Ketamine Treatment Effects on Synaptic Plasticity in Depression

NCT04091971 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 7847
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Synaptic Density

  PET imaging measure of synaptic density (\[11C\]UCB-J binding potential, BPND) before and after ketamine treatment. This type of brain scan takes pictures to measure the density of synapses, or connections between brain cells (neurons), in the brain. \[11C\]UCB-J is a radiotracer specific for SV2A, a protein present in presynaptic vesicles. \[11C\]UCB-J BPND was quantified in a brain region called the medial prefrontal cortex; previous studies have found lower levels of \[11C\]UCB-J binding in patients with more severe depression. BPND is the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue. Time frame of assessment: Time frame 1 = baseline. This pre-treatment PET scan was acquired as close as possible prior to the first ketamine infusion, up to 7 days prior to first ketamine infusion. Time frame 2 = post-treatment. This post-treatment PET scan was acquired 24-48 hours following the final (4th) ketamine infusion.

  Measured at two time frames: Time frame 1 = Baseline. Time frame 2 = post-treatment

Secondary Outcomes (1)

• 17-item Hamilton Depression Rating Scale

  Measured at 3 time frames. Time frame one = Baseline: 24 hours prior to infusion one ("PRE"). Time frame two = 24 hours following ketamine infusion 4 ("POST1"). Time frame three = one week following ketamine infusion 4 ("POST2").

Study Arms (1)

Depressed adults with current MDD

EXPERIMENTAL

Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.

Drug: Ketamine

Interventions

Ketamine DRUG

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).

Depressed adults with current MDD

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• New York State Psychiatric Institute: lead

Study Sites (1)

New York State Psychiatric Institute/Columbia University

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Jeffrey Miller, M.D.
• Organization: NYSPI

jeffrey.miller@nyspi.columbia.edu

646-774-7613

Study Officials

• Jeffrey Miller, MD

  New York State Psychiatric Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Brain Imaging, Division of Molecular Imaging and Neuropathology

Model Details: Depressed adults with current major depressive disorder

Study Record Dates

• First Submitted: September 11, 2019
• First Posted: September 17, 2019
• Study Start: October 9, 2020
• Primary Completion: May 1, 2022
• Study Completion: May 1, 2022
• Last Updated: November 13, 2023
• Results First Posted: November 13, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share

Locations

US (1)