Circadian Influence on Prolonged Exposure Therapy for PTSD

NCT05453162 | Active Not Recruiting DMC

• 2 other identifiers: 2021p003356R21MH128619
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

PTSD

Keywords

PTSD; Circadian; Exposure Therapy; Sleep; Cortisol

Outcome Measures

Primary Outcomes (6)

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (18)

• Subjective Units of Distress (SUDS): Secondary Mechanistic Outcome

  Day 14 Peak SUDS during PE therapy session 3

• SUDS: Secondary Mechanistic Outcome

  Day 21 Peak SUDS during PE therapy session 4

• SUDS: Secondary Mechanistic Outcome

  Day 28 Peak SUDS during PE therapy session 5

• SUDS: Secondary Mechanistic Outcome

  Day 35 Peak SUDS during PE therapy session 6

• SUDS: Secondary Mechanistic Outcome

  Day 42 Peak SUDS during PE therapy session 7

Other Outcomes (13)

• Salivary cortisol

  Between days -7 to -1, baseline

• Salivary cortisol

  Day 0, therapy session 1

• Salivary cortisol

  Day 7, therapy session 2

Study Arms (2)

Early morning PE

EXPERIMENTAL

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

Late afternoon PE

EXPERIMENTAL

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

Interventions

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.

Early morning PE; Late afternoon PE

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

VA Boston Healthcare System

Boston, Massachusetts, 02130-4817, United States

Location

Related Publications (6)

• 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.

  PMID: 23992769 BACKGROUND

• 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.

  PMID: 25894546 BACKGROUND

• 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.

  PMID: 27664810 BACKGROUND

• 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.

  PMID: 26034578 BACKGROUND

• 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.

  PMID: 25462905 BACKGROUND

• 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.

  PMID: 30962423 BACKGROUND

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Study Officials

• Edward F Pace-Schott, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Suzanne L Pineles, PhD

  VA Boston Health System, Boston University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Therapists will be unaware of study hypotheses. therapy supervisor and assessors will be unaware of hypothesis and participants' treatment arms
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Psychiatry

Model Details: 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.

Study Record Dates

• First Submitted: June 29, 2022
• First Posted: July 12, 2022
• Study Start: July 1, 2022
• Primary Completion: August 1, 2025
• Study Completion (Estimated): September 1, 2026
• Last Updated: May 18, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Study data will become available following the end of the study and the publication of results.
• Access Criteria: Investigators can apply to the NIMH Data Archive (NDA) for permission to use these data.

Locations

US (1)