Combined Internet-Based Cognitive Behavioral Therapy With Transcranial Magnetic Stimulation for Patients With Major Depressive Disorder
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of California, Los Angeles

 
 
 
Version Date:  
29 September 2020 
iCBT With TMS in Patients 
With MDD 
NCT05988619 Study protocol with SAP 
BENJAMIN ROSENBERG 

Version: 29 September 2020 
Internet-based Cognitive Behavioral Therapy in Transcranial Magnetic Stimulation 
 
Question: Does the addition of internet-delivered Cognitive Behavior Therapy (iCBT) to TMS 
improve immediate and long-term symptom, functioning and cognitive outcomes 
 
Background and Significance: 
Major Depressive Disorder (MDD) is a common diagnosis, with an estimated lifetime morbid 
risk of approximately 30% (Kessler et al., 2012). while there are many approaches to the 
treatment of MDD, Current treatments of MDD frequently fail to substantially reduce depressive 
symptoms among those in need of care, with individual interventions leading to remission in 
approximately one-third of patients (Trivedi et al., 2006, Rush et al., 2006). Prior research 
suggests that combining cognitive-behavioral therapy (CBT) and psychopharmacology can 
produce optimal treatment outcomes compared to the use of either treatment individually (March 
et al., 2004; Pampallona et al., 2004; Cuijpers et al., 2009).  
 
Non-invasive brain stimulation presents an exciting alternative to these interventions. 
Transcranial Magnetic Stimulation (TMS) is one especially promising brain stimulation 
approach used to treat MDD, especially among patients with treatment-resistant symptoms 
(Diefenbach et al., 2016; Dilkov, et al., 2017). Like psychopharmacological interventions, TMS 
may produce optimal treatment outcomes when paired with CBT. However, standard TMS 
protocols are time-intensive, typically requiring daily doctor visits for one hour of six to eight 
weeks. Therefore, an internet-delivered CBT protocol may augment the effects of TMS without 
substantially increasing patient burden. To that end, the present study will assess if a combined 
TMS and internet-delivered CBT protocol may produce superior treatment outcomes compared 
with TMS alone. 
 
Design: 
Randomization to one of two treatments; primary outcomes assessed at  
(a) Baseline  
(b) Post-treatment (6 weeks, or 30 TMS session) 
(c) 8 months after study entrance (~6 months post treatment) 
(d) 11 months after study entrance (~9 months post treatment) 
 
Other measures are collected at baseline, mid-treatment (3 weeks, or 15 TMS session) and post-
treatment.  
 
Participants: We will enroll 40 Subjects who will be assigned to iCBT or a mental health video 
series with 20 enrolled in each group.  The same inclusion/exclusion criteria as the TMS clinic 
will be employed for eligibility. This involves a minimum score of 17 on HAM-D, evidence of 
treatment resistance, and evaluation by a study investigator.  Participants must be right-handed 
and between 18-70 years of age.  
 
Inclusions: Subjects with Major Depressive Disorder who are receiving a full course of TMS 
treatment in at the UCLA TMS Clinic. Participants must be willing to undergo 10-Hz TMS 
treatment at the outset of treatment. 
 

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Exclusions: Any indications of metal implants, pregnancy, psychosis, Obsessive compulsive 
disorder (OCD), autism spectrum disorders, complex regional pain syndromes, substance use 
dependence and comorbidities that would interfere with treatment response. The criteria are 
assessed using MINI interview and Hamilton Depression scale conducted by trained and certified 
interviewers. Participants may not participate if they are currently completing CBT outside of the 
study. 
 
Eligibility will be determined by TMS physicians who are co-investigators on this study.  
 
Interventions: 
 
RANDOMIZATION 
WEEK 1-6 
TMS 
TMS + Mental Health Television Episode 
TMS + ICBT 
TMS + ICBT 
 
TMS: 
We will evaluate standard of care for TMS, which involves some flexibility but typically 
includes 6 weeks, five days per week, followed by a weaning from 3 to 1 times per week for the 
next 3 weeks.   
 
Some flexibility is permitted due to scheduling difficulties; require a minimum of 8 sessions 
within any given 14 day period during the first six weeks.   
 
Post-treatment will be standardized at 6 weeks (after 30 TMS).  
 
Mental Health Videos or iCBT will occur weekly, according to each participant’s schedule. 
Participants will additionally schedule one weekly coaching session to discuss the viewed 
material. These coaching sessions will occur via HIPAA-compliant Zoom meetings arranced 
through the UCLA health system. 
 
Qualitative Electroencephalograph: QEEG will be performed at the UCLA TMS Research 
area. Recordings will be performed while the subjects are resting in the eye-closed, maximally 
alert state. Electrodes will be attached to the subjects’ scalps either with individual silver 
chloride electrodes, paste, and nylon electrode cap or net.  All of these types of electrodes are 
non-invasive, apply easily and quickly with little or no discomfort to the subject, and are easily 
removed with minimal clean up. During the recordings, subjects will either sit in a comfortable 
chair while the electrodes are applied. The recording will then be performed and the technicians 
will alert subjects if any signs of drowsiness appear. A CPz-referential montage will be used with 
electrodes placed according to the 10-20 system (Leuchter et al., 1992; Dunkin et al, 1995). 
Signals will be digitally recorded (bandpass 0.3-70 Hz) and analyzed. The EEG procedure 
should not take more than ninety (90) minutes; generally speaking, the actual recording takes 
about twenty (40) minutes. QEEG studies may be repeated up to three (3) sessions under this 
protocol, depending upon subject’s willingness to record.  
 
Neuropsychological testing: This testing involves completing specific tests measuring cognitive 
functioning, such as concentration, ability to think, and memory. In addition, subjects may be 

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asked about their feelings, thoughts, activities, or emotional well-being. Our neuropsychological 
testing battery may require up to two (2) hours of participation. 
 
iCBT:  
Existing standard program (ThisWayUp) 
 
Once per week for weeks 1 through 6.  
 
Plus access to iCBT at other times. 
 
Keep track of usage.  
Orientation to program by research staff at first occasion, who will also be available to answer 
questions (research staff at TMS clinic, who are trained by DGC team- Madison Schmidt)  
 
The protocol for "This Way Up" utilizes the following lesson plan: 
 
Lesson 
number 
Content 
Homework exercise 
1 
Psychoeducation about anxiety and depression, the 
fight or flight response, controlled breathing, and 
physical exercise 
Controlled breathing, 
physical exercise 
  
2 
Cognitive therapy components: education about the 
cognitive model, cognitive distortions, and introduction 
to thought monitoring; activity planning 
Thought monitoring, 
activity planning 
  
3 
Thought challenging/cognitive restructuring; 
challenging positive and negative metacognitive beliefs 
about repetitive negative thinking; shifting attention, 
hunt for positives 
Thought challenging, 
hunt for positives 
  
4 
Education about avoidance and safety behaviors; 
graded exposure and structured problem solving 
Graded exposure and 
structured problem 
solving 
  
5 
Advanced graded exposure (imaginal exposure, 
interoceptive exposure); troubleshooting difficulties 
with graded exposure 
Graded exposure 
6 
Relapse prevention 
Relapse prevention plan 
 

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Lesson content is presented in the form of an illustrated story about two fictional characters who 
are anxious and depressed, but who gain mastery over their problems using CBT techniques. 
Following each lesson, participants download a document that summarizes the key information 
in each lesson, and includes practical homework exercises that reinforce the content of the 
lesson. Participants are encouraged to practice their lesson homework for at least 2 hours in the 
3-4 days before starting the next lesson.  
 
Participants also have access to: 
1)  frequently asked questions about each lesson  
2)  "Patient Recovery Stories" from former patients, and  
3)  extra resources on a range of topics such as sleep hygiene, medications and panic    
     attacks.  
 
Once participants download their homework, they will be considered to have completed the 
lesson. Lessons will be completed sequentially. "This Way Up" will be hosted locally on our 
secure server and can be directly accessed via the website https://ucla.thiswayupclinic.com/. 
 
The "This Way Up" program is hosted on the Semel-NPI server architecture. After being 
registered by a study clinician, participants log-in to access lesson content only, no identifiable e-
mail other than name and e-mail are stored in the system. 
 
Mental Health Television Episodes 
 
The existing program, Stories of the Mind, was originally developed for the Public Broadcast 
Service (PBS) and affiliated broadcasts. It is freely available at 
http://mentalhealthchannel.tv/series/stories-of-the-mind.  
 
Participants will view a video once per week for weeks 1 through 6. Although they have access 
to all videos of the program, they will be specifically instructed to view materials according to 
the following schedule: 
 
Lesson 
number 
Episode Title 
Episode Description 
1 
Overcoming Depression 
A writer, a musician and a video blogger 
find three surprising paths to recovery, 
with powerful takeaways for all viewers. 
2 
Beating Anxiety 
Three characters in different times of their 
lives use different tactics to manage their 
anxiety, the most common type of mental 
health disorder for Americans. 

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3 
Get your Sleep 
Sleep deprivation affects everything, from 
memory to mood to decision making. In 
our 36-hour No Sleep Challenge, 
researchers track 4 participants to see just 
how vital sleep is to your mental health. 
4 
Coping with Illness 
When your physical health suffers, your 
mental state may too. Meet three people 
who practice good mental health despite 
physical conditions.  
5 
A Place to Belong 
Being part of a strong community is good 
for anyone's mental health. 
6 
Ways to Wellness 
Five ways for every viewer to achieve 
optimum mental fitness, told through the 
personal experiences of fascinating, 
diverse characters. 
 
Study Schedule: 
 
 
 
The frequency of follow-up assessments may be modified depending on patient availability, or 
subject willingness to undergo more or less assessment.  
 
Primary Dependent Measures: 
 

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The primary analyses for this study will involve multilevel modeling of longitudinal data over 
the course of treatment (e.g. baseline, mid-assessment, post-assessment). We hypothesize that the 
iCBT + TMS will demonstrate more rapid improvement in these five symptom scales compared 
with TMS alone.  
 
In addition, secondary analyses will involve multilevel modeling of symptom score relapse (e.g. 
baseline, end of treatment, 6 months post-treatment, 9 months post-treatment). We hypothesize 
that iCBT + TMS will demonstrate more lasting change in these five symptom scales compared 
with TMS alone, such that the combined treatment reduces the likelihood of symptom relapse. 
 
Finally, analyses will assess changes in cognitive functioning during the course of treatment, 
using a electroencephalography (baseline, mid-assessment) and a well-validated Stroop Task 
(baseline and post-treatment). Changes in cognitive functioning will be assessed with multilevel 
modeling in parallel to the primary analyses above as a means of exploring whether changes in 
cognitive functioning coincide with changes in treatment. 
 
Symptom Scales:  
HAM-D (baseline, mid, post, 6 months) 
IDS (Inventory for Depression Symptomatology) (weekly from baseline to end of TMS, and at 6  
         month and 9 month follow-up) 
DARS (Dimensional Anhedonia Rating Scale) (baseline, mid, post, 6 months, 9 months) 
GAD-7 (baseline, mid, post, 6 months, 9 months) 
 
Functioning Scale: 
Sheehan Disability scale (baseline, mid, post, 6 months, 9 months) 
 
Cognitive Functioning: 
EEG (baseline, mid) 
STROOP (baseline, post) 
 
Additional Measures: 
Patient Attitude and Expectancy Form  
Demographics and medical status 
 
Modified intent-to-treat analyses will be conducted using linear multilevel modeling in Stata 
18.0 using the mixed function. All models include random effects of the intercept and fixed 
slopes for each participant. Group will be included as a categorical variable in all analyses. Time 
will be included as a continuous variable in primary analyses, with secondary analyses including 
Time as a categorical variable to evaluate pairwise Group comparisons. Age (continuous) and 
Gender (categorical) will be included in all analyses as covariates.