Suvorexant and Trauma Related Insomnia

Disturbed sleep is one of the most common and distressing responses to exposure to severe
trauma and can persist in many of those affected with and without accompanying posttraumatic
stress disorder (PTSD). Insomnia is a risk factor for many of the conditions that are
prevalent in trauma-exposed populations including PTSD, depression, and physical health
conditions such as obesity, and cardiovascular disease. Trauma-related insomnia (TRI) is not
typically differentiated in studies characterizing insomnia and its treatment, and insomnia
accompanying PTSD has been shown to be relatively refractory to the treatments that are
established for PTSD. Thus treatment of TRI presents an unmet need that has implications for
the large and growing groups of people exposed to trauma in terms of relieving distress and
preventing further psychiatric and medical morbidity.

Most of the data on TRI comes from research on populations with PTSD. Difficulty initiating
and maintaining sleep is designated as one of the heightened arousal symptoms of PTSD in the
DSM. Sleep studies have suggested increased wake after sleep onset (WASO), reduced slow wave
sleep (SWS) in some PTSD populations and fragmented rapid eye movement (REM) sleep when PTSD
is developing, and during its more acute stages. Suvorexant is a first in class orexin
antagonist and is approved by the FDA for the indication of insomnia. Orexin antagonists
dampen the activity of a specific arousal enhancing system in the brain during sleep. In
rodent models suvorexant has been shown to enhance, and in healthy humans, to not affect slow
wave and REM activity (in contrast with traditional hypnotics which can diminish both).
Reducing arousal during sleep while reducing WASO and maintaining REM and slow wave sleep is
a promising profile for the treatment of TRI. We are therefore proposing a placebo controlled
evaluation to assess the efficacy of suvorexant for treating TRI with and without PTSD and
its tolerability in these populations. We will include polysomnography (PSG) in order to have
objective sleep outcomes and probe potential mechanisms and biomarkers predicting response.
The proposed study will meet the objective below and test the following hypotheses:

Objective. To evaluate the efficacy of suvorexant for participants that meet criteria for
insomnia and who identify a severely threatening event (DSM criterion A trauma) as a
precipitant or a factor that significantly exacerbated their sleep disturbance.

The investigators hypothesize that suvorexant will improve subjective and objective indices
of sleep disturbance; specifically, our primary outcome the polysomnographic (PSG) measure of
sleep efficiency will be increased in the group receiving suvorexant compared with the group
receiving placebo.

The effect of suvorexant versus placebo on the secondary outcome measures of the Insomnia
Severity Index (ISI) scores and co-occurring symptoms of PTSD will also be evaluated.

Exploratory analyses will include comparison of response patterns among those with versus
without significant symptoms of PTSD and relationships between increased in slow wave and
rapid eye movement (REM) sleep and improvement in ISI scores and PTSD symptoms.

Adverse experiences and the tolerability of suvorexant in the recruited population with TRI
will also be evaluated.

Inclusion Criteria:

- Physically healthy adults age 18-55 who meet DSM-5 criteria for insomnia and Criterion
A (exposure to a traumatic event) for PTSD. The index trauma must have occurred within
the past 5 years and at least 3 months before enrolling, and insomnia symptoms must
have started or worsened after the exposure to the index trauma

Exclusion Criteria:

- Psychiatric disorders other than insomnia, PTSD and specific phobias; including
bipolar and psychotic disorders and meeting criteria for DSM-5 moderate alcohol or
drug use disorders within the past year.

- Diagnosis of a sleep disorder other than insomnia including PSG findings of
apnea/hypopnea or periodic limb movement indices > 10/hour;

- Medical conditions that require consistent use of medication or compromise sleep;

- History of moderate to severe traumatic brain injury or mild traumatic brain injury
with ongoing post-concussive symptoms;

- Suicidal ideation with intent to act or with specific plan and intent in the past 6
months (Type 4 - 5 ideation on the Columbia Suicide Severity Rating Scale) or a
concerning history of prior suicidal behavior.

- Caffeine use exceeding 5 cups of coffee per day or its equivalent;

- Habitual bedtimes after 3 AM, habitual rise times after 10 AM, or habitual napping >
1hour/day;

- Pregnancy or breastfeeding, or expecting to conceive while in study;

- Positive urine toxicology.