Examination of Glutamate and mGluR5 in Psychiatric Disorders

December 22, 2025 updated by: Yale University
This research study is designed to look at the involvement of the glutamate system in depression. Each subject will undergo a screening appointment to determine study eligibility. Thereafter, the study will take 2 or 3 visits depending on schedule availability and will consist of one MRI scan, and PET scan. Subjects will also participate in cognitive testing. Depending on camera time, staff availability and subject schedule, total study participation may last 1-2 months.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

With the recent advancements in positron emission tomography (PET) and radioligand development, the investigators are now able to image and quantify the metabotropic glutamatergic system (mGluR5) in vivo in human subjects. The study proposes a novel investigation of mGluR5 in depression to obtain critical data to advance understanding of the etiology of depression and its associated symptoms of cognitive dysfunction.

Aim 1: To determine mGluR5 availability in individuals with mood disorders compared to healthy controls as measured with PET brain imaging.

Hypothesis 1: The study hypothesizes a decrease in mGluR5 availability in individuals with mood disorders in regions responsible for emotional and cognitive processes, including the amygdala, hippocampus, thalamus, anterior cingulate, and frontal cortices.

Aim 2: To determine if glutamate cycling in individuals with mood disorders is altered as compared to healthy controls as measured with [1H]MRS and [13C]MRS.

Hypothesis 2: The study hypothesizes an increase in glutamate number in individuals with mood disorders as compared to controls.

Aim 3: To determine if the PET alterations in the glutamatergic system of depressed individuals are associated with cognitive deficits observed in depression, including concentration, attention, memory, distractibility, and startle.

Hypothesis 3: The study hypothesizes a positive relationship between mGluR5 availability and cognitive functioning, such that individuals with higher receptor availability will perform better on tests of concentration, attention, memory, distractibility, and startle than individuals with lower receptor availability.

Aim 4: To determine mGluR5 availability in individuals with anxiety and schizophrenia compared to healthy controls as measured with PET brain imaging.

Hypothesis 4: Anxiety disorders such as obsessive compulsive disorder, and delusional disorders such as schizophrenia are frequently comorbid with mood disorders, and the glutamatergic system has been observed to be compromised in these individuals as well. This study will examine if there are regional differences in mGluR5 availability between individuals with depression, bipolar disorder, obsessive compulsive disorder, and schizophrenia.

Aim 5: To examine whether changes in mGluR5 availability are dependent on state, or whether the lower availability is due to trait.

Hypothesis 5: Due to changes in endogenous GLU shown with MRS studies, this study hypothesizes normalization (or increase) in mGluR5 availability in euthymia as compared to depressed state.

Study Type

Interventional

Enrollment (Estimated)

180

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06519
        • PET Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

General inclusion criteria:

  • Subjects will be between the ages of 18-70 years old
  • English speaking
  • No other DSM-5 diagnosis present, besides required as below

Inclusion criteria for acute depressed subjects:

  • Clinical diagnosis of a current depressive episode
  • Medication-free for at least 2 weeks or medicated with a permissible medication

Inclusion criteria for PTSD subjects:

  • Clinical diagnosis of current PTSD as per DSM-5
  • Medication free for at least 2 weeks or medicated with a permissible medication

Inclusion criteria for healthy controls:

  • No current, or history of, any DSM-5 diagnosis

Exclusion Criteria:

  • Have a current or past significant medical, neurological or metabolic disorder or head injury that lead to significant long term decline in cognitive abilities as seen by decline in grades or work performance
  • Have significant medical illness such that would contraindicate study participation based on above criteria and PI/MD history review
  • Have active, significant suicidal ideation
  • Have implanted metallic devices or any MR contraindications
  • Are women who are pregnant or breastfeeding
  • Met DSM-5 criteria for mild substance use disorder (except nicotine and marijuana) within the past 6 months or met DSM-5 criteria for moderate to severe substance use disorder (except nicotine and marijuana) within the past year
  • Have 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
  • Have given a blood donation within eight weeks of the start of the study
  • Have history of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Cognitive Testing
Cognitive assessments
Behavioral: Cognitive Testing
Verbal assessments as well as computer testing.
Active Comparator: Magnetic Resonance Imaging
All subjects will have one MRI with a possibility of one functional MRI (fmri).
Other: MRI
Anatomical MRIs will be performed on a Siemens 3T Trio at Yale. MR acquisition will be a Sag 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence with 3.34 ms echo time, 2,500 ms repetition time, 1,000 ms inversion time, 7 degree flip angle, and 180 Hz/pixel bandwidth. The image dimensions will be 256 x 256 x 176 and pixel size 0.98 x 0.98 x 1.0 mm. Resting state MRIs will also be obtained as follows: We will be doing 2 six minute scans with subjects in the scanner, eyes open, fixating a cross. TR = 3 secs 45 slices x 3 mm slice thickness = 13.5 cm. In plane resolution = 3 x 3 mm, slice acquisition order = ascending.
Other Names:
  • Magnetic Resonance Imaging
Active Comparator: Positron Emission Tomography
All subjects will have PET scan using FPEB or ABP688.
Radiation: PET
High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available, or HR+ will be used to image subjects. Vital signs (blood pressure, pulse, respiration) will be obtained before and after radiotracer administration. An antecubital venous catheter will be used for IV administration of the radiotracer and for venous blood sampling. A radial artery catheter will be inserted by an experienced physician before the PET scan. At the beginning of each scan, the subject's head will be immobilized and a 6 minute transmission scan using an orbiting 137Cs (HRRT) or 68GE (HR+) point-source is obtained and used for attenuation correction. PET scans will be acquired using bolus or bolus plus constant infusion administration of FPEB or ABP688.
Other Names:
  • Positron Emission Tomography

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Evidence of glutamate availability (mGluR5) in psychiatric disorders confirmed by MRI and PET data.
Time Frame: Through study completion date, an average of 4 years.
Through study completion date, an average of 4 years.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

VA Office of Research and Development

Investigators

  • Principal Investigator: Irina Esterlis, PhD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 21, 2012

Primary Completion (Actual)

January 13, 2022

Study Completion (Actual)

January 13, 2022

Study Registration Dates

First Submitted

March 17, 2016

First Submitted That Met QC Criteria

April 4, 2016

First Posted (Estimated)

April 5, 2016

Study Record Updates

Last Update Posted (Estimated)

December 30, 2025

Last Update Submitted That Met QC Criteria

December 22, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1101007933

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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