Treatment of Stress-Related Psychopathology: Targeting Maladaptive and Adaptive Event Processing
Phase: NA
Conditions: Major Depressive Disorder, Post Traumatic Stress Disorder
Sponsor: Case Western Reserve University

 
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[USE THIS BIOMEDICAL PROTOCOL TEMPLATE IF YOUR PROJECT INVOLVES ANY 
PHYSICAL CONTACT OR MEDICAL INTERVENTIONS WITH PARTICIPANTS]   
 
INSTRUCTIONS: 
• 
Depending on the nature of your research, some sections may not be applicable to your research. 
These sections can be removed as needed. 
• 
When you write a protocol, keep an electronic copy. You will need to modify this copy when 
making changes.  
 
PROTOCOL TITLE: 
 
Treatment of Stress-Related Psychopathology: Targeting Maladaptive and Adaptive Event 
Processing 
 
PRINCIPAL INVESTIGATOR: 
 
Norah Feeny 
 
Psychological Sciences 
 
(216) 368-2695 
 
ncf2@case.edu 
 
UH FACULTY ADVISOR: 
If the principal investigator’s primary role at UH is resident, fellow or student, identify a faculty 
advisor. 
 
☒ N/A 
 
OTHER DEPARTMENTS INVOLVED IN THIS STUDY (IF APPLICABLE):     
☒  N/A    
 
VERSION NUMBER: 
 
Include the version number of this protocol if assigned by an outside entity. 
N/A 
 
DATE:  
 
12/14/2021 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Objectives  
Directions: Describe the purpose, specific aims or objectives. Be sure to also include the hypothesis being 
tested 
 
Positive Processes and Transition to Health (PATH) includes six, 90-min sessions that target 
maladaptive event processing (unproductive processing, avoidance, and impaired reward sensitivity), 
while also promoting parallel adaptive event processing (constructive processing, approach, and reward 
seeking) for destabilizing life events and for positive events. PATH uses a platform of narrative revisiting 
of destabilizing life events, as well as positive life event reminiscence. Patients will be selected for having 
experienced a destabilizing life stressor and related psychopathology. The R61 trial (N = 45) will examine 
whether PATH engages the therapeutic targets, with clear Go/No Go rules. In the R33, patients (N = 135) 
will be randomized to PATH or progressive muscle relaxation (PMR) and assessed over a 3-month 
follow-up.  
 
The Specific Aims are:  
Specific Aim 1: Engage Therapeutic Targets (R61): In an open trial (N = 45), we will examine whether 
PATH changes therapeutic targets (unproductive processing, avoidance, impaired reward processing) 
from pre- to 3-month follow-up, with at least medium effects (d = 0.60) on two of three primary target 
measures and at least (d = 0.50) on one secondary target measure. We will examine dosing and timing of 
effects. 
Specific Aim 2: Replication of Target Engagement (R33): In a randomized control trial (N = 135), we 
will examine whether PATH alters therapeutic targets from pre- to 3-month follow-up in comparison to 
PMR.  
Specific Aim 3: Link Changes in Targets to Changes in Stressor-related Outcomes (R33): We will 
examine whether changes in therapeutic targets (pre- to post-) predict improvement in PTSD and 
depression symptoms (pre- to 3-month follow-up).  
Specific Aim 4: Feasibility and Dropout/Acceptability of PATH (R61/R33): We will examine whether 
patients perceive PATH as helpful and complete/adhere to treatment, and therapist fidelity. 
 
There is an urgent need to develop novel treatments, given the prevalence, impact, and cost of PTSD and 
MDD (e.g., Hoge & Chard, 2018). PATH is an innovative intervention that targets three interrelated, 
transdiagnostic processes that maintain stressor-related psychopathology. PATH’s unique early and 
sustained focus on positive emotions could improve adherence and outcome, particularly in those with the 
reward deficits commonly seen in PTSD and MDD. Further, PATH’s focus on positive emotions and 
“stuck” processing targets unique processes largely absent in current PTSD therapeutics. PATH is novel 
in in applying exposure principles to depression, not just PTSD. This brief, positive, mechanistically 
precise, transdiagnostic treatment has the potential to improve treatment engagement and outcomes, 
identify clear therapeutic targets that predict better outcomes, and ultimately reduce the costly burden of 
stressor-related psychopathology.  
 
We hypothesize that (1) those in PATH will have significant changes in the therapeutic targets, (2) those 
in PATH will show a greater change in therapeutic targets than those receiving Progressive Muscle 
Relaxation (PMR), (3) changes in therapeutic targets predict improvement in PTSD and depression 
symptoms, and (4) those in PATH will perceive the intervention as helpful and adhere to treatment. 
 
 

 
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Background 
Directions: Describe the relevant prior experience and gaps in current knowledge describing how it will 
add to existing knowledge. Include any relevant preliminary data. 
      
Novel, more effective, efficient, tolerable, transdiagnostic interventions are needed. Posttraumatic 
stress disorder (PTSD) and depression (MDD) frequently co-occur (more than 60%; Rytwinski, Scur, 
Feeny, & Youngstrom, 2013), with shared distress-related symptoms and substantial impairment and 
disease burden (Post, Zoellner, et al., 2011; WHO, 2004). State-of-the-art psychotherapies for PTSD and 
MDD show clinically meaningful gains (Cuijpers et al., 2014; Watts et al., 2013). Yet, there is substantial 
room for improvement, given considerable dropout rates, time-intensive and emotionally taxing 
interventions, and a significant minority left with debilitating symptoms and risk for relapse. Emerging 
models of psychopathology (e.g., Hayes et al., 2015; McNally, 2016) propose that negative and positive 
feedback loops create vicious cycles that increase the risk of getting “stuck” in pathological states (e.g., 
Holtzheimer & Mayberg, 2011; van de Leemput et al., 2014). Accordingly, next-wave psychotherapies 
must target key maladaptive processes and facilitate transition to more adaptive ones (Hofmann & Hayes, 
2019). Therapies following stressful life events focus almost exclusively on negative emotion, which may 
contribute to dropout. Capitalizing on positive emotions early may make treatment less daunting and 
harness the power of the positive affect system.  
 
Exposure to destabilizing life events (e.g., sudden loss of loved one, sexual assault, job loss) ranges from 
50-89.5% in the U.S. population (Kessler, 1995; Kilpatrick et al., 2013). There is compelling support for 
the etiological role of such stressful life events for a range of psychopathology (Harkness & Monroe, 
2016), including persistent problems in the negative and positive valence systems related to PTSD and 
MDD. Decades of research have isolated central maladaptive and adaptive processes linked to 
psychopathology and resilience following destabilizing life events (Aldao et al., 2010; Hayes et al., 2015; 
Waugh & Koster, 2015). These therapeutic targets include: unproductive/constructive event processing 
(e.g., rumination vs. updating with corrective information, meaning-making); avoidance/approach (e.g., 
disengagement vs. engagement); and impaired reward sensitivity/positive emotion engagement (e.g., 
impaired reward processing vs. reward seeking). Together, these maladaptive processes are hypothesized 
to form a “stuck” system that prolongs negative mood, interferes with adaptive event processing, and 
increases reactivity to future stressful events, whereas their adaptive counterparts disrupt this system and 
promote resilience. 
 
Positive Processing and Transition to Health (PATH)  
PATH targets three transdiagnostic maladaptive processes and facilitates their more adaptive 
counterparts: 1) unproductive and constructive processing, 2) avoidance and approach, and 3) impaired 
reward sensitivity and positive emotional engagement and reward seeking. PATH is designed for 
individuals who have stressor-related psychopathology and can treat symptoms of PTSD or depression or 
the combination.   
 
 
 
 
 
 
 

 
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Inclusion and Exclusion Criteria 
Describe how individuals will be screened for eligibility. Using the tables below, describe the inclusion 
and exclusion criteria that will define who will be included and excluded in your final study sample. 
  
 
Inclusion Criteria 
1. 
Destabilizing life event involving profound loss or threat, with a minimum 
duration of 12 weeks since the event. 
2. 
Between the ages of 18 and 65. 
3. 
Elevated target:  Scores of at least moderate (1 or higher) on at least 2 of the 3 
target mechanisms: re-experiencing or ruminative processing of the destabilizing 
event (PSS-I items: 1, 2, 3, 4 or QIDS-C item 11), avoidance (PSS-I items 6, 7, 8), 
or reward deficits (PSS-I items 12, 13, or QIDS-C item 13) 
4. 
Elevated symptoms on either the PSS-I or QIDS-C (at least moderate): 18 on PSS-
I (Foa et al., 2016) and/or 11 on QIDS (moderate depression severity; Rush et al., 
2003), with symptoms persisting for 1 month or longer. 
 
 
Exclusion Criteria 
1. 
Current diagnosis of psychotic, bipolar, or substance use disorder. 
2. 
Severe self-injurious behavior or suicide attempt within the prior 3 months. 
3. 
Unwilling or unable to discontinue current CBT or unstable dose of psychotropic 
mediations within prior 3 months.   
4. 
Ongoing intimate relationship with the perpetrator (in assault-related event). 
5. 
6. 
No clear memory of event or occurred more than 5 years ago. 
Residence outside of the states of Ohio, Delaware, or Washington 
 
Number of Research Participants 
Directions: Indicate the maximum number of research participants to be accrued locally, and, if this is a 
multi-site study, indicate the maximum number of research participants to be accrued across all sites.  
 
This study is being conducted in collaboration with the University of Washington and the University of 
Delaware. In total, for the R61, 45 participants will be evenly accrued across all sites, and for the R33, 
135 participants will be evenly accrued across all sites.  
 
Recruitment Methods  
Describe how subjects will be identified (the source of potential research participants), and also how, 
when, and where they will be recruited.  Describe all methods of contact / communication. 
 
We will emphasize online advertising (e.g., Craigslist and study website, pathway2help.com). We will 
increase our visibility in the community by boosting awareness of our programs and ongoing research. 
This includes routine postings on free advertising websites (e.g., Craigslist and study website). We expect 
that the bulk of our study participants will come from online advertisement. 
In addition to online advertising, we will also send letters describing the study to healthcare providers 
who can bring this study to the attention to their patients who may be eligible. We will also send these 
providers brochures that they can distribute to interested patients. These brochures contain a site-specific 
phone number and a link to the study website so that interested participants can contact the study team to 
learn more about this project. Finally, we will also post paper flyers for the study throughout the 

 
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community, such as on college campuses, churches, grocery stores, libraries, etc. 
 
Setting 
Directions: Make sure to describe: 
1) The sites and locations where your research team will conduct the research.  
2) Where your research team will identify and recruit potential research participants, and  
3) Include the physical location where research procedures will be performed. 
 
Adults will be recruited from the Cleveland, OH area. Interviewers will collect demographic data and 
complete an eligibility screening form (type of destabilizing event, inclusion/exclusion criteria) via phone 
screens. Potentially eligible individuals will be scheduled for an intake and complete informed consent in-
person before doing an assessment; those excluded will be given referrals. All assessments and 
intervention sessions will take place in the Mather Memorial building at Case Western Reserve 
University, in Room 137. (However, see below for COVID-19 changes to the study setting.) Adults will 
also be recruited from Wilmington/Newark, DE (University of Delaware) and Seattle, WA (University of 
Washington).  
 
COVID-19 Changes 
For the foreseeable future, due to the COVID-19 pandemic and current restrictions on in-person research 
across all three sites, all study procedures will take place remotely and online, rather than in-person. 
Specifically, the different procedures are as follows: 
-Participants will be recruited from across states instead of across cities. That means adults can reside 
anywhere in Ohio, Delaware, and Washington, instead of just the Cleveland, Wilmington/Newark, and 
Seattle areas. 
-Intakes will occur via the secure videoconferencing platform Zoom.us (HIPAA compliant and currently 
used by the University Counseling Center), rather than in-person. Participants will review and sign 
informed consent forms via REDCap, while the assessor is on Zoom with them.  
-The participants will receive the PATH intervention through Zoom rather than in-person. 
-For participants without technology to complete the measures, a member of the study team will drop or 
mail the Kindles off at their home in sealed envelope and receive them after subjects complete all study 
procedures. 
 
There is a potential we will go back to in-person procedures in the future (i.e., when restrictions are 
lifted), should we reach that point, we will modify the protocol to reflect this change. 
 
Consent Process 
Describe if the study will be obtaining consent, or if the study will be applying for a waiver of consent. 
 
Potentially eligible individuals will complete their informed consent in-person before starting intake (see 
below for COVID-19 changes). Participants will be informed that participation is optional and that they 
may discontinue participation at any time. Participants will be provided with the contact information for 
study staff and the Human Subjects division.  
 
COVID-19 CHANGES 
Potentially eligible individuals will complete their informed consent via REDCap, while an assessor is on 
Zoom with them. Assessors will provide participants with the same information as above. Consent forms 
have been uploaded that reflect changes to an online and remote intervention and assessments. Assessors 
will also ask about collecting emergency contact information, in case it’s ever needed. 

 
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Sharing of Results with Research Participants 
Directions: Describe whether results (study results or individual subject results such as results of 
investigational diagnostic tests, genetic tests, or incidental findings) will be shared with the research 
participants or others (e.g. the subject’s primary care physicians) and if so, describe how the results will 
be shared.  
 
☒  Results will not be shared with research participants 
 
☒  Results will not be shared with research participants’ doctors 
 
Study Design 
Directions: Describe and explain the overall study design. (eg: single visit, single-blind, double-blind, 
non-randomized, randomized, blood draw, investigational drug, device etc.) 
 
Open Trial of PATH: Engage the Targets (R61) 
The R61 will be an open trial to determine if Positive Processes and Transition to Health (PATH) engages 
the proposed targets: unproductive processing, avoidance, and reward deficits in a sample of 45 adults 
who have experienced a destabilizing life event involving profound loss or threat, report persistent 
stressor-related symptoms of PTSD and/or depression, and are elevated on symptoms related to 2 of the 3 
therapeutic targets. Patients will receive six 90 minute sessions of PATH (with 2 boosters, if partial 
responders). Primary targets will be assessed at pre-treatment, week 3, post-treatment, and at 1- and 3-
month follow-up; secondary targets at pre-treatment, weekly during treatment, post-treatment, and at 1- 
and 3-month follow-ups. If GO criteria are achieved (Table 3), we will proceed to the R33.  
 
RCT of PATH: Target Engagement and Link to Clinical Outcomes (R33) 
The R33 will examine target engagement (unproductive processing, avoidance, and reward deficits) and 
whether change in PATH targets predict functional outcomes (PTSD, depression). The sample will be 
135 adults who have experienced a destabilizing life event and report persistent stressor-related symptoms 
(Table 1). Patients will be randomized to PATH or progressive muscle relaxation (PMR; six 90 minute 
sessions) and assessed on the same schedule as in the R61. See Figure 2 for study design.   
 

 
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Study Procedures 
Directions: 1) Provide a description of all study-related research procedures being performed 2) include 
procedures being performed to monitor research participants for safety or minimize risks 3) include all 
drugs and/or devices used in the research and the purpose of their use and their regulatory approval 
status 4) describe the source records including medical or educational records, which will be used to 
collect data about subjects. 
 
Session 1 (Overview) provides the PATH rationale and a review of life events (PATH of life: negative 
and positive). Therapists explain that unproductive processing, avoidance, and reward deficits work 
together to prolong distress and will be the targets of PATH. Therapists describe parallel processes of 
constructive processing, approach, and positive emotional engagement that help one to move forward and 
make meaning. In line with this, a rationale for an explicit focus on positive events/emotions will be 
provided.   
 
Sessions 2-4 focus on a verbal narrative of the destabilizing life event (revisiting negative event and 
processing as is done in imaginal exposure), reminiscence and processing of a major positive life event, 
and real-life practice to enact what was taught. In positive reminiscence, clients vividly remember the 
positive event providing details and focus on positive emotions. Therapists will encourage savoring of the 
experience and encourage facial expression of the positive emotions, so that clients do not dampen, avoid, 
or minimize the experience. This is particularly relevant with depression.  
 
In Session 2 (Unproductive Processing), therapists will describe in more depth the unproductive 
processing loop that can keep people locked in recurrent thinking and worrying as they try to make 
meaning of difficult life events. The therapist will describe how one can repetitively try to make sense of 
the event without updating meaning and overgeneralize across situations and beliefs about the self, others, 
and future, which can be overwhelming. In Session 3 (Avoidance), avoidance will be described as the 
tendency to push away feelings, thoughts, memories, people, and situations to attempt to reduce distress. 

 
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Clients are taught that avoidance often backfires and is associated with intrusions, re-experiencing, and 
rumination. In Session 4 (Reward Deficits), therapists will describe in depth how reward deficits can 
perpetuate distress and interfere with the benefits of positive emotion and reward processing.  
 
Sessions 5 (Integration) focuses on constructive processing and provides opportunity for integration and 
consolidation of learning. Session 6 (Future Events) focuses on future negative and positive events to 
promote application of new learning and resilience. Booster sessions focus on positive and negative life 
events since the last session and adaptive processes (constructive processing, approach, and reward). All 
sessions will include cultivation and elaboration of positive emotions to promote engagement and to build 
on the benefits of positive emotion.   
 
Progressive Muscle Relaxation (PMR). PMR is for the R33 as one of the randomization conditions and 
will be adapted from Berstein, Borkoveck, and Hazlett-Stevens (2000). PMR will be conducted in six, 60-
90 min individual weekly sessions with a study therapist, helping control for non-specific effects of 
contact time, treatment expectancy, and general support. This intervention is likely to be credible because 
of the focus on stress management, and it does not focus directly on the PATH targets. Muscle groups are 
tightened and then relaxed with the attention of the patient focused on the contrast between tension and 
relaxation. Through regular practice, the person becomes more aware of tension in the body and can 
induce relaxation as needed (Field, 2009). During the six sessions of training, patients will be encouraged 
to practice PMR and learn how to deliberately induce physical relaxation to reduce stress and mental 
tension. Sessions will move from relaxation of 16-muscle groups to 7 muscle groups, 4 muscle groups, 
and finally to relaxation by recall. Patients will be instructed to practice daily, if possible, but at least two 
or three times a week, and to integrate the practice into their daily life. Every session, patients will be 
provided with audio recordings of the PMR conducted that session with their therapists, as well as 
homework reporting forms to assist their home PMR exercises. 
 
Study Timeline 
Directions: State approximately how long each visit will take, how long total study enrollment will last. 
 
 
Year 1 
Year 2 
Year 3 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
PATH Pilot Study (Study 1) 
 
 
 
 
 
 
 
 
 
 
 
 
  Procedures Finalized and Staff Trained  
X 
 
 
 
 
 
 
 
 
 
 
 
  Final IRB Approval and Material Prep  
X 
 
 
 
 
 
 
 
 
 
 
 
  Assessor and Therapist Training  
X 
 
X 
 
X 
 
 
 
 
 
 
 
  Recruit Participants  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
  Patient Treatment  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
  Assessment  
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
  DSMB Annual Report/Meeting 
 
 
 
X 
 
 
 
 
 
 
 
 
  25% Recruitment Target (n = 12)  
 
 
X 
 
 
 
 
 
 
 
 
 
  50% Recruitment Target (n = 22)  
 
 
 
X 
 
 
 
 
 
 
 
 
  75% Recruitment Target (n = 34)  
 
 
 
 
X 
 
 
 
 
 
 
 
  100% Recruitment Target (n = 45)  
 
 
 
 
 
X 
 
 
 
 
 
 
  Analyzing and Interpreting Results 
 
 
 
 
 
 
X 
X 
 
 
 
 
  Evaluation of Go/No-Go Rules  
 
 
 
 
 
 
 
X 
 
 
 
 
  Manuscript Preparation and Submission 
 
 
 
 
 
 
 
 
X 
X 
 
 
General Grant Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
  Research Performance Progress Reports  
 
 
 
X 
 
 
 
X 
 
 
 
 
  Data Sharing NDCT  
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Year 3 
Year 4 
Year 5 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
PATH RCT (Study 2) 
 
 
 
 
 
 
 
 
 
 
 
 
  Refine PATH  
X 
 
 
 
 
 
 
 
 
 
 
 
  Procedures Finalized and Staff Trained  
X 
 
 
 
 
 
 
 
 
 
 
 
  Final IRB Approval and Material Prep  
X 
 
 
 
 
 
 
 
 
 
 
 
  Assessor and Therapist Training 
X 
 
 
 
X 
 
 
 
X 
 
 
 
  Recruit Participants  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

 
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  Patient Treatment  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  Assessment  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  25% Recruitment Target (n = 34)  
 
 
X 
 
 
 
 
 
 
 
 
 
  50% Recruitment Target (n = 67)  
 
 
 
 
X 
 
 
 
 
 
 
 
  75% Recruitment Target (n = 101) 
 
 
 
 
 
 
X 
 
 
 
 
 
  100% Recruitment Target (n = 135)  
 
 
 
 
 
 
 
 
X 
 
 
 
  Analyzing and Interpreting Results 
 
 
 
 
 
 
 
 
 
X 
X 
X 
  Manuscript Preparation and Submission 
 
 
 
 
 
 
 
 
 
X 
X 
X 
General Grant Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
  Research Performance Progress Reports  
 
 
 
X 
 
 
 
X 
 
 
 
X 
  Data Sharing NDCT  
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Phone Screening. Members of the study team will collect demographic data and complete an 
eligibility screening form (type of destabilizing event, inclusion/exclusion criteria). Brief versions of the 
PSS-I and QIDS-C will be used. Potentially eligible individuals will be scheduled for an intake; those 
excluded will be given referrals and we will retain their demographic information and reason for 
exclusion for the creation of consort diagrams. All clinical data will not be utilized and ultimately deleted. 
 
Pre-treatment Assessment. After informed consent, a study team member (licensed therapist or 
under the supervision of someone licensed) will administer measures of PTSD (PSS-I), depression 
(QIDS-C), and suicidality (C-SSRS). Assessors will be blind to treatment assignment (in R33). Patients 
will complete baseline self-reports and laboratory paradigms. See Figure 2.  
 
Active Treatment. Someone on the study team (licensed or under the supervision of someone 
licensed) will administer the treatment sessions. In the R61, all patients will receive PATH. In the R33, 
patients will be randomized to PATH or PMR, using a computerized algorithm accounting for initial 
symptom severity. 
 
Post-Treatment Assessment. A study team member, either someone licensed or under the 
supervision of a licensed therapist, will re-administer PSS-I, QIDS-C, and C-SSRS; patients will 
complete self-reports and tasks of target engagement. Treatment dropouts will be immediately assessed 
and will stay in the assessment portion of the study. 
Booster Sessions. Partial responders (less than 20% reduction on PTSD or MDD symptoms; 
Graham et al., 2017) to the 6 sessions of PATH or PMR will receive 2 booster sessions from members of 
the study team (licensed or under the supervision of someone licensed). All others will enter follow-up. 
This will provide dosing and timing information by examining how many participants respond to 6 
sessions, and how many become responders with the booster sessions.  
 
1- and 3-Month Follow-up Assessments. Patients will be re-evaluated 1 and 3 months after 
treatment by a member of the study team (licensed or under the supervision of someone licensed). The 
PSS-I, QIDS-C, and C-SSRS will be re-administered, and all self-reports and tasks of targets engagement 
will be completed. Additional treatment will be documented and referrals provided as needed.  
 
 
Data to be Collected for your study  
(AFTER consent and HIPAA Authorization have been obtained) 
List all data to be collected for the research study or attach a data collection sheet (e.g. laboratory values, 
physician notes, length of stay, etc.)   
 
At the beginning of the intake, participants will complete the informed consent process prior to the 
collection of study data. After the informed consent process, information for the NIMH Data Archive 
GUID (full name, sex, date of birth, and city of birth) will be collected at baseline. More information 
about the GUID can be found in section 9 of the supplemental protocol. During intake, also after the 
informed consent process, a participant information and history interview, a destabilizing life event 
history interview, and a brief goal assessment interview will be conducted. 
 

 
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All of the following measures (either given by a study team member or self-report), except for the 
Working Alliance Questionnaire, treatment acceptability and feasibility measures, and the Hassles and 
Uplifts Scale, are assessed at every time point: pre-treatment, after session 3 of the intervention, post-
treatment, and at the 1- and 3-month follow-ups. The Treatment Credibility scale is administered at 
session 1 of the intervention and post-treatment, the Utility of Techniques Inventory at session two 
through six, the Perceived Stress Scale at pre-treatment, mid-treatment (after session 3), and post-
treatment, and the Client Satisfaction Questionnaire at post-treatment assessment, and the 1- and 3-month 
follow-ups. The Working Alliance Questionnaire will be administered after sessions one through six. The 
Posttraumatic Cognitions Inventory, Behavioral Activation for Depression Scale, and Snaith-Hamilton 
Pleasure Scale will be administered at pre-treatment, every treatment session, post-treatment intervention, 
and at the 1- and 3-month follow-ups. The Hassles and Uplifts Scale is a very brief ecological momentary 
assessment (EMA) that will be administered daily for one week pre-treatment (i.e., after the intake and 
before the first session of PATH), one week mid-treatment (i.e., one week after third session of PATH), 
and one week post-treatment (i.e., after the sixth and final session of PATH and before the post-treatment 
assessment). The phone screen will be done over the phone and entered into REDCap. However, see 
below for specific COVID-19 changes. 
 
COVID-19 CHANGES 
Independent evaluator assessments, dependent on the sites’ rules and regulations on in-person research at 
the time, will be administered over Zoom, with any paper copies being stored in double-locked cabinets. 
All self-report measures will be answered by participants on REDCap. Either participants will use their 
own technology, or we will provide them Kindles to complete the measures. For the foreseeable future, 
however, all data will be collected online and remotely as a consequence of the COVID-19 pandemic.  
 
Target Engagement for R66 and R31  
Each target will be assessed in two ways: laboratory task and self-report. The laboratory tasks are 
objective assessments of the targets. The complementary self-report measures are well-validated, 
sensitive to treatment change, and reliably associated with psychopathology (PTSD, MDD).  
 
Target: Unproductive Processing. 
Affective Updating (Primary Measure; Pe et al., 2013; Pe, Raes, et al., 2013). The Affective Updating 
task will be administered online through Inquisit Lab on Millisecond. The Affective 2-back task will 
measure updating of affective information in working memory. The task requires participants to 
continuously monitor and modify relevant affective information in working memory. Performance is 
inhibited by rumination. At each trial, participants must remove previously relevant affective information 
from working memory, which has now become irrelevant (trial n-3), encode and identify newer, relevant 
affective information in working memory (trial n), and match the valence of this new information with 
relevant but old affective information (trial n-2). Forty-seven positive and 49 negative words are included. 
Under high levels of stress, deficits in affective updating predict more depressive symptoms over one year 
(Pe et al., 2016) and efficiency of reappraisal (Pe et al., 2013). Effective updating in contrast, predicts 
subjective well-being (Pe et al., 2013).  
Posttraumatic Cognitions Inventory (Secondary Measure; PTCI; Foa et al., 1999). The PTCI is a 36-
item self-report of negative, overgeneralized stressor-related thoughts. Each item (e.g., “The world is a 
dangerous place”, “I am inadequate”) is rated from 1 (totally disagree) to 7 (totally agree); higher scores 
reflect more rigid negative cognitions. The PTCI has excellent convergent and discriminant validity, 
internal reliability, and good test-retest reliability (Foa et al., 1999). Total scores will be used. In 6-
sessions of PE, the PTCI was sensitive to change from pre- to post-treatment (d = 0.80; Zoellner et al., 
2017).  
 
Target: Avoidance. 

 
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Idiographic Behavioral Approach Task (Primary Measure; BAT). Each BAT is unique to each 
participant, so a file of the measure has not been uploaded to the IRB. An idiographic BAT (e.g., Mori & 
Aermendariz, 2001; Haynes, 2001) will use in vivo confrontation with feared or avoided stimuli (e.g., 
news/videos of similar events, pictures of loved one, related objects), measuring avoidance behavior. 
BATs have consistently demonstrated treatment sensitivity, often showing large effects (e.g., η2 = .35, 
Wolitzky & Telch, 2009). A general list of idiographic stimuli will be developed and reviewed with 
participants at pre-treatment, and up to 3 situations will be selected. Each BAT will last approximately 5 
min, with a 2-min baseline and 3-min task. There will be a 5-min baseline prior to the first task and a 
resting period between tasks. 
 
Behavioral Activation for Depression Scale (Secondary Measure; BADS; Kanter et al., 2006) is a 25-
item self-report of approach and avoidance in cognitive and behavioral domains not specific to 
depression. Items are rated from 0 = Not at all to 6 = Completely. Total scores will be used. The BADS 
has good factor structure, internal consistency, construct, and predictive validity (Kanter et al., 2009; 
Manos et al, 2011) and sensitivity to change (d =.86; CBT for depression, O’Mahen et al., 2017).  
 
Target: Reward Deficits. 
Probabilistic Reward Task (Primary Measure; PRT; Pizzagalli et al., 2005). The PRT assesses reward 
responsivity (e.g., Der-Avakian et al. 2013; Pizzagalli et al., 2005, 2008, 2008). In each trial, participants 
choose which of 2 difficult-to-differentiate stimuli was presented. Stimuli are cats and dogs in ratios of 
6:10. At the start of the task, a fixation cross appears on the screen. After a delay of 500ms, a 
constellation of dog and cat faces appear, with one of the animal faces appearing more frequently than the 
other. Participants decide whether more cats or dogs were presented. Unknown to them, correct 
identification of the “rich stimulus” is rewarded 3 times more frequently (“Correct! You won 5 cents”). 
Reward propensity is calculated by increase in response bias during the final block relative to the first. 
Degree of response bias toward the frequently reinforced alternative is a robust measure of reward 
sensitivity (Pizzagalli et al., 2005, 2008; Vrieze et al., 2013). Performance has been found to be 
modulated by dopaminergic compounds (d = 1.45; Pizzagalli et al., 2008) and to improve with treatment 
(Burkhouse et al., 2018). The PRT will be administered online through GitHub on www.cognition.run. 
Snaith-Hamilton Pleasure Scale (Secondary Measure; SHAPS; Snaith et al., 1995). The SHAPS is a 14-
item self-report measuring the capacity to experience pleasure. On a four-point scale (1 = Strongly Agree 
to 4 = Strongly Disagree), varying statements are rated (e.g., “I would find pleasure in small things”; “I 
would find pleasure in a telephone call from a friend”). The measure has good convergent and 
discriminant validity and reflects a unidimensional construct of anhedonia (Leventhal et al., 2006; 
Nakonezny et al., 2010).   
 
Additional Assessment Instruments for the R61 and R33 
 
The Everyday Discrimination Scale – Revised (EDS-R; Williams et al., 1997) is a 9-item self-report 
measure of subjective experiences of discrimination, with a follow-up question querying what they 
believe to be the main reason for those experiences. Items are rated on a Likert scale ranging from 1 
(never) to 6 (almost every day). Total scores range from 9 to 54, with higher scores indicating higher 
perceived everyday discrimination. 
 
The Pandemic Emotional Impact Scale (PEIS; Palsson et al., 2020) is a 16-item self-report measure 
assessing the effects of COVID-19 on the lives and emotional wellbeing on participants. For each item on 
the PEIS, respondents are asked how much their wellbeing and functioning has been different recently, 
compared to how it was before the beginning of the pandemic. The response options are “Not at all (0)”, 
“A little bit (1)”, “Moderately (2)”, “A lot” and “Extremely (3)”. The index score is the sum number of all 
PEIS items given a "Moderate" or greater rating by each respondent. 

 
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The Hassles and Uplifts Scale (DeLongis et al., 1988) can be adapted to be a brief, self-report, EMA that 
assesses daily positive and negative experiences. Specifically, participants are asked to rate on each day 
whether 8 domains (i.e., relationships; work/education; finances; health; social, political, and 
environmental issues; recreational activities; home and lifestyle management; and other) were a “Hassle,” 
“Uplift,” “Both,” or “None.” For the domains that participants rate as a “Hassle,” “Uplift,” or “Both,” 
they are further asked to rate how much of a hassle or uplift the events were by selecting from the 
following result options: “None or not applicable (0)”, “Somewhat (1)”, “Quite a bit (2)”, “A great deal 
(3).” Furthermore, participants are asked to rate how they coped with the hassles and uplifts they endorsed 
with the following response options: “Not at all (0)”, “A little bit (1)”, Some (2)”, and “A lot (3)”. Lastly, 
participants are asked to what extend they have generally felt positive emotions or negative emotions 
throughout the day of the assessment with the following response options: “Not at all (0)”, “A little bit 
(1)”, Some (2)”, “A lot (3)”. 
 
Because the number of items a participant completes depends on how many domains they endorse as a 
“Hassle,” “Uplift,” or “Both,” the number of items completed each day ranges from a minimum of 10 (if 
participants report that all domains are “None” a hassle nor an uplift) to a maximum (if participants report 
all domains were “Both” a hassle and an uplift) of 34 items. 
 
The Perceived Stress Scale (PSS; Cohen, Kamarck & Mermelstein, 1983) is a 10-item self-report measure 
that assesses participants’ self-perception of stress in their lives. More specifically, the PSS measures the 
extent to which participants think their lives are unpredictable, uncontrollable, and overloaded. Items are 
rated on a Likert scale ranging from 0 (never) to 4 (very often). Total scores range from 0 to 40, with 
higher scores indicating higher levels of perceived stress. 
 
The Working Alliance Questionnaire (WAQ; Falkenström, 2015) is a 6-item self-report measure 
assessing the participants’ thoughts and feelings about the relationship with their therapist. Items are rated 
on a 6-point Likert scale from 0 (not at all) to 5 (completely). Total scores range from 0 to 30 with higher 
score indicating higher working alliance. 
 
The EDS-R and PEIS will be given at the pre- and post-treatment assessments. The PSS will be given at 
pre-treatment, mid-treatment, and post-treatment. As noted, the Hassles and Uplifts Scale will be given 
daily for one week pre-treatment, one week mid-treatment, and one week post-treatment.  
 
Psychopathology Symptom Measures  
Both PTSD and depression will be assessed with state-of-the-art, psychometrically-validated interview 
and self-report measures (PTSD Symptom Scale-Interview, PSS-I-5; PTSD Diagnostic Scale, PDS-5; Foa 
et al., 2015; Quick Inventory of Depressive Symptomatology-C, QIDS-C; Quick Inventory of Depressive 
Symptomatology-SR, QIDS-SR; Rush et al., 2003). The Structured Clinical Interview for DSM-5 (SCID-
5-RV; First et al., 2015) and the Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al., 2009) 
will be administered by members of the study team (licensed or under the supervision of a licensed 
therapist) used to assess inclusion/exclusion criteria and monitor suicidality. 
 
Positive and Negative Affect Scale (PANAS; Watson et al., 1988) will be used to assess state affect 
across assessments and sessions, particularly for examining dose and timing of PATH in Specific Aim 1.  
 
Response to Positive Affect – Dampening Subscale (RPA-D, Feldman et al., 2008) is an 8-item self-
report measure assessing dampening responses to positive affect states. Respondents rate the items on a 4-
point Likert scale, ranging from 1 (almost never) to 4 (almost always). 
 

 
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All self-report psychopathology symptom measures will be given at each assessment point and at each 
session.   
 
Treatment Engagement, Acceptability, and Feasibility 
 
Treatment dropout, defined as completing fewer than 4 sessions. Homework adherence between sessions 
will be assessed using a modified version of the Utility of Techniques Inventory (UTI, Foa et al., 1999). 
As is standard in many cognitive and behavioral treatment approaches, therapists will also complete an in-
session record of client engagement/adherence; specifically, therapists will complete the Negative Event 
Revisiting Recording Form, on which they record clients’ subjective units of distress (SUDs) every 5 
minutes while clients engage in the negative event revisiting exercise during sessions 2 through 6. 
Similarly, therapists will complete the Positive Event Reminiscence Recording Form, on which they 
record clients’ subjective units of pleasure (SUPs) every 5 minutes while clients engage in the negative 
event revisiting exercise during sessions 2 through 6. Treatment credibility (Treatment Credibility Scale, 
CS, Addis & Carpenter, 1999) and client satisfaction (Client Satisfaction Questionnaire, CSQ-8; 
Attkisson & Greenfield, 1994; 2004) will also be assessed. Finally, therapist adherence will be rated via 
independent rater using a to-be-developed checklist based on a random subset of 10% session recordings.  
 
Milestones (Go/No Go Criteria) 
 
Go/No Go Criteria. For "Go" to be achieved and to proceed to the R33, two criteria must be met. See 
Table 3. The first is that at least 2 of the 3 primary targets must change. A moderate effect size (d = 0.60) 
was chosen to reflect evidence of clinically meaningful target engagement (see Gold et al., 2017), in line 
with NIMH guidelines for a preliminary signal of target engagement/efficacy in intervention trials. 
  
Second, at least one of the secondary measures must show a moderate effect (d = 0.50) from pre- to post-
treatment. We included measures of each of the targets, as they are conceptualized as interrelated parts of 
a "stuck" system. For “Go” to an R01 after the R33, in addition to target engagement, primary outcomes 
of PTSD and depression must show clinically meaningful gains (e.g., Barth et al., 2016; Cusak et al., 
2016).   
R33 PATH Refinement. Beyond examining outcome data from the R61, we will: 1) conduct interviews 
with standardized questions with 20% of patients, selecting those with small and large gains on 
therapeutic targets; 2) conduct a feedback session with therapists to identify aspects of the manual that 
need refinement; and 3) examine booster session data regarding whether additional sessions are needed 
for the R33. The interview guides will be submitted as through a modification before they are conducted. 
Table 3.  Target Mechanism Engagement 
 
 
Phase 
 
 
Target Mechanism/Outcome 
 
 
Primary Indicator 
 
 
Secondary  
(self-report) Indicator 
Go/No Go1 
Pre-Post Effect 
Size  
(Cohen’s d) 
R61 
Unproductive Processing 
Affective Updating Task 
 
d > 0.60 
 
Posttraumatic Cognitions 
Inventory 
d > 0.50 
Avoidance 
Idiographic Behavioral Approach 
Task 
 
d > 0.60 
 
Behavioral Activation for 
Depression Scale 
d > 0.50 
Reward Deficit 
Probabilistic Reward Task 
 
d > 0.60 
 
Snaith-Hamilton Pleasure 
Scale 
d > 0.50 
R33 
Posttraumatic Stress Severity 
 
PTSD Symptom Scale-Interview 
 
d > 0.80 
Depression Severity 
Quick Inventory of Depressive 
Symptomatology-Interview  
 
d > 0.80 
Note.  1For Go to R33, at least 2 of the 3 primary mechanism indicators must change and at least one of the secondary indicators must change.  For 

 
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Data Analysis Plan 
Directions: Describe the data analysis plan, including any statistical procedures. If applicable, provide a 
power analysis, describe primary and secondary study endpoints including safety endpoints. 
 
General Analytic Strategy 
For Specific Aims 1–3, we will use random effects models, a specific application of general linear mixed 
models (GLMMs) that helps to address common issues with longitudinal clinical treatment data, 
including missingness, serial correlation, and time-varying covariates (e.g., Gallop & Tasca, 2009). These 
models allow for person-specific deviations from overall mean time effects and are robust to missing data, 
using maximum likelihood estimation in cases of ignorable non-response. This analytic approach allows 
for initial modeling of different covariance structures, as well as non-linear time transformations that are 
especially useful when between-assessment intervals are not consistent across time. For Aim 3, mediation 
will be tested using the product of coefficients method with bootstrapped standard errors (MacKinnon, 
2009) and based on a lagged mediation design (e.g., Hofmann, 2006). This approach addresses the need 
for temporal precedence of predictor to outcome and accounts for change between time points of a target 
DV. Analyses involving secondary metrics (i.e., PTCI, BADS, SHAPS) will shift to a more conservative 
GLM framework. 
Data will be screened for accuracy, missing values, and fit with the assumptions of GLMM (e.g., 
linearity, multivariate normality; Tabachnick & Fidell, 2007). Data transformations or model re-
specifications will be performed, if needed. Outcome data will be plotted against time to guide selection 
of applicable time variables; similarly, covariance matrices will be examined to inform selection of the 
best covariance structure. Best fitting models will be evaluated based on these plots and model fit 
information (e.g., AIC, BIC). We will use pattern-mixture models to examine whether missingness can be 
considered ignorable. For non-ignorable missing data, values will be multiply imputed and data 
recombined (Rubin, 1987) in the mixed model program or comparable model-supported approaches. We 
will examine associations between primary dependent variables with factors such as gender and time 
since event and make appropriate adjustments (e.g., covarying predictors). In analyses nesting subjects 
within treatments (Aim 2), dummy codes will be used (Snijders, 2005).  
Power Analysis 
Our approach to power analyses aims to balance pragmatic factors with analytic considerations. We focus 
primarily on Specific Aim 1 (R61) and Specific Aim 2 (R33). Primary analyses for both aims will involve 
random effects models; however, because it is difficult to accurately estimate covariance structures of 
such models, a priori power or sample size estimations have limited value. Fang (2006) has shown that 
ideal sample sizes often far exceed clinical resources for conventional trials, whereas other studies have 
shown that small sample sizes do not bias estimates of fixed effects (e.g., Bell et al., 2008). Accordingly, 
we frame our power calculations in line with GLM models that mirror the primary tests and hypotheses of 
our more complex random effects/GLMM models. In general, estimates were calculated based on α = .05 
and power (1 – b) = .80, using intent-to-treat, repeated-measures designs (e.g., paired t-tests). Power 
calculations were completed using G*Power (Faul et al., 2007). For Aim 1, with an estimated pre-post 
effect size of d = 0.60 (one-tailed tests), we are well-powered with a sample of 45. In fact, for a sample 
size of 45, an alpha of .05, and power of .80, we will be able to detect a small to moderate effect size of 
.38. For Aim 2, we based power estimates on a primary comparison of time by treatment interaction in an 
RMANOVA model. For a five time points, two groups, RMANOVA with a correlation of r = .70 

 
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between measures, we are well powered to detect treatment X time small effect size of .07 with 67 
patients per treatment. For Specific Aim 3, using Monte Carlo simulations in MPlus 6.0 (Muthen & 
Muthen, 2002) with the same alpha, power, and sample size of at least 67 per condition, we are 
adequately powered to detect an indirect effect size as small as d = .50.  
Specific Aim 1: Engage Targets (R61) 
We will examine whether PATH engages targets with at least medium-size effects (d = 0.60) on 2 of 3 of 
primary targets from pre- to post-intervention. Primary target dependent variables are: Affective 
Updating, BAT, and PRT. We will conduct a planned contrast of pre- and follow-up time points within 
each separate model. This test is analogous to a contrast in ANOVA or a paired t-test, but superior in 
terms of estimation of missing data and modeling of covariates. The resulting test yields an effect size that 
can be converted to a d (Feingold, 2013) and compared to our target threshold of d = 0.60 for all three 
models as part of our Go/No-Go rules. For secondary measures of PTCI, BADS, and SHAPS, we will use 
the GLM approach described above and compare to our target threshold of d = 0.50 as part of our Go/No-
Go rules.  
Dosing and timing of treatment effects. Dosing will be assessed by graphing individual symptom 
trajectories to identify groups of individuals who may need more treatment, including specifically the 
shift of positive and negative affect over time (PANAS). To understand timing of effects, primary 
analyses will be augmented with tests focused on brief, critical change intervals, yoked to the introduction 
of new target-related content (session k). We will compare residualized change in target (primary 
measures: Affective Updating, BATs, PRT) in the pre-introduction phase (session k-1 to session k) to 
change in the post introduction phase (session k+1 to session k+2). These windows will differ for each 
target, as they are introduced sequentially (e.g., reward deficits, pre-introduction = session 1 and 2, post-
introduction = session 3 and 4). Change scores will be compared using t-tests. Similar analyses will be 
utilized with the PANAS.    
Specific Aim 2: Replication of Target Engagement (R33) 
We will examine whether PATH alters therapeutic targets in comparison to PMR. Primary dependent 
variables are Affective Updating, BATs, PRT. Secondary dependent variables are PTCI, BADS, and 
SHAPS. We will compare the main effect of treatment (PATH or PMR) over time separately in each of 
three models. These models will estimate the effects of treatment on both the level of the target at 3-
month follow-up and change over time (slope). Random intercepts and random coefficients for time-
varying covariates (e.g., time) will be specified, if the model fit is better than a fixed effects model. For 
example, yik = β0 + β1 Timeik + β2 Treatment + β3 (Treatment i x Time ik) + v0i + v1I Timeik + εik where 
Treatment represents a dummy-coded effect (Group = 0 for PATH, 1 for PMR), i=subject, k=time, and y 
= DV of interest. We hypothesize that differences will emerge between PATH and PMR specifically for 
Affect Updating, BAT, and PRT. For secondary measures, we will use the GLM approach above in an 
ANCOVA-like design to test the interaction of treatment and time.  
Specific Aim 3: Linking Changes in Targets to Changes in Stressor-related Symptoms (R33):  
We will examine whether changes in target mechanisms (pre- to post-) predict improvement in PTSD 
(PSS-I) and depression (QIDS-C) at pre-, mid, post-, 1-, 3-month follow-up. In GLMs, we will evaluate 
targets from pre- to post-treatment and at 3-month follow-up, with corresponding metrics to assess change 
in symptoms (PSS-I, QIDS-C). In the GLMs, treatment will predict changes in symptoms from pre- to 
post-treatment (controlling for baseline levels) and pre- to follow-up. GLMMs will be conducted as 
above, and treatment will be used to predict levels and change in symptoms. Next, in GLMs, we will 

 
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predict pre-post change in target mediators (unproductive processing, avoidance, reward deficits) from 
treatment (A path) and follow-up outcomes from the mediator (B path), controlling for treatment and 
baseline symptoms. GLMM will test for mediation by predicting the mediator at all time points from 
treatment, and the outcome at all time points from the mediator, controlling for treatment. Similar 
analyses will be used for secondary measures.   
Specific Aim 4: Feasibility and Dropout/Acceptability of PATH Intervention (R61/R33): 
We will examine feasibility and acceptability of PATH. Dependent variables are treatment helpfulness 
(CS, CSQ), adherence (UTI), completion, and therapist fidelity. For the R61, we will use benchmarks 
from our PTSD RCT (Zoellner et al., 2019) for CS (M = 37.26, SD = 7.33) and CSQ scores (M = 11.70, 
SD = 4.76). We hypothesize PATH scores will not significantly differ from benchmarks, based on a sign 
test. Adherence (UTI) is expected to exceed 50% in PATH, dropout to be below 20%, and therapist 
fidelity to exceed 80%. In the R33, PATH and PMR will be compared via t test and chi-square analyses 
across these indices.  
Risks to Research Participants 
List the reasonably foreseeable risks such as breach of confidentiality, discomforts, hazards, or 
inconveniences to the research participants related to their participation in the research. Include a 
description of the probability, magnitude, duration, and reversibility of the risks. Include the physical 
psychological, social, legal, and economic risks.  
Risks associated with PATH are mild to moderate discomfort when exposed to distressing memories. All 
event processing will be carried out with the full knowledge and consent of the patient. Exposure-based 
therapies for both PTSD and depression have produced considerable benefit to patients (e.g., Cusack et 
al., 2016; Hayes et al., 2005; 2007; Grosse-Holforth et al., 2012; 2017). Although some patients do not 
benefit from these treatments, there are only a handful of reports of negative side effects, such as an 
increase in PTSD symptoms in five combat veterans (Pitman et al., 1991). None of the patients in our past 
or current treatment studies sustained prolonged negative reactions to exposure (e.g., Foa, Zoellner, 
Feeny, Hembree, & Alvarez Conrad, 2002; Jayawickreme et al., 2014). 
 
There is the possibility that participants will not exhibit significant symptom reduction to the PATH 
program or PMR. Further, there is the possibility of a return of clinically significant symptoms during the 
follow-up phase (i.e., relapse).   
 
Provisions to Protect the Privacy Interests of Research Participants 
Directions: Describe the steps that will be taken to protect research participants’ privacy interests.  
(Consider issues such as physical space, proximity to other, and participant preferences)  
 
Participants will be instructed that information shared in sessions is confidential. Participants will be 
instructed about the limitations and obligations in regard to reporting of elder abuse, child abuse, 
suicidality and homicidality. We will follow state laws and professional ethics in handling these issues. 
Participants will be reminded at each appointment that they do not need to disclose any information that 
they are not comfortable with sharing. Participants will be given the phone number for Case Western staff 
and will be given the Cuyahoga County 24-hour crisis hotline (216) 623-6888. 
 
Potential Benefit to Research Participants 
Describe the potential benefits that individual research participants may experience from taking part in 
the research. Include the probability, magnitude, and duration of the potential benefits.  If there is no 
direct benefit, state the potential benefit to society. 

 
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We anticipate that receiving PATH will lead to improvements in functioning for participants, including 
reduced symptoms of PTSD, depression, and functioning. However, this cannot be guaranteed.  
 
Withdrawal of Research Participants 
Directions: Describe the anticipated circumstances under which research participants will be withdrawn 
from the research without their consent. Also include the procedures that will be followed when a 
research participant withdraws or are withdrawn from the research, including partial withdrawal from 
procedures with continued data collection. 
 
At every session, patients will be clinically monitored for suicidal risk or serious depression, and 
withdrawn from the study if these conditions are present and preclude participation. If research 
participants choose to withdraw from the study, they will do so by contacting the local investigator (Dr. 
Feeny). 
 
Alternatives to Participation 
Directions: List other available clinical treatments, what would be included if a subject continued on 
standard of care therapy. If this is not a clinical trial, you may select the box indicating that the 
alternative is not to participate. If there is a viable alternative you must list it in the consent. 
 
Individuals are free not to participate in this study, free to not answer questions, and free to stop being in 
the study at any time. As an alternative to this study, individuals may choose to receive counseling or 
therapy from another community provider. If individuals choose to do this, we will provide them with 
contact information for other counselors who work with survivors of trauma. This therapy will be at the 
individual’s own cost.  
 
Costs to Research Participants 
Describe what costs research participants will be responsible for as a result of their participation in the 
research, including but not limited to: clinical services required by the protocol deemed billable to 
insurance, transportation to study visits, parking, costs of drugs, cost of therapy, lost broken or stolen 
devices, etc.  Explain who will be responsible for payment of provided services in the event of 
insurance denials.  List what procedures, drugs, devices, supplies will be paid by the study sponsor or 
covered by other funding. List the other funding source. 
 
N/A There will be no cost to research participants. 
 
Research Participant Compensation 
Describe the schedule, payment method, and payment total of any incentives or compensation that 
research participants will receive for participation in the research (e.g., gift cards or cash with 
amount, t-shirts, devices, bags, swag, etc.) 
Describe the schedule, payment method, and payment total of any reimbursement that research 
participants will receive for participation in the research (e.g., gift cards or cash with amount, etc.) 
 
During the intervention, there is no monetary compensation for participation. Participants will be 
compensated $50 per assessment after treatment (post-treatment, 1- and 3-month follow up assessments) 
and up to $7 per Probabilistic Reward Task assessment (assessed up to 5 timepoints). Participants can 
earn up to $185 total for completing all assessments.  
 

 
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Provisions to Monitor the Data to Ensure the Safety of Research Participants 
Describe how often the data will be monitored for completeness, accuracy and adherence to the protocol. 
Indicate if there will be a Data and Safety Monitoring Board or Committee.  Provide information about 
the DSMB/C including the contact information of the committee member(s) (as applicable); whether it is 
independent from the study sponsor; how often it meets; the type of data that will be used; written reports, 
etc. 
 
We will create a Data Safety and Monitoring Board (DSMB). We will include experts in statistics, PTSD 
and depression psychotherapy and clinical trials. These individuals will be experts in their fields and not 
associated with the trial in any manner. The DSMB will review the research protocol and plans for data 
safety and monitoring. They will be responsible for evaluating the progress of the RCT including 
recruitment, retention, and ongoing risk benefit ratio. The DSMB will receive an annual report that 
reviews recruitment, randomization, preliminary results for intervention, and safety data. Masked data 
will be presented to the DSMB, with the PI and investigational team remaining blind to the ongoing trial 
results. Only members of the DSMB will see interim data. The DSMB will also consider factors external 
to the study, such as scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the study. The DSMB will convene annually to review this report and provide 
written feedback for the PI on questions or concerns related to the trial that need to be addressed. The PI 
will respond within 24 hours to any serious concerns raised by the DSMB. Each year the DSMB will 
recommend continuation or stoppage of the trial. 
 
Drs. Zoellner, Hayes and Feeny will be responsible for data and safety monitoring and will provide 
continuous, close data monitoring at each site.  Dr. Zoellner will follow UW’s SAE reporting policy in 
promptly reporting serious adverse events to the UW Institutional Review Board (IRB) and to NIMH.  
Dr. Feeny will follow CWRU/UHC SAE reporting policy in promptly reporting serious adverse events to 
the CWRU/UHC Institutional Review Board (IRB) and to NIMH.  Dr. Hayes will follow UD’s SAE 
reporting policy in promptly reporting serious adverse advents to the UD Institutional Review Board 
(IRB) and to NIMH. Drs. Feeny, Hayes and Zoellner will report all SAEs to their respective IRBs within 
24 hours.  A report of all non-serious adverse events will be provided to the IRB yearly.  NIMH will be 
informed of all actions taken by the IRB as part of its continuing review. 
 
Oversight of the data and safety monitoring will be the responsibility of the CWRU IRB, the UW IRB, 
the UD IRB, and the DSMB. The investigators will ensure that procedures are reviewed and approved by 
the IRB before beginning any new study procedures. A report will be provided to the IRB and DSMB 
following each annual meeting that will include recommendation for continuation or conclusion of the 
study.  
 
Drugs or Devices 
 
N/A 
 
Additional Information 
Directions: If you have any additional information regarding your study not covered in the template, 
please include it here. 
 
All patients in the PATH program will be assigned a therapist throughout the study, who will carefully 
monitor clinical state and therapy effects. Patient symptoms will be assessed at each visit.  Moreover, to 
minimize risk, actively suicidal patients or those deemed to be at high risk (i.e., severe self-injurious 
behavior or suicide within the previous three months) will not be eligible for this study. We will conduct a 

 
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thorough assessment of current suicidality and suicide history at the intake (Columbia-Suicide Severity 
Rating Scale; C-SSRS; Posner et al., 2009). If an individual reports thoughts about harming themselves or 
others during the phone screen, the phone screen assessor will conduct a thorough assessment of suicidal 
and/or homicidal ideation and contact their supervisor, who will make a determination about whether the 
individual is at high risk and needs to be referred for immediate crisis services, such as going to the ER or 
calling the mobile crisis unit. Individuals who are deemed to be at lower risk (i.e., suicidal ideation 
without current method, plan, or intent) will complete a safety plan with the supervisor and agree to 
contact crisis services or go to the ER if their suicidal ideation worsens. Referrals for treatment will also 
be provided. Suicide risk will be discussed for each participant in our weekly team meeting prior to entry 
into the trial, and to reiterate, patients at high risk will not be eligible but will be provided with referrals 
for immediate treatment. During active treatment, suicidal ideation will be clinically monitored by study 
clinicians. The QIDS-SR will be used specifically to monitor suicide risk. At follow-up assessments, 
suicidal ideation will be routinely assessed by independent evaluators. Using these procedures in our most 
recent clinical trial, in which over 60% of patients have current MDD, has allowed us to safely manage 
risk.  
 
Potential side effects from PATH (i.e., temporary emotional reactions) will be addressed by 
reassuring patients that these reactions are common for a subset of individuals and unrelated to whether 
they have long-term improvement. The therapist will also be trained to help titrate emotional responding 
during life event exposure. In the first exposure session, the patient will be given control over the level of 
detail in recounting the traumatic memory. During subsequent sessions, the therapist will use procedures 
to promote increased detail, vividness, and emotionality when the client seems uninvolved. When the 
patient is too emotional, reassurance and distancing techniques will be used (e.g., allowing the patient's 
eyes to remain open).  
 
Non-response and relapse of responders are possibilities. Throughout the course of the study, 
patients’ current symptoms, including suicidality, will be carefully assessed. Before every treatment 
session and at every assessment, patients will complete self-report ratings of their PTSD (PDS-5) and 
depression (QIDS-SR). The treatment provider (PATH or PMR) at the start of the session will review 
symptom ratings. For those with suicidal risk or serious depression, patients will be withdrawn from the 
study if these conditions are present and preclude participation. If a clinician is concerned about the level 
of a client’s suicide risk based on client verbalization or QIDS-SR, the session will focus on risk 
assessment and management. If necessary, procedures are in place for imminent at risk patients to be 
escorted to local emergency rooms. If a patient calls their treatment provider or the research coordinator 
in crisis, an emergency session will be scheduled immediately. All concerns about suicide risk will be 
brought to the attention of the PIs (licensed clinical psychologists) immediately. All patients will be given 
24-hour suicide prevention hotline numbers at the beginning of the trial and reminded of this on as needed 
basis. In addition, patients will have access to the emergency rooms at University Hospital of Cleveland 
(UHC, CASE's affiliate), Wilmington Hospital and Christiana Care Hospital in Delaware, and at UW 
Medical Center, and to study clinicians within 24 hours. Finally, built into the protocol is the provision of 
up to two Adjunctive Services and Attrition Prevention (ASAP) sessions to address emergent clinical 
issues. In our prior trials, we have not needed to exceed the provision of two ASAP sessions. Taken 
together, we have used these procedures successfully for the past decade in our previous trials to manage 
risk successfully. Non-responders will be offered continued treatment, as outlined in Approach Section, 
free of charge or various referral options. Relapsed patients in the follow-up phase will be offered 
additional treatment sessions or various referral options. The referral options include treatment through 
outpatient psychiatry at CASE, UD (Wilmington Hospital, Christiana Care Hospital), or UW.  
 
 
Community-Based Participatory Research 
Describe the involvement of the community in the design and conduct of the research. 

 
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Note: Community based research is research that is conducted as an equal partnership between academic 
investigators and members of a community. In Community Based Participatory Research (CBPR) protects, the 
community participates fully in all aspects of the research process.   
 
N/A 
 
International information 
If you will be conducting international research, address the following issues: 
- 
Sites/locations 
- 
Data sharing 
N/A 
 
 
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