Suvorexant and Sleep's Benefits to Therapeutic Exposure for Posttraumatic Stress Disorder

Cognitive behavioral therapies (CBT) that include exposure to trauma memories are considered
first line treatments for PTSD. However, approximately 1/3 of patients who complete CBT for
PTSD do not achieve remission, and hyperarousal symptoms including sleep disturbances are
less responsive to CBT than other PTSD symptoms. Despite these limitations, CBT outcomes are
generally superior to outcomes of pharmacotherapy. It is, therefore, imperative to identify
strategies to improve effectiveness of treatments for PTSD, particularly hyperarousal
symptoms.

Disturbed sleep is common in PTSD. Studies of PTSD and anxiety and mood disorders have shown
that impaired sleep before psychotherapy predicted less favorable responses. Sleep has been
implicated in learning processes that are a key to adaptive processing of trauma memories
such as extinction learning and generalization of extinction. Our recent PTSD study showed
that preserved slow-wave sleep (SWS), less increase in rapid-eye-movement (REM) density, and
reduced wake after sleep onset (WASO) during sleep following an evening session of written
narrative exposure (WNE: writing about one's traumatic experience) was associated with
greater PTSD symptom reduction. These findings suggest that increased nocturnal arousal
compromises sleep's benefits to emotional processing of trauma memories. Identifying
strategies to reduce nocturnal arousal and promote sleep characteristics associated with
emotional adaptation could enhance PTSD treatment outcomes.

Orexins are neuropeptides implicated in regulating both sleep/wakefulness and emotional
behaviors, including anxiety. Inhibiting the orexin system promoted slow-wave patterns and
reduced wake in animal models. The first orexin receptor antagonist (suvorexant) was recently
approved for treatment of insomnia. Suvorexant reduced WASO and latency to persistent sleep
and increased SWS and REM sleep in humans with insomnia. In addition, administrations of
orexin-A increased anxiety-like behaviors in rodents, and administrations of an orexin
receptor-1 antagonist to mice facilitated extinction of conditioned fear, an animal model of
recovery from PTSD and anxiety disorders.

Objective: To examine effects of blocking the orexin system with suvorexant after WNE on
sleep, PTSD symptoms, and intersession habituation.

The investigators will utilize the WNE paradigm in which participants with PTSD write about
their traumatic experiences in the evening and morning sessions with intervening sleep.
Suvorexant or placebo will be administered after the evening WNE, and sleep will be recorded.

The investigators hypothesize that 1) Suvorexant will promote the sleep characteristics that
have been associated with more favorable treatment outcomes and emotional adaptation (e.g.,
increased SWS and REM sleep, reduced WASO) compared with placebo; 2) Participants given
suvorexant will have greater PTSD symptom reduction and intersession habituation indexed by
reduction of maximum pulse rate compared with participants given placebo; and 3) The greater
PTSD symptom reduction and intersession habituation in the suvorexant group will be accounted
for by effects of the medication on sleep.

Inclusion Criteria:

- Adult men and women (age 18 or older) who meet the Diagnostic and Statistical Manual of
Mental Disorders - Fifth Edition (DSM-5) criteria for PTSD.

Exclusion Criteria:

- Medical or psychiatric conditions that require consistent use of medication that
affects sleep or psychiatric symptoms, except for hormonal contraceptives

- Any persistent medical condition that affects sleep

- Inability to remember most details of the index event

- Diagnosis of a sleep disorder other than insomnia including polysomnography findings
of apnea/hypopnea index > 10/hour

- Consumption of more caffeine than 5 cups of coffee/day equivalent

- Smoking > 20 cigarettes/day

- Habitual bedtimes after 3AM, habitual rise times after 10AM, or average napping > 2
hour/day in a given week

- Moderate or severe alcohol use disorder within the past 6 months or moderate or severe
drug use disorder within the past year

- Positive urine toxicology for illicit drugs including cannabis

- A history of psychotic disorders or bipolar disorder

- Current depression with history of recurrent depression that precedes exposure to a
traumatic event

- 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 (C-SSRS)] or
history of a suicide attempt

- Completion of exposure-based therapy targeting the index trauma

- Pregnancy or breast feeding

- Known sensitivity or allergy to an orexin receptor antagonist

- Limited ability to read or write English.