Ketamine Treatment Effects on Synaptic Plasticity in Depression
Ketamine Treatment Effects on Synaptic Plasticity in Depression
Depression is the leading cause of disability globally (1, 2). One-third to one-half of
 patients suffering from major depressive disorder (MDD) do not achieve remission even after
 multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic
 medication that at subanesthetic doses leads to rapid antidepressant and anti-suicidal
 ideation effects in hours, rather than weeks, following administration. Despite these
 promising findings, a key limitation of ketamine treatment is that it only yields an
 antidepressant response in approximately 50% of those treated. The goal of this project is to
 A) elucidate ketamine's mechanism of action and B) identify biomarkers predicting treatment
 outcome to ketamine which could be used to match patients to treatment based on the
 likelihood of effectiveness at the individual level. Data from animal models suggests that
 ketamine acts by enhancing the connections between neurons through a process known as
 synaptic plasticity (4-7), and that these biological changes are responsible for the
 sustained behavioral effects of ketamine (8). A newly available tool allows us to image the
 density of these synaptic connections in the living brain using PET (positron emission
 tomography) imaging with a radiotracer called [11C]UCB-J, which is a marker of synaptic
 density. We propose to directly quantify synaptic density in depressed patients before and
 after a course of ketamine, to examine changes in density following treatment. In exploratory
 analyses, we will examine synaptic density as a mediator of the sustained antidepressant
 effects of ketamine and as a predictor of treatment outcome. To study these questions, we
 will quantify synaptic density using PET imaging before and after a course of 4 sequential
 intravenous infusions of ketamine administered over a two week period. Study participation
 involves an inpatient stay of approximately three weeks at the New York State Psychiatric
 Institute at no cost.
Depression is the leading cause of disability globally (1, 2). One-third to one-half of
 patients suffering from major depressive disorder (MDD) do not achieve remission even after
 multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic and
 non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Recent randomized
 trials demonstrate that subanesthetic doses of ketamine lead to rapid antidepressant and
 antisuicidal ideation effects in individuals with MDD and bipolar depression (reviewed in
 (9)). In contrast to current FDA-approved antidepressants, ketamine exerts antidepressant
 effects in hours, rather than weeks, following administration. Despite these promising
 findings, a key limitation of ketamine treatment is that it only yields an antidepressant
 response in approximately 50% of those treated. In addition, ketamine's clinical utility is
 limited by its acute dissociative side effects, a one to two-week duration of action as
 monotherapy, its addictive potential, and long term safety concerns related to cognition and
 interstitial cystitis (9-11). Given the profound benefit of ketamine for some individuals yet
 these key limitations, developing a precision medicine research strategy for ketamine's
 antidepressant effects could be of tremendous scientific and clinical benefit, in order to A)
 elucidate ketamine's mechanism of action, to advance the development of safer alternative
 agents and B) identify biomarkers predicting treatment outcome to ketamine, which could be
 used to match patients to treatment based on the likelihood of effectiveness at the
 individual level.

 There is evidence of brain atrophy in depression: gray matter volume is reduced in the
 prefrontal cortex (PFC) and in the hippocampus (HC) in depressed individuals (12). Postmortem
 studies in depression show low expression of several genes related to synaptic function and
 decreased synapse number in the dorsolateral PFC (13). Chronic stress, a risk factor for
 depression, precipitates neuronal atrophy and dendritic spine loss in HC and PFC (14, 15).
 Preclinical work in rodents suggests that ketamine may exert antidepressant effects by
 reversing neuronal atrophy, specifically through the formation of new dendritic spine
 synapses in the brain. In rodents, ketamine induces rapid synaptogenesis via stimulation of
 mechanistic target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), leading
 to a reversal of chronic, stress-induced neuronal atrophy (4-7).

 A recently developed research tool enables examination of synaptic density in vivo in humans.
 [11C]UCB-J is a PET radiotracer that is specific for synaptic vesicle glycoprotein 2A (SV2A)
 (16, 17), providing a quantitative measure of synaptic density in vivo in the brain in
 humans. A recent PET imaging pilot study identified low [11C]UCB-J binding in the PFC of
 individuals with current MDD as compared to healthy volunteers, providing early evidence that
 this synaptic density biomarker may quantify a disease-relevant process in depression (18).
 Furthermore, PET imaging with [11C]UCB-J displays outstanding test-retest reliability, with
 absolute test-retest variability of only 4-5% in brain regions of interest in this study
 (19), making it an outstanding tool for longitudinal studies of the effects of treatment
 interventions. We therefore propose to directly quantify synaptic density in depressed
 patients to investigate whether it is increased by treatment with ketamine in a
 regionally-specific manner. Moreover, we will examine synaptic density as a mediator of the
 sustained antidepressant effects of ketamine and as a predictor of treatment outcome. We will
 quantify synaptic density using PET imaging before and after a course of 4 sequential
 intravenous infusions of ketamine administered over a two-week period. Study participation
 involves an inpatient stay of approximately three weeks at the New York State Psychiatric
 Institute at no cost.
Inclusion Criteria:

 -  Unipolar, major depressive episode (MDE), with 17-item Hamilton Depression Rating
 Scale score ≥16. Patients may be psychiatric medication- free, or if currently taking
 psychiatric medication, not responding adequately as evidenced by current MDE.

 -  18-55 years old

 -  Female patients of child-bearing potential must be willing to use an acceptable form
 of birth control during study participation such as condoms, diaphragm, oral
 contraceptive pills.

 -  Must be enrolled in division's umbrella research protocol

 -  Able to provide informed consent

 -  Agrees to voluntary admission to an inpatient research unit at The New York State
 Psychiatric Institute (NYSPI) for baseline PET imaging and Magnetic Resonance Imaging
 (MRI), ketamine infusion, and repeat PET imaging

 Exclusion Criteria:

 -  Unstable medical or neurological illness including: A) baseline hypertension
 (BP>140/90); B) significant history of cardiovascular illness; C) Platelet count <
 80,000 cells/uL; and D) Hemoglobin < 11 g/dL for females and < 12 g/dL for males

 -  Significant electrocardiogram (ECG) abnormality (e.g., Ventricular tachycardia,
 evidence of myocardial ischemia, symptomatic bradycardia, unstable tachycardia, second
 degree (or greater) atrioventricular (AV) block).

 -  Pregnancy, currently lactating, or planning to conceive during the course of study
 participation.

 -  Diagnosis of bipolar disorder or current psychotic symptoms.

 -  Current or past ketamine use disorder (lifetime); any drug or alcohol use disorder
 within past 6 months

 -  Inadequate understanding of English.

 -  Prior ineffective trial of or adverse reaction to ketamine.

 -  A neurological disease or prior head trauma with evidence of cognitive impairment.

 Subjects who endorse a history of prior head trauma and score ≥ 1.5 standard deviations
 below the mean on the Trailmaking A&B will be excluded from study participation.

 - Metal implants or paramagnetic objects contained within the body (including heart
 pacemaker, shrapnel, or surgical prostheses) which may present a risk to the subject or
 interfere with the MRI scan, according to the guidelines set forth in the following
 reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic
 objects," F.G. Shellock, Lippincott Williams and Wilkins NY 2001. Additionally transdermal
 patches will be removed during the MR study at the discretion of the investigator.

 -  Current, past, or anticipated exposure to radiation, that may include: **

 -  being badged for radiation exposure in the workplace

 -  participation in nuclear medicine research protocols in the last year

 -  Claustrophobia significant enough to interfere with MRI scanning

 -  Weight that exceeds 325 lbs or inability to fit into MRI scanner

 -  Individuals taking prescribed opioid medication, using opioids recreationally, or
 taking naltrexone at the time of enrollment 14. Daily use of: benzodiazepine, zolpidem
 (Ambien), zaleplon (Sonata), or eszopiclone (Lunesta) for ≥2 weeks at time of consent