Examining Changes in Microbiota Over the Course of PTSD Treatment
Phase: NA
Conditions: Posttraumatic Stress Disorder, Depression
Sponsor: Rush University Medical Center

Examining Changes in Microbiota Over the Course of PTSD 
Treatment Protocol 
 
NCT04109196 
 
1 September 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Examining Changes in Microbiota over the Course of PTSD Treatment  
The overall goals of this project are to evaluate the use of 5-day intensively-delivered Cognitive 
Processing Therapy to treat PTSD and to determine the associations between the microbiome, 
salivary cytokines, and the presence of and recovery from PTSD. Specifically, this study is 
designed to 1) determine whether individual Cognitive Processing Therapy (CPT) delivered 
twice per day over 5 consecutive days (CPT-5) is tolerable, acceptable, and effective in reducing 
PTSD symptoms, 2) determine the microbial signatures associated with PTSD, 3) evaluate 
whether the abundance and composition of microbiota and salivary cytokine levels change over 
the course of PTSD treatment, and 4) examine whether changes in microbial signatures are 
associated with changes in cytokine levels.  
Scientific Review:  
Cognitive Processing Therapy (CPT) is an evidence-based psychotherapy for posttraumatic 
stress disorder (PTSD; Resick, Monson, & Chard, 2016) that has demonstrated efficacy and 
effectiveness in a large range of settings and a variety of populations (Monson et al., 2006; 
Resick et al., 2017; Resick, Nishith, Weaver, Astin, & Feuer, 2002; Resick, Williams, Suvak, 
Monson, & Gradus, 2012). Clinical outcome data from the Road Home Program Intensive 
Outpatient Program (IOP), which offers CPT daily over the course of three weeks to treat 
veterans with PTSD, show that participation in the IOP produces large PTSD and depression 
symptom reductions. This suggests that patients are able to safely and effectively work on their 
trauma on a daily basis with CPT and that the daily delivery of CPT may also be acceptable and 
effective.  
While existing evidence-based interventions for PTSD, such as CPT, have been shown to be 
effective for the treatment of the disorder, it has also been suggested that underlying biology may 
contribute to treatment refractory PTSD. The microbiome has received increased attention and 
been proposed as an important factor that impacts brain function and mental health through what 
is referred to as the gut-brain-axis (Carabotti et al., 2015; Collins et al., 2014; Heijtz et al., 2011). 
However, it has yet to be determined what role microbiota play in PTSD and whether the 
abundance of various microbiota changes over the course of evidence-based PTSD treatment.  
The proposed project will address these questions by examining microbial signatures of 
individuals with PTSD to establish whether previously identified microbial signatures (cf. 
Hemmings et al., 2017) can be found in another sample and whether those signatures can be 
found in oral microbiota in addition to fecal microbiota. The project will also examine whether 
microbial signatures change over the course of PTSD treatment to determine whether symptom 
improvement and changes in inflammatory marker levels are associated with changes in 
microbiota.  
Inclusion and Exclusion Criteria:  
Inclusion Criteria:  
Individuals are eligible for the current study if they:  

1. Are 18 years or older  
2. Are fluent in English  
3. Have experienced a Criterion A traumatic event during their lifetime  
4. Have a PTSD diagnosis verified by the Clinician Administered PTSD Scale for DSM-5  
5. Are interested in receiving evidence-based treatment (CPT) for PTSD and able to attend 
10 therapy sessions over the course of one week (5 days)  
6. Are willing and interested to complete self-report measures and clinician-rated 
assessments at multiple time points over the course of the study  
Exclusion Criteria:  
Individuals are excluded from the current study if:  
1. The traumatic event occurred in the past month  
2. They are currently suicidal or homicidal  
3. They have a history of psychosis or mania  
4. They have not been on a stable dose of medication for at least one month  
5. They made changes to the diet in the past month or are planning to make changes over 
the course of therapy  
6. They have completed an evidence-based PTSD treatment in the past 3 months or are 
currently receiving an evidence-based PTSD treatment  
7. They have mental retardation or significant cognitive impairment that would prevent 
them from engaging in CPT  
8. They have a serious or unstable medical illness or instability for which hospitalization 
may be likely within the next year  
9. They have an active substance use disorder (within the past 3 months)  
10. They are involved with current legal actions related to the traumatic event that is 
anticipated to be targeted during treatment  
11. They have a history (within the past year) or presence of an eating disorder  
12. They are currently taking or have taken an antibiotic in the past 30 days  
13. They are currently taking a corticosteroid  
14. They have had part of the digestive tract removed or altered within the past year  
15. They have had any surgery or procedure within the past 30 days that has required fasting 
for more than 12 hours or bowel preparation beforehand  
16. They have a visual or auditory impairment that would prevent them from fully 
participating in study activities  
Research Plan:  
Study Population:  
Trauma-exposed individuals will be recruited from the Rush Department of Psychiatry, 
Department of Behavioral Sciences, the Rush newsletters, the Rush website, Road Home 
Program: Center for Veterans and their Families, other Rush clinics, and postings to Rush/Road 
Home Program social media pages and website. Local first responders will also be recruited. 
Recruitment flyers will be posted in waiting areas in the Rush Departments of Psychiatry and 

Behavioral Sciences. Approximately 200 individuals will be screened, anticipating that 40% of 
those screening positive on the phone and expressing interest in the study will be eligible and 
willing to participate (~40% of 200 screened = 80 participants). We plan to enroll at least 80 
trauma-exposed individuals who meet the diagnostic criteria for PTSD, as assessed by a gold 
standard clinician-administered PTSD assessment, for the single-arm, open-label trial.  
Study Activities:  
Eligibility Phone Screening:  
Individuals who are interested in participating in the proposed study will call in response to study 
recruitment flyers or will be called by the study staff once they have been referred, and they will 
then be screened via phone by a member of the study staff to be examined for eligibility. 
Individuals who meet exclusion criteria or who choose not to participate will be referred for 
other treatment as indicated. Potentially eligible and interested individuals will be scheduled for 
an in-person intake session, which may be conducted in 1-2 sessions based on the participant’s 
scheduling availability. Informed consent will be obtained and signed at the beginning of the in-
person assessment, prior to the conduct of any study activities. Alternatively, potentially eligible 
and interested individuals may schedule a telephone/video intake session. All telephone/video 
sessions will be conducted via a HIPAA compliant platform. Individuals who schedule 
telephone/video intakes will be sent a link to an electronic version of the consent form via 
REDCap prior to the conduct of any study activities.  
Intake Assessment:  
The intake assessment will be used to confirm the fit for the proposed project. Clinical 
interviewers with a minimum of a Master’s degree in Psychology who are not providing the 
treatment will administer structured diagnostic interviews (e.g. CAPS and DIAMOND). Study 
staff will administer brief computerized assessments (e.g. Stroop task) and a full self-report 
assessment battery via Qualtrics. Participants will also be emailed a link to an internet-based 
dietary assessment. If participants consent to providing biosamples, study staff will also collect 
microbiota, salivary cytokine samples, and human DNA extracted from whole saliva. 
Completion of the intake assessment may take up to 4 hours and may take place over 1-2 days, 
depending on the participant’s availability. Telephone/video intake assessments will include the 
administration of a brief computerized assessment and the provision of fecal samples but will not 
include the provision of saliva samples. Study staff will securely email the full self-report 
assessment battery to telephone/video intake participants via Qualtrics. Study staff will also 
securely email participants a link to the brief computerized assessment. All intake assessments 
will be audio recorded to establish diagnostic reliability. Intake assessments may also be audio 
and/or video recorded for research purposes.  
Intensive Week-Long Cognitive Processing Therapy (CPT):  
The eligible individuals will undergo a course of 1-week-long Cognitive Processing Therapy 
(CPT-5). CPT-5 will be delivered twice per day over the course of five business days (Monday 
through Friday; 10 sessions total) at approved study sites or via the HIPAA compliant platform. 

Each 50 minute session will closely follow the CPT protocol and will be conducted by either Dr. 
Held, other doctoral-level psychologists, postdoctoral fellows, or other Master’s level (or higher) 
clinicians who have received the official two-day CPT training and who are not involved in 
study assessments. All CPT sessions will be audio and/or video recorded and an independent 
fidelity rater with experience in the treatment will randomly select and review 20% of all therapy 
audio recordings to ensure that the intervention is provided with fidelity, which will be defined 
as 80% or more of the maximum possible score on the official CPT fidelity rating scales. CPT 
worksheets and homework assignments may be collected and copied for research purposes. 
Individuals with telephone/video sessions will have the option to complete electronic versions of 
CPT worksheets and to upload them to a secure folder accessible only by the individual and 
study staff.  
Changes in PTSD severity and other relevant symptoms will be assessed before, during, and after 
the course of CPT using well-validated clinician-administered, self-report, and computerized 
assessments. Completion of assessments may take between 20 minutes for self-report measures 
and 90 minutes for combined self-report, computer-based, and clinician-administered 
assessments. Fecal- and oral-derived microbiota as well as salivary cytokines will also be 
assessed at various pre-treatment, post-treatment, and follow-up time points to determine 
whether the microbiome and cytokine levels change over the course of CPT. Participants will 
have the option to opt out of providing these biological samples and still receive CPT-5. 
Participants completing telephone/video sessions can provide optional fecal samples and will 
complete brief computerized assessments, but will not provide saliva samples.  
Booster Sessions:  
Following their completion of the course of CPT, participants will be given the option to 
schedule up to three in-person or telephone/video booster sessions of CPT with their study 
therapist. If a participant decides to use any booster sessions, they must be used by the date of the 
participant’s 3-month follow-up visit. All booster sessions will be audio and/or video recorded. 
CPT worksheets and homework assignments may be collected and copied for research purposes. 
Participants will complete self-report measures at each booster session they choose to use.  
Measures:  
Self-report measures, clinician-rated assessments, a computerized task, and biological sample 
collection will be used during the study. The assessment schedule below details the different 
assessment time points for each measure. Measures may also be administered as needed at 
clinically relevant intervals.  

 
Note: 
CAPS-5 = Clinician Administered PTSD Scale for DSM-5; C-SSRS = Columbia-Suicide 
Severity Rating Scale; DIAMOND = Structured Diagnostic Interview for Anxiety, Mood, OCD 
and related Neuropsychiatric Disorders; Ohio TBI Screen = Ohio Traumatic Brain Injury 
Screen; PCL-5 = PTSD Checklist- Identified Patient Version; PHQ-9 = Patient Health 
Questionnaire; GAD-7 = Generalized Anxiety Disorder – 7-item; PTCI = Post-Traumatic 
Cognitions Inventory; ADL = Activities of Daily Living; AUDIT-C = Alcohol Use Disorders 
Identification Test; DAST-10 = Drug Abuse Screening Test; CD-RISC-10 = Connor-Davidson 
Resilience Scale – 10 items; PROMIS-SF-8 = Patient-Reported Outcomes Measurement 
Information System Satisfaction with Participation in Social Roles Short Form; PROMIS-SD- 
SF = Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short 
Form; PROMIS-SRI-SF = Patient-Reported Outcomes Measurement Information System 

Sleep-Related Impairment Short Form; RAND-12+ = The Veterans Rand 12-Item Health 
Survey; FFQ = VioScreen Food Frequency Questionnaire  
*Fecal collection will take place within one day of the assessment and prior to the following 
assessment. The CPT-5 Day 1 sample should ideally be collected on Sunday, one day before the 
first session, or as soon as possible after. For participants who did not complete the intensive 
CPT, follow-up intervals will follow the same schedule as for individuals who complete 
treatment. 
+These assessments will not be administered to participants who opt to participate via 
telephone/video. 
Biological sample collection will involve the collection of fecal- and oral-derived microbiota, 
salivary cytokines, and human DNA from whole saliva. Fecal samples will be collected by 
participants using a home collection kit. Participants will be provided instructions and all 
necessary equipment for sample collection and storage by a member of the study staff and will 
bring samples to their next treatment session. For participants completing telephone/video 
session, a home fecal sample collection kit as well as sample collection instructions, storage 
instructions and pre-paid return mailing information will be shipped to them. Salivary samples 
will be collected by study staff during study visits. Participants will be instructed to drink water 
prior to the session to ensure hydration and to rinse their mouth with water 10 minutes before the 
testing session with no other food or drink after. Participants will be instructed to refrain from 
the following activities prior to the saliva testing sessions: visiting the dentist within 48 hours, 
drinking alcohol and taking over-the-counter medications within 24 hours, drinking caffeine, 
smoking, and engaging in vigorous exercise within 2 hours, eating a major meal within 1 hour, 
and eating or drinking products with dairy, high levels of sugar, or high acidity within 20 
minutes. Salivary cytokines and oral microbiota samples and human DNA from whole saliva will 
be collected by a member of the study staff during the study visit.  
Biosample Analysis:  
To assess whether microbial signatures change over the course of PTSD treatment and are 
different with regards to diversity and total abundance for trauma-exposed individuals with 
PTSD, total microbial DNA will be extracted from oral saliva and colonic fecal samples and 
processed using high-throughput 16S ribosomal RNA gene Illumina amplicon sequencing 
followed with bioinformatics analysis at RUMC. Human DNA will also be extracted from whole 
saliva and processed. De-identified samples may be transferred to a qualified external laboratory 
upon the completion of the study solely for the purposes of processing and analysis.  
Risks:  
The risks associated with this study are no greater than those associated with standard evidence- 
based treatment for PTSD. This study uses CPT, an existing evidence-based treatment for PTSD 
that has been shown to be both effective and safe. To date, no adverse events have been 
associated with intensive CPT, suggesting that intensively-delivered treatment is tolerable.  
It is possible that participants may experience distress during CPT treatment. Participants’ 
suicidality will be assessed by the treating clinicians on an ongoing basis and assessed formally 

at the intake, 1-week post-treatment, 1-month follow-up, and 3-months follow-up assessment 
points using the Columbia Suicide Severity Rating Scale (C-SSRS). If a participant indicates 
having “Thoughts that [they] would be better off dead or of hurting [themselves] in some way” 
more than half the days (2) or nearly every day (3), the study clinician will conduct a safety 
assessment. If any participant becomes actively suicidal with intent, the study clinician will refer 
the participant to a higher level of care (i.e., psychiatric, medical, or emergency services). All 
sessions will take place during regular business hours, and clinical staff will be present and 
available to assist in the case of a crisis during an in-person session. In the case of a crisis during 
a telephone/video session, the study clinician will be available to assist or will instruct the 
participant to call 911 or go to their nearest emergency room. Prior to the start of any 
telephone/video session, the provider will inquire about the current location to have this 
information in case of an emergency. Individuals will no longer be able to continue this course of 
CPT if they are actively suicidal, but may be able to enroll at a later time after reaching stability 
per eligibility requirements.  
While risk is minimal, a loss of confidentiality is possible, although unlikely. All study staff will 
work diligently to ensure that all data is stored securely and that study-related files are password 
protected so that only members of the study staff will have access to identifiable data. To protect 
confidentiality, each subject is assigned a unique code. Only study personnel will be able to link 
patient name to the identification number. All telephone/video sessions will be conducted using 
HIPAA compliant platforms. In addition, a Certificate of Confidentiality will be obtained. No 
identifiable data will ever be disclosed to any outside parties. De-identified data may be reported 
in aggregate for internal clinical use, publications, or other presentations.  
Benefits:  
Participants in this study may experience direct benefits. Given that CPT is an effective 
evidence- based treatment for PTSD, it is likely that participants may experience a significant 
reduction in their PTSD and depression symptoms by the end of treatment. The reduction in 
symptoms may enable participants to re-engage in daily functions. Participants may help 
advance our understanding of PTSD treatment and its biological effects on the body. Findings 
from this study may allow researchers to learn more about the physiological biomarkers 
associated with PTSD and how they are impacted by the current clinical practices that are used to 
treat individuals with PTSD.  
Data Storage:  
Specify the site at which the data will be stored and how it will be stored:  
Audio recordings, video recordings, copies/scans of CPT session materials, and all electronic 
data collected through computerized tasks, the internet-based assessment, and Qualtrics-
delivered self-report assessments will be de-identified, password-protected, and stored in a 
restricted folder within the RUMC secure network infrastructure. Audio recordings will be 
uploaded to the secure server within one business day and will be deleted from the recording 
device immediately upon upload. Telephone/video visit audio and video recordings from the 
HIPAA compliant telephone/video platform will be uploaded to the secure server within one 

business day and will be deleted from the platform immediately upon upload. CPT worksheets 
electronically uploaded to the secure folder accessible only to the participant and study staff will 
be deleted from this folder following the participant’s final study visit. Copies of the worksheets 
will be saved to a separate restricted study folder on the RUMC network infrastructure. When 
personally identifying data cannot be removed (as may be the case with audio or video files), 
they will be provided with a unique de-identified code and stored in a separate and secure 
network location.  
Saliva and fecal samples will be stored in a -80 degree freezer in the locked laboratory of the 
Department of Psychiatry and Behavioral Sciences at RUMC until analyzed. No biological data 
sources will contain information that will personally identify subjects. To protect confidentiality, 
each subject is assigned a unique code for these specimens. Only study personnel will be able to 
link patient name to the identification number. All information and data related to the biological 
specimens collected in the study will be kept in a password protected computer file on the 
Department of Psychiatry and Behavioral Sciences secure server or in a secure locked cabinet in 
the Department of Psychiatry and Behavioral Sciences.  
How long will the data be maintained and/or stored?  
All biological and electronic data collected will be stored for least 5 years. Once the necessary 
analyses have been conducted after at least 5 years, all data will be securely deleted from the 
secure, password-protected file and system. Saliva and fecal specimens will be destroyed once 
necessary analyses have been conducted.  
Who, other than the specified study team, will have access to the study records or data? 
Specify their name, role, and affiliation. 
The principal investigator will monitor all access to data. Only study staff listed on and approved 
by the IRB will have access to the data for research purposes. Audio and/or video recordings 
may be shared with approved external collaborators for analysis through encrypted software 
shared on a secure web-based storage site. Participants in audio and/or video recordings will be 
identified by coded subject IDs. Upon completion of data collection, de-identified samples may 
be transferred to a qualified external laboratory solely for the purposes of conducting laboratory 
assays to generate necessary data for the study team. This laboratory will not utilize data 
generated from specimens for research purposes.  
In line with the NIH Guidance on Consent for Future Research Use and Broad Sharing of Human 
Genomic and Phenotypic Data Subject to the NIH Genomic Data Sharing Policy 
(https://osp.od.nih.gov/wpcontent/uploads/NIH_guidance_elements_consent_under_gds_policy.
pdf), some de-identified study data, including data generated from biospecimens may be placed 
into one or more scientific databases or shared with other researchers. Only approved researchers 
will be given access to these databases.  
Justify your needs to collect PHI in this study:  
PHI will be collected in order to characterize the participant sample and to maintain contact with 
participants throughout the study, deliver assessments, and document the treatment progress. The 

internet-based measure (FFQ) requires the collection of PHI to identify respondents. The FFQ is 
an online measure delivered by VioScreen. All PHI collected from this measure will be 
converted to coded subject IDs before storage in the secure RUMC network infrastructure, and 
no PHI collected from this measure will be used for research purposes. Audio and video 
recordings may also contain PHI that can potentially identify respondents. As PHI cannot be 
removed from audio and video files, these files will be provided with de-identified codes and 
stored in a separate and secure network location.  
Describe how and where PHI will be destroyed following the completion of the study:  
Not applicable. No identifiable data will ever be shared by the study team with personnel outside 
of the approved study staff. Any data shared with external laboratories or other researchers will 
be de-identified. All the findings in this study will be de-identified or reported at a group level or 
in aggregate with no risk of identifying individual participants.  
Will subjects be able to request that their information be removed from the data bank?  
Yes. However, it may not be possible to withdraw or delete materials or data in the event that 
they have already been shared with other researchers.  
Costs:  
There will be no direct cost to participants to participate in this study. All clinical, professional, 
diagnostic and laboratory services related to the study will be provided at no cost to participants. 
However, participants will be responsible for their phone service provider’s standard charges as 
they apply to any study-related phone calls.  
Compensation:  
 
 
Intake CPT 
Day 1  
1- Week 
Post  
2- Week 
Post  
1- Month 
Post  
3- Month 
Post  
Total 
Completion of Measures & Provision 
of Saliva Samples*  
$20  
N/A  
$40  
$15  
$40  
$50  
$165  
Provision of Optional Fecal Sample  $10  
$ 10  
$10  
N/A  
$10  
$10  
$50  
Completion of Optional Semi- 
Structured Interview  
 
 
$15  
 
 
 
$15  
Total Compensation Possible  
$30  
$10  
$65  
$15  
$50  
$60  
$230  
* Provision of saliva samples not available to participants who opt to participate via 
telephone/video.