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 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