Biomarker Assessment of Glutamatergic Target Engagement

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
Biomarker Assessment of Glutamatergic Target Engagement

Conditions
-----------------
Healthy Controls

Intervention / Treatment
-----------------
* Drug: Ketamine
* Drug: Normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ketamine<br>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<br>* intravenous infusion of saline solution with ketamine<br>* Other names: ketamine hydrochloride;|
| Placebo Comparator: Placebo<br>Placebo group will receive normal saline | Drug: Normal saline<br>* Normal saline will be used for placebo in this group<br>* 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 |