PET Imaging of mGLuR5 With Drug Challenge

Study Overview
=================
Brief Summary
-----------------
This study is designed to look at that involvement of a process in the brain called the glutamate system in depression. Participants will undergo a screening session, up to two functional Magnetic Resonance Imaging (fMRI) scans, and up to three Positron Emission Tomography (PET) scans, as well as cognitive testing at each scan session. For one of the PET scans, a drug (either ketamine or n-acetyl cysteine) will be administered. Hypothesis 1: The investigators hypothesize administration of ketamine or n-acetylcysteine (NAC) will lead to a decrease in mGluR5. Hypothesis 2: The investigators hypothesize an improvement in memory and attentional skills after drug challenge. Hypothesis 3: The investigators hypothesize an increase in mGluR5 availability and change in MRI measures post drug challenge as compared to baseline, signifying synaptogenesis. Hypothesis 4: We expect there should not be a significant difference in reduction in mGluR5 availability due to differences in ABP688 radiotracer infusion.

Detailed Description
-----------------
Aim 1: To determine the acute effect of medication-induced glutamate release on mGluR5 availability in human subjects. Hypothesis 1: We hypothesize administration of ketamine or n-acetylcysteine (NAC) will lead to a decrease in mGluR5 availability. Aim 2: To determine if glutamate release via administration of ketamine or NAC has pro cognitive benefits. Hypothesis 2: We hypothesize an improvement in memory and attentional skills after drug challenge. Aim 3: To determine if there is synaptogenesis detectable by PET and MRI post ketamine or NAC within a week of drug challenge (at the time of greatest antidepressant response). Hypothesis 3: We hypothesize an increase in mGluR5 availability and change in MRI measures, post drug challenge as compared to baseline, signifying synaptogenesis. Aim 4: To determine if there is a difference in reduction of mGluR5 availability after ketamine administration when radiotracer is administered bolus as compared to bolus to constant infusion in the same subjects (ABP688 radiotracer only). Hypothesis 4: We expect there should not be a significant difference in reduction in mGluR5 availability due to differences in ABP688 radiotracer infusion.

Official Title
-----------------
PET Imaging of mGluR5 With Drug Challenge

Conditions
-----------------
Major Depressive Disorder, Post-Traumatic Stress Disorder (PTSD)

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18-65 years old English speaking No other Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) diagnosis present, besides required as below. Inclusion criteria for depressed subjects clinical diagnosis of a current or past depressive episode medication free for at least 2 weeks Score >16 on Hamilton Depression Rating Scale (HDRS) if currently depressed or <11 if not currently depressed treatment or non-treatment seeking who understand that this study is for research purposes only Inclusion criteria for healthy controls no current, or history of, any DSM-IV diagnosis no first-degree relative with history of psychotic, mood, or anxiety disorder Inclusion criteria for PTSD subjects current Post-Traumatic Stress Disorder, as determined by the Structured Clinical Interview for DSM-IV-Text Revision (TR) (SCID) patient research edition Clinician Administered PTSD Scale for DSM-IV-TR (CAPS) score of 50 or higher Inclusion criteria for trauma control subjects -history of trauma (meeting the criterion A of PTSD but not a full diagnosis of PTSD) Exclusion Criteria: Current or past significant medical, neurological, or metabolic disorder or loss of consciousness for 5 minutes or more active, significant suicidal ideation implanted metallic devices or any Magnetic Resonance (MR) contraindications women who are pregnant or breastfeeding met DSM-IV criteria for alcohol/illicit substance dependence in their life-time or met alcohol/illicit substance abuse within past year history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year blood donation within eight weeks of the start of the study radiation exposure at work that precludes study participation blood pressure >140/80

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>All subjects will receive ketamine | Drug: Ketamine<br>* All subjects will receive ketamine to induce glutamate release in the brain<br>* Other names: ketamine IV;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glutamate Levels at Baseline and After Ketamine Administration as Confirmed by Positron Emission Tomography (PET) Imaging | PET imaging obtained in healthy and Major Depressive Disorder (MDD) subjects. Glutamate levels determined by radiotracer uptake in PET images. | 1st scan: 90 minute baseline scan; 2nd scan: 90 minutes, ketamine administration at start of scan; scan 3: 90 minute scan 24 hours post ketamine | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, Ketamine, PET, PTSD