Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition
Phase: PHASE1
Conditions: Depression
Sponsor: Rebecca Price

Page 1 of 10 
 
Study Protocol  
 
 
 
 
 
 
Official Title: Intravenous Ketamine Plus Neurocognitive Training for Depression 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT03237286 
 
Initial IRB approval: 08/14/2017 
 
Protocol Date: 08/07/2020; Amended/modified version (study exclusion #19 added) 
 
 
 
 

Page 2 of 10 
 
Scientific Background 
Ketamine is a glutamatergic agent used routinely for induction and maintenance of anesthesia. In 
randomized controlled trials, subanesthetic (typically, 0.5mg/kg) intravenous ketamine exhibits 
well-replicated, rapid, potent (i.e., metaanalytic Cohen’s d=1.4, a large effect) antidepressant 
effects, even in difficult-to-treat conditions such as treatment-resistant depression and bipolar 
depression. Antidepressant effects begin app. 2 h post-infusion (after acute dissociative and 
euphoric side effects subside) and continue far beyond the drug’s elimination half-life of 2.5-3h. 
However, effects also dissipate rapidly, with efficacy over placebo fading by 7 days post-
infusion. To date, the only strategy shown in replicated datasets to extend ketamine’s rapid 
effects is to give continued ketamine infusions; while some clinicians now offer this service 
directly to patients, there are substantial feasibility and safety concerns for long-term use, 
including potential neurocognitive impact and neurotoxicity, dissociative/psychotomimetic side 
effects, addiction/abuse liability, and burden on patients (e.g., high out-of-pocket expense in 
community settings) and the healthcare system (e.g., intravenous administration; legal 
constraints given US schedule III controlled substance status). Alternative administration routes 
(e.g., intranasal) are under development, but do not circumvent many of these challenges. 
Attempts to develop alternative pharmaceuticals that either reproduce ketamine’s rapid 
antidepressant effects or extend them after an initial ketamine infusion (e.g., ketamine followed 
by oral D-cylcoserine, which showed promise in a case series of 7 patients) are advancing 
rapidly, but so far no controlled study demonstrates both rapidity and durability in patients. 
While these avenues hold tremendous potential, psychiatric care is likely to benefit from a 
diversity of approaches, including those that efficiently mobilize learning mechanisms to 
generate gains that are both rapid and enduring. 
The rapidity and magnitude of ketamine’s effects on depressive-like behavior are attributed to its 
ability to rapidly and profoundly reverse neuroplasticity deficits. According to neuroplasticity 
models of depression, chronic stress leads to sustained decreases in neuroprotective factors [e.g., 
brain-derived neurotrophic factor (BDNF) expression and signaling] that damage plasticity, 
fostering neuronal atrophy and synaptic depression, particularly in the PFC and hippocampus. 
This results in deficient adaptation to the environment, compromising learning and stress coping, 
and to downstream gain of activity in some ‘salience network’ (SN) regions (e.g., amygdala) 
regulated by the PFC. Conversely, when neuroplasticity is enhanced (e.g., by treatment), 
synaptic contacts increase, enhancing adaptability by allowing activity-dependent competition to 
stabilize the neural structures that best represent internal and external conditions. 
A rigorous animal literature converges on a fundamental role for increases in neuroplasticity in 
mediating ketamine’s effects on depressive-like behavior. While debate continues about the 
precise molecular cascades involved, a recent breakthrough linked ketamine’s antidepressant 
effects in mice to a specific ketamine metabolite, hydroxynorketamine (HNK), which induces 
AMPA receptor activation and was both necessary and sufficient to decrease depressive-like 
behavior. AMPA activation is linked, in turn, to a range of cascading neuroplasticity increases, 
each previously implicated in ketamine’s antidepressant action (e.g., increased BDNF, overall 
PFC synaptogenesis and synaptic activation). Such effects have been studied primarily in 
AMPA-rich areas of hippocampus (e.g., CA1) and medial (m)PFC—areas also showing 
plasticity deficits in depression. Convergently, using rigorous optogenetic and molecular 
blockade techniques, synaptic potentiation within a ventral hippocampal (vHipp)-mPFC pathway 
was both necessary and sufficient for ketamine’s antidepressant-like effects. However, glutamate 

Page 3 of 10 
 
receptors are ubiquitous throughout the brain, suggesting the potential for far-reaching, rapid 
functional reorganization, as observed in patients and monkeys 24-hrs post-ketamine. 
Given that synaptic plasticity involving glutamatergic receptors is considered the major 
molecular substrate of learning and memory in the brain, these findings suggest the novel 
hypothesis—testable with the proposed experimental therapeutics design—that ketamine-
induced neuroplasticity opens a clinical ‘window of opportunity’ for new, protective learning. By 
introducing a Cognitive Training protocol into the neuroplasticity window, we propose to be 
strategic regarding the neural structures that will be repeatedly activated during the experience-
dependent ‘competition’ phase. 
 
Challenge: Disorders of negative affect (anxiety, depression) are the most prevalent and costly 
class of mental health condition, with a collective public disease burden of staggering 
proportions. While efficacious treatments have been available for decades, remission rates are 
low, relapse rates are high, and disorder prevalence rates remain notably consistent, with only 
12.7% of patients receiving minimally adequate treatment. In recent years, two potential 
breakthroughs have ignited hopes for turning a corner in the clinical management of these 
disabling disorders. First, rapid-acting pharmacological agents—most notably intravenous 
ketamine—have shown promise in dramatically reducing symptoms within the space of 2-24 
hours, overcoming the sluggish response to conventional therapies (e.g., 4-6 week delays) which 
prolongs suffering, creates non-compliance issues, and fails to address urgent clinical needs (e.g., 
suicidality and other psychiatric crises). Second, intervention development has increasingly 
sought to take advantage of technology to increase patient access, reduce cost, and minimize 
aversive consequences through the use of automated, computer-based procedures. The current 
proposal aims to synergistically combine the benefits of these two approaches. 
The rapidity of ketamine’s effects offers the promise of a breakthrough in the way that disorders 
of negative affect are managed, but this promise remains unfulfilled to date. Rapidly dissipating 
effects, coupled with substantial concerns regarding safety and feasibility of repeated infusions, 
limit ketamine’s clinical impact. The standard paradigm in ketamine research, as in much of 
psychopharmacology research, has been to focus on molecular mechanisms of action that are 
linked to depressive-like behaviors in pre-clinical animal studies, or in humans using in vivo 
molecular assays. While molecular effects are critical for pharmacological treatment 
development, a narrow focus on one level of analysis hinders a comprehensive understanding of 
the pathophysiology of affective dysfunction and treatment mechanisms, leaving sizable 
knowledge gaps in the pathway that leads from ketamine’s molecular effects to profound, rapid 
changes in complex human experiences (thoughts, moods). Consistent with the NIMH RDoC 
and experimental therapeutics initiatives, we propose to fill in these gaps and integrate 
knowledge across cognitive and negative valence systems by examining ketamine’s rapid effects 
on neural, cognitive and implicit information processing indices. 
While exciting and substantial advancements have recently been made in understanding 
ketamine’s molecular mechanisms of action, translation to safe, effective pharmacology can be 
slow and uncertain. Furthermore, long-term pharmacological intervention is unlikely to be 
beneficial, feasible, and appealing to every patient. A large majority of patients (e.g., up to 91% 
of depressed patients enrolling in drug trials) consistently express preference for behavioral or 
combined behavioral/pharmacological treatments, in part reflecting the belief that such 
treatments will introduce new learning that will solve the core problem and instantiate lasting 
change. Pharmacological regimens are challenging to maintain in the long term due to patient 

Page 4 of 10 
 
discontinuation and the rarity of follow-up opportunities in community practice. A more 
integrative model of ketamine’s impact—in particular, anticipated increases in flexible 
processing across cognition, information processing, and neural networks—reveals a previously 
unforeseen opportunity to test for synergistic effects when ketamine is coupled with a brief, 
automated cognitive training intervention designed to consolidate beneficial forms of cognitive 
processing while neuroplasticity is high. Thus, this project will push the boundaries of how 
rapid-acting agents could be used clinically, i.e. as short-term cognitive flexibility enhancers. 
Here, rapid-acting pharmacology becomes merely the first step in a novel treatment algorithm 
designed to foster relief that is both rapid and durable, simultaneously taking advantage of 
technology’s potential for low-cost, portable, safe, dissemination-ready intervention. Consistent 
with findings suggesting gold-standard behavioral treatments can prevent depression relapse in 
the absence of ongoing care, and preliminary evidence that brief cognitive training approaches 
can likewise have enduring effects over 1-year, we propose that the introduction and facilitation 
of new learning during a ketamine-induced window-of-opportunity will provide an efficient path 
to relief that is both rapid and enduring. 
 
 
 
 
 
Study Objectives 
This project seeks to identify the neural and cognitive changes that accompany rapid relief from 
depressive symptoms following intravenous ketamine. We will then test whether these changes 
promote the uptake of helpful information delivered by a computer-based training protocol. This 
work could ultimately lead to the ability to treat depression more efficiently by rapidly priming 
the brain for helpful forms of learning. 
 
 
 
 
Study Design & Methods 
 
This study is a randomized, double-blind, parallel arm, controlled trial. A target sample size of 
150 patients exhibiting the target deficits (negative self-representations and elevated depressive 
symptoms) will be randomized 2:1 to intravenous ketamine (0.5mg/kg) or saline, followed by 
either a computer-based cognitive training protocol designed to implicitly instill positive self-
representations via Evaluative Conditioning (n=100 drawn from either the ketamine or saline 
groups) or a sham variant (n=50, from the ketamine group only). Both males and females age 18-
60 will be enrolled. 
 
All infusions will be given over 40 minutes and administered in the MUH-CTRC by an 
experienced team with a linked ACLS-certified code team in a medical hospital setting, with 
safety/adverse event monitoring sustained for 4-hours post-infusion. Patient 
safety/decompensation will be monitored at every visit using appropriate exit/referral plans. 
Patients will be instructed to have nothing by mouth (except for water and coffee) the morning of 
the infusion and until 2 hours post-infusion. 

Page 5 of 10 
 
 
Randomized, blinded, controlled trials provide the most rigorous method to test intervention 
effects at any level of analysis. A parallel arm design was selected for primary hypothesis tests 
due to previously observed cross-over effects in ketamine studies(114) and an anticipated 
increased risk of unblinding (for both ketamine and CT) if participants can directly compare 
treatment experiences (e.g., side effects, positive vs. neutral CT stimuli). 2:1 ketamine:saline 
followed by 2:1 CT:sham randomization was selected to increase probability of benefit to 
participants(115) and improve recruitment given substantial interest in ketamine from patients 
and referring clinicians, while maximizing statistical power for key comparisons: ket (n=100) vs. 
saline (n=50); ket+CT (n=50) vs. ket+sham (n=50) vs. saline+CT (n=50). A 1-month acute 
follow-up period is feasible and ethical for this initial efficacy study and, if supported, would 
have a clinically relevant impact, reducing safety and feasibility concerns regarding frequent 
infusions(28); 12m naturalistic follow-up will further characterize durability and inform 
frequency for future trials. 
 
Participants will not be withdrawn from existing depression treatments (e.g., medications, 
therapy). They may continue in existing therapies for the duration of the study, provided they 
meet all inclusion/exclusion criteria. 
 
 
Summary of data collection timeline: 
The timeline below represents the target day for each set of procedures. At the PI's discretion, the 
precise day of assessments (e.g., number of days post-infusion) may be adjusted slightly in order 
to accommodate participant and research facility schedules. 
 
All participants will undergo a medical screening and thorough psychiatric evaluation consisting 
of a structured diagnostic interview as well as self-report questionnaires to determine eligibility 
for study participation. Screening assessments for exclusion criteria: 
• Initial phone screen 
• General demographic and medical history forms 
• Medical intake and comprehensive screening assessments performed by clinical research staff 
at Bellefield Towers or 3501 Forbes Ave (Oxford Building). Findings will be reviewed for 
eligibility and signed by a board-certified physician co-investigator (Dr. Howland) prior to the 
infusion. A drug test will also be obtained at intake; urine pregnancy tests may be obtained prior 
to fMRI scans at the MRRC. 
 
Screening/baseline procedures include pre-infusion psychiatric evaluation, medical screening, 
and assessment battery (depression/emotional functioning assessments, neuroimaging, cognitive 
tasks)=1-2 visits over approximately 1-3 weeks 
 
Infusion (ketamine or saline) visit (“Intervention Day 1” in consent form)=one visit, completed 
within approximately 1 week of baseline assessments 
 
24-hours post-drug assessment battery (“Intervention Day 2” in consent form) 
(depression/emotional functioning assessments, neuroimaging, cognitive tasks)=one visit 
completed 24-hours after drug infusion 

Page 6 of 10 
 
 
Cognitive training sessions and brief assessment battery (“Intervention Days 2,3,4,5” in consent 
form) (depression and suicidality assessments)=eight 15-20min sessions completed 2x/day 
(sessions separated by >=20 min) on days 1-4 post-infusion 
 
Infusion +5-days assessment battery (“Intervention Day 6” in consent form) 
(depression/emotional functioning assessments, neuroimaging, cognitive tasks)=one visit 
completed following completion of all cognitive training sessions 
 
Infusion +7 days remote (questionnaire) assessment (depression assessments) 
 
Infusion +12 days assessment battery (depression/emotional functioning assessments, cognitive 
tasks) 
 
Infusion +21 days remote (questionnaire/phone) assessment (depression and suicidality 
assessments) 
 
Infusion +30-days assessment battery (depression/emotional functioning assessments, 
neuroimaging, cognitive tasks) 
 
Infusion +2, 3, 4, 5, 6 & 12-months remote, naturalistic follow-up assessments 
(depression/emotional functioning assessments)=questionnaires completed monthly 2-6 months 
post-infusion and then once more at 12-months follow-up 
 
Total duration of acute study period (after screening is completed)=approximately 4-5 weeks. 
Includes 1 infusion visit, 5 in-person assessment visits, 2 remote assessments, and 8 brief 
cognitive training sessions (twice-daily for 4 days post-drug infusion). 
 
Total duration of naturalistic follow-up period=1-year. 
Naturalistic follow-up visits will occur monthly in months 2-6 post-infusion and again at 12 
months post-infusion. In addition to other assessments collected during the acute study period, a 
comprehensive, community treatment questionnaire will be administered to assess the type, dose 
and duration of medications, psychotherapy, other depression interventions and total 
inpatient/outpatient visits. 
 
 
 
Eligibility Criteria: 
Inclusion Criteria: 
Participants will: 
1) be between the ages of 18 and 60 years, 
 

Page 7 of 10 
 
2) have not responded to one or more adequate trials of FDA-approved antidepressants within 
the current depressive episode, determined by Antidepressant Treatment History Form (ATHF) 
criteria [score ≥ 1] 
 
3) score ≥ 25 on the Montgomery Asberg Depression Rating Scale (MADRS)(123) 
 
4) score >1SD above the normative mean on the Cognitive Triad Inventory (CTI(127)) “self” 
subscale(128,129), a well-validated self-report measure of maladaptive self-representations 
*OR* <1SD below the normative mean on the Rosenberg self-esteem scale, a widely used self-
report measure of self-esteem 
 
5) possess a level of understanding sufficient to agree to all tests and examinations required by 
the protocol and must sign an informed consent document 
 
6) agree to sign a release of information (ROI), identifying another individual [friend, family 
member, etc.] as a contact person while the patient is enrolled in the study. 
 
Exclusion Criteria: 
1) Presence of lifetime bipolar, psychotic, or autism spectrum; current problematic substance use 
(e.g., substance use disorder); or lifetime recreational ketamine or PCP use 
 
2) Use of a Monoamine Oxidase Inhibitor (MAOI) within the previous 2 weeks 
3) Failure to meet standard MRI inclusion criteria: those who have cardiac pacemakers, neural 
pacemakers, cochlear implants, metal braces, or other non-MRI-compatible metal objects in their 
body, especially in the eye. Dental fillings do not present a problem. Plastic or removable dental 
appliances do not require exclusion. History of significant injury or surgery to the brain or spinal 
cord that would impair interpretation of results. 
 
4) Current pregnancy or breastfeeding, or failure to engage in an effective birth control strategy 
throughout the duration of the study 
 
5) Acute suicidality or other psychiatric crises requiring treatment escalation. We will use the 
Columbia-Suicide Severity Rating Scale (C-SSRS; Version 1/14/09) as both an initial exclusion 
criteria (C-SSRS “Baseline/Screening” Version for past 1-month period) and as grounds for 
rescue/removal (C-SSRS “Since Last Visit” form). The C-SSRS will be administered using a 
paper form by an experienced and thoroughly trained clinical assessor on the study team. 
Subjects with C-SSRS suicide ideation scores scored “yes” on items 4 (active suicidal ideation 
with some intent to act) and/or 5 (active suicidal ideation with specific plan and intent) will be 
excluded from the study, and if enrolled, will be exited from the study and referred immediately 

Page 8 of 10 
 
to the nearest emergency mental health facility for additional thorough assessment and 
appropriate treatment referral. 
 
6) Changes made to treatment regimen within 4 weeks of baseline assessment 
 
7) Reading level <6th grade as per patient self-report 
 
8) For study entry, patients must be reasonable medical candidates for ketamine infusion, as 
determined by a board-certified physician co-investigator during study Screening. Serious, 
unstable medical illnesses including respiratory [obstructive sleep apnea, or history of difficulty 
with airway management during previous anesthetics], cardiovascular [including ischemic heart 
disease and uncontrolled hypertension], and neurologic [including history of severe head injury] 
will be exclusions. 
 
9) Clinically significant abnormal findings of laboratory parameters [including urine toxicology 
screen for drugs of abuse], physical examination, or ECG. 
 
10) Uncontrolled or poorly controlled hypertension, as determined by a board-certified physician 
co-investigator's review of vitals collected during screening and any other relevant medical 
history/records. 
 
11) Patients with one or more seizures without a clear and resolved etiology. 
 
12) Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening. 
 
13) Past intolerance or hypersensitivity to ketamine. 
 
14) Patients taking medications with known activity at the NMDA or AMPA glutamate receptor 
[e.g., riluzole, amantadine, memantine, topiramate, dextromethorphan, D-cycloserine], or the 
mu-opioid receptor.  
 
15) Patients taking any of the following medications: St John’s Wort, theophylline, tramadol, 
metrizamide 
 
16) Patients who have received ECT in the past 6 months prior to Screening. 
 
17) Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive 
transcranial stimulation (rTMS). 
 
18) Patients taking benzodiazepines or GABA agonists (within 8 hours of infusion) 
 
**Revised/additional exclusion criterion added on IRB’s instruction, effective 08/07/2020 
through the end of study** 
19) Patients with diabetes 
Rationale: For the duration of the COVID-19 pandemic, patients with diabetes, who are 
increased risk of serious complications from COVID-19 exposure, will be excluded. 

Page 9 of 10 
 
 
 
 
 
Statistical Considerations and Statistical Analysis Plan 
 
Sample Size 
150 depressed adults will be enrolled in the study and randomized to one of the three treatment 
arms: ketamine + cognitive training (n=50); ketamine + sham training (n=50); or saline + 
cognitive training (n=50). Enrollment will continue until a final sample is acquired that includes 
the full target of n=150 patients who complete, at a minimum, (1) an infusion day, (2) a 24-hour 
assessment visit, and (3) ≥75% of intended Neurocognitive Training (active or sham NT) visits, 
and will thus be considered to have received their NT allocation. 
 
Power Analyses 
Previous studies comparing intravenous ketamine to inert and psychoactive comparators (e.g., 
midazolam) report large effects at 24-hours (d=.80 for depression; d>3 for brain activation). The 
PI’s previous mechanistic CT study in depression found large effects (d=.7-1.0) on symptom and 
performance-based cognitive measures. Clinically, we are interested in observation of moderate-
large effects. The proposed design will yield 80% power to detect moderate effects based on 
comparisons of 100 ketamine and 50 saline patients (d≥.49 and r≥.31 using α=.05). Based on 
comparisons of 50 patients in each of the ketamine+CT, ketamine+sham, and saline+CT 
conditions and 80% power, effects of d≥.57 will be detectable (using α=.05). Power for primary 
mixed effects analyses comparing treatment groups, which increases with additional repeated 
measures, will be higher than for such post-hoc single-point contrasts. 
 
Analytic Plan 
Infusion Phase. Mixed models regression with timepoint (baseline, infusion+24-hours) as a 
continuous within-subject factor, drug condition (ketamine vs. saline) as a fixed between-subject 
factor, and subject as a random factor will be applied to test hypothesized time*drug interactions 
on outcomes. For outcomes where time*drug interactions are observed, direction of effects 
within each drug condition will be disambiguated using baseline vs. post-infusion contrasts.  
Neurocognitive Training Phase. Mixed models regression with timepoint (24-hrs to 30 days) as a 
continuous within-subject factor, condition (ketamine+NT, ketamine+sham, saline+NT) as a 
fixed between-subject factor, and subject as a random factor will be applied to test hypothesized 
treatment and time*treatment interactions on outcomes. Saline+CT will serve as the reference 
group to test for enduring (main) effects of treatment and for time*treatment interactions.  
Exploratory analysis 1 will extend mixed models analysis of depressive symptoms into the 12-
month naturalistic follow-up using self-report (primary self-report outcome=QIDS-SR). 
Exploratory analysis 2 will utilize a validated data-driven approach to identify 
integrative/combined moderators of CT effects (DV=MADRS slope), quantified as the optimal 
weighted combination of moderators (via elastic net w/cross-validation) across all primary + 
exploratory indices (e.g., fMRI, HNK/BDNF levels, etc.) assessed after ketamine (n=100), 
defining the data-driven, integrative brain state that optimizes benefit from CT.  
Sensitivity analyses will be applied to all hypotheses to explore the impact of main and 
moderating effects of key biological variables: sex (stratified at randomization to ensure ~60% 

Page 10 of 10 
 
female within-cell), age; and baseline clinical variables: treatment-resistance (stratified), 
concurrent medication.  
Exploratory analyses will probe for generalization to other neurocognitive indices and self-
report measures [e.g., depressive schemas (CTI); PROMIS measures; QIDS-SR; WHO 
Disability Assessment Scale].