Healthy Controls
Conditions
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.
Interventions
DRUGKetamine
intravenous infusion of saline solution with ketamine
DRUGNormal saline
Normal saline will be used for placebo in this group
Sponsors
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glutamate + Glutamine (Glx) Response | Day 1 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacological Blood-oxygen-level Dependent (pharmacoBOLD) Response | Day 14 | 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 |
Countries
United States
Participant flow
Pre-assignment details
65 subjects were randomized, with results (Number started) reported for the 59 subjects randomized subjects with at least one valid scan
Participants by arm
| Arm | Count |
|---|---|
| Ketamine randomized to ketamine | 39 |
| Placebo randomized to placebo | 20 |
| Total | 59 |
Baseline characteristics
| Characteristic | Ketamine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 31.1 years STANDARD_DEVIATION 9.6 | 32.2 years STANDARD_DEVIATION 10.2 | 31.5 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 21 Participants | 16 Participants | 37 Participants |
| Sex: Female, Male Male | 18 Participants | 4 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 20 |
| other Total, other adverse events | 6 / 39 | 0 / 20 |
| serious Total, serious adverse events | 0 / 39 | 0 / 20 |
Outcome results
Primary
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.
Time frame: Day 1
Population: Glx response in 1st 15 minutes post ketamine
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Glutamate + Glutamine (Glx) Response | 0.015 Glx over creatinine ratio | Standard Error 0.002 |
| Placebo | Glutamate + Glutamine (Glx) Response | 0.007 Glx over creatinine ratio | Standard Error 0.003 |
Other Pre-specified
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
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Pharmacological Blood-oxygen-level Dependent (pharmacoBOLD) Response | .91 BOLD signal units | Standard Error 0.1 |
| Placebo | Pharmacological Blood-oxygen-level Dependent (pharmacoBOLD) Response | -0.27 BOLD signal units | Standard Error 0.14 |