Conditions: Depression, Unipolar
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
In this project, the investigators will administer a single infusion of IV ketamine to depressed patients and randomize the patients to receive either a) usual/typical infusion conditions or b) mindfulness training and exercises in conjunction with the infusion. Investigators will test whether the conjunction of ketamine + mindfulness enhances the reductions in depression following a single ketamine infusion.

Detailed description:
NOTE: The study's target sample size was revised after beginning the study, based on a revised available budget.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Intravenous Ketamine intervention 2: Brief Mindfulness Exercises intervention 3: Academic Exercises
Intervention descriptions: intervention 1: Single infusion of intravenous racemic ketamine (0.5mg/kg over 40min) intervention 2: 30min guided training in mindfulness meditation immediately prior to infusion intervention 3: 30min of mental math and other academic cognitive puzzles completed silently/mentally

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 8 
 
Study Protocol  
 
 
 
 
 
 
Official Title: Ketamine plus mindfulness for depression  
 
 
ClinicalTrials.gov ID (NCT number): NCT05168735 
 
 
 
Protocol Date: 06/09/2022 
 
 
 
 


Page 2 of 8 
 
Scientific Background 
Depression is one of the most prevalent and costly mental health 
conditions, 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. 
 
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. 
 
The rapidity and magnitude of ketamine’s effects on depressive-like 
behavior are attributed, at the neurobiological level, to its ability to 
rapidly and profoundly reverse neuroplasticity deficits. However, little is 
known regarding whether ketamine's mechanisms of antidepressant 
action also involve psychological shifts in the patient's state of 
consciousness which are evident during the infusion itself. One such 
theorized mechanism involves a possible amplification of present-
moment mindful awareness, which is a psychological state that has also 
been strongly linked with protection against depression in prior work. 
For example, during and just after a ketamine infusion, awareness of 
present-moment perceptual experiences may be enhanced due to their 
deviations from normal consciousness, and these shifts are experienced 
by some patients as 'mystical,' 'holy,' or 'spiritual' and as fostering 
meaningful insights that they view as linked to therapeutic benefits. 
However, many other patients do not spontaneously report such 
experiences, suggesting that the infusion may interact with other pre-


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disposing factors to produce a more mindful and/or 'mystical' state in 
some patients than in others. 
 
Furthermore, although effective, ketamine as a stand-alone treatment 
may not be fully optimized, as it leads to a robust treatment response 
only in 50-70% of depressed patients, and the impact is relatively short-
lived, with symptoms generally returning to baseline within 1-2 weeks. 
 
In this study, we will utilize ketamine as a rapid-acting experimental 
probe to decrease clinical symptoms and enhance neuroplasticity, and 
will experimentally assess (through a randomized design) whether the 
resulting effects on depression, as well as on a neurocognitive battery of 
performance-based and psychological measures, are amplified by 
explicitly invoking a mindful state of awareness just before, during, and 
after the infusion. In particular, we will test whether the adjunctive 
mindfulness exercises lead to a larger and/or more enduring benefit in 
terms of depression symptoms, self-reported mindful awareness, and 
neurocognitive performance-based markers. 
 
Findings will help in building a more integrative model of depression 
mechanisms and possible synergistic treatment approaches. In particular, 
anticipated heightened perceptual experiences and anomalies, as well as 
generalized increases in flexible processing across cognition, 
information processing, and neural networks which we posit will be 
induced by IV ketamine, may acutely promote the achievement of a 
mindful state of awareness, which may in turn yield larger and/or more 
enduring downstream improvements in depression. 
 
The aims of the project are innovative in several key respects. First, 
although prior studies among substance use disorder patients have 
incorporated mindfulness training/exercises into the context of a single 
ketamine infusion and have reported correlational findings linking 
corresponding 'mystical' experiences during the infusion with abstinence 
following the infusion, no prior study has examined the role of mindful 
awareness or mystical experiences during ketamine infusion in 


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potentially promoting antidepressant benefits among depressed patients. 
There is considerable debate regarding whether the altered state of 
consciousness that ketamine induces during the infusion itself is 
therapeutically relevant at all. This is noteworthy considering that 
depression has been a key clinical target for stand-alone IV ketamine 
treatments as well as for behavioral mindfulness-based interventions. 
Furthermore, no prior study (in any clinical population) has used a 
randomized design to experimentally manipulate mindful awareness 
during a ketamine infusion. This information is vital for the development 
and assessment of novel, potentially synergistic interventions and to 
inform practice guidelines for ketamine therapy, which in community-
based clinical settings routinely espouse to induce a "transformative," 
"trance"-like, mindful and/or mystical/spiritual experience. 
Second, little prior work has examined the degree to which a range of 
neurocognitive performance-based biomarkers may be altered by a 
single dose of ketamine, with or without adjunctive mindfulness 
exercises. Thus, our study has the potential to illuminate the 
neurocognitive mechanisms underlying ketamine's rapid antidepressant 
effects, which could yield an improved understanding both of ketamine's 
mechanisms of action as well as the pathophysiology of depression 
itself. 
 
 
 
 
 
 
Study Objectives 
In this project, we will administer a single infusion of IV ketamine to 
depressed patients and randomize the patients to receive either a) 
usual/typical infusion conditions or b) mindfulness training and 
exercises in conjunction with the infusion. We will test whether the 
conjunction of ketamine + mindfulness enhances the reductions in 
depression following a single ketamine infusion. 
 


Page 5 of 8 
 
Building on our prior work, we will examine how a single dose of 
ketamine, with vs. without adjunctive mindfulness training, alters 
depressive symptoms, self-reported mindfulness, and neurocognitive 
performance-based markers related to depression risk. 
 
Aim 1) To examine the extent to which adjunctive mindfulness 
exercises, delivered in conjunction with a single dose of ketamine, 
enhances the effect size and/or duration of ketamine's rapid 
antidepressant effect. 
 
Aim 2) To examine the extent to which adjunctive mindfulness 
exercises, delivered in conjunction with a single dose of ketamine, 
enhances self-reported mindful awareness and 'mystical' experiences, 
during and just after the infusion. 
 
Aim 3) To examine the extent to which adjunctive mindfulness 
exercises, delivered in conjunction with a single dose of ketamine, 
enhances the effect size of post-infusion shifts in neurocognitive 
performance-based markers related to depression risk. 
 
 
 
 
Study Design & Methods 
 
Enroll 60 adults to complete 40 patients in final sample. Participants will 
complete baseline clinical, self-report, and neurocognitive performance-
based assessments, followed by a single dose of ketamine. Patients will 
be randomly allocated to receive either standard/typical infusion 
conditions, or adjunctive training in mindfulness exercises. All patients 
will then complete post-infusion assessments over a 1-month follow-up 
interval. 
 
 
 


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Eligibility Criteria: 
Inclusion Criteria: 
All participants will: 
1) be between the ages of 18 and 65 years, 
2) score ≥ 14 on the modified 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: 
1) Presence of lifetime bipolar, psychotic, or autism spectrum; current 
problematic substance use (e.g., ongoing moderate-to-severe 
substance use disorder); 
2) 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. 
3) Changes made to treatment regimen within 4 weeks of baseline 
assessment. 
4) Reading level <6th grade as per patient self-report. 
5) Patients who have received ECT in the past 2 months prior to 
Screening. 
6) Current pregnancy or breastfeeding 
7) Patients must be reasonable medical candidates for ketamine infusion, 
as determined by a physician co-investigator. Serious, unstable medical 


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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. 
8) Clinically significant abnormal findings of laboratory parameters 
[including urine toxicology screen for unreported drugs of abuse], vitals, 
or ECG. Patients with prolonged QT or Torsade will not be eligible to 
receive Zofran PRN, but remain eligible for all other study procedures 
9) 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. 
10) 
Patients with one or more seizures without a clear and resolved 
etiology. 
11) 
Patients starting hormonal treatment (e.g., estrogen) in the 3 
months prior to Screening. 
12) 
Past intolerance or hypersensitivity to ketamine. 
13) 
Patients taking medications with known activity at the NMDA or 
AMPA glutamate receptor [riluzole, amantadine, memantine, 
topiramate, dextromethorphan, D-cycloserine], or the mu-opioid 
receptor [opiate medications--morphine, oxycodone, heroin, fentanyl)]. 
However, lamotrigine will not be a study exclusion given that it has been 
shown not to impact ketamine's safety profile or its antidepressant 
efficacy. 
14) 
Patients taking any of the following medications: St John’s Wort, 
theophylline, tramadol, metrizamide. 
15) 
Patients who report meditating with mindfulness techniques >1 
hour weekly (on average) for the past 6 months or longer. 
 
 
 
Statistical Considerations and Statistical Analysis Plan 
This is a pilot study, designed to develop novel study infrastructure and 
novel intervention methods, leading to small numbers of patients in each 
treatment arm. Descriptive statistics (means, standard deviations) will be 
reported without statistical analysis to directly compare the two groups 
(mindfulness training vs. academic training), given the small number of 
patients within each group, which yields low statistical power for 
between-group comparisons. Exploratory inferential statistical analyses 


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and effect size comparisons (with 95% CIs) will include appropriate 
comparisons of groups on all primary and secondary endpoints, and on 
other pre-specified outcomes as warranted.