Adapted Cognitive Behavioral Treatment for Depression in Patients With Moderate to Severe Traumatic Brain Injury
Phase: NA
Conditions: Major Depressive Disorder, Traumatic Brain Injury
Sponsor: Massachusetts General Hospital

 
 
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Adapted Cognitive Behavioral Treatment for Depression in Patients with Moderate to 
Severe Traumatic Brain Injury 
 
Principal Investigator: Lauren Fisher, PhD 
 
DETAILED PROTOCOL v. 18.0 
Version Date: March 14, 2023 
 
I. BACKGROUND SIGNIFICANCE 
TBI: Scope of the Problem: Approximately 1.7 million traumatic brain injury (TBI) related 
emergency department visits, hospitalizations, and deaths occur each year in the US.1 Further, 
both military and civilian medical centers are confronted with an influx of TBI cases due to 
military involvement in Iraq and Afghanistan.2 Following TBI, individuals face physical, 
cognitive, emotional, and behavioral consequences that impair overall functioning, such as 
dependence upon others, inability to work, and problems with interpersonal relationships. About 
1.1% of the US population is living with long-term disability as a result of TBI3 and one of every 
five individuals hospitalized due to a TBI does not return to work one year later.4 Estimates of 
the cost of TBI are substantial, ranging from $60.4 billion4 to $221 billion annually,5 accounting 
for medical costs, productivity loss, and lost quality of life. Patients with moderate to severe TBI 
endure average healthcare costs 5.75 times greater than matched controls.6 In addition, roughly 
40% of TBI patients suffer from two or more psychiatric disorders,7 and the cost of care is 3.4 
times greater for patients with moderate to severe TBI and psychiatric illness than patients with 
TBI and no psychiatric illness.6 
Depression after TBI: Major Depressive Disorder (MDD) is the most common psychiatric 
illness in patients with TBI,8 often impeding the recovery process and resulting in long-term 
impairment in functioning.9 The prevalence of depression in TBI has ranged from 6% to 77% 
using clinical rating scales10 and from 17% to 61% using diagnostic criteria.11 Although the risk 
for developing MDD is significant in the first year after TBI (53.1% of patients hospitalized for 
TBI),12 increased risk for depression persists many years after the injury.13 Depressive symptoms 
are associated with worse global outcomes in the first six months,14 and up to five to seven years 
after the injury.15 Individuals with MDD following TBI experience greater problems with 
attention, memory, processing speed, and executive functioning than patients with TBI and no 
depression.16,17 Further, MDD following TBI is associated with higher prevalence of 
aggression18 and suicidal behaviors.19,20,21 
The mechanisms of post-TBI depression are not well understood. It is reasonable to 
hypothesize that some processes driving the onset and maintenance of post-TBI depression may 
be specific to TBI, while some may be shared with individuals without TBI.9 TBI may cause 
changes in brain function that initiate the development of symptoms that mimic the clinical 
presentation of MDD in the acute or subacute post-TBI phase.22 Some evidence suggests that 
neuronal and glial loss in the prefrontal and hippocampal regions of the brain may contribute to 
post-TBI depression.23,24 Genetic, developmental, and psychosocial factors may also contribute 
to the development of post-TBI depression.25 Psychological vulnerability, awareness of 
disability, activity or physical limitations, and social disruption following TBI may contribute to 
the maintenance or delayed onset of chronic psychiatric symptoms.24 Some studies have 
suggested that psychologic and environmental factors may be more critical in the development of 
post-TBI depression than changes in brain function caused by the TBI.26,27 One model of post-

 
 
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TBI depression suggests that negative self-appraisal and self-appraisal of disability are strongly 
correlated with depression, and that depression is significantly related to functional outcome 
independent of injury severity and disability.27 Taken together, current evidence supports a 
biopsychosocial model of post-TBI depression that is likely to have significant treatment 
implications.   
Treatment of Depression in TBI: Similar to our understanding of the mechanisms of post-TBI 
depression, there is limited understanding about the efficacy of treatment. Further, there are no 
evidence-based guidelines for the treatment of MDD in patients with TBI. Standard treatments 
for depression in patients with TBI and mood symptoms, such as pharmacological 
treatments,11,28,29,30,31 cognitive behavioral therapy (CBT),32,33,34,35 physical exercise,36,37,38,39,40 
and multidisciplinary, psychosocial interventions41,42 have been examined and present mixed 
findings.43 Moreover, most studies did not require subjects to meet criteria for MDD and were 
not designed to prospectively treat MDD. The majority of these studies did not have the 
methodological rigor (i.e., randomized controlled trials, large samples, clear entry criteria) 
necessary to draw definitive conclusions on the efficacy of traditional treatment for MDD in 
patients with TBI, and clinicians are forced to rely on clinical judgment and recommendations 
used for other populations.44 Relying on guidelines developed for the general population is 
problematic given that patients with TBI and psychiatric problems may not respond as well as 
patients without TBI to traditional psychotherapeutic interventions as a result of TBI-specific 
impairments (i.e., impaired cognition).45 A recent meta-analysis of treatments for depression 
following mild TBI revealed that active treatment is no more beneficial than placebo,46 
suggesting that standard depression treatment may not be enough and needs to be adapted to 
address other issues following TBI. 
Given the strong association between self-appraisal of post-TBI ability and depression27 and 
the effectiveness of CBT for depression in the general population,47,48 CBT may be an ideal 
intervention to adapt for individuals with MDD and TBI. As such, studies on CBT for depressive 
symptoms in TBI have been encouraging. However, effects were modest, often indicating only 
partial symptom reduction and large variability.11,43 Moreover, none of the four studies that 
included cognitive behavioral interventions for depression in TBI and demonstrated some 
improvements in depressive symptoms32,33,34,35 were designed specifically to treat individuals 
with MDD. This is problematic because the efficacy of CBT for MDD following TBI cannot be 
concluded from studies of individuals with subthreshold symptoms, given that comparatively 
greater illness severity, impairment in functioning, number of recurrent episodes, and risk of 
relapse are often evident in individuals with MDD.49 Further, the intervention tested by Bradbury 
et al.34 was education-matched (not randomized controlled), designed to treat “emotional 
distress,” and included individuals with TBI as well as non-traumatic brain injuries (i.e., due to 
stroke, tumor, fall). Topolevec-Vranic et al.32 executed a study of internet-delivered CBT that 
was not controlled and Tiersky et al.33 examined a comprehensive treatment program that 
presents significant challenges to feasibility (i.e., cost, resources) and implementation. Finally, 
Bédard et al.35 did not find consistent reductions in depressive symptoms across measures, 
resulting in inconclusive results about the superiority of mindfulness based cognitive therapy 
over wait-list control for individuals with depressive symptoms following TBI. Taken together, 
small samples, imprecise study criteria, and heterogeneous selection of assessment measures and 
study design limit the ability to make comparisons across studies and draw definitive conclusions 
about the efficacy of CBT interventions in this population.  

 
 
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Nonetheless, CBT has significant promise in the treatment of MDD following TBI when it is 
effectively adapted to address the needs of individuals with TBI. Two recent studies of TBI-
tailored CBT were prospectively designed to target depression. Fann et al.50 examined telephone 
and in-person CBT for DSM-IV51 diagnosed MDD tailored for individuals with TBI. Although 
preliminary findings suggest that minimally adapted CBT may be more helpful in treating MDD 
than a control group after 8 weeks, the study had 1) inconsistent findings across primary and 
secondary measures, 2) a study design that included choice stratification and a biased usual care 
group, and 3) small, heterogenous sample (18 subjects completed in-person CBT). After 16 
weeks, the outcomes for the CBT group were similar to the usual care group. Ashman et al. 52 
compared the efficacy of TBI-tailored CBT and supportive psychotherapy in a sample of 77 
individuals with depression and mild to severe TBI and found no differences in outcomes 
between interventions. Of note, the study was comprised of a heterogeneous sample in terms of 
1) TBI severity and 2) duration of time since injury (average > 10 years), and it demonstrated 
overall low response to treatment. Relatively long duration of time since injury may suggest a 
sample of participants with treatment resistant depression who are likely to be qualitatively 
different from individuals who have experienced less time since TBI. In addition, the study 
utilized a very active comparison group and found no significant moderating variables, thus 
providing no clear explanation about the lack of significant findings. Given the paucity of 
research and outstanding questions about the efficacy of an adapted CBT for MDD in individuals 
with TBI, further research is needed.50,52 
Adapting Cognitive Behavioral Treatment will Improve Outcomes: Despite the promise of 
CBT in treating MDD in patients with TBI, there are a number of difficulties that distinguish 
depressed individuals with TBI from depressed individuals without TBI.16 Thus, there have been 
strong recommendations to modify psychological interventions to address the specific needs of 
individuals with TBI.53 Individuals with TBI typically experience significant neuropsychiatric 
sequelae, which can impede the rehabilitation process.54,55 Some of the most persistent cognitive 
problems after TBI include difficulties with attention, concentration and memory.56 Attention 
impairments among those with TBI are multifaceted but can include lowered vigilance, increased 
distractibility, slowed processing time, and impaired ability to attend to various aspects of one’s 
environment.57 Many individuals also experience deficits in executive functioning skills, such as 
problem solving, working memory, abstract reasoning, planning, conceptual flexibility, and 
organization.55,58 In addition, patients with moderate to severe TBIs often experience deficits in 
social cognition (e.g., emotion perception, cognitive empathy)59 which can interfere with 
interpersonal relationships and efforts to use psychological treatment strategies. 
Standard CBT for depression involves 50-minute weekly, individual psychotherapy sessions 
and assumes an adequate degree of cognitive functioning such that patients are able to 1) learn 
and apply new coping skills in the context of sessions, and 2) complete self-monitoring, skills 
practice, and follow through on experiments and activities between sessions.60,61 Yet, given the 
cognitive sequelae of TBI, patients with TBI and MDD are likely to struggle with the 
assumptions inherent in standard CBT for depression. In fact, low adherence rates and feedback 
from an online CBT study highlighted patients’ limitations with reading, comprehension and 
memory.32 Notably, the only randomized controlled trial of (standard) CBT for post-stroke 
depression, another condition with significant cognitive deficits, did not demonstrate superiority 
of CBT over the control group.62 However, efforts at adapting CBT to compensate for the 
neuropsychiatric sequelae of TBI have been beneficial in improving emotional well-being34 and 
reducing anxiety in patients with TBI.63 (See Table 2 for adaptations).  

 
 
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The current protocol will pilot an adapted cognitive behavioral treatment for Major 
Depressive Disorder for patients who have sustained a moderate to severe TBI. The intervention, 
CBT-TBI, retains a focus on standard CBT for depression,60 and adapts it by taking into account 
the challenges faced by individuals with TBI (e.g., problems with attention, memory, and 
executive function). The acceptability of the intervention will be examined in open study of 10 
subjects, and the potential efficacy of the intervention on depression will be tested in a 
randomized sample of 40 subjects. The proposed project is the first, necessary step in obtaining 
funding for an R01 application to conduct a larger, well powered, randomized controlled trial. If 
CBT-TBI proves to be effective, it will be one of the first evidence-based psychosocial treatments 
for MDD following moderate to severe TBI. If effective, CBT-TBI can eventually be 
disseminated and used to train clinicians throughout the fields of mental health and rehabilitation 
medicine, with varying levels of education and experience. Improved treatment of MDD in 
patients with TBI could lead to significant improvements in overall functioning and reduced 
burden of disability in the U.S.  
 
PRELIMINARY STUDIES 
Past Performance as a Traumatic Brain Injury Model Systems (TBIMS) Site: TBIMS is a 
longitudinal, multi-center study which investigates the course of recovery and outcomes 
following acute neurotrauma and inpatient rehabilitation. Spaulding Rehabilitation Hospital 
(SRH), our primary recruitment site, enrolled patients in the TBIMS National Database from 
January 1999 through 2007. SRH enrolled a total of 350 subjects into the TBIMS National 
Database during the 8.75-year period, averaging 40 subjects per year (exceeding the national 
benchmark of 35 per year). Between January 2002 and September 2007, following expansion of 
the SRH Brain Injury Unit, the Spaulding TBIMS enrolled 279 subjects into the database, 
averaging 49 cases per year. After the TBIMS inclusion criteria were expanded to include those 
injured within 72 hours (previously 24 hours), during the period between January 2006 and 
September 2007, 100 subjects were enrolled for an average of 57 annually. As a TBIMS 
National Database Follow-up Center (2007-2011), 345 interviews have been completed, 
averaging 69 per year. High level performance as a TBIMS Center demonstrates the strong 
commitment to clinical research and high-volume availability of potential research subjects at 
SRH. The Spaulding-Harvard TBI continuum of care was awarded the model systems again from 
2012-2017. 
TBIMS Secondary Data Analysis: The PI examined TBIMS follow up data for participants 
who completed a measure of depression (PHQ-9) one (n=3,182), two (n=3,142), five (n=2,792), 
ten (n=1,598), fifteen (n=372), and twenty (n=214) years following their injury.13 After one year, 
28.1% of patients endorsed the presence of 5 or more depressive symptoms at least several days 
over the last 2 weeks (score of ≥1 on the PHQ-9), with at least one symptom being depressed 
mood or anhedonia, which was used to indicate the likely presence of MDD. Prevalence of MDD 
remained relatively stable two (27.8%), five (26.9%), ten (26.3%), fifteen (26.3%), and twenty 
(24.8%) years post injury. In comparison, only 6.6% of the US population will experience MDD 
in a given year,64 highlighting the high rates of depression in individuals who have sustained 
moderate-severe TBIs. One year following TBI, individuals with depression demonstrate 
elevated rates of suicidal ideation (31.2%) and suicide attempts (3.5%), which persist after two 
years (suicidal ideation 21.1%, suicide attempts 2.4%). Thus, there is a critical need for effective 
treatment of MDD in this population.  
 
INNOVATION 

 
 
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There are no evidence-based guidelines for the treatment of MDD in patients with TBI. Review 
of pharmacological studies provides some suggested treatment strategies; however, the majority 
of depressed patients prefer psychotherapy,65 which is important given that receiving a preferred 
treatment leads to more clinically meaningful outcomes.66 As described above, there is 
insufficient evidence to support clinical practice recommendations for psychotherapeutic 
interventions for MDD in individuals with TBI.11,44 Nevertheless, MDD following TBI is highly 
prevalent and clinicians are forced to rely on evidence from clinical trials that examine 
treatments for depression in the general population. CBT offers an efficacious treatment for 
depressed patients without comorbid conditions and preliminary findings suggest that it could be 
beneficial for patients with TBI. However, Beck initially conceptualized cognitive therapy as a 
treatment for depressed individuals in the general population. Since its inception, CBT has been 
adapted for a variety of psychiatric conditions (i.e., suicide, phobias, and personality disorders)67 
and tailored for some difficult-to-treat disorders, such as schizophrenia68 and adult attention 
deficit disorder.69 Successful adaptations of CBT have even been developed for depressed 
patients with multiple sclerosis,70 Parkinson’s Disease,71 and Alzheimer’s Disease.72 Yet, CBT 
for depression has not been adequately adapted for individuals with TBI who are faced with a 
multitude of specific challenges (i.e., problems with attention and concentration, memory, and 
executive functioning). The proposed research is innovative, in that it demonstrates the first, 
necessary step in developing and prospectively evaluating a cognitive behavioral intervention 
for MDD that has been adapted for individuals with moderate to severe TBI. Eventual findings 
may be used to inform the development of guidelines for depression treatment and inform 
changes in the standard of care in this population. 
 
II. 
SPECIFIC AIMS 
 
Aim 1: Manual Development. To develop a structured, cognitive behavioral treatment manual 
for depression adapted for individuals with moderate to severe traumatic brain injury (CBT-
TBI), as well as evaluate its acceptability and tolerability in an open 12-week pilot trial (N=10). 
Hypothesis 1a: Participants will report high satisfaction with and acceptability for CBT-TBI 
per clinical interview and Satisfaction with Therapy and Therapist Scale – Revised (STTS-R). 
Hypothesis 1b: Subject adherence to the protocol, including clinician-rated, self-report, and 
neuropsychological battery, will be high (at least 80% will complete all sessions). 
 
Aim 2: To evaluate the acceptability and tolerability of, and adherence to, CBT-TBI in a 
randomized waitlist-controlled, 12-week pilot trial (N=40). 
Hypothesis 2a: Participants will report high satisfaction with and acceptability for the revised 
CBT-TBI per clinical interview and STTS-R. 
Hypothesis 2b: Eighty percent of subjects receiving CBT-TBI will complete the study. 
 
EXPLORATORY AIM 
 
Aim 3: To evaluate the potential efficacy of CBT-TBI for depression in the randomized pilot 
trial (N=40) and possible moderators and mediators of outcome. 
Hypothesis 3a: CBT-TBI will result in a greater decrease in IDS-C scores after 12 weeks 
(primary outcome) compared to waitlist control.  

 
 
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Hypothesis 3b:  CBT-TBI will produce an increase in coping skills, adaptive thinking, positive 
self-appraisal, social functioning, and activity level compared to waitlist control, and these 
factors will mediate depressive outcomes.  
Hypothesis 3c: Degree of cognitive impairment at baseline will moderate response to 
treatment. 
 
III. 
SUBJECT SELECTION 
 
Inclusion criteria: 
1. Adults aged 18 and older 
2. English language proficiency 
3. Ability to provide written, informed consent; OR consent provided by legally authorized 
representative with assent from subject 
4. Ability to see and hear (hearing or visual loss cannot impair ADLs or in-room conversation) 
5. Has access to a smartphone/tablet/computer with internet and video capabilities for virtual 
sessions  
6. Having been hospitalized for moderate to severe TBI that occurred at least 3 months prior to 
study entry 
7. Meeting ANY ONE of the following severity criteria, as documented in electronic medical 
record (EPIC) or available outside records: 
a. GCS 3–12 with GCS motor score ≤ 5 within 4 hours after injury 
b. GCS 3–12 with GCS motor score =6 within 4 hours after injury AND documented 
intracranial abnormalities on imaging 
c. GCS 13–15 within 4 hours after injury AND documented intracranial abnormalities on 
imaging 
d. Loss of consciousness (LOC) > 30 min. 
e. Post-traumatic amnesia (PTA) > 24 hours 
8. Out of PTA at the time of enrollment (GOAT>75) 
9. Clinically significant depressive symptoms: meets criteria for Major Depressive Episode on 
the MINI or has a total score ≥ 23 on the Inventory of Depressive Symptomatology – 
Clinician rated (IDS-C) 
 
Exclusion criteria: 
1. Uncontrolled medical illness  
2. Behavioral dyscontrol, defined as the presence of verbally or physically aggressive behavior 
in the past month, as evidenced in medical records, pre-screening interviews, or observed by 
any study staff 
3. Presents with PTSD as the primary diagnosis, as determined by a clinician  
4. Substance use disorder, moderate or severe, within the past 6 months                   
5. Has bipolar disorder, a primary psychotic disorder or current psychotic symptoms, or acute 
suicidality or homicidality 
6. Currently receiving regular (≥ 2 times/ mo.) psychosocial treatment for depression 
7. Has participated in CBT for depression within the past 6 months 
8. Individuals with history of dementia or severe cognitive impairment that is not related to TBI 
(e.g., cognitive impairment requiring assistance with basic activities of daily living, such as 
getting ready in the morning)  

 
 
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Recruitment: Subjects will be recruited through a number of sources. Spaulding Rehabilitation 
Hospital (SRH) will be the main recruitment site.  
 
Outpatient Clinics 
The PI obtained commitment from the Director of the Outpatient and Community Brain Injury 
Rehabilitation Program (Mel Glenn, MD) to support recruitment of depressed patients from the 
TBI outpatient program. The outpatient clinic screens approximately 200 new patients for TBI 
evaluations each year, and anecdotal reports from providers suggest that more than half of those 
patients experience notable depressive symptoms. We will collaborate with the manager and 
director of outpatient clinics in order to recruit through advertisements, clinicians (physiatrists, 
physical therapists, occupational therapists, social workers, psychologists), and direct mailings. 
One strategy includes study staff review of SRH outpatient clinic schedules and Electronic 
Health Records of current patients in order to identify patients who may be eligible. When 
potentially eligible subjects are identified via chart review, we will either 1) approach the 
treating physician about their potential eligibility and then mail an IRB-approved letter signed by 
the physician or 2) we will mail them a letter directly from the PI to share information about the 
study. . Clinical staff will obtain verbal consent for interested patients to be contacted by our 
study staff and may provide information about our study. When possible, a member of our study 
staff may be on site to share more information about our study with interested patients in person. 
Finally, we will utilize the Research Patient Data Registry (RPDR) to identify potential subjects 
across MGB based on key inclusion criteria (e.g., ICD codes indicative of moderate to severe 
TBI, ICD codes for depressive disorders, age 18 and over) and mail them research invitations, 
unless they have opted out (in accordance with July 2021 revised MGB policy). 
 
 
SRH Inpatient Units 
Subjects will be recruited from the inpatient brain injury rehabilitation units at Spaulding 
Rehabilitation Network facilities. Electronic Health Records will be reviewed by study staff to 
identify potentially-eligible subjects and relevant inclusion/exclusion criteria. Clinical staff will 
obtain verbal consent for interested patients [or surrogates for inpatient] to be contacted by our 
study staff and may provide information about our study. When possible, a member of our study 
staff may be on site to share more information about our study with interested patients in person.  
 
We will plan to attend the Outpatient Brain Injury Advisory Group (OBIAG), the TBI Work 
Group and other arenas in the hospital where we can address large audiences of clinicians. Using 
population management tools, we will also ask providers for permission to send mailings to 
patients. We will concentrate our efforts at Spaulding Rehabilitation Hospital, which is the hub 
of the Spaulding Rehabilitation Network (SRN), and is located in Charlestown, MA, which is a 
short distance from MGH and provides a free and easy shuttle service between the facilities. 
Some subjects will also be recruited from other outpatient clinics in the SRN, located throughout 
the greater Boston area and the state. Recruitment efforts will expand outside SRN to other 
Partners and non-Partners institutions who treat patients with TBI. 
 
Some subjects will also be recruited from the pool of callers to the MGH Depression Clinical and 
Research Program who are interested in research. In addition, we will advertise the study through 

 
 
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internal research listings distributed via e-mail and posted online by MGH, RSVP for Health (a 
registry run by MGH and the Brigham and Women’s Hospital where individuals interested in 
clinical research can receive information about research studies), a listing on ClinicalTrials.gov, 
and flyers posted on hospital-approved bulletin boards or in local health clinics. We will also 
speak with colleagues in the Department of Speech, Language, and Swallowing Disorders, who 
have occasionally sought CBT services from the PI for patients who are engaged in cognitive 
remediation. We will also reach out to the Neurology Department at MGH. Finally, we will 
coordinate with other community organizations to recruit subjects who are not MGH patients, 
particularly the Brain Injury Association of Massachusetts. We will utilize social media to 
advertise the study, including Twitter and online forums/groups specifically for individuals with 
traumatic brain injury. These strategies are intended to publicize the study to as large a group as 
possible of people who are interested in research, who suffer from the target conditions, and who 
are likely to be willing and able to come to MGH for the study.  
 
In collaboration with our colleagues at the VA Rocky Mountain Mental Illness Research 
Education and Clinical Center (directed by Lisa Brenner, PhD), potentially eligible patients will 
be identified and referred from within the VA Healthcare System. Approval for all recruitment 
through the VA will be obtained by the VA IRB. We will utilize Electronic Health Record chart 
review to identify potentially eligible subjects. 
 
Additional subjects will be recruited through our partnership with Community Rehab Care in 
Watertown, MA (Medical Director, Mel Glenn, MD, Spaulding Rehab). Staff at Community 
Rehab Care who are briefed on study protocol will gauge client interest in participation and 
encourage interested clients to contact study staff directly or obtain consent from clients to be 
contacted by study staff. Study staff will then screen these participants for eligibility. Study 
clinicians may conduct study procedures (i.e. CBT Treatment, assessment visits) at Community 
Rehab Care in Watertown, MA in order to minimize participant burden. 
 
Prospective subjects will participate in a brief telephone prescreen by a research coordinator, 
using the standard prescreening format used by the DCRP with IRB approval plus TBI-related 
questions, also IRB-approved. The standard prescreen consists of questions about common 
psychiatric symptoms, comorbidities, psychiatric treatment, and demographic data that would be 
relevant to the inclusion/exclusion criteria, thus decreasing the likelihood that a patient who 
clearly does not meet study inclusion/exclusion criteria (e.g., who has been hospitalized for 
bipolar disorder) will be put to the inconvenience of coming for a screen. TBI-specific questions 
will relate to the inclusion and exclusion criteria for the study (e.g., degree of severity, diagnosis 
and timing of TBI). If interested and deemed likely to be eligible, prospective participants will be 
scheduled for a screening visit in person at the DCRP office. 
 
IV. 
SUBJECT ENROLLMENT 
 
A total of up to 70 subjects who demonstrate clinically significant depressive symptoms and 
moderate to severe traumatic brain injury (TBI) will be enrolled in the entire study. A Study 
Coordinator will determine possible subject eligibility by phone and those that are deemed 
eligible after the preliminary phone screen will be invited for an screen visit with a DCRP 
clinician to determine eligibility. The screening visit, which is about 4-6 hours long, will consist 

 
 
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of a meeting with a clinician for a structured diagnostic interview and assessment of depressive 
severity and neuropsychiatric symptoms, the completion of self-report questionnaires, and 
neuropsychological testing. This visit may be split into two parts, with the neuropsychological 
assessment occurring during the second part, in order to accommodate subjects’ potential 
limitations due to fatigue. 
 
In the first phase of recruitment, we will enroll 10 subjects in order to pilot test the newly 
developed manual in a nonrandomized, open trial. Based on objective and qualitative feedback 
from participants, the CBT-TBI manual, which includes materials such as CBT homework and 
study diaries, will then be revised. 
 
Once the CBT-TBI manual has been revised, we will enroll up to 60 subjects in the second phase 
of recruitment with the goal of randomizing 40 participants. They will be enrolled using the same 
procedure as described in the open trial (N=10), but eligible participants will be randomly 
assigned in consecutive order to intervention or waitlist control group. Given that history of pre-
injury MDD is the strongest predictor of post-TBI depression12 and the higher incidence of MDD 
in women than in men,73 randomization will be stratified by history of MDD and gender, so that 
both conditions include the same number of subjects with and without pre-injury MDD, as well 
as males and females. The randomization list will be provided by the biostatistician and 
maintained by the research staff. During the first 12 weeks, as per the schedule outlined below, 
participants randomly assigned to the waitlist control group will be seen only for assessments. 
Control arm participants will receive treatment as usual outside of our clinic and scheduled 
assessments in our clinic for 12 weeks. After 12 weeks, they will be offered the CBT-TBI 
treatment. 
 
 
Independent evaluators are masters and doctoral-level staff members from the DCRP who donate 
time to serve as raters for research studies. Full-time psychologists, psychiatrists, and fellows 
devote 10 hours per week to DCRP research activities, including conducting assessment visits or 
treatment for studies. Research fellows and advanced practicum students also contribute hours to 
DCRP research activities as part of their training. DCRP clinicians regularly complete rater 
trainings for structured diagnostic interviews and measures of depressive severity. DCRP 
clinicians will be included as study staff and be able to obtain informed consent. 
  
Procedures for obtaining informed consent:  
Informed consent will be obtained at the time of the screening visit, prior to the collection of any 
data for the study (such as questionnaires or diagnostic interview). Before meeting with the study 
clinician, subjects will receive a written copy of the consent form that includes an easy-to-read 
description of the protocol, risks and benefits, privacy concerns, and provisions for subjects who 
decide to discontinue the study. The Study Info sheet will be emailed or mailed to patients on a 
case-by-case basis as a supplement to consent review, in order to help patients with cognitive 
impairments process the important information and help them better gauge their potential interest 
in the study. Subjects will be informed that they may voluntarily discontinue participation in the 
study at any time. Repetition of consent information can improve subject understanding,74 which 
may be particularly important with this population given expected cognitive impairments. A 
clinician will then review the consent form with the participant and provide the opportunity for 
the subject to ask questions. The clinician will utilize the University of California San Diego 

 
 
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Brief Assessment of Capacity to Consent (UBACC)75 to guide his or her assessment of the 
subject’s capacity for consent. All clinicians will be trained in the administration of this measure 
prior to beginning recruitment. The 10-item scale includes questions about the study that 
evaluate the subject’s understanding, appreciation, and reasoning about protocol elements that 
are critical to meaningful consent. The UBACC typically takes less than 5 minutes to administer. 
Each item is scored on a scale of 0 to 2 points, with 0 indicating a clearly incapable response and 
2 indicating a clearly capable response. Prior to the start of the study, my mentors and I will 
prepare a list of answers that will receive a score of 2 on each item. If the subject obtains 2s on 
all of the items, he/she will sign/date the consent form along with the clinician. If the subject 
obtains 0s or 1s, the information on the items missed and specific questions will be repeated up 
to 3 times, consistent with scale administration instructions, in order to clarify any ambiguous or 
uncertain answers and make a determination about capacity. Consenting clinicians will be 
encouraged to consult with the PI and her mentors in any questionable cases to determine 
appropriate action. If it is determined by the consenting clinician that the subject does not have 
capacity to consent based on inadequate answers to the UBACC, a legally authorized 
representative may provide written consent along with the subject’s assent.  
 
In addition to consent for study participation, subjects will be asked to provide optional 
consent for audio/video taping of sessions. The purpose of audiotaping, measuring therapist 
adherence to the treatment manual, will be explained. Subjects who decline consent to 
audio/video tape will be enrolled in the study and their sessions will not be recorded. Further, 
subjects will be presented with information about between session contact (for those receiving 
the intervention), which will be delivered using telephone calls, text message, or email, 
depending on patient preference. Between session contact utilizing a variety of media will be 
used with the goal of increasing treatment adherence and engagement. On the consent form, 
subjects will be asked to list their preferred methods of communication and will be presented 
with pertinent information about the risks of the various methods of communication. This will be 
reviewed again at the time of the intervention by the study therapist in order to assure ongoing 
consent/assent. 
 
Once the consent form has been signed and participants have provided the address at which they 
will be completing most CBT sessions, study staff will identify the contact information for local 
law enforcement and emergency services nearest to this address in case of emergency. This 
information will be stored for quick access in the master log.  
 
V. 
STUDY PROCEDURES 
 
The primary aim of this study is to develop a highly acceptable, manualized treatment (CBT-
TBI) for MDD in patients with moderate to severe TBI. After developing the manual (Phase 1), a 
nonrandomized trial (Phase 2) will be conducted to test its acceptability and tolerability. Based 
on objective and qualitative feedback from participants and input from mentors and consultants, 
the CBT-TBI manual will be revised (Phase 3). We will then pilot test the efficacy of the 
intervention to reduce depressive symptoms (IDS-C30) after 12 weeks using the revised CBT-
TBI manual compared to a waitlist control group in a randomized pilot trial (Phase 4). Once the 
randomized pilot study is complete, the CBT-TBI manual will be finalized with additional 
feedback from subjects, mentors, and therapists.  
 

 
 
11 
 
For both phases of recruitment, the same study procedures will be used (unless procedures are 
modified in Phase 3, which will then be submitted for IRB review). The proposed study involves 
the following points of contact: (1) Obtaining informed consent and screening (may be broken up 
into multiple visits), (2) biweekly clinician assessments of depressive and neuropsychiatric 
symptoms (weeks 2, 4, 6, 8, 10), (3) weekly self-report assessments of depressive symptoms for 
those receiving the intervention, (4) 12 weekly individual CBT-TBI sessions for those 
randomized to the intervention, (5) a comprehensive assessment at week 12 (primary endpoint), 
which includes the neuropsychological battery, and (6) a 3-month follow-up assessment for those 
who received the intervention (randomized pilot only, phase 4). Assessment visits during the 12 
weeks of treatment may be completed by phone. The week 12 visit can be split into two parts, 
with the neuropsychological assessment occurring during the second part, in order to 
accommodate subjects’ potential limitations due to fatigue.  
 
In the context of the COVID-19 pandemic, all in-person procedures will shift to virtual 
administration via Zoom videoconferencing and/or telephone. When clinical research is safe to 
resume in-person, select procedures may occur in office when they are unable to occur remotely. 
For example, participants who do not have access to a computer may go to the Depression 
Clinical and Research Program to complete computer-based neuropsychological testing (CNS 
Vital Signs) on a clinic computer. Parking will be reimbursed per standard Depression Clinical 
and Research Program protocol if participants park in a designated MGH garage.   
 
 
The following list includes descriptions of each measure being used in the proposed study. 
 
Screening Measures:  
UCSD Brief Assessment of Capacity to Consent (UBACC)75: 10 item scale assessing capacity for 
consent.  
Demographics Questionnaire: includes age, sex, gender, ethnicity, education, and employment.  
Mini-International Neuropsychiatric Interview (MINI)76: A brief structured diagnostic interview 
permitting rapid diagnosis of major psychiatric disorders.  
Ohio State University TBI Identification Method – Interview Form134: A brief interview form for 
obtaining TBI history and severity. 
SCID Psychiatric History: A brief, semi-structured interview form for obtaining basic 
psychiatric history. 
Galveston Orientation and Amnesia Test (GOAT)77: A measure of orientation to place, time, and 
personal information used to assess post-traumatic amnesia. 
 
Cognitive Therapy Awareness Scale (CTAS)78: A 40-item, self-report, true-false measure of 
knowledge of basic CBT skills. The CTAS is a simple, brief measure that has been used in a 
number of studies.78,79,80,81 A score of 20 is suggested to be the average score obtained by 
individuals with no awareness of cognitive therapy.82 
 
Substance Use Questionnaire: A 15-item, self-report questionnaire that assesses if the patient 
used psychoactive substances in the last 30 days. 
 

 
 
12 
 
The Alcohol Use Disorders Identification Test: A 3-item, clinician-rated measure of alcohol 
consumption that can help identify individuals who are hazardous drinkers or have active alcohol 
use disorders.83 
 
PROMIS Pain Intensity: Measures how much a person hurts.84 
 
PROMIS Pain Interference: Measures consequences of pain on relevant aspects of one’s life. 
This includes the extent to which pain hinders engagement with social, cognitive, emotional, 
physical, and recreational activities.85 
 
Depression Measures:  
Inventory of Depressive Symptomology (IDS-C30)86 (primary outcome): 30-item clinician rated 
scale that assesses severity of depression according to the nine DSM-IV51 symptom domains. 
Quick Inventory of Depressive Symptomatology, Clinician-Rated (QIDS-C)87: 16-item clinician-
rated scale that assesses severity of depression according to the nine DSM-IV51 symptom 
domains. 
Columbia-Suicide Severity Rating Scale (C-SSRS)88: Clinician assessment of recent through 
lifetime suicidal ideation and behavior (i.e., attempts, interrupted and aborted attempts, 
preparatory behavior, and nonsuicidal self-injury).  
 
Beck Depression Inventory II (BDI-II) 89: A 21-item self-rated questionnaire that assesses 
severity of depression. 
 
Hospital Anxiety and Depression Scale (HADS) 90: A 14-item self-rated questionnaire that 
assesses severity of anxiety and depression.  
 
PROMIS Bank v1.0: Depression: A 28 item, self-rated, Computerized Adaptive Test that 
assesses severity of depression. The first item is fixed for all participants, but participants’ 
response will determine which item is selected next by the program; this is repeated for all 
subsequent items. 
 
Modified Beck Hopelessness Scale135: A self-report measure of negative expectations for the 
future that has been modified from the 20-item BHS 136. The 10-item modified BHS uses a 5-
point Likert scale, ranging from 0 (not at all) to 4 (very much), with total scores ranging from 0 
to 40.  
 
Neurological Measures:  
Information about TBI diagnosis and severity will be obtained via interview and review of 
medical records (i.e., duration of unconsciousness, Glasgow Coma Scale (GCS)91 score, duration 
of posttraumatic amnesia (PTA), neuroimaging results, and inpatient and/or outpatient 
rehabilitation services). A Release of Information will be obtained at the screening visit in order 
to access the subject’s medical records. 
 
Neuropsychological Measures:  
Rivermead Postconcussion Symptom Questionnaire (RPQ)92: A self-report questionnaire that 
assesses presence and severity of somatic, cognitive, and emotional symptoms after TBI.  
Wechsler Adult Intelligence Scale IV (WAIS-IV): Similarities and Digit Span subtests93: The 
WAIS-IV is a standardized neuropsychological test battery designed to assess cognitive ability 

 
 
13 
 
and intelligence. The selected subtests assess verbal comprehension, working memory, and 
processing speed. 
Test of Premorbid Functioning (TOPF)94: A standardized neuropsychological test that estimates 
an individual’s premorbid cognitive and memory functioning. 
Wechsler Memory Scale IV (WMS-IV), Logical Memory subtest95: A subtest of the WMS-IV 
designed to measure immediate, delayed, and auditory aspects of memory. 
CNS Vital Signs: Brief, computerized, remotely administered neurocognitive test battery 
comprised of seven “core” subtests and three “optional” subtests measuring memory, reaction 
time, processing speed, executive functioning, attention, cognitive flexibility, social perception 
and aspects of cognition. The measures have been normed, and validity and reliability has been 
demonstrated in peer-reviewed publications since 200696. 
Neuro-QOL Item Bank v2.0 Cognition Function Short Form97: An 8-item, self-rated 
questionnaire assessing cognitive function.  
Measures of Global Outcome: 
Glasgow Outcome Scale (GOS-E)98: A clinician-administered tool that assesses global 
functioning after brain injury using a structured interview and assigns an individual to one of 
eight functional categories, ranging from 1 (dead) to 8 (upper good recovery).  
 
Measures of Social Functioning:  
Neuro-QOL Item Bank v1.0 – Ability to Participate in Social Roles and Activities Short Form: 
An 8-item scale that assesses perceived ability to perform one’s usual social roles and 
activities.99  
Neuro-QOL Item Bank v1.1 –Satisfaction with Social Roles and Activities Short Form: An 8-
item scale that assesses satisfaction with performing one’s usual social roles and activities.100 
Measures of Emotion Regulation: 
NIH Toolbox Anger-Affect Fixed Form: A 5-item self-rated questionnaire assessing the patients’ 
experience of anger.100 
 
Neuro-QOL Item Bank v1.0 Emotional and Behavioral Dyscontrol101: An 8-item self-rated 
questionnaire assessing the patients’ experience of emotional and behavioral dyscontrol. 
 
Automatic Thoughts Questionnaire-Revised (ATQ-R) 102: A 40-item self-rated questionnaire that 
assesses the frequency with which an individual endorses positive and negative self-statements. 
Measures of Coping and Awareness:  
Coping Attitudes Scale (CAS)103: A 23-item, self-report measure of positive attitudes, reflective 
of patients recovered from depression.104  
Awareness Questionnaire (AQ)105: A 17-item measure of impaired self-awareness with patient 
and family member forms. 
NIH Toolbox Item Bank v2.0 Meaning and Purpose101: An 8-item self-rated questionnaire 
assessing the patients’ feelings of meaning and purpose. 
 
Measure of Activity: Each participant will be provided with an activity tracker while receiving 
the intervention (e.g. Fitbit Charge 3™, Fitbit Charge 4TM,or a pedometer-like device) which will 
measure number of steps walked as an index of behavioral activation. Devices will be wireless-
enabled and will sync to a computer, allowing for real time, quality controlled access to data. 
Patients will be provided with the device at the first psychotherapy visit (week 1). Behavioral 

 
 
14 
 
treatment adherence data from the activity trackers will be downloaded weekly and used to 
inform treatment. Specific information about the devices will be submitted to the IRB once it is 
obtained. 
 
Acceptability and Satisfaction:  
Satisfaction with Therapy and Therapist Scale – Revised (STTS-R)106: A 12-item self-rated 
questionnaire assessing the satisfaction with the therapy and therapist.  
  
Working Alliance Inventory (WAI)107: A clinician-rated and a self-rated 12-item questionnaire 
assessing the alliance between the clinician and patient. 
 
Post Treatment Visit Assessment: A brief survey assessing the perceived helpfulness of the 
subject matter discussed at each treatment visit. 
 
End of Treatment Assessment: A brief survey assessing the feasibility and perceived helpfulness 
of the intervention. 
 
Other: 
Epidemic – Pandemic Impacts Inventory (EPII) 108: a newly developed measure designed to learn 
about the impact of the coronavirus disease pandemic and future epidemics and pandemics on 
various domains of personal and family life.  
 
All data will be entered directly into REDCap by the study clinicians and subjects. Completion 
of web-based, self-report measures via computer or tablet is likely to be more appealing to the 
study population who may experience physical injuries that impact writing abilities. Further, use 
of REDCap will likely minimize missing self-report study data and allow for immediate follow 
up on missing items, which is likely to be relevant for individuals who have sustained TBIs and 
frequently experience problems with attention and concentration. In the event that circumstances 
inhibit the ability to directly enter the data electronically (via computer or tablet), paper copies 
will be provided for clinician-rated or self-report administration. These paper copies will be 
directly downloaded from REDCap to ensure that the measures look identical to the electronic 
copies.  
 
Table 1 below outlines the schedule of assessments for each phase of the study 
 

 
 
15 
 
Table 1: Schedule of Assessments for Active CBT Patients 
Assessment 
Screen 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Wk 8 
Wk 9 
Wk 10 
Wk 11 
Wk 12 / 
Last Visit 
3mo F/u  
 
Informed Consent; 
UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
Contact Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician Administered 
Psychiatric History Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
OSU TBI Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Release of Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
GOAT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AUDIT-C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Treatment 
Log  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Adverse Events 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CTAS 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
IDS-C 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
GOS-E  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
QIDS-C 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PROMIS Depression 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
BDI-II 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HADS 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
RPQ 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Neuropsych Battery 
(see separate table for 
individual tests) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Neuro-QOL Cognition 
Function – SF 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

 
 
16 
 
Anger-Affect Fixed 
Form  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Neuro-QOL Ability to 
Participate in Social 
Roles and Activities-SF 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Neuro-QOL Satisfaction 
with Social Roles and 
Activities-SF 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Neuro-QOL Emotional 
and Behavioral 
Dyscontrol-SF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Coping Attitudes Scale 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Awareness 
Questionnaire (patient) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
NIH Toolbox Meaning 
and Purpose 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
ATQ-R 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Activity Tracker (data  
syncs wirelessly) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
WAI-SF 
 
 
 
 
 
 
X 
(patient 
version 
only) 
 
 
 
 
 
X 
 
PROMIS Pain Intensity 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
PROMIS Pain 
Interference 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Beck Hopelessness Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
STTS-R and interview 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Post treatment 
assessment (participant) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Homework Compliance 
(therapist) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
End of Treatment 
Feedback 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
COVID-19 
Supplemental Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Approximate Time 
Estimate 
240 
min 
< 10 
min 
30 
min 
< 10 
min 
30 
min 
< 10 
min 
45 
min 
< 10 
min 
30 
min 
< 10 
min 
30 min 
< 10 
min 
180 min 
60 min 

 
 
17 
 
Table 2. Schedule of Assessments for Waitlist Patients (note: after WL week 12 patients continue with Active CBT 
Assessments for 12 weeks)  
Assessment 
Screen 
WL Wk 2 
WL Wk 4 
WLWk 6 
WL Wk 8 
WL Wk 10 
WL Wk 12 / 
Last Visit 
Informed Consent; 
UBACC 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Demographics/ 
Contact Information 
X 
 
 
 
 
 
 
Clinician Administered 
Psychiatric History Form 
X 
 
 
 
 
 
 
OSU TBI Form 
X 
 
 
 
 
 
 
Release of Information 
X 
 
 
 
 
 
 
GOAT 
X 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
AUDIT-C 
X 
 
 
 
 
 
X 
Substance Use 
Questionnaire 
X 
 
 
 
 
 
 
Concomitant Treatment 
Log  
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
CTAS 
X 
 
 
 
 
 
X 
IDS-C 
X 
 
 
 
 
 
X 
GOS-E  
X 
 
 
 
 
 
X 
QIDS-C 
 
X 
X 
X 
X 
X 
 
PROMIS Depression 
X 
X 
X 
X 
X 
X 
X 
BDI-II 
X 
X 
HADS 
X 
 
 
 
 
 
X 
RPQ 
X 
 
 
X 
Neuropsych Battery 
(see separate table for 
individual tests) 
X 
 
 
 
 
 
X 

 
 
18 
 
Neuro-QOL Cognition 
Function – SF 
X 
 
 
 
 
 
X 
Anger-Affect Fixed 
Form  
X 
 
 
 
 
 
X 
Neuro-QOL Ability to 
Participate in Social 
Roles and Activities-SF 
X 
 
 
 
 
 
X 
Neuro-QOL Satisfaction 
with Social Roles and 
Activities-SF 
X 
 
 
 
 
 
X 
Neuro-QOL Emotional 
and Behavioral 
Dyscontrol-SF 
X 
 
 
 
 
 
 
X 
Coping Attitudes Scale 
X 
 
 
 
 
 
X 
Awareness 
Questionnaire (patient) 
X 
 
 
 
 
 
X 
NIH Toolbox Meaning 
and Purpose 
X 
X 
ATQ-R 
X 
 
 
 
 
 
X 
PROMIS Pain Intensity 
X 
 
 
 
 
 
X 
PROMIS Pain 
Interference 
X 
 
 
 
 
 
X 
Beck Hopelessness Scale 
X 
 
 
 
 
 
X 
COVID-19 
Supplemental Survey 
X 
 
 
 
 
 
X 
Approximate Time 
Estimate 
240 min 
30 min 
30 min 
30 min 
30 min 
30 min 
120 min 

 
19 
 
Table 3. Schedule of Neuropsychological Assessments for Open Trial (Phase 2) and 
Randomized Pilot Study (Phase 4)  
 
Assessment 
Screen 
Week 12 / Last Visit 
WAIS-IV Similarities 
X 
 
WAIS-IV Digit Span 
X 
X 
Test of Premorbid Functioning 
(TOPF) 
X 
 
WMS-IV Logical Memory 
X 
X 
CNS Vital Signs 
X 
X 
Estimated time  
1.5 hours 
1 hour 
 
 

 
20 
 
Randomized Pilot Study (Phase 4): Individuals who are randomized to the wait-list control arm 
will be offered the opportunity to receive 12 weeks of CBT-TBI after they complete the week 12 
visit. They will not receive additional compensation if they opt to receive the intervention. 
 
Study Intervention 
 
Study Therapists and Training: Clinicians at the DCRP, including Dr. Fisher, will administer 
the treatment protocol. Therapists will be required to have a master’s degree and will be 
supervised and trained by Drs. Pedrelli and Fisher.  
 
Treatment Fidelity: Recommendations suggested by the NIH Behavior Change Consortium 
workgroup on treatment fidelity will be implemented.109 Therapists will be trained on the 
treatment, and adherence to the manual will be monitored. When participants provide consent, 
sessions will be audiotaped in order to facilitate supervision and manual adherence by Dr. 
Pedrelli and the PI. Weekly supervision with study therapists includes regular review of session 
recordings and feedback on adherence to the manual.  
 
Content of the Treatment (CBT-TBI):  
 
Introduction (Sessions 1-2). A gradual introduction to treatment with strong emphasis on 
rapport building, given that participants will likely have cognitive deficits (and some might have 
deficits in social cognition or a degree of paranoia54). Emphasis on psychoeducation about 
depression after TBI, as well as the CBT model. 
 
Behavioral Techniques (sessions 3-4), including: 1) Symptom self-monitoring. 2) Introduction 
to behavioral activation and identifying strategies to increase engagement with outside world. 
Increased interactions with family and friends may create opportunities for positive social 
experiences and foster a sense of belonging in one’s environment, which may help to improve 
depression.110 3) Collaborative identification of SMART goals (Specific, Measurable, 
Achievable, Realistic and Relevant, Time Limited) broken down into achievable components.111 
A problem solving approach will be used to address possible barriers to achieving goals.112 4) 
Aspects of social skills training113 will be used to address interpersonal and communication 
difficulties.  
 
Cognitive Techniques (sessions 5-7). The cognitive model will be illustrated with concrete 
examples reviewed multiple times. Strategies to identify cognitive distortions, challenge negative 
thoughts, and develop rational responses will be reviewed and simple thought records will be 
used. Cognitive restructuring will help patients challenge negative beliefs that maintain their 
depression and develop more realistic, adaptive ways of thinking.94 We will elicit patients’ 
automatic thoughts about their injury. For example, catastrophizing and demoralization about 
current inadequacies are often observed in depressed stroke patients who frequently compare 
current functioning with pre-stroke level of functioning.114 We will work with patients to identify 
similar distortions and on learning to accept and adjust to life after their injury, while learning to 
identify their values. Research has shown that increased sense of meaning in life is associated 
with lower levels of depression.115 
 
Combining Techniques/Coping Skills (sessions 8-11). Focus on integrating concepts via 
practice, repetition, and specific techniques: 1) Behavioral chain analysis to promote the 
relationship between one’s thoughts, feelings, and behaviors. Facilitates conceptualization of 
target problems, identifies gaps in skills, provides opportunity for discussion of adaptive coping 
skills, and facilitates engagement in treatment.116 2) Identification of behavioral coping strategies 
that can be used when the patient identifies unhelpful thoughts or urges to act aggressively or 

 
21 
 
respond impulsively, such as habit reversal centering on a competing response (e.g., fold your 
hands together and squeeze them so you can’t use them) or stimulus control strategies (e.g. play 
a musical instrument, reminder notes) which are often useful for patients with impulse control 
disorders.117 By facilitating adaptive coping skills, the therapist can help minimize the 
psychological effects of stressful events that contribute to depression.118,119 3) Behavioral 
experiments as a vehicle for new learning and belief appraisal,120 particularly when addressing 
difficulties with adjustment and changes in identity.121 
 
Summary, Review, and Relapse Prevention (session 12): Summary of progress, with emphasis 
on recognizing and responding to signs of relapse. Discussions about further treatment planning, 
when applicable. Some assistance with referrals for further treatment may be provided. No 
follow up care will be provided at the DCRP. 
 
Strategies for Tailoring the Treatment include: 1) between session check-ins (via phone, text 
message, or email) to monitor progress on goals, provide homework reminders, troubleshoot 
barriers, 2) flexible length of weekly sessions (60 min or less), 3) focus on 1-2 key concepts per 
session, emphasizing repetition and checks for understanding, 4) written session summaries, 5) 
therapeutic use of baseline neuropsychological assessment, 6) use of patient workbook, 7) 
external memory compensations (i.e., calendar, notebook), and 8) inclusion of support person, if 
applicable (see details in Table 2).  
 
Table 2. Strategies for Tailoring the Treatment 
Adaptation 
Details 
Impairment 
Addressed 
Rationale 
Length and 
structure of 
treatment 
• 12 weekly individual sessions, 
up to 60 min. each (shorter if 
needed) 
• Focus on 1-2 key concepts per 
session, emphasizing repetition 
and checks for 
understanding.122  
Information 
processing; 
Memory 
impairment; 
Attention deficits 
Studies of CBT for depression include 
similar number of sessions.62,123 
Treatments of similar length showed 
improvement in symptoms of anxiety63 
and depression35,50 in TBI patients. 
Between 
session  
‘check-ins’ 
• 2 contacts, occurring every 2 
days (±1 day to account for 
weekends) delivered in various 
formats depending on patient 
preference: phone, text 
message, email, etc. 
• Monitor progress on goals, 
provide homework 
reminders/prompts, 
troubleshoot barriers 
Memory; 
Executive 
function 
Reinforces concepts reviewed in session. 
Troubleshooting allows sessions to be 
more efficient. 
Use of electronic memory aids has been 
beneficial in improving memory deficits 
for TBI patients engaged in 
neuropsychological rehabilitation.124,125 
 
Session 
summaries  
• Written plan summarizes main 
concepts covered; outlines 
work for upcoming week, 
compensatory strategies to be 
used and details of between-
session reminder(s). 
Recall; 
Information 
Processing; 
Impaired 
Learning 
Modeling what is required for successful 
homework completion can be a 
successful strategy to enhance executive 
function.126 
Therapeutic 
Use of 
Baseline 
Neuro-
• Results from 
neuropsychological testing will 
be compiled for the therapist 
prior to the treatment in order 
Memory 
impairment; 
Executive 
function; 
Allows compensatory strategies to be 
individually tailored to each participant 
and maximizes real-world validity, as 

 
22 
 
psychological 
Assessment 
to inform the selection of 
individualized strategies 
Information 
Processing 
speed; 
Attention/ 
Concentration; 
Social Cognition 
opposed to providing a “one-size-fits-
all” manual. 
 
Adaptations utilized in a previous trial of 
CBT for the treatment of emotional 
distress after acquired brain injury.34 
 
Will utilize strategies that have been 
successfully employed with adults with 
attention deficit hyperactivity disorder 
(ADHD).69 
Individually 
tailored 
compensatory 
strategies 
• With input from mentors and 
didactics, a list of strategies 
will be included in the manual; 
therapists are also encouraged 
to develop strategies with each 
patient. 
• Examples: audiotape sessions, 
reminder/prompting system 
(i.e., alarm), rehearsal, carry 
index card in wallet, post it 
note on mirror 
Provide 
patient 
workbook  
 
 
• Includes numerous handouts 
with key information and 
summaries. Wherever possible, 
handouts include options for 
selection rather than blank 
spaces  
Learning 
Executive 
Function  
Helps participants remain organized. 
Handouts with options minimize the 
extent to which patients must rely on 
their ability to generate new ideas and 
rely on memory of strategies. 
External 
memory 
compensation
s 
• Such as notebooks and 
calendars 
Memory 
impairment 
Useful strategies for patients with TBI 
and memory problems,127 as well as 
adults with ADHD.69 
Include 
support 
person  
(when 
possible) 
• Helps with treatment planning 
and carrying out homework 
assignments 
Impaired insight 
Problems with 
generalization 
Increased repetition/prompting likely to 
improve self-awareness, follow through 
and generalization of skills 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Preliminary analyses will describe the participants’ sociodemographic and clinical 
characteristics. Comparisons will be made using Mann-Whitney or chi-square tests to determine 
if the randomization provided a balanced sample and if patients who dropped out differ from 
those who did not. All analyses will be conducted using the SPSS and/or Stata statistical 
packages. 
 
Aim 1 (Manual Development and Acceptability and Tolerability in Open Trial): We will use 
descriptive statistics to report the number of intervention sessions attended (we expect > 80%), 
number of assessment sessions attended (we expect > 80%), number of study completers (we 
expect >80%), and rate of satisfaction with treatment (total STTS-R score). 
 
Aim 2 (Acceptability, Tolerability, and Adherence in Randomized Trial): We will use 
descriptive statistics to report the number of intervention sessions attended (we expect > 80%), 
number of participants recruited per month (we expect 3/mo), randomization rate (number 
randomized/number consented; we expect about 67% of those consented will be randomized), 
number of assessment sessions attended (we expect > 80%), retention (number of study 
completers/number randomized; we expect >80%), and rate of satisfaction with treatment (total 
STTS-R score). 
 
EXPLORATORY AIM 
 

 
23 
 
Aim 3 (To evaluate the potential efficacy of CBT-TBI for depression in the randomized pilot 
trial (N=40) and possible moderators and mediators of outcome):  
 
Hypothesis 3a: CBT-TBI will result in a greater decrease in IDS-C scores after 12 weeks 
(primary outcome) compared to waitlist control. Response over 12 weeks defined by 50% or 
greater decrease on IDS-C total; remission ≤6 on IDS-C total. Continuous variables will be 
analyzed by generalized mixed effect modeling, which impute missing values based on 
maximum likelihood estimates of missing parameters, allowing analysis of all participants. A 
time-by-condition interaction will be analyzed to test the intervention’s efficacy. Relevant 
potential covariates (e.g., caregiver presence) will also be examined. The percent of responders 
and remitters in each group will be computed in order to estimate an effect size for the R01. 
Although I will test for statistical significance, the primary aim of this pilot RCT is to estimate 
the intervention’s effect size to conduct a larger, more adequately powered R01 study, as is 
outlined in NIH guidelines for developing behavioral interventions128. Given that some prior 
studies utilizing CBT in patients with TBI suggest large effect sizes for reducing emotional 
distress and depressive symptoms,32,34 we expect similar findings.  
 
Hypothesis 3b:  CBT-TBI will produce an increase in coping skills, adaptive thinking, positive 
self-appraisal, social functioning and activity level compared to waitlist control, and these 
factors will mediate depressive outcomes. To evaluate the indirect effect of CBT-TBI to 
depression (IDS-C) through coping skills, adaptive thinking, positive self-appraisal, social 
functioning, and activity level, we will employ an SPSS macro (PROCESS) to test the 
significance of the indirect effect with a bootstrapping approach to obtain confidence intervals.129 
The constructed conditional process model proposes that CBT-TBI will lead to increased coping 
skills, adaptive thinking, positive self-appraisal, social functioning and activity level, and that 
increase in these mediators will result in reduced depression. Bootstrapping is superior to other 
methods for determining the significance of indirect effects, as the assumption of normality for 
the sampling distribution is not required and power is improved.130  
 
Hypothesis 3c: Degree of cognitive impairment at baseline will moderate response to treatment. 
We will run a hierarchical regression model. The main predictor variables (CBT-TBI, cognitive 
impairment) will be mean centered based on previous research.131 Their interaction will then be 
entered to examine the moderating effect of cognitive impairment on the relationship 
between CBT-TBI and depression after entering the covariates (i.e., caregiver presence). To 
examine the moderation hypotheses, we will employ an SPSS macro (MODPROBE) to test 
whether there is a significant interaction.132  
 
VII. 
RISKS AND DISCOMFORTS 
 
There are some potential risks and burdens to participating in the study. Risks and discomforts 
associated with receiving psychotherapy are generally considered modest, but can include a 
worsening of psychiatric symptoms as well as psychological discomfort associated with 
discussion of one’s difficulties. Patients will be given telephone numbers of the doctors involved 
in the study if they would like to talk about any discomforts. Second, answering detailed 
questionnaires and completing neuropsychological testing may create a mild degree of 
inconvenience for the subjects, and attending individual sessions plus rater assessments may be 
seen as time-consuming and inconvenient. For study visits involving assessments and not 

 
24 
 
treatment, we have provided compensation for subjects’ time, commensurate with hourly 
compensation for non-treatment studies being conducted at the DCRP. Third, a general risk 
associated with treatment for depression includes the risk that depression may not respond to 
treatment. Subjects will be informed of all of the aforementioned risks during the consent 
process. 
 
VIII. POTENTIAL BENEFITS 
 
It is possible that the participants may not receive any direct benefit other than a detailed 
psychiatric evaluation. However, it is hoped that the intervention could provide relief from 
depressive symptoms and improve the level of functioning exhibited in some participating 
patients with TBI and MDD.  
 
Subjects participating in this study may experience individual benefits from receiving the 
intervention. The intervention, which will be conducted by a master’s or doctoral-level clinician, 
will be provided to the participants at no charge. Subjects will receive $40 for completion of the 
entire screen visit and $30 each for completion of the endpoint and 3 month follow up visits. If 
patients do not complete the entire screen visit due to ineligibility, they will receive $20 to cover 
the cost of transportation. If patients complete the entire screen, but are deemed ineligible after 
the visit based on their medical records, the patient will receive $40 to compensate for their 
travel and time spent in our clinic. Patients will not be compensated for treatment sessions. 
Patients who complete the 12-week study will have the option of keeping the Fitbit Charge 3 
activity tracker (valued at $150 retail) or Fitbit Charge 4 (valued at $130 retail) for their personal 
use. This compensation was chosen after consultation with the director of the Depression 
Clinical and Research Program (DCRP) to be consistent with the compensation for non-
treatment studies at the DCRP.  
 
Benefits to future patients, researchers and clinicians could include the development of more 
effective treatment for major depressive disorder experienced by individuals who have sustained 
a moderate to severe traumatic brain injury. 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
Data Safety 
 
The principal investigator and study staff will review all Adverse Events (AEs) and Serious 
Adverse Events (SAEs) experienced by subjects and report them to the IRB according to the 
guidelines for Adverse Event Reporting.  “Serious adverse events are events that result in any of 
the following outcomes: death; a life threatening experience; inpatient hospitalization or 
prolongation of existing hospitalization; a persistent or significant disability/incapacity; or a 
congenital anomaly/birth defect. In addition, events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above.” SAEs will be discussed with Dr. 
Fisher’s primary mentor and co-mentors. 
 
Notification will be sent to the IRB by phone, email or a fax transmittal of the report within 
24 hours of the SAE’s occurrence. The sponsor will be notified according to its regulations 

 
25 
 
governing SAE reporting.  Relevant information regarding the SAE will be included in this 
report, including information about the event and its outcome, the history of all study 
interventions, all concomitant medications, the subject’s medical history and current conditions, 
and all relevant laboratory data.  This information will be expeditiously reviewed and the 
possible relevance of the SAE to the study intervention will be assessed.   
 
Data Monitoring 
 
All data will be entered into REDCap directly by subjects and clinicians via computer or 
tablet. Use of REDCap will likely minimize missing study data and allow for immediate follow 
up on missing items, which is likely to be especially pertinent to the study population, many of 
whom will experience problems with attention and concentration. 
 
To insure the usability of self-report data, the research coordinator will review all self-report 
measures to insure their completeness. The PI (or, in rare cases, her designee) will review all 
self-report assessment forms and clinician-administered instruments within one week of their 
completion to assure that they are being completed correctly.  Any errors in completion will be 
reviewed to determine if directions or procedures for the assessments need to be altered.  In this 
case, permission from the IRB will be requested to change any procedure. The intervention 
sessions are also audiotaped and a random selection rated for competence and adherence to the 
protocol.  This will also insure the usability of the data. 
 
In addition, a data safety monitoring board will be assembled prior to the start of the study. 
This will consist of at least three staff-level investigators, independent of the current group of 
mentors; one will have expertise clinical interventions with individuals who have sustained a 
traumatic brain injury; the second will have expertise in clinical trial design; the third will serve 
as a statistical consultant. The DSMB will meet at least quarterly per year to review study 
progress, address any difficulties with recruitment, and address any safety related matters that 
may arise. Details of the logistics of the DSMB are as follows: 
a. Unblinded Reporting – Safety information for this study will be reported to the DSMB in an 
unblinded manner.  
b. Range of Safety Reporting to the DSMB – It is considered necessary for the purpose of 
monitoring the safety of the study that the DSMB review not only adverse events (AEs) and 
serious adverse events (SAEs), but other data that may reflect differences in safety between 
treatment groups. This includes treatment retention rates and reasons for drop-out. 
c. Serious Adverse Events – Expedited review will occur for all events meeting the FDA 
definition of SAEs – 
i.e., any fatal event, immediately life-threatening event, permanently or substantially disabling 
event, event requiring or prolonging inpatient hospitalization, or any congenital anomaly. This 
also includes any event that a study investigator or the DSMB judges to impose a significant 
hazard, contraindication, side effect, or precaution. For purposes of this study, all SAEs will be 
required to be reported to the DSMB, regardless of any judgment of their relatedness to the study 
intervention. All relevant information will be reported to the DSMB for each SAE including 
information about the event and its outcome, concomitant medications, the subject’s medical 
history and current conditions, and all relevant laboratory data. Notification by e-mail, and FAX 
transmittal of all related study forms shall be made to the DSMB within 2 days of the occurrence 
of any SAE. Information will be reviewed and a determination made of whether there was any 
possible relevance to the study intervention. Additional reporting to local IRBs will be done 

 
26 
 
within 24 hours of the SAE. Reporting to the NIH will be made according to their respective 
regulations governing SAE reporting. 
d. Non-Serious Adverse Events – At periodic intervals (quarterly during the course of the study 
and then again at its completion), the DSMB will be provided with un-blinded summaries of the 
numbers and rates of adverse events by treatment group. These reports will include types of 
events, severity, and treatment phase. 
Data on individual non-serious adverse events is not expected to be needed for this review. 
e. Other Safety-Related Reports – At twelve-month intervals throughout the course of the 
study, the DSMB will also receive unblinded summary reports of treatment retention and reasons 
for drop-out, by treatment arm and study phase. 
f. Study Stopping Rules – If at any time during the course of the study, the DSMB judges that 
risk to subjects outweighs the potential benefits, the DSMB shall have the discretion and 
responsibility to recommend that the study be terminated. 
 
Digital Monitoring Device Data Collection: 
Phase I: Data collected from the current study will not be sent to research collaborators outside 
of Partners. 
Phase II: Partners investigators will not send research data outside of Partners. Use of Fitbit 
necessitates collection of digital monitoring device (DMD) data through the Fitbit application. 
Study staff will set up deidentified accounts for all participants in the Fitbit group. Account set 
up requires entries in fields for first and last name, and we will use “Participant” in the first name 
field and a de-identified component of the participant’s last name in the last name field. Account 
set up also requires entry of approximate height and weight (self-reported by the participant) and 
birthday. To deidentify birth dates, we will standardize approximate birthdays as the first day of 
the month and year of the participant’s birth. Participant DMD data will be processed securely 
though the Fitbit data collection company, Fitabase. Fitabase does not store identifiable data and 
all data synced from the Fitbit is uploaded through encrypted server communication and stored in 
a highly secure infrastructure. 
Zoom Videoconferencing for Completion of Virtual Procedures: 
A Partners Enterprise Zoom account will be used for all study visits. Zoom links will be 
provided directly to study participants before treatment or assessment sessions. The waiting 
room will be enabled, and the meeting will be locked once all participants have entered. 
Participants will be provided with written guidelines and recommendations for all 
videoconferencing sessions (e.g., use in a private, secure area). 
 
X. 
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