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NCT Number: NCT05453162

Circadian Influence on Prolonged Exposure Therapy for PTSD

Proposed research will examine time-of-day effects on trauma-related fear extinction using Prolonged Exposure Therapy (PE) telemedicine for Posttraumatic Stress Disorder (PTSD) in the National Center for PTSD (NCPTSD). The primary mechanistic outcome measure will be change in psychophysiological reactivity to script-driven imagery (SDI-PR) measured, in person, at pre-treatment, after 5 PE sessions (mid-treatment), and after all 10 PE sessions (post-treatment). A secondary mechanistic outcome will be session-to-session reduction in peak subjective units of distress (SUDS) ratings to imaginal exposures. The primary clinical outcome will be change in Clinican Administered PTSD Scale (CAPS-5) severity score; a secondary clinical outcome will be session-to-session reduction in self-reported PTSD symptoms using the PTSD checklist (PCL-5). Participants meeting inclusion criteria (described below) will be randomized to either PE sessions that begin from 07:00 to a time no later than 2 hours past a participant's customary rise time, or to the last treatment session of the day beginning at 16:00 or later (26 per arm). Participants will complete daily at-home imaginal-exposure homework within the same time frame as their PE sessions are scheduled, i.e., within 2 hours of awakening for morning (AM) group and between 16:00 and 2 hours before bedtime for late afternoon (PM) group.

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Key information

Conditions

PTSD Mental Disorders Stress Disorders, Post-Traumatic Stress Disorders, Traumatic Trauma and Stressor Related Disorders

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

VA Boston Healthcare System

Boston, Massachusetts, 02130-4817, United States

About this study

Proposed research will examine time-of-day effects on trauma-related fear extinction using PE therapy for PTSD in the National Center for PTSD (NCPTSD). The primary mechanistic outcome measure will be change in SDI-PR; a secondary mechanistic outcome will be session-to-session reduction in peak SUDS ratings to imaginal exposures. The primary clinical outcome will be change in CAPS-5 severity score; a secondary clinical outcome will be session-to-session reduction in self-reported PTSD symptoms (PCL-5). Participants meeting inclusion criteria (described below) will be randomized to either PE sessions that begin from 07:00 to a time no later than 2 hours past a participant's customary rise time, or to the last treatment session of the day beginning at 16:00 or later. Participants will complete daily at-home imaginal-exposure homework within the same time frame as their PE sessions are scheduled (i.e., within 2 hours of awakening for morning group and between 16:00 and 2 hours before bedtime for late afternoon group). The assessment schedule will be identical for all participants. Participants who meet study inclusion criteria at screening will first begin a 7-day, pre-study sleep-monitoring period with wrist actigraphy, sleep diaries and completion of a diurnal profile of salivary cortisol levels. Trauma-related fear will be assessed using the standard SDI procedures detailed below at pre-treatment, after 5 PE sessions (mid-treatment), and after all 10 PE sessions (post-treatment). The CAPS-5 will be administered at these same times. PCL-5 measurements will be obtained at each treatment session and SUDs will be obtained during all treatment sessions that include imaginal exposure (sessions 3-8). All SDI sessions will be carried out at a standardized time of day in the late-afternoon (15:00-17:00). PE treatment will be administered at a targeted rate of once per week. At each PE and assessment session, pre-session saliva samples will be obtained for cortisol measurement and normalized using the diurnal profile of cortisol obtained during the sleep-assessment week. Participants will wear the wrist actigraph and complete sleep diaries throughout PE. The diurnal cortisol profile will be repeated at the post-treatment assessment.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • a diagnosis of PTSD as defined by DSM-5, with a minimum CAPS severity score of 26, a minimum PCL-5 score of 31, or a score of 2 or above on CAPS-5 Item B2 (concerning distressing dreams)
  • interest in starting a course of PE
  • availability for appointments at that will either begin from 07:00 to a time no longer than 2 hours past their customary rise time, or to the last treatment session of the day beginning at 16:00 or later
  • Age range of 18-70
  • A Morningness-Eveningness Questionnaire (MEQ) score above 25.
  • Non-exclusionary psychotropic medications must have been stable for 3 weeks prior to Screening/Assessment with intention to remain stable throughout participation.

Exclusion criteria

  • current or past history of bipolar I disorder, schizophrenic or other psychotic disorders,
  • current organic brain disorder including moderate to severe traumatic brain injury
  • factitious disorder or malingering
  • pregnant or planning to become pregnant in the next four months at time of screening [if a participant does become pregnant during study procedures, the situation will be reviewed on a case-by-case basis and the participant's wishes will be considered in deciding whether the participant will continue with the study or withdraw.]
  • current moderate or severe substance use disorder with symptoms present within the past three months
  • diagnosed moderate to severe sleep apnea, narcolepsy, periodic limb movement, or restless legs syndrome that result in daytime sleepiness indicated by Epworth Sleepiness Scale (ESS) above 10
  • active risk of harm to self or others
  • evidence of clinically significant hepatic or renal disease or any other acute or unstable medical condition that might interfere with safe conduct of the study
  • current participation in trauma-focused cognitive-behavioral therapy (e.g., Cognitive Processing Therapy, Written Exposure Therapy, Eye Movement Desensitization and Reprocessing Therapy)
  • prior treatment with an adequate dose of PE (i.e., 8 or more sessions) to the traumatic event that would be the index trauma for treatment in the study
  • having no memory of their traumatic event
  • daily use of benzodiazepines
  • methadone or suboxone maintenance therapy for past opioid addiction
  • diagnosis of Cushing's disease, Addison's disease or use of medications that target cortisol directly such as those used to treat Cushing's disease [ketoconazole, mitotane (Lysodren), metyrapone (Metopirone), and Mifepristone (Korlym, Mifeprex)], those used to treat Addison's disease [Hydrocortisone (Cortef), prednisone or methylprednisolone], as well as cortisone or dexamethasone.
  • persons who would habitually awaken so early that more than 2 h would elapse before a morning PE session could occur; or those who engage in habitual shiftwork or transmeridian travel

Treatment and study plan

Prolonged Exposure Therapy for Posttraumatic Stress Disorder

Behavioral

Manualized procedures deliver ten 90-minute sessions targeted to occur weekly and administered via tele-health with the same study therapist. Session 1 will focus on psychoeducation. Session 2 involves construction of the in vivo exposure hierarchy. Sessions 3-10 focus on in-session imaginal exposures to the worst trauma memory for 45-60 min followed by 15-20 min of processing the imaginal exposure. For homework, participants will be instructed to confront situations on their hierarchy on a daily basis using recording of their imaginal exposure. Subjective Units of Distress (SUDS) ratings will be taken throughout imaginal exposure exercises.

Primary outcomes

  1. Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome

    Time frame: Between days -7 to -1, Baseline

    This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.

  2. Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome

    Time frame: Between days 29-34, mid-treatment

    This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.

  3. Psychophysiological reactivity to script-driven imagery (SDI-PR: )Primary Mechanistic Outcome

    Time frame: Between days 64-71, post-treatment

    This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.

  4. Clinician-Administered PTSD scale for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition (CAPS-5): Primary Clinical Outcome

    Time frame: Between days -7 to -1, Baseline

    This primary clinical outcome is the gold standard clinical interview for assessing PTSD severity. In CAPS-5, each of the 20 symptoms of PTSD is rated on a 5-point severity scale ranging from 0 (absent) to 4 (extreme). Total scores range from 0 to 80.

  5. CAPS-5: Primary Clinical Outcome

    Time frame: Between days 29-34, mid-treatment

    This primary clinical outcome is the gold standard clinical interview for assessing PTSD severity. In CAPS-5, each of the 20 symptoms of PTSD is rated on a 5-point severity scale ranging from 0 (absent) to 4 (extreme). Total scores range from 0 to 80.

  6. CAPS-5: Primary Clinical Outcome

    Time frame: Between days 64-71, post-treatment

    This primary clinical outcome is the gold standard clinical interview for assessing PTSD severity. In CAPS-5, each of the 20 symptoms of PTSD is rated on a 5-point severity scale ranging from 0 (absent) to 4 (extreme). Total scores range from 0 to 80.

Secondary outcomes

  1. Subjective Units of Distress (SUDS): Secondary Mechanistic Outcome

    Time frame: Day 14 Peak SUDS during PE therapy session 3

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  2. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 21 Peak SUDS during PE therapy session 4

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  3. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 28 Peak SUDS during PE therapy session 5

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  4. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 35 Peak SUDS during PE therapy session 6

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  5. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 42 Peak SUDS during PE therapy session 7

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  6. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 49 Peak SUDS during PE therapy session 8

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  7. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 56 Peak SUDS during PE therapy session 9

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  8. SUDS: Secondary Mechanistic Outcome

    Time frame: Day 63 Peak SUDS during PE therapy session 10

    A rating scale from 0 to 100 where zero represents no distress at all and 100 represents very extreme distress, fear, or anxiety. SUDS ratings are subjective and different individuals may rate the same situation differently. An individual anchors their own ratings with personal recollection of situations considered "No Distress" to "Moderate" to "Extreme Distress".

  9. PCL-5: PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition: Secondary Clinical Outcome

    Time frame: Day 0 PCL-5 score at PE therapy session 1

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  10. PCL-5: Secondary Clinical Outcome

    Time frame: Day 7 PCL-5 score at PE therapy session 2

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  11. PCL-5: Secondary Clinical Outcome

    Time frame: Day 14 PCL-5 score at PE therapy session 3

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  12. PCL-5: Secondary Clinical Outcome

    Time frame: Day 21 PCL-5 score at PE therapy session 4

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  13. PCL-5: Secondary Clinical Outcome

    Time frame: Day 28 PCL-5 score at PE therapy session 5

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  14. PCL-5: Secondary Clinical Outcome

    Time frame: Day 35 PCL-5 score at PE therapy session 6

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  15. PCL-5: Secondary Clinical Outcome

    Time frame: Day 42 PCL-5 score at PE therapy session 7

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  16. PCL-5: Secondary Clinical Outcome

    Time frame: Day 49 PCL-5 score at PE therapy session 8

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  17. PCL-5: Secondary Clinical Outcome

    Time frame: Day 56 PCL-5 score at PE therapy session 9

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

  18. PCL-5: Secondary Clinical Outcome

    Time frame: Day 63 PCL-5 score at PE therapy session 10

    Self-ratings of how much one is bothered by each of the 20 symptoms of PTSD on a 5-point severity scale ranging from 0 (Not at all) to 4 (extremely).

Other outcomes

  1. Salivary cortisol

    Time frame: Between days -7 to -1, baseline

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  2. Salivary cortisol

    Time frame: Day 0, therapy session 1

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  3. Salivary cortisol

    Time frame: Day 7, therapy session 2

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  4. Salivary cortisol

    Time frame: Day 14, therapy session 3

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  5. Salivary cortisol

    Time frame: Day 21, therapy session 4

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  6. Salivary cortisol

    Time frame: Day 28, therapy session 5

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  7. Salivary cortisol

    Time frame: Between days 29-34, mid-treatment assessment

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  8. Salivary cortisol

    Time frame: Day 35, therapy session 6

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  9. Salivary cortisol

    Time frame: Day 42, therapy session 7

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  10. Salivary cortisol

    Time frame: Day 49, therapy session 8

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  11. Salivary cortisol

    Time frame: Day 56, therapy session 9

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  12. Salivary cortisol

    Time frame: Day 63, therapy session 10

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

  13. Salivary cortisol

    Time frame: Between days 64-71, post-treatment

    Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay

Sponsors and collaborators

Lead sponsor

Massachusetts General Hospital

Other

Collaborators

  • National Institute of Mental Health (NIMH)
  • VA Boston Healthcare System

Registry information

Official study title

Circadian Influence on Fear Extinction Resulting From Prolonged Exposure Therapy for PTSD

Important dates

Study start
2022
Primary completion
2025
Study completion
2026
First posted
Jul 12, 2022
Registry last updated
May 18, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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