Biomarker Assessment of Glutamatergic Target Engagement

The purpose of this study is to assess the relative feasibility of 2 potential functional measures of target engagement (Glx MRS, BOLD fMRI) to systematically assess mGluR 2/3 in drug development for psychotic spectrum disorders.

Study Overview

• Status: Completed
• Conditions: Healthy Controls
• Intervention / Treatment: Drug: Ketamine; Drug: Normal saline

Detailed Description

This is a pilot study of healthy subject to assess the feasibility of Glx MRS and BOLD fMRI to measure ketamine induced changes in glutamatergic indices. The investigators will randomize 18 subjects at each site. Subjects will be randomized to ketamine or placebo in a 2:1 ratio and receive two drug challenges separated by at least two weeks. Ketamine challenge is used to induce a "glutamate surge" within prefrontal brain regions that can be detected using neurochemical and functional imaging techniques. Each subject will receive MRS and BOLD fMRI during each challenge day. The goal of the pilot study is to assess the feasibility of both the proposed ketamine challenge paradigm and of the proposed imaging-based biomarkers. Specific indices to be used in assessing feasibility will include effect size, cross-site and cross-subject reliability, safety, and subject tolerability as similar studies will be performed independently at Yale and UC Davis. Second this information will be used to select and refine final study parameters for a subsequent full proof-of-clinical mechanism (POCM) study investigating the effect of Pomaglumetad on ketamine-induced MRS and fMRI effects.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-55
• Negative Urine Toxicology
• No present or past psychiatric conditions (including substance abuse or dependence, with the exception of nicotine dependence)
• No family history of schizophrenia in a first-degree relative

Exclusion Criteria:

• Any current DSM IV Axis I disorder and/or past substance abuse of dependence (nicotine dependence is allowed)
• Any current use of amphetamines, opiates, cocaine, sedative-hypnotics, or cannabis
• Current (i.e., within the last 3 months) treatment with any psychotropic medications
• Pregnancy, lactation, or lack of use of effective birth control
• Presence of positive history of significant medical or neurological illness (including any history of seizure), including high blood pressure (SBP >140, DBP >90), low blood pressure (SBP <100, DBP <60), orthostatic BP change>20% (1/3 SBP + 2/3 DBP) or cardiac illness or resting heart rate >100 or <50
• History of significant violent behavior
• History of recreational ketamine use, recreational PCP use, or an adverse reaction to ketamine. Subjects who have participated prior research ketamine studies will be eligible providing they have participated in no more than 5 previous research ketamine infusions. Subjects can have infusions not more frequently than biweekly and not more than 1/month on average, therefore subjects entering the study will need to wait 1 month if they had a single infusion and 6 weeks if they have had two closely spaced infusions.
• Contraindication to MRI scanning, including metal implants or claustrophobia. Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan, as determined in consultation with a neuroradiologist and 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
• Color Blindness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ketamine; IV infusion of ketamine 0.23mg/kg bolus over 1 minutes followed by 0.58 mg/kg/hr over 30 minutes then 0.29mg/kg/hr over 64 minutes	Drug: Ketamine; intravenous infusion of saline solution with ketamine; Other Names: ketamine hydrochloride
Placebo Comparator: Placebo; Placebo group will receive normal saline	Drug: Normal saline; Normal saline will be used for placebo in this group; Other Names: saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glutamate + Glutamine (Glx) Response	Compare changes in Glx response to infusion of ketamine vs placebo, as measured by proton magnetic resonance spectroscopy (¹H MRS). Calculated by post-pre changes in the Glx over creatinine ratios, with higher values indicating higher Glx/creatinine ratios.	Day 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacological Blood-oxygen-level Dependent (pharmacoBOLD) Response	Compare changes inpharmacoBOLD in response to infusion of ketamine vs. placebo, as measured by resting state functional magnetic resonance imaging. Calculated by post-pre changes, with higher values indicating higher response	Day 14

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Jeffrey A Lieberman, MD, New York State Psychiatric Institute

Publications and helpful links

General Publications

• Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Corlett PR, Rothman DL, Mason G, Qiu M, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman JA. Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Jan 1;75(1):11-19. doi: 10.1001/jamapsychiatry.2017.3572.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: May 7, 2014
• First Submitted That Met QC Criteria: May 7, 2014
• First Posted (Estimate): May 9, 2014

Study Record Updates

• Last Update Posted (Actual): August 17, 2018
• Last Update Submitted That Met QC Criteria: August 15, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 6925; HHS-N-271-2012-0000-7-I (Other Identifier: NIH/NIMH contract number)