Imaging mGluR5 and Synaptic Density in Psychiatric Disorders

NCT03898297 | Active Not Recruiting

• 3 other identifiers: 20000201861R01MH116657-01A11K23DA045957-01
• Study Type: observational
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is designed to look at the involvement of the glutamate system and synaptic density in depression and bipolar disorder. Each participant 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 a combination of one magnetic resonance imaging (MRI) or functional magnetic resonance imaging (fMRI) scan, one proton magnetic resonance spectroscopy (MRS) and/or one C13 MRS scans, and up to two positron emission tomography (PET) scans. Participants will also participate in cognitive testing. Depending on camera time, staff availability and subject schedule, total study participation may last 1-2 months.

Conditions

Major Depressive Disorder; Bipolar Disorder; Healthy

Keywords

Depression; Bipolar; Mood disorder; PET; mGluR5; glutamate system; MRI

Outcome Measures

Primary Outcomes (2)

• mGluR5 availability using [18F]FPEB

  Glutamate (major excitatory neurotransmitter)is widespread throughout the brain \& likely modulates some symptoms present in individuals w/mood disorders. Glutamate neurotransmission is regulated by ionotropic \& the G-protein coupled metabotropic glutamate receptors (mGluR) which are divided into 3 groups: group I (mGluR1 and 5), group II (mGluR2 and 3) \& group III (mGluR4, 6, 8). The group I mGluRs couple to phospholipase C, \& stimulate cyclic AMP formation \& arachidonic acid release \& thus impact neuroplasticity, neuronal excitability, synaptic transmission \& gene expression. mGluR5 receptors are located post synaptically \& on glia,\& have highest density in hippocampus, intermediate in caudate/putamen, cerebral cortex, deep cerebellar nuclei, \& thalamus, \& lowest in the cerebellum. mGluR5 are considered to be pivotal in the functioning of the glutamatergic system especially as it pertains to cognitive performance. \[18F\]FPEB: high affinity radiotracer used to image mGluR5 receptor.

  Through study completion date: 5 years

• Synaptic density using [11C]APP311

  Synaptic density differences using \[11C\]APP311 between individuals with mood disorders compared to healthy controls. Synaptic density and \[11C\]APP311: There is strong preclinical evidence showing that chronic stress and depression lead to structural changes, which include neuronal atrophy, reduced synaptic density and cell loss. \[11C\]APP311 (also referred to as \[11C\]UCB-J) was developed at the Yale University PET Center as a novel PET radioligand for synaptic vesicle glycoprotein 2A (SV2A). SV2A is an integral membrane protein located in presynaptic vesicle membranes, similar to synaptophysin (SYN). SV2 has 3 isoforms, with SV2A being the only isoform which is ubiquitously located in synaptic vesicles across the brain. Thus, PET quantification of SV2A signal may be an excellent in vivo biomarker of synaptic density.

  Through study completion date: 5 years

Secondary Outcomes (2)

• glutamate cycling using MRS

  Through study completion date: 5 years

• Cognitive Functioning Assessed with CogState Software

  Through study completion date: 5 years

Study Arms (3)

Healthy control

60 psychiatrically-healthy subjects will be enrolled as controls may participate in MRI or fMRI, \[1H\]MRS and/or \[13C\]MRS, \[18F\]FPEB and/or \[11C\]APP311 PET scans, cognitive testing

Radiation: [18F]FPEB; Radiation: [11C]APP311

MDD

30 subjects with major depressive disorder (MDD) may participate in MRI or fMRI, \[1H\]MRS and/or \[13C\]MRS, \[18F\]FPEB and/or \[11C\]APP311 PET scans, cognitive testing

Radiation: [18F]FPEB; Radiation: [11C]APP311

Bipolar

30 subjects with bipolar disorder may participate in MRI or fMRI, \[1H\]MRS and/or \[13C\]MRS, \[18F\]FPEB and/or \[11C\]APP311 PET scans, cognitive testing

Radiation: [18F]FPEB; Radiation: [11C]APP311

Interventions

[18F]FPEB RADIATION

Radiotracer: \[18F\]FPEB

Bipolar; Healthy control; MDD

[11C]APP311 RADIATION

Radiotracer: \[11C\]APP311, \[11C\]UCB-J

Also known as: [11C]UCB-J

Bipolar; Healthy control; MDD

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

60 psychiatrically-healthy controls 30 MDD 30 bipolar

You may qualify if:

• years old English speaking

You may not qualify if:

• Current or past significant medical, neurological, or metabolic disorder
• history of head injury that led to significant long term decline in cognitive abilities as seen by decline in grades or work performance
• history of significant medical illness such that would contraindicate study participation based on above criteria and PI/MD history review
• Active, significant suicidal ideation
• Implanted metallic devices or any MR contraindications
• women who are pregnant or breastfeeding
• Met Diagnostic and Statistical Manual of Mental Disorders(DSM)-5 criteria for mild substance use disorder in the past 6 months or moderate to severe substance use disorder within the past year (except marijuana or nicotine)
• 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
• Current, past, or anticipated exposure to radiation in the work place within one year of proposed research PET scans
• Blood donation within 8 weeks of the start of the study
• History of a bleeding disorder or currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto)

Sponsors & Collaborators

• Yale University: lead
• National Institute of Mental Health (NIMH): collaborator
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Yale University PET Center

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Bipolar Disorder; Depression; Mood Disorders

Interventions

1-((3-(methylpyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one

Condition Hierarchy (Ancestors)

Depressive Disorder; Mental Disorders; Bipolar and Related Disorders; Behavioral Symptoms; Behavior

Study Officials

• Irina Esterlis, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2018
• First Posted: April 1, 2019
• Study Start: January 11, 2017
• Primary Completion: April 1, 2026
• Study Completion: April 1, 2026
• Last Updated: June 24, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)