Clinical trial NCT05453162: Circadian Influence on Prolonged Exposure Therapy for PTSD
Official title: Circadian Influence on Fear Extinction Resulting From Prolonged Exposure Therapy for PTSD
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: PTSD
Keywords: PTSD
Circadian
Exposure Therapy
Sleep
Cortisol
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: VA Boston Healthcare System
name: National Institute of Mental Health (NIMH)
First posted: 2022-07-12
Enrollment: 52
Sex: ALL
Minimum age (years): 25
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome
timeFrame: Between days -7 to -1, Baseline
measure: Psychophysiological reactivity to script-driven imagery (SDI-PR): Primary Mechanistic Outcome
timeFrame: Between days 29-34, mid-treatment
measure: Psychophysiological reactivity to script-driven imagery (SDI-PR: )Primary Mechanistic Outcome
timeFrame: Between days 64-71, post-treatment
measure: Clinician-Administered PTSD scale for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition (CAPS-5): Primary Clinical Outcome
timeFrame: Between days -7 to -1, Baseline
measure: CAPS-5: Primary Clinical Outcome
timeFrame: Between days 29-34, mid-treatment
measure: CAPS-5: Primary Clinical Outcome
timeFrame: Between days 64-71, post-treatment
Secondary outcomes:
measure: Subjective Units of Distress (SUDS): Secondary Mechanistic Outcome
timeFrame: Day 14 Peak SUDS during PE therapy session 3
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 21 Peak SUDS during PE therapy session 4
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 28 Peak SUDS during PE therapy session 5
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 35 Peak SUDS during PE therapy session 6
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 42 Peak SUDS during PE therapy session 7
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 49 Peak SUDS during PE therapy session 8
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 56 Peak SUDS during PE therapy session 9
measure: SUDS: Secondary Mechanistic Outcome
timeFrame: Day 63 Peak SUDS during PE therapy session 10
measure: PCL-5: PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition: Secondary Clinical Outcome
timeFrame: Day 0 PCL-5 score at PE therapy session 1
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 7 PCL-5 score at PE therapy session 2
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 14 PCL-5 score at PE therapy session 3
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 21 PCL-5 score at PE therapy session 4
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 28 PCL-5 score at PE therapy session 5
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 35 PCL-5 score at PE therapy session 6
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 42 PCL-5 score at PE therapy session 7
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 49 PCL-5 score at PE therapy session 8
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 56 PCL-5 score at PE therapy session 9
measure: PCL-5: Secondary Clinical Outcome
timeFrame: Day 63 PCL-5 score at PE therapy session 10
Other outcomes:
measure: Salivary cortisol
timeFrame: Between days -7 to -1, baseline
measure: Salivary cortisol
timeFrame: Day 0, therapy session 1
measure: Salivary cortisol
timeFrame: Day 7, therapy session 2
measure: Salivary cortisol
timeFrame: Day 14, therapy session 3
measure: Salivary cortisol
timeFrame: Day 21, therapy session 4
measure: Salivary cortisol
timeFrame: Day 28, therapy session 5
measure: Salivary cortisol
timeFrame: Between days 29-34, mid-treatment assessment
measure: Salivary cortisol
timeFrame: Day 35, therapy session 6
measure: Salivary cortisol
timeFrame: Day 42, therapy session 7
measure: Salivary cortisol
timeFrame: Day 49, therapy session 8
measure: Salivary cortisol
timeFrame: Day 56, therapy session 9
measure: Salivary cortisol
timeFrame: Day 63, therapy session 10
measure: Salivary cortisol
timeFrame: Between days 64-71, post-treatment
Locations:
city: Boston
country: United States
facility: VA Boston Healthcare System
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Edward F Pace-Schott, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: VA Boston Health System, Boston University
name: Suzanne L Pineles, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
citation: 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.