Circadian Influence on Prolonged Exposure Therapy for PTSD

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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PTSD

Intervention / Treatment
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* Behavioral: Prolonged Exposure Therapy for Posttraumatic Stress Disorder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a diagnosis of PTSD as defined by DSM-5, with a minimum CAPS severity score of 26 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 25-45 Veteran Intermediate (neither type) score of 42-58 on the Morningness-Eveningness Questionnaire (MEQ). 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 pregnancy current substance use disorder 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) having no memory of their traumatic event daily, or as-needed, 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 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 Non-exclusionary psychotropic medications must have been stable for 3 months prior to enrollment and remain stable throughout participation.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early morning PE<br>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<br>* 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.<br>|
| Experimental: Late afternoon PE<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, Circadian, Exposure Therapy, Sleep, Cortisol