Biomarker Assessment of Glutamatergic Target Engagement

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.

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