families” 
 
Response: At the time of consent, participants will receive clear instructions for how to reach study staff 
during the daytime, and how to access after-hours coverage as provided through each site. Psychiatry 
residents-in–training who receive emergency calls from participants after-hours will be instructed to call the 
local principal investigator immediately, regardless of the time of day. The PI or designated co-I will be 
continuously available to the respective on-call residents to guide crisis management and assess for the 
primary suicidal endpoints, if necessary by phone. 
 
5) “As part of the consent process, consider having explicit discussion with relevant family members, 
guardians, or friends that includes the risks inherent when study participants are suicidal (risk of death, side 
effects of treatment)” 
 
Response: Involvement of the participant’s family will be encouraged, starting by asking potential 
participants to bring their families to the first face-to-face screening visit.  
 
6) “Consider and identify the limits of confidentiality with respect to suicidality, as well as other circumstances” 
 
Response: When a participant has emergent suicidality defined as an increase of 6-points (one standard 
deviation of SSI scores in Dr McCall’s outpatients), we will inform the participant of our intent to share this 
with the relevant family, and the consent form will reflect this. 
 
7) “Consider the impact of suicidality on the study participant’s capacity to give informed consent” 
 
Response: Consent will be obtained only from persons who normally would not meet criteria for emergent 
psychiatric hospitalization, i.e., C-SSRS suicidal ideation score < 4.  
 
8) “Determine whether additional safeguards are needed to ensure the safety of the study participants” 
 
Response: No additional safeguards needed 
 
9) “Consider situations in which a trial would be terminated prematurely” 
 
Response: As this is a pilot study with only 20 participants, we have no statistical endpoints for early 
termination of the study. However, the trial would be terminated prematurely only if the Medical Monitor 
determined that there was a systematic increase in risk, according to the Data Safety Monitoring Plan, 


 
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17 
 
below. 
 
6.e. 
Data Safety Monitoring Plan 
 
Dr. Brian Miller of the Department of Psychiatry and Health Behavior will serve as in the internal 
Medical Monitor for this study. Dr. Miller will have no other relationship with this study or any other study on 
which Dr. McCall is the principal investigator.  All serious adverse events (SAEs) will be reported immediately 
to Dr. Miller. Otherwise Dr Miller will review the case report forms for the Scale for Suicide Ideation, vital signs, 
and AEs after the third and sixth patients are completed.  
 
6.f. 
Confidentiality of subjects’ responses 
 
All participants are assured of confidentiality of the information obtained during their participation, with the 
exception of the expression of imminent suicidality. We will make every attempt to secure the participant’s 
permission to share a high risk of suicide with the participant’s family. All participants are assigned a subject 
number for the internal purposes of the research, and the patients’ identity on Case Report Forms is indicated 
only by their subject number and initials.  Case Report Forms are locked in the research offices of the principal 
investigators. Original source documents relevant to the delivery of clinical care are kept in the patient file 
office of the Department of Psychiatry and Health Behavior which is continuously staffed or locked, and these 
clinic files do not circulate beyond the Department. Participants will be advised that confidentiality could be 
breached in the event of an audit by the parent institution or the sponsor. 
 
 6.g. 
Research procedures   
Risks of teratogenicity will be limited by obtaining a pregnancy test from each women of childbearing potential 
before exposure to the first week of outpatient treatment and by counseling on the need for birth control. 
Pregnancy will be an exclusion criterion for study entry or for continued study participation. The research 
procedures include weekly assessment of suicidal ideation (the SSI and C-SSRS) and side effects related to 
medication. A study psychiatrist will examine each participant weekly during routine study visits and will 
clinically assess the risk of suicide. Participants judged to be at imminent risk of suicide will be managed as 
described above. Participants will only be given enough study medication to last until their next research visit.  
The principal investigators or designated co-Is will be available 24-hours per day by phone and beeper in the 
event of a participant’s medical emergency for the entire duration of the trial. Subjects will be provided with a 
business sized card to carry in their wallets. This card will include contact information for the physicians and 
staff members. In addition, it will include a 24-hour number to call in case of emergency. This number will put 
the subject in touch with the Resident-On-Call provided by the Departments of Psychiatry and Health Behavior. 
The Resident will be able to put the subject in touch with the PI if needed.  
 
 
6.h. 
Risk/benefit ratio 
 
6.h.1.  Risks  
Emergent suicidal ideation or behavior is a risk of mental disorders. We have operationalized emergent 
suicidal ideation as a 6-point increase. These risks will be discussed with the participant as part of the consent 
process. The risk of a fatal outcome from a suicide attempt is mitigated by limiting access to study medication. 
The likelihood of side effects related to prazosin is primarily hypotension and fainting. The risk of side effects 
might be severe if the patient took an intentional overdose, although limited reports of overdose suggest a low 
acute toxicity.{Lip, 1995 1447 /id}  Mechanisms will be in place to mitigate suicide risk. 


 
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18 
 
 
6.h.2. Benefits   
Benefits of participation include nightmare treatment at no cost to the patient. Treatment of nightmares should 
bring lessened psychic distress and perhaps lessen suicidal risk. The frequency and intensity of patient 
monitoring for suicidal thinking is greater than that seen in routine care, and is an additional benefit. The overall 
benefit/risk ratio in this clinical trial is highly favorable, with a large potential impact upon public health policy in 
the management of depression with insomnia. 
 
6.i Gender and minority recruitment   
It is expected that women will constitute approximately 50% of the sample, since women represent both the 
majority of persons suffering with either depression or insomnia.   Minorities, chiefly African-Americans, will 
comprise approximately 15% of the total sample.  


 
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19 
 
 
 6.j Targeted/Planned Enrollment 
Table 3. 
Targeted/Planned Enrollment 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
Not Hispanic or Latino 
12 
6
18 
Ethnic Category Total of All Subjects* 
12 
6
18 
Racial Categories 
 
American Indian/Alaska Native 
0 
0
0 
Asian 
0 
0
0 
Native Hawaiian or Other Pacific Islander  
0 
0
0 
Black or African American  
2 
0
2 
White 
12 
6
18 
Racial Categories: Total of All Subjects * 
14 
6
20 
 
6.k. 
Children and adolescents    
Children under 18 years old will be excluded since the safety of prazosin for nightmares has not been 
examined. 
 
7. Vertebrate Animals   
N/A 
 
 


 
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20