Ketamine Treatment Effects on Synaptic Plasticity in Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Intervention: Ketamine
Intervention description: Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.
Ketamine is administered at a dose of 0.5mg/kg intravenously as a slow continuous infusion over approximately 40 minutes, with 4 sequential infusions over an approximately two week period (two infusions per week for two weeks).
Intervention MeSH terms: Ketamine
Phase: Phase 4
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Intervention model description: Depressed adults with current major depressive disorder
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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