Circadian Influence on Prolonged Exposure Therapy for PTSD

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05453162
• Collaborator: VA Boston Healthcare System (U.S. Fed), National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 52
• Arms: 2
• Anticipated Duration (Months): 22

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
PTSD	Behavioral: Prolonged Exposure Therapy for Posttraumatic Stress Disorder	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants (52 total) will be randomized, 26 to each of 2 arms one of which has 8 weekly PE sessions in early morning (between 07:00-10:00) and the other 8 sessions PE at 16:00 or later. Homework exposures will occur at the same time of day as PE. Primary outcomes measured at beginning, middle and end of treatment will be psychophysiological reactivity to trauma recall (mechanistic outcome) and CAPS-5 (clinical outcome). Secondary mechanistic outcome is peak SUDS during PE and clinical is PCL-5 measured at each PE session. Endogenous salivary cortisol levels will be tested as a mechanism of circadian effect. Data will be analyzed using multilevel, mixed-effects models.Participants (52 total) will be randomized, 26 to each of 2 arms one of which has 8 weekly PE sessions in early morning (between 07:00-10:00) and the other 8 sessions PE at 16:00 or later. Homework exposures will occur at the same time of day as PE. Primary outcomes measured at beginning, middle and end of treatment will be psychophysiological reactivity to trauma recall (mechanistic outcome) and CAPS-5 (clinical outcome). Secondary mechanistic outcome is peak SUDS during PE and clinical is PCL-5 measured at each PE session. Endogenous salivary cortisol levels will be tested as a mechanism of circadian effect. Data will be analyzed using multilevel, mixed-effects models.
• Masking: Double (Care Provider, Outcomes Assessor)
• Masking Description: Therapists will be unaware of study hypotheses. therapy supervisor and assessors will be unaware of hypothesis and participants' treatment arms
• Primary Purpose: Treatment
• Official Title: Circadian Influence on Fear Extinction Resulting From Prolonged Exposure Therapy for PTSD
• Anticipated Study Start Date: Jul 1, 2022
• Anticipated Primary Completion Date: Apr 30, 2024
• Anticipated Study Completion Date: Apr 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early morning PE 26 participants randomized to 10 weekly PE sessions in early morning (between 07:00-10:00) with homework exposures occurring occur at this same time of day.	Behavioral: Prolonged Exposure Therapy for Posttraumatic Stress Disorder; 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.
Experimental: Late afternoon PE 26 participants randomized to 10 weekly PE sessions in late afternoon (16:00 or later) with homework exposures occurring occur at this same time of day.	Behavioral: Prolonged Exposure Therapy for Posttraumatic Stress Disorder; 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.

Outcome Measures

Primary Outcome Measures

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

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

1. Salivary cortisol [Between days -7 to -1, baseline]

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

2. Salivary cortisol [Day 0, therapy session 1]

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

3. Salivary cortisol [Day 7, therapy session 2]

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

4. Salivary cortisol [Day 14, therapy session 3]

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

5. Salivary cortisol [Day 21, therapy session 4]

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

6. Salivary cortisol [Day 28, therapy session 5]

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

7. Salivary cortisol [Between days 29-34, mid-treatment assessment]

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

8. Salivary cortisol [Day 35, therapy session 6]

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

9. Salivary cortisol [Day 42, therapy session 7]

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

10. Salivary cortisol [Day 49, therapy session 8]

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

11. Salivary cortisol [Day 56, therapy session 9]

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

12. Salivary cortisol [Day 63, therapy session 10]

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

13. Salivary cortisol [Between days 64-71, post-treatment]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. a diagnosis of PTSD as defined by DSM-5, with a minimum CAPS severity score of 26

2. interest in starting a course of PE

3. 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

4. Age range of 25-45

5. Veteran

6. Intermediate ("neither type") score of 42-58 on the Morningness-Eveningness Questionnaire (MEQ).

Exclusion Criteria:

1. current or past history of bipolar I disorder, schizophrenic or other psychotic disorders,

2. current organic brain disorder including moderate to severe traumatic brain injury

3. factitious disorder or malingering

4. pregnancy

5. current substance use disorder

6. active risk of harm to self or others

7. 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

8. current participation in trauma-focused cognitive-behavioral therapy (e.g., Cognitive Processing Therapy, Written Exposure Therapy, Eye Movement Desensitization and Reprocessing Therapy)

9. prior treatment with an adequate dose of PE (i.e., 8 or more sessions)

10. having no memory of their traumatic event

11. daily, or as-needed, use of benzodiazepines.

12. methadone or suboxone maintenance therapy for past opioid addiction

13. 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.

14. persons habitually waking up after 8 AM or who would habitually awaken so early that more than 2 h would elapse before a morning PE session could occur

15. Non-exclusionary psychotropic medications must have been stable for 3 months prior to enrollment and remain stable throughout participation.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Edward F Pace-Schott, PhD, Massachusetts General Hospital
• Principal Investigator: Suzanne L Pineles, PhD, VA Boston Health System, Boston University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Brueckner AH, Lass-Hennemann J, Wilhelm FH, Ferreira de Sá DS, Michael T. Cortisol administration after extinction in a fear-conditioning paradigm with traumatic film clips prevents return of fear. Transl Psychiatry. 2019 Apr 8;9(1):128. doi: 10.1038/s41398-019-0455-0.
• Meuret AE, Rosenfield D, Bhaskara L, Auchus R, Liberzon I, Ritz T, Abelson JL. Timing matters: Endogenous cortisol mediates benefits from early-day psychotherapy. Psychoneuroendocrinology. 2016 Dec;74:197-202. doi: 10.1016/j.psyneuen.2016.09.008. Epub 2016 Sep 15.
• Meuret AE, Trueba AF, Abelson JL, Liberzon I, Auchus R, Bhaskara L, Ritz T, Rosenfield D. High cortisol awakening response and cortisol levels moderate exposure-based psychotherapy success. Psychoneuroendocrinology. 2015 Jan;51:331-40. doi: 10.1016/j.psyneuen.2014.10.008. Epub 2014 Oct 16.
• Pace-Schott EF, Germain A, Milad MR. Effects of sleep on memory for conditioned fear and fear extinction. Psychol Bull. 2015 Jul;141(4):835-57. doi: 10.1037/bul0000014. Epub 2015 Apr 20. Review.
• Pace-Schott EF, Germain A, Milad MR. Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory. Biol Mood Anxiety Disord. 2015 May 29;5:3. doi: 10.1186/s13587-015-0018-9. eCollection 2015.
• Pace-Schott EF, Spencer RM, Vijayakumar S, Ahmed NA, Verga PW, Orr SP, Pitman RK, Milad MR. Extinction of conditioned fear is better learned and recalled in the morning than in the evening. J Psychiatr Res. 2013 Nov;47(11):1776-84. doi: 10.1016/j.jpsychires.2013.07.027. Epub 2013 Aug 28.

• Responsible Party: Edward F. Pace-Schott, Assistant Professor of Psychiatry, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT05453162
• Other Study ID Numbers: 2021p003356; R21MH128619
• First Posted: Jul 12, 2022
• Last Update Posted: Jul 12, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Edward F. Pace-Schott, Assistant Professor of Psychiatry, Massachusetts General Hospital: PTSD; Circadian; Exposure Therapy; Sleep; Cortisol
• Additional relevant MeSH terms: Stress Disorders, Post-Traumatic

Study Results

No Results Posted as of Jul 12, 2022