Clinical trial NCT04916548
Conditions: Depression, Unipolar
Sponsor: Rebecca Price
Start date: 2021-09-16; Completion date: 2023-08-15
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this project, we will A) track the functioning of a collection of potential neurobiological targets for depression over time, B) examine how fluctuations in the functioning of those targets relates to real-world functioning, and C) in a subset of the sample, determine how the functioning in those targets is altered by a single dose of ketamine.

Detailed description:

Arms: arm 1: Open-label ketamine infusion
Interventions: intervention 1: Intravenous Ketamine
Intervention descriptions: intervention 1: Single infusion of intravenous racemic ketamine (0.5mg/kg over 40min)

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 8 
 
Study Protocol  
 
 
 
 
 
 
Official Title: Repeated neurocognitive measurements in depressed 
patients 
 
 
ClinicalTrials.gov ID (NCT number): NCT04916548 
 
 
 
Protocol Date: 06/03/2021 
 
 
 
 


Page 2 of 8 
 
Scientific Background 
Depression is one of 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. A more integrative model of 
depression mechanisms—in particular, anticipated increases in flexible 
processing across cognition, information processing, and neural 
networks—requires strongly validated measurements with good 
psychometric properties, and strong relationships to both naturally 
occurring and experimentally induced (i.e., via ketamine) changes in 
depressive symptoms. The proposed study will enable us to develop and 
refine a battery of neurocognitive and performance-based measures that 
meet these criteria, and will reveal new knowledge about the 
mechanisms of depression. 
 
The proposed project is not a simple extension of any one of the 
investigators’ programs of research. Rather, it leverages the overlapping 
and unique expertise of the research team in order to advance a set of 
shared aims that no member of the collaborative would be able to 
accomplish on their own. Dr. Fournier brings expertise in longitudinal 
neuroimaging and in examining how individual differences in the 
functioning of the emotion regulation and self-related processing neural 
circuitry among depressed adults affects treatment response and real-
world functioning. Dr. Price has expertise in longitudinal neuroimaging 
and the study of intravenous ketamine’s rapid impact on both depressive 
symptoms and neurocognitive markers (including fMRI indices). Dr. 
Young brings expertise in examining neural responses during positive 
memory recall as a biomarker of major depressive disorder, with a focus 
on developing neurobehavioral interventions targeting these responses. 
Dr. Pecina has over ten year of experience conducting longitudinal 
interventional studies in patients with depression using multimodal 
neuroimaging in order to identify specific mechanisms through which 
specific treatments exert their effects. Dr. Jones has expertise in 


Page 3 of 8 
 
examining the mechanisms through which self-referential, cognitive, 
motivational, and emotional systems assessed at multiple levels (e.g., 
structural MRI, functional MRI, peripheral psychophysiology, and 
ecological momentary assessment) give rise to depression, anxiety, and 
related disorders. 
 
The aims of the project are innovative in several key respects. First, 
almost nothing is currently known about the true natural stability of 
potential biomarkers of depressive illness. This information is vital for 
the development and assessment of novel interventions, and it may help 
to resolve some of the heterogeneity and conflicting results in the 
published literature. Second, to our knowledge, no prior work has 
examined the degree to which the biomarkers proposed above may be 
altered by a single dose of ketamine. Third, very little work has 
examined the unfolding relationship of abnormalities in brain function 
and real-world functional outcomes. This information is critical for 
understanding not only the practical significance of abnormalities in 
brain function but for beginning to unpick possible mechanisms through 
which differences in biological functioning can affect an individual’s 
lived experience. The expertise of each member of the collaborative, 
detailed above, is necessary to achieve these aims. Moreover, the results 
of this work will lay a core foundation for future, mutually beneficial 
collaborative work among members of the research team as they seek to 
identify and develop more effective ways to treat depression that are 
grounded in neuroscience. 
 
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. 


Page 4 of 8 
 
The rapidity and magnitude of ketamine’s effects on depressive-like 
behavior are attributed to its ability to rapidly and profoundly reverse 
neuroplasticity deficits. In this study, we will utilize ketamine as a rapid-
acting experimental probe to decrease clinical symptoms and enhance 
neuroplasticity, and will measure the resulting effect on our 
neurocognitive battery and relationships to symptoms. 
 
 
 
 
Study Objectives 
 
In this project, we aim to harness our collective expertise in 
neuroimaging and treatment research to A) track the functioning of a 
collection of potential neurobiological targets for depression over time, 
B) examine how fluctuations in the functioning of those targets relates to 
real-world functioning, and C) in a subset of the sample, determine how 
the functioning in those targets is altered by a single dose of ketamine. 
We expect this work to provide the critical foundation for several 
collaborative future projects aimed at developing novel therapeutics. It 
will provide vital pieces of information regarding the stability, real-
world importance, and malleability of possible neurobiologically based 
treatment targets.  
 
Building on our prior work, we plan to evaluate the natural stability and 
fluctuations in four potential neural biomarkers for depression: 1) altered 
self-related processing, 2) deficits in autobiographical recall of positive 
events, 3) deficits in cognitive control, and 4) dysfunction in the 
communication among large-scale cortical networks. In addition, we 
will evaluate whether variability in the functioning of these systems is 
associated with real-world outcomes, including interpersonal 
functioning, employment functioning, and quality of life. Finally, as a 
proof of concept that these markers are alterable, we will examine how a 
single dose of ketamine alters the functioning of these targets. 
 


Page 5 of 8 
 
Aim 1) track the functioning of a collection of potential neurobiological 
targets for depression over time. 
 
Aim 2) examine how fluctuations in the functioning of those targets 
relates to real-world functioning. 
 
Aim 3) in a subset of the sample, determine how the functioning in those 
targets is altered by a single dose of ketamine. 
 
 
Study Design & Methods 
 
A target sample of 40 depressed participants will complete baseline 
clinical, quality of life, cognitive, and functional magnetic resonance 
imaging (fMRI) assessments, followed by repeated assessments of each 
of these measures to examine their natural course over the consecutive 
month. In addition, in an open-label, single-arm design, a subset of 
participants (n=15) will receive a single dose of ketamine and a final 
fMRI assessment shortly after the 1-month follow-up. 
 
 
Eligibility Criteria: 
Inclusion Criteria: 
All participants will: 
1) be between the ages of 18 and 60 years, 
2) score ≥ 14 on the Hamilton Depression Rating Scale (Ham-D) 
3) possess a level of understanding sufficient to agree to all tests and 
examinations required by the protocol and must sign an informed consent 
document 
Exclusion Criteria: 
All participants: 


Page 6 of 8 
 
1) Presence of lifetime bipolar, psychotic, or autism spectrum; current 
problematic substance use (e.g., ongoing moderate-to-severe substance use 
disorder); 
2) 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. History of significant injury or 
surgery to the brain or spinal cord that would impair interpretation of results. 
3) Acute suicidality or other psychiatric crises requiring treatment escalation. 
We will use the Columbia Suicide Severity Rating Scale (CSSRS) as both an 
initial exclusion criteria (CSSRS “Baseline/Screening” Version for past 1month 
period) and as grounds for rescue/removal (CSSRS “Since Last Visit” form). 
The CSSRS will be administered using a paper form by an experienced and 
thoroughly trained clinical assessor on the study team. Subjects with CSSRS 
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 to the nearest emergency mental health 
facility for additional thorough assessment and appropriate treatment referral. 
4) Changes made to treatment regimen within 4 weeks of baseline 
assessment. 
5) Reading level <6th grade as per patient self-report. 
6) Patients who have received ECT in the past 2 months prior to Screening. 
 
Ketamine phase subsample additional exclusion criteria: 
1) Patients currently taking any psychotropic medication. 
2) Lifetime recreational ketamine or PCP use 
3) Current pregnancy or breastfeeding 
4) For ketamine phase entry, patients must be reasonable medical candidates 
for ketamine infusion, as determined by a physician co-investigator. Serious, 
unstable medical illnesses including respiratory [obstructive sleep apnea, or 
history of difficulty with airway management during previous anesthetics], 


Page 7 of 8 
 
cardiovascular [including ischemic heart disease and uncontrolled 
hypertension], and neurologic [including history of severe head injury] will be 
exclusions. 
5) Clinically significant abnormal findings of laboratory parameters [including 
urine toxicology screen for drugs of abuse], physical examination, or ECG. 
6) Uncontrolled or poorly controlled hypertension, as determined by a 
physician co-investigator's review of vitals collected during screening and any 
other relevant medical history/records. 
7) Patients with one or more seizures without a clear and resolved etiology. 
8) Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior 
to Screening. 
9) Past intolerance or hypersensitivity to ketamine. 
10) Patients taking medications with known activity at the NMDA or AMPA 
glutamate receptor [riluzole, amantadine, lamotrigine, memantine, topiramate, 
dextromethorphan, Dcycloserinem, Sonata, Ambien, Lunesta, Acamprosate], 
or the mu-opioid receptor [opiate medications--morphine, oxycodone, heroin, 
fentanyl)]. 
11) Patients taking any of the following medications: St John’s Wort, 
theophylline, tramadol, metrizamide. 
 
Statistical Considerations and Statistical Analysis Plan 
This is a pilot study, designed to develop novel study infrastructure and 
novel measurement and analytic methods, leading to a small number of 
patients particularly for the open-label treatment arm. Analytic methods 
for all neurocognitive measures will be refined, optimized, and finalized 
based on the test-retest phase, such that they maximize psychometric 
properties of the metrics such as test-retest reliability and validity. 
Descriptive statistics (means, standard deviations) will be reported 
without statistical analysis, given the small number of patients receiving 
the study intervention, which yields low statistical power. Exploratory 
inferential statistical analyses and effect size comparisons (with 95% 
CIs) will include appropriate within-group comparisons of pre- and post-


Page 8 of 8 
 
treatment scores on all primary and secondary endpoints, and on other 
pre-specified outcomes as warranted.