Circadian Influence on Prolonged Exposure Therapy for PTSD

PTSD Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05453162
• Other study ID #: 2021p003356
• Secondary ID: R21MH128619
• Status: Recruiting
• Phase: N/A
• Start date: July 1, 2022
• Est. completion date: April 30, 2024

Study information

• Verified date: February 2023
• Source: Massachusetts General Hospital
• Contact: Edward F Pace-Schott, PhD
• Phone: 508-523-428
• Email: epace-schott[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: April 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• PTSD
• Stress Disorders, Post-Traumatic

Intervention

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.

Locations

Country	Name	City	State
United States	VA Boston Healthcare System	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Massachusetts General Hospital	National Institute of Mental Health (NIMH), VA Boston Healthcare System

Country where clinical trial is conducted

United States, 

References & Publications (6)

Brueckner AH, Lass-Hennemann J, Wilhelm FH, Ferreira de Sa 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Between days -7 to -1, baseline
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 0, therapy session 1
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 7, therapy session 2
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 14, therapy session 3
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 21, therapy session 4
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 28, therapy session 5
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Between days 29-34, mid-treatment assessment
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 35, therapy session 6
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 42, therapy session 7
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 49, therapy session 8
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 56, therapy session 9
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Day 63, therapy session 10
Other	Salivary cortisol	Concentration in saliva sample obtained by passive drool and analyzed by enzyme immunoassay	Between days 64-71, post-treatment
Primary	Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome	This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.	Between days -7 to -1, Baseline
Primary	Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome	This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.	Between days 29-34, mid-treatment
Primary	Psychophysiological reactivity to script-driven imagery (SDI-PR: )Primary Mechanistic Outcome	This primary mechanistic outcome is a unitary discriminant canonical variable measuring psychophysiological reactivity while listening to personalized recorded scripts describing an index trauma.	Between days 64-71, post-treatment
Primary	Clinician-Administered PTSD scale for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition (CAPS-5): Primary Clinical Outcome	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.	Between days -7 to -1, Baseline
Primary	CAPS-5: Primary Clinical Outcome	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.	Between days 29-34, mid-treatment
Primary	CAPS-5: Primary Clinical Outcome	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.	Between days 64-71, post-treatment
Secondary	Subjective Units of Distress (SUDS): Secondary Mechanistic Outcome	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".	Day 14 Peak SUDS during PE therapy session 3
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 21 Peak SUDS during PE therapy session 4
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 28 Peak SUDS during PE therapy session 5
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 35 Peak SUDS during PE therapy session 6
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 42 Peak SUDS during PE therapy session 7
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 49 Peak SUDS during PE therapy session 8
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 56 Peak SUDS during PE therapy session 9
Secondary	SUDS: Secondary Mechanistic Outcome	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".	Day 63 Peak SUDS during PE therapy session 10
Secondary	PCL-5: PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition: Secondary Clinical Outcome	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).	Day 0 PCL-5 score at PE therapy session 1
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 7 PCL-5 score at PE therapy session 2
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 14 PCL-5 score at PE therapy session 3
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 21 PCL-5 score at PE therapy session 4
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 28 PCL-5 score at PE therapy session 5
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 35 PCL-5 score at PE therapy session 6
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 42 PCL-5 score at PE therapy session 7
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 49 PCL-5 score at PE therapy session 8
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 56 PCL-5 score at PE therapy session 9
Secondary	PCL-5: Secondary Clinical Outcome	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).	Day 63 PCL-5 score at PE therapy session 10