Pomaglumetad Effects on Glutamate Biomarkers

Study Overview
=================
Brief Summary
-----------------
The study will evaluate the effects of the mGluR2/3 partial agonist LY2140023 (Pomaglumetad Methionil, POMA) at selected doses on ketamine-stimulated glutamate release in prefrontal cortex as measured by pharmacoBOLD fMRI (also termed resting BOLD fMRI).

Detailed Description
-----------------
This study evaluates the effects of POMA at selected doses on ketamine-stimulated glutamate increase in the prefrontal cortex hypothesized to simulate the synaptic dysregulation that occurs endogenously in the pathogenesis of schizophrenia. The purpose of this is: 1) to determine whether the low dose (40 mg BID) utilized in recent (failed) clinical trials is sufficient to engage the primary target and 2) whether a higher (160 mg BID) dose, representing the maximum tolerated dose of POMA, engages the target to a greater degree. This study will further validate pharmacoBOLD as biomarker of mGluR2/3 target engagement, permitting its future use in other glutamatergic drug development.

Official Title
-----------------
Biomarker Assessment of Pomaglumetad on Glutamate Targets: Proof of Clinical Mechanism of Action (POCM)

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

Intervention / Treatment
-----------------
* Drug: POMA
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Medically healthy Capable of understanding the study procedures and able to provide informed consent Men and women must agree to use a reliable method of birth control during the study. Women who are post-menopausal or otherwise not of childbearing potential are also eligible Exclusion Criteria: Current or past Axis I psychiatric history Positive urine toxicology History of recreational ketamine use, recreational PCP use, or an adverse reaction to ketamine. Subjects who have participated in prior research ketamine studies will be eligible. 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 one month if they had a single infusion and 6 weeks if they have had two closely spaced infusions. History of first-degree relative with schizophrenia History of violence Presence or positive history of significant medical illness Presence or positive history neurological illness or any other disease/procedure/accident/intervention association with significant injury to or malfunction of the central nervous system (CNS) or history of significant head injury Pregnancy or breast feeding Metal implants, pacemaker, other metal or paramagnetic objects contained within the body Medicinal patch, unless removed prior to MRI scan Currently taking any psychotropic medication, including antidepressant medications, benzodiazepines, antipsychotic medications, mood stabilizers, anti-epileptic medications and stimulants. Claustrophobia Suicidal ideation with intent or plan in the 6 months prior to screening Weight > 86.95 kg (191.2 lbs) Subthreshold pharmacoBOLD response during screening ketamine infusion

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: POMA 40 mg BID<br>40 mg BID for 10 days | Drug: POMA<br>* Pomaglumetad (POMA) is a mGluR 2/3 partial agonist<br>* Other names: Pomaglumetad;|
| Experimental: POMA 160 mg BID<br>160 mg BID for 10 days | Drug: POMA<br>* Pomaglumetad (POMA) is a mGluR 2/3 partial agonist<br>* Other names: Pomaglumetad;|
| Placebo Comparator: Placebo<br>Placebo BID for 10 days | Drug: placebo<br>* matching placebo tablets<br>* Other names: placebo comparator;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PharmacoBOLD change | pharmacoBOLD change, as summarized by the Amplitude measure | Day 1 to Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brief Psychiatric Rating Scale (BPRS) | Clinical rating scale assessing common psychiatric symptoms | Day 1 to Day 10 | 
| Clinician Administered Dissociative States Scale (CADSS) | Rates dissociative symptoms | Day 1 to Day 10 |