Medication-assisted Psychotherapy: Using Ketamine-enhanced Radically Open Dialectical Behavior Therapy (RO DBT) to Target Neural and Behavioral Mechanisms of Action in Adults With Moderate to Severe Depression
Phase: PHASE1
Conditions: Treatment Resistant Depression
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Medication-assisted psychotherapy: Using ketamine-enhanced RODBT to target 
neural and behavioral mechanisms of action in emerging adults with moderate to 
severe depression 
 
 
 
Principal Investigator:  Kirsten Gilbert, PhD 
NCT Number: NCT06138691 
 
 
 
 
 
 
 
Version Date/Number:  Version 7--   9/26/25 
 
 
 
 

 
 
 
 
 
 
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A Introduction 
 
A1 
Study Abstract 
Heightened performance monitoring and overcontrol (HPM/OC) is a 
transdiagnostic phenotype characterized by checking behaviors, cognitive 
inflexibility/rigidity, and social concern/perfectionism and underlies treatment 
resistant depression (TRD). TRD presents a sizeable public health concern with 
higher hospitalizations, suicide, disability and mortality rates compared to major 
depression, and $44 billion yearly in societal cost. The goal of this project is to 
examine feasibility and efficacy of a cutting-edge medication-assisted 
psychotherapy, ketamine-enhanced Radically Open Dialectical Behavior Therapy 
(RODBT) in 15 emerging adults with moderate to severe depression. We aim to 
test whether ketamine-enhanced RODBT targets the purported mechanism of 
action, HPM/OC. RODBT alone has not enacted neural change and ketamine 
may prove as a catalyst to treatment-response. Given the current mental health 
crisis, only exacerbated by COVID-19, synergistically targeting TRD with fast-
acting (ketamine) and durable (RODBT) mechanistic treatment, early in the 
developmental course, is imperative in lessoning the lifelong burden of 
psychiatric illness.  
 
 
A2 
Primary Hypothesis 
Aim 1: Examine preliminary feasibility and efficacy of ketamine-enhanced 
RODBT. Hypothesis 1a: Ketamine infusions 1-2 days prior to RODBT 
psychotherapy sessions will be well-tolerated and feasible. Hypothesis 1b: Using 
individual session data, ketamine will catalyze psychiatric symptom change in 
RODBT and ketamine-enhanced RODBT will be associated with decreasing 
trajectories of depressive symptoms.  
Aim 2: Examine preliminary efficacy of ketamine-enhanced RODBT in 
engaging neural and behavioral mechanistic targets in young adults with 
moderate to severe depression. H ypothesis 2a: Ketamine-enhanced RODBT 
will be associated with neural ERN reductions and neural RewP increases. H 
ypothesis 2b: Ketamine-enhanced RODBT will be associated with behavioral 
cognitive flexibility, openness, reward responding and social functioning 
improvements.  

 
 
 
 
 
 
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A3 
Purpose of the Study Protocol 
The current study will be the first to test ketamine-enhanced RODBT in young 
adults with TRD, providing preliminary evidence of a more potent, fast-acting and 
durable treatment for the intractable presentation of TRD by examining to how 
ketamine may enhance or catalyze response to RODBT. Moreover, medication-
assisted psychotherapy is still in its infancy, and the current project will be the 
first to mechanistically target HPM/OC using ketamine, examining whether the 
combination of ketamine and ROBDT engage neural and behavioral mechanistic 
targets.  
Additionally, taking both a deep-dive approach via individual session data as well 
as examining neural change across treatment will provide an encompassing 
methodological picture of how ketamine and RODBT synergistically impact 
outcomes. The combination of fast-acting ketamine with a psychosocial 
intervention shown to provide longer-term outcomes may lead to lessened 
severity, chronicity, impairment (and societal cost) across the lifespan for 
emerging adults with moderate to severe MDD and TRD.  
 
B Background 
 
B1 
Prior Literature and Studies 
 
Self-control is adaptive and protective against onset of multiple forms of 
psychopathology. (1) A lack of self-control, or undercontrol, has been widely 
studied and exhibits across multiple psychiatric disorders. However, perhaps 
equally important and far less understood is excessive control, or ‘overcontrol’. 
Although adaptive to monitor one’s performance to learn from mistakes, 
heightened performance monitoring is associated with checking, perfectionism, 
anxious apprehension and cognitive inflexibility/rigidity.(2,3,7,17) Heightened 
performance monitoring and overcontrol (HPM/OC) is evident across multiple 
treatment-resistant psychiatric disorders, including Treatment Resistant 
Depression (TRD). Major depressive disorder (MDD) is highly common and often 
treatable, but for the 30% who do not respond to treatment, an especially 
pernicious course of suffering, disability and mortality often ensues (3). 
Individuals with TRD have early onset, more psychiatric comorbidities, higher 
suicide rates and are twice as likely to be hospitalized than those with MDD (4,5). 

 
 
 
 
 
 
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The total annual cost associated with TRD in the US is an estimated $44 billion 
(47% of the financial burden of MDD) (6). In line with NIMH’s focus on targeting 
mechansims in the treatment for psychiatric illness and given TRD is an 
intractable psychiatric presentation with a significant societal burden, there is a 
critical need to develop innovative and durable treatment modalities that directly 
target transdiagnostic mechanisms in TRD, such as HPM/OC. 
 
Although psychotherapy has been neglected in TRD,(7) a novel psychotherapy, 
Radically Open Dialectical Behavior Therapy (RODBT) directly targets the 
underlying mechanism of HPM/OC evident in TRD.(1) Rather than targeting 
psychiatric symptoms, RO DBT targets underlying and transdiagnostic HPM/OC 
by focusing on decreasing rigid behavioral patterns, increasing receptivity and 
openness to new experiences and feedback, and increasing social 
connectedness.(8) RODBT demonstrates empirical support in TRD, including a 
recent multi-site RCT.(9,10) Recent findings, including those from the PI and 
prior CTRFP funding, demonstrate that RODBT not only decreases psychiatric 
symptoms, but also improves behavioral flexibility, reward responding and quality 
of life and decreases maladaptive behavioral HPM/OC.(11,12) Moreover, the PI 
has recently demonstrated that change in mechanistic processes relevant to 
HPM/OC (i.e., increasing flexibility and social functioning), is directly associated 
with decreased depressive symptoms in a large RCT for TRD.(13) This provides 
direct evidence that targeting core processes evident in HPM/OC is associated 
with psychiatric symptom change. Yet, in the only study testing neural 
mechanistic target engagement in RO DBT, the PI found no change in 
electroencephalogram (EEG) based neural indicators relevant to HPM/OC, one 
assessing heightened performance monitoring, the error-related negativity (ERN) 
and one assessing reward responding: the reward positivity (RewP).(12) 
Although preliminary evidence indicates RODBT can engage a behavioral 
mechanistic target, and this target engagement is associated with decreased 
psychiatric symptoms, neural change associated with RODBT has not yet been 
detected in treatment-resistant psychiatric presentations. 
 
Ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) receptor(14) and 
has repeatedly shown to be a safe, tolerable,(15) and effective means of treating 
depression, in particular TRD.(16) The therapeutic mechanisms of ketamine are 
not fully understood; however, ketamine is associated with changes in synaptic 
function and neuroplasticity, and these changes are correlated with a decrease in 
depressive symptoms(17). It has been theorized that ketamine’s effectiveness, is 
in part because it, “...promotes a time-out from ordinary, usual mind, relief from 
negativity, and an openness to the expansiveness of mind...” (p. 191).(18) 
Although anecdotal, ketamine may theoretically aid in in increasing openness 
and decreasing negative rigidity, core features of the HPM/OC phenotype and 
vital aspects of RODBT treatment. Ketamine’s effects are fast-acting and 
transient, which has led to growing interest in combining ketamine with 
psychotherapy(17,18). Facilitating new neural connections make ketamine a 
powerful adjunct to existing therapy, and in particular might be amenable to 

 
 
 
 
 
 
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facilitating change in RODBT. Ketamine has demonstrated change in neural 
reward responding and has improved social functioning in depression,(18) both 
of which are central to the HPM/OC phenotype. Indeed, work from key personnel 
on this proposal demonstrate that in adults with TRD, ketamine infusions 
demonstrate response-dependent changes in functional connectivity in the 
anterior cingulate cortex (ACC), default mode network and limbic/reward 
structures, including the amygdala and nucleus accumbens.(19) Of note, the 
ACC has been repeatedly implicated in performance and error-monitoring (e.g., 
HPM/OC),(20) and is where the EEG-based neural marker, the ERN is thought to 
originate(21) while the nucleus accumbens is a reward structure where the RewP 
is theorized to originate from.(22) Together, ketamine may provide initial, fast-
acting change to catalyze and facilitate longer-term neural and psychiatric 
change in RODBT in individuals with TRD. Ketamine-assisted psychotherapy is 
still in early stages of study,(18) so the current proposal will take a ‘deep-dive’ 
examination of feasibility and session-by-session change in ketamine- enhanced 
RODBT. This will allow us to a) test whether ketamine acts as a catalyst to 
RODBT, increasing openness and flexibility for RODBT therapy sessions and b) 
examine trajectories of change across the treatment, assessing when ketamine 
induced plasticity is associated with the largest drop in psychiatric symptoms 
(Aim 1). Additionally, repeated EEG neural assessments (baseline, post-
ketamine and post-RODBT) will allow us to a) test whether a shorter course of 
RODBT, boosted with concurrent ketamine (8 weeks) is enough to enact neural 
change, or, whether the full course of ROBDT (16 weeks) is necessary to elicit 
neural change and b) assess whether targeting the neural and behavioral 
mechanism of HPM/OC is directly associated with improving MDD symptoms 
and functioning (Aim 2). 
 
B2 
Rationale for this Study 
Given TRD is characterized by chronicity and high societal cost(6,7), effectively 
treating it early in its’ course is imperative for lessening burden over the lifespan. 
TRD has earlier onset than treatment-responsive MDD, thus, persistent 
moderate to severe depression during emerging adulthood may be an early 
manifestation of TRD and a window of opportunity for early intervention.(4) 
Moreover, since the start of the COVID-19 pandemic, MDD rates have 
significantly increased, especially for individuals under age 40 and students.(23) 
Thus, given the current mental health crisis, targeting TRD with fast-acting and 
durable mechanistic treatment at the earliest developmental timepoint is 
imperative. The current research team brings together relevant expertise across 
adolescent/young adult (Gilbert, Nicol) and adult (Farber, Lenze) populations to 
conduct highly innovative medication-assisted psychotherapy research that could 
profoundly impact new lines of treatment research. The current project brings 
together this distinct expertise into a novel collaboration that we have reason to 
believe may synergistically lead to both fast-acting (ketamine) and also longer-

 
 
 
 
 
 
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lasting (RODBT) mechanistic change in a highly treatment- resistant psychiatric 
presentation that demonstrates increased prevalence during the transition into 
adulthood.  
 
C Study Objectives 
 
C1 
Primary Aim 
 
Aim 1: Examine preliminary feasibility and efficacy of ketamine-enhanced 
RODBT. Hypothesis 1a: Ketamine infusions 6-24 hours prior to RODBT 
psychotherapy sessions will be well-tolerated and feasible. Hypothesis 1b: Using 
individual session data, ketamine will catalyze psychiatric symptom change in 
RODBT and ketamine-enhanced RODBT will be associated with decreasing 
trajectories of depressive symptoms.  
C2 
Secondary Aim 
Aim 2: Examine preliminary efficacy of ketamine-enhanced RODBT in 
engaging neural and behavioral mechanistic targets in young adults with 
moderate to severe depression. Hypothesis 2a: Ketamine-enhanced RODBT 
will be associated with neural ERN reductions and neural RewP increases. 
Hypothesis 2b: Ketamine-enhanced RODBT will be associated with behavioral 
cognitive flexibility, openness, reward responding and social functioning 
improvements.  
 
C3 
Rationale for the Selection of Outcome Measures 
The outcome measures of neural and behavioral HPM/OC and neural reward 
and social responding have been chosen to assess the purported underlying 
mechanisms of change contributing to symptom presentations. We also included 
functioning and psychiatric symptoms to assess whether targeting a mechanism 
also influences symptom presentation. 
D Investigational Agent  
 

 
 
 
 
 
 
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D1 
Dose Rationale and Risk/Benefits  
Details of Infusion 
To ensure dose accuracy, participants will have weight confirmed prior to each 
infusion. All female participants will complete a urine pregnancy test immediately 
prior to their first ketamine infusion and will be informed that it is not advised to 
have unprotected sex throughout the ketamine infusion period (1 month). After 
safety ratings (see table below) are performed, an IV line will be inserted into 
upper extremity by research personnel. The ketamine will be infused using an IV 
infusion pump at a rate of 0.5 mg/kg of body weight over 40 minutes. Heartrate, 
blood pressure, and pulse-oximetry will be routinely monitored throughout the 
infusion and for approximately up to two hours after the end of the infusion. 
Safety ratings will be repeated prior to discharge. After normalization of any 
psychotomimetic symptoms or blood pressure elevation and IV removal, 
participants will be discharged.  
Direct physical or psychological risks are minimal in the administration of 
behavioral and electrophysiological measures. Individual psychosocial therapy 
sessions can elicit some psychological distress while group sessions can elicit 
some psychological distress or social anxiety. Behavioral tasks can lead to some 
concern of performance or frustration. Additionally, participants may become 
bored or tired during the experimental sessions. Some mild discomfort may be 
associated with the application of the miniature surface electrodes and when skin 
is mildly abraded. At no time will subjects be coerced to participate in any aspect 
of testing, subjects will be told that at any time they wish to terminate the 
experiment or therapy, they are free to do so. There is also always a risk of loss 
of confidentiality; although this risk is minimal given data are stored electronically 
behind Washington University’s firewall. Lastly, there is a risk of time burden.  
 
Risks of Ketamine infusion: 
Likely 
• Feeling light-headed, “high,” exhilarated, and/or 
happy 
• Having perceptual changes or hallucinations, 
floating sensations 
• Difficulty concentrating, paying attention, or 
remembering as many items as usual from a list 
(like items on a grocery list). 
• Mild and temporary increases in blood pressure 
• Feeling nauseated. 
Less Likely 
• Feeling dizzy, sleepy, anxious, and suspicious. 
Rare 
• Feeling sad, scared, confused, and/or disoriented. 
• Moderate and temporary increases in blood 
pressure. 
• Future abuse of ketamine 
• Prolonged psychosis in individuals with a pre-

 
 
 
 
 
 
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existing psychiatric condition 
 
Risks of Blood Draws: 
 
The blood draw may cause bleeding bruising, or pain. Some people may become 
dizzy or feel faint. There is also a rare risk of infection. 
 
Risks of an EKG:  
 
After an EKG, participants may have mild irritation, slight redness, and itching at 
the places on their skin where the recording patches are placed. 
 
Risks of Radically Open Dialectical Behavior Therapy: 
 
Participants are informed that participation in this research is strictly voluntary, 
they are free to discontinue participation in the experimental session or 
psychosocial therapy at any time, and that information obtained is confidential. 
We will minimize discomforts and fatigues associated with the performance-
based behavioral and EEG assessments by allowing participants to take breaks 
as needed. Participants will be encouraged to take breaks as frequently as 
desired and to discuss questions and concerns in any nature. Breaks will be 
offered during the EEG procedure. Experimenters will regularly ask adolescents 
and caregivers how they are feeling and remind them to ask questions or 
express any concerns that come to mind. Similarly, study therapists will conduct 
weekly check-in’s with clinical trial participants regarding how they are feeling 
and if they have any questions or concerns about their treatment. Study 
therapists will assess if participant weight loss is occurring or psychiatric mental 
status is declining, and if so, they will be stepped up to a higher level of care.  
Subject confidentiality will be assured through a multi-layered approach, entirely 
compliant with HIPAA regulations. First, all demographic and other identifying 
information will be stored under at least two locks/passwords (in a password 
protected document on a password protected computer in a locked office or in a 
locked cabinet in a locked office). The participants’ name and study number will 
be stored in a master file that contains no other demographic or research 
information. This master file will be a password protected document and stored 
on a password-protected computer. All other non-identifying information will only 
be assigned an ID and will also be protected under two locks/passwords. Only 
Dr. Gilbert and designees will have access to this information. Under no 
circumstances will individually identifiable data be released to anyone without 
written consent of the subject. Any data analyses and publications from this study 
will not individually identify participants and will focus on grouped data. The 
research data (including clinical adolescent and caregiver-reported assessments) 
will be examined as it is collected to review any clinical implication of the 
information. If any incidental findings are uncovered or clinical attention 
warranted at any point during study participation, this will be immediately 

 
 
 
 
 
 
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discussed with the principal investigator (Dr. Gilbert), a licensed clinical 
psychologist, and this information and will be discussed with participants. 
Similarly, research study therapists will have weekly ongoing supervision and 
consultation meetings to discuss therapy cases. If increased clinical attention is 
warranted at any point during the four-month therapy, this will be immediately 
discussed with the PI and, if needed, the participant will be stepped up to a 
higher level of care.  
 
Benefits: 
 
The experimental research measures in this project will not directly benefit the 
participants, other than the knowledge that they are contributing to our 
understanding of the underlying factors that may cause treatment-resistance to 
previous treatments and may provide insight into a novel medication-enhanced 
psychotherapy and thus, there is a benefit of contribution to society. In the 
therapy portion of the project, it is also possible that participants may experience 
improved symptoms of depression, mood, anxiety, as well as reduced tendencies 
of HPM/OC. As part of the ketamine treatment, participants may also experience 
improved symptoms of depression and anxiety. There is a possible effect that the 
combination of ketamine and RO DBT will be especially beneficial in 
combination, although this is unknown, as it is a goal of the study to test the 
combined treatment. As mentioned above, measures are being taken to minimize 
any potential risks. 
 
 
E 
Study Design  
 
E1 
Overview or Design Summary 
Eligible patient (n=15) young adults will attend a baseline session where they will 
undergo an ERP neural assessment and fill out questionnaires. Then, 
participants will complete 4 weeks of ketamine and 4 months of RO DBT. 
Participants will start with 2 weeks of individual therapy (RODBT) to orient to 
therapy and infusion protocols. Then, participants will complete a 4-week course 
of twice weekly 40-minute ketamine infusions administered 6-24 hours prior to 
RO DBT psychotherapy (also when RO DBT group therapy will commence). 
Following completion of the 4-week ketamine-enhanced RO DBT, participants 
will complete another in-person session with an EEG and behaiovral 
assessment. Next, participants will continue to complete RO DBT treatment of 
individual and group treatment for an additional 16 weeks. At the end of this 
treatment, participants will complete a third session where they will undergo an 
ERP neural assessment and fill out questionnaires. Participants will also 
complete self-reported questionnaires following each ketamine and RO DBT 

 
 
 
 
 
 
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session (4 weeks) and weekly self-reported questionnaires during non-ketamine 
RO DBT. 
E2 
Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
Young adults with treatment-resistant depression: Inclusion criteria:  
• Males and females aged 18-65 
o Moderate to severe persistent depression [treatment resistant 
depression – TRD] (exhibiting 2+ unipolar major depression 
episodes (non-delusional) with prior treatment non-response to 
antidepressant or psychosocial treatment 
§ Treatment-resistant depression: defined as unipolar major 
depressive disorder, that persists despite ≥ 2 adequate 
antidepressant trials of different classes in the current 
episode; including at least one evidence-based second-line 
treatment in the current episode (including serotonin 
norepinephrine reuptake inhibitors, bupropion, tricyclics, 
monoamine oxidase inhibitors, or augmentation with an 
atypical antipsychotic, stimulant, bupropion, lithium, or 
Triiodothyroinine) 
o higher proportion of OC words endorsed compared to UC words on 
the Word Pairs Checklist 
o no current or past psychosis 
o English speaking 
o Able to attend in-person behavioral sessions and ketamine/therapy 
visits 
o Willingness to have RO DBT as only psychosocial treatment 
engaged in (medication treatment may continue—but see below for 
exclusion)  
 
 
2.a 
Exclusion Criteria  
Exclusion criteria:  
• Outside age range 
• Significant neurological condition (i.e., seizure, stroke, severe head injury) 
or mental retardation (IQ<70) 
• Current or recent substance use disorder, actively suicidal or homicidal 
(e.g., requires hospitalization) 
• Use of naltrexone, memantine or medication considered contraindicated 
with ketamine 
• Baseline systolic BP > 150 systolic or 90 diastolic at evaluation. 
Participants who initially present with elevated blood pressure may be re-
assessed; and if needed, referred to their healthcare provider for 
hypertension management 

 
 
 
 
 
 
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• Taking more than 2 adequately-dosed oral antidepressants 
• Inability to understand, speak and read English sufficiently 
• Not be pregnant or at risk of becoming pregnant 
• Medical conditions or medication usage that in the judgement of the 
investigators puts the patient at unreasonable safety risk 
• First degree relative with a psychotic diagnosis involving hallucinations, 
delusions, or disorganized thinking and speech (e.g. schizophrenia, 
schizoaffective disorder, etc) 
 
 
2.b 
Ethical Considerations  
Re: Thearpy and ketamine trial-- Participants are not randomized. They will be 
fully informed of the free therapy and ketamine trial and will not be coerced into it. 
Free therapy and ketamine will be provided to all patients (as this is a feasibility 
and acceptability study). If any patient participating in the study needs a higher 
level of care, they will immediately be removed from the treatment protocol and 
will be coordinated with other providers to ensure they get the care necessary. If 
any patient participating in the study decides they no longer want to be in the 
trial, they can end at any point and it will be coordinated to help them continue 
treatment with other providers. 
 
Re: experimental session—all participation is voluntary, including answering 
questions and participating in the ERP.  
2.c 
Subject Recruitment Plans and Consent Process 
 
Study population: 
Young adults age 18-65 years with TRD who exhibit HPM/OC. 
Consent process: If an interested participant contacts the research team about 
the study, a member of the research team will provide information about the 
study and required elements of consent over the telephone (see attached 
“Consent for Phone Screen”) prior to obtaining the participants verbal consent to 
participate in the screening elements of the study. This phone screen will allow 
possible participants to ask questions and clarifications prior to coming in person 
for the in-person consent process (and includes the child having the opportunity 
to ask questions). If a participant meets eligibility criteria for enrollment in the 
study based on their Initial Phone/Exclusion Screen and the participant indicates 
they wish to continue with the study, the participant will receive an email to 
complete the a measure of HPM/OC, the Word Pairs Checklist. The participant 
must consent to complete these questionnaires. If the participant is eligible 
following completion of the phone screen and questionnaires, the research team 
will notify the participant of their eligibility and ask whether they want to continue 
with the study. If the participant is unsure, the research assistant will provide 

 
 
 
 
 
 
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unlimited time for the participant to consider whether they would like to 
participate in the study and a research assistant will notify the participant they 
can contact the research team if they would like to potentially participate in the 
future (they may have to re-complete the phone screen at that future time). If the 
person is still interested, the research team will schedule an in-person session. 
The consent process will take place in person at Washington University in St. 
Louis Department of Psychiatry in a private room with a research team member. 
The consent process will include providing ample time for the young adult to 
read/review the consent form. This consent will consents for the experimental 
sessions and the free ketamine and therapy portion. There is no randomization: if 
an potential patient participant is interested in the free ketamine/therapy, they 
can participate in that until we have 15 participants in the therapy portion. A 
trained research assistant will also discuss the procedures of the study and will 
answer any questions the participant may have prior to signing. Research team 
members will remind participants that their participation is completely voluntary 
and they can choose to withdraw at any time.  
 
 
 
2.d 
Early Withdrawal of Subjects  
Participants can withdraw at any point if they desire. Participants in need of 
higher levels of care will be withdrawn by the PI if medically/psychologically 
unstable or if they express active suicidal ideation. 
2.e 
When and How to Withdraw Subjects  
Participants in need of higher levels of care will be withdrawn by the PI at any 
point if medically/psychologically unstable or if they express active suicidal 
ideation and need to be hospitalized. If a participant desires to withdraw, as soon 
as they inform the study team, the team will remove the participant fro current 
and future study procedures. 
 
2.f 
Data Collection and Follow-up for Withdrawn Subjects  
Data will not be collected for withdrawn subjects once they withdraw. Follow-up 
for withdrawn subjects will not be done, unless the patient reaches out to us and 
would like to continue the therapy or study. At this point they would sign another 
consent form to agree to their continued participation. 
 
F 
Study Procedures  
 

 
 
 
 
 
 
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F1 
Screening for Eligibility 
Consent process: If an interested participant contacts the research team about 
the study, a member of the research team will provide information about the 
study and required elements of consent over the telephone (see attached 
“Consent for Phone Screen”) prior to obtaining the participants verbal consent. 
This phone screen will allow possible participants to ask questions and 
clarifications prior to coming in person for the in-person consent process. If a 
participant meets eligibility criteria for enrollment in the study based on their Initial 
Phone/Exclusion Screen and the participant indicates they wish to continue with 
the study, The participant will receive an email  to complete the Word Pairs 
Checklist. The participant must consent to complete this questionnaire. If the 
participant is eligible following completion of the phone screen and questionnaire, 
the research team will notify the participant of their eligibility and ask whether 
they want to continue with the study. If the participant is unsure, the research 
assistant will provide unlimited time for the participant to consider whether they 
would like to participate in the study and a research assistant will notify the 
participant they can contact the research team if they would like to potentially 
participate in the future (they may have to re-complete the phone screen at that 
future time). If the person is still interested, the research team will schedule an in-
person session. 
 
F2 
Visit 1  
After the consent process, participants will be assessed for eligibility. After 
participants will have blood drawn and then have an EKG done. Then 
participants will be taken to the ERP (event related potential) room. Participants 
will wear an EEG cap and will complete three computer tasks during which EEG 
recordings will be obtained. The EEG cap takes 20 minutes to configure. Small 
dots of non-toxic gel are put on the head to connect the electrodes to the scalp. 
The participant will complete a Flanker Task, where participants start by seeing a 
fixation cross, and then a screen depicting a sets of arrowheads ("<<<<<", 
"<<><<", ">>>>>", or ">><>>"). Participants are instructed to press a key on the 
left or right side of the keyboard to indicate the direction of the center arrow. This 
allows for two congruent conditions ("<<<<<", ">>>>>") and two incongruent 
conditions ("<<><<", ">><>>"). Participants complete blocks of trials with breaks 
in between and told to respond as quickly and accurately as possible.This task 
takes approximately 15 minutes and behavioral responses will be recorded and 
EEG will be recorded during the task and used to measure the ERN. Participants 
will then complete the Doors Task, where they have chances to win or lose 
points (in reality, all participants will make the full amount of $5. Each trial will 
start with a screen with a fixation cross, followed by a screen with graphic of two 
doors side by side. Participants will be instructed that if they chose the correct 
door, they can accrue points, while if they chose the incorrect door, they lose 
points. Participants are told points will be tallied to make extra money they could 
make (in reality, all participants will make the full amount of $5). Participants will 
use a videogame controller and will see a screen with two doors and asked to 

 
 
 
 
 
 
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14 
choose a door and the doors will remain on the screen until the participant 
chooses a door. Then a fixation mark is presented, followed by a feedback arrow: 
a green upward facing arrow indicates a correct guess (i.e., they won points), 
while a red downward facing arrow indicates an incorrect guess (i.e., they lost 
points). A fixation mark is then presented and then a screen that states, “Click for 
next round" is presented until a response in made. Behavioral responses will be 
recorded and EEG will be recorded during the task and used to measure the 
RewP. Participants will the complete 6 minutes of resting state EEG where they 
will keep their eyes closed for 1 minute, followed by eyes open for 1 minute, for 6 
consecutive minutes where they will be told to ‘do nothing.’In total, the ERP 
portion of the task will take approximately 1.5 hours. 
 
Following the ERP/EEG session, participants will meet with a researcher and 
complete a structured clinical interview, the Montgomery and Asberg Depression 
Rating Scale (MADRS) to assess current depressive symtpoms. Participants will 
also complete the Mini International Neuropsychiatric Interview (MINI) as part of 
this clinical interview as well. This should take approximately 30 minutes. 
 
Participants will then sit at a computer and complete online questionnaires on 
REDCap. Questionnaires will take approximately 20 minutes and can be 
completed at home as well. Questionnaires include: 
 
Acceptance and Action Questionnaire-II (AAQ-II): This measure assesses 
psychological inflexibility. Pathological Obsessive Compulsive Personality Scale 
(POPS): This measures personality traits related to the HPM/OC personality, 
including emotional overcontrol, perfectionism, rigidity. Social Connectedness 
Scale- Revised (SCS-R): This measure assesses the degree to which 
participants feel socially connected to others. UCLA Loneliness Scale Revised: 
This measures one’s subjective feelings of emotional and social loneliness. 
Temporal Experience of Pleasure Scale (TEPS): This measure assesses 
anticipatory pleasure and consummatory or outcome pleasure. Patient Health 
Questionnaire – 9 (PHQ-9): This is a measure of depressive symptoms. 
Generalized Anxiety Disorder Questionnaire – 7 (GAD-7): This is a measure of 
anxiety symptoms. Quality of Life Questionnaire (QOL) – A 16-item measure for 
assessing quality of life in groups with chronic illness. Personaly Need for 
Structure – This measures assesses the extent to which participants need 
structure in their daily lives.  Social Safeness and Pleasure Scale – This measure 
assesses feelings of positive emotions and pleasure in social situations.  Emotion 
Regulation Questionnaire (ERQ) – The Emotion Regulation Questionnaire (ERQ) 
was developed to measure two specific constructs related to emotion control: 
cognitive reappraisal and expressive suppression. The ERQ is a 10-item self-
report measure employed to measure dispositional use of the emotion regulation 
strategies of emotional suppression and reappraisal. The items use a 7-point 
Likert scale with responses ranging from one (strongly disagree) to seven 
(strongly agree). Responses to Positive Affect (RPA) –.  (RPA; Feldman et al., 
2008). The RPA is a 17-item measure rated on a 1 (almost never respond in this 

 
 
 
 
 
 
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15 
way) to 4 (almost always respond in this way) scale that assesses emotion 
regulation specifically during positive emotional experiences. The RPA has three 
factor-derived subscales, including Emotion-focused and Self-focused positive 
rumination and Dampening, which assesses ways positive emotion might be 
diminished (e.g., “Think about things that could go wrong”).  The two positive 
rumination subscales are often studied in the context of bipolar disorder and are 
associated with elevated manic symptoms, while elevated dampening has been 
associated with both current and predictive depressive symptoms in both mood 
disordered (bipolar and depressed) and non-clinical populations (Johnson, 
McKenzie & McMurrich, 2008).  In the current study we are using the Dampening 
eight item subscale only. Ask Suicide-Screening Questions (ASQ)- The ASQ is is 
a brief (5 questions) assessment to gauge suicide risk in participants. OC Trait 
Rating Scale – This scale assesses maladaptive aspects of the HPM/OC 
'overcontrolled phenotype' that we will use to assess whether ketamine and RO 
DBT are targeting the mechanistic processes inherent in the overcontrolled 
phenotype. 
 
Ketamine session questionnaires: 
In addition to completing the above mentioned PHQ-9 and GAD-7 at each 
ketamine infusion, participants will also complete: 
 
Brief Psychiatric Rating Scale- positive (psychotic) symptoms subscale (BPRS+): 
This measures transient neuropsychiatric changes that might occur in response 
to the ketamine infusions. KetRO Clinical Events Checklist: This measure 
assesses common adverse side effects of using ketamine. Clinical Administered 
Dissociative State Scale (CADSS) – Modified – This measure assesses 
dissociative symptoms after using ketamine. 
 
Before the ketamine administration, participants will have vital signs collected in 
addition to and ECG and blood chemistry tests. 
 
During the ketamine + RO DBT portion of the study, participants will also 
complete the PHQ-9 and GAD-7 following each RO DBT session. Following 
completion of the ketamine portion, and ongoing weekly RO DBT therapy, 
participants will complete the PHQ-9 and GAD-7 weekly following their individual 
therapy sessions. 
 
At the end of treatment, participants will be asked to complete a post-treatment 
questionnaire. The participants’ therapists will also be asked to complete a 
separate end of therapy questionnaire.   
 
Visit 2 etc.  
The mid-treatment (post-ketamine) and post-RO DBT treatment in-person 
assessments will include the idendical ERP and questionnaire data.  
 
Ketamine protocol:  

 
 
 
 
 
 
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16 
Participants will be admitted to the Washington University Clinical Trial Research 
Unit (CTRU) to receive 0.5mg/kg intravenous ketamine given over 40 minutes, as 
is routinely done in ketamine treatment.(16) Participants will have same-room 
observation during and 1hr post-infusion to monitor blood pressure, oxygen 
saturation and to manage psychotomimetic adverse events by highly trained 
medical support staff. Side effects will also be monitored (e.g., light-headed, 
“high,” exhilarated, perceptual changes, hallucinations, nauseated). If a 
participant is unable to receive IV ketamine (e.g., because of lack of IV access), 
he or she can receive IM ketamine as a bolus. The dosage will be the same (0.5 
mg/kg) because its bioavailability is 93% and its plasma half-life is similar to IV. 
We will also use clonidine as needed, taken orally the night prior to or morning of 
infusion to prevent distressing symptoms. Ketamine is completely cleared from 
the body 15 hours later; thus, key personnel have deemed that infusions will take 
place 1-2 days prior to RODBT individual/group sessions to maximally enhance 
the plasticity and potentially catalyzing effects of ketamine on psychotherapy 
sessions.   
 
Therapy:  
RO DBT therapy includes attending weekly one hour therapy and weekly 1.5 
hours skills class sessions for approximately 16 weeks. These weekly individual 
therapy sessions (but not skills class sessions) will be videotaped uploaded to 
the WUSTL Box.com website, which is secure and encrypted. Up to 15 
participants can participate in this option. RO DBT helps individuals with 
HPM/OC relax rigid and extreme inhibitory control, be receptive and open to new 
experiences and feedback and increasing social connectedness by activating the 
social safety system. RO-DBT treatment themes include: 1) hyper-detail-focused 
and overly cautios behavior, 2), rigid and rule governed behavior 3) inhibited and 
disingenuous emotional expression 4) distant and aloof social connectedness 
and relationships and 5) high social comparisons and envy. 
Clinicians will be Molly Fennig, BA, Cherie Massmann, MA, LPC, Michael 
Mullins, MSW, LCSW, Gregory Peebles, MA, LPC and Mariah Saldena, MA. 
Cherie Massman, Michael Mullins, Gregory Peebles and Mariah Saldena are all 
licenced therapists in the St. Louis community and Molly Fennig is a PhD clinical 
pychology graduate student in the Department of Psychology at Washington 
University. All clinicians have been intensively trained in RO DBT. Group skills 
classes will be run by both the PI, Kirsten Gilbert, Whig Mullins and/or another 
clinician. Paper notes will be kept in a locked file cabinet in locked offices. De-
idnetified therapy notes will be uploaded to a secure Wustl box.com folder for the 
study. At the end of therapy, the clinician will complete an “End of Therapy 
Progress” questionnaire to assess progress made or not made across the 
research study. In addition, the participant will be contacted via phone call and 
asked several questions about their experience with RO DBT along with their 
perceptions of treatment outcomes. In addition, research team member will contact 
subjects who have dropped out of the study or who have completed treatment.   The 
participant will be contacted via phone call to and invited to participate in a follow up 
interview.  They will be asked several questions about their experience with 

 
 
 
 
 
 
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17 
Ketamine enhanced RO DBT along with their perceptions of treatment outcomes. 
This will be conducted over zoom and be recorded or over the phone and audio 
recorded to an handheld recorder.  The recording will be immediately transferred to 
wustl box, in a secured password protected account.  The data from the recording wil 
be deleted immediately from the handheld recorder.  At the end of the study a 
research team member will transcribe the recordings and save the transcriptions to a 
wustl box folder.  All audio and video recordings will be deleted at that time. 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
Using G*Power, power for Aim 1 (MDD symptoms) was based on a) a pilot of 
RODBT from the PI, b) Lynch et al. (2020),(9) a multi-cite RCT of RODBT in TRD 
and c) Zarate et al (2006)(37), an original RCT of ketamine in TRD. With α=.05 
and power of 80%, we would need a sample of 8 to detect an effect from 
RODBT, and n=5 with ketamine. For Aim 2, we used a) Baudinet et al (2021)(11) 
who tested RODBT change in behavioral flexibility and reward processing and b) 
a pilot of RODBT from the PI. With α=.05 and power of 80%, we would need a 
sample of 5-15 participants to detect behavioral change in mechanistic process. 
Power for neural change in HPM/OC has not been computed because no 
previous studies have targeted HPM/OC with ketamine. However, our sample is 
similar to other medication-assisted psychotherapy pilot studies.   
G2  Interim Monitoring and Early Stopping 
This is part of Analysis 1a below. Specifically, side effects and symptoms will be 
monitored at each ketamine and RO DBT session for 4 weeks while they are 
running concurrently. If there are any issues with running a ketamine session and 
a psychotherapy session within 1-2 days of each other, protocols can be 
modified or stopped, if necessary. 
G3  Analysis Plan 
Analysis 1a: No analyses will be completed for H1a; qualitative data from session 
questionnaires regarding side-effects, symptoms and functioning will be 
continually monitored, to assess if there is a need to modify protocols. H1b: 
Using individual session data, ketamine will catalyze psychiatric symptom 
change in RODBT and ketamine-enhanced RODBT will be associated with 
decreasing trajectories of depressive symptoms. Analysis 1b: Multilevel linear 
modeling (MLM) with random intercepts and slopes will model trajectories of 
depressive symptoms across treatment.  
Aim 2: Examine preliminary efficacy of ketamine-enhanced RODBT in 
engaging neural and behavioral mechanistic targets in young adults with 

 
 
 
 
 
 
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18 
moderate to severe depression. 
H2a: Ketamine-enhanced RODBT will be associated with neural ERN reductions 
and neural RewP increases. Analysis 2a: Using baseline, mid- and post-
treatment assessments, change in the ERN (and in a separate model, the RewP) 
will be assessed using a MLM. H2b: Ketamine-enhanced RODBT will be 
associated with behavioral cognitive flexibility, openness, reward responding and 
social functioning improvements. Analysis 2b: Using baseline, mid- and post-
treatment assessments, change in behavioral mechanisms will, similar to 
Analysis 2a, be assessed using a MLM.  
 
G4 Statistical Methods  
See above 
G5  Missing Outcome Data 
If missing outcome data exists, that participant will be excluded for that analysis. 
Of note, when modeling data, missing data does not mean the participant can be 
excluded. 
 
 
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