Imaging mGluR5 and Synaptic Density in Psychiatric Disorders

Yale University

Status: Enrolling

Conditions: Healthy; Major Depressive Disorder; Bipolar Disorder

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

Study type: Observational

Funder types: Other; NIH

Identifiers

NCT03898297

1K23DA045957-01 (U.S. NIH Grant/Contract)

2000020186

1R01MH116657-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

With the recent advancements in the 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 investigators propose a novel investigation using [18F]FPEB in depression and bipolar disorder to obtain critical data to advance the understanding of the etiology of depression and bipolar disorder and its associated symptoms of cognitive dysfunction. The findings with mGluR5 by themselves are limited. Changes in mGluR5 availability could be due to changes in synaptic density. Recently, the Yale PET center synthesized a new radioligand [11C]UCB-J (referred to as [11C]APP311 at the Yale University PET Center) that binds to synaptic vesicle glycoproteins (SV2A), which represent the number of synapses in the brain. Thus, the investigators will also measure synaptic density in the brain and relate to mGluR5 availability.

Aim 1: To determine mGluR5 availability with mood disorders compared to healthy controls as measured with PET brain imaging using [18F]FPEB.

Hypothesis 1: 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: 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, and memory (cognitive testing performance), and distractibility and startle.

Hypothesis 3: 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 examine whether changes in mGluR5 availability are dependent on state, or whether the lower availability is due to trait.

Hypothesis: normalization (or increase) in mGluR5 availability in euthymia as compared to depressed state.

Aim 5: To examine synaptic density changes associated with mood disorders using [11C]APP311 Hypothesis 5: lower synaptic density in individuals with MDD and bipolar disorder (BD), and associations between synaptic density changes and mood severity. Investigators also hypothesize there might be a relationship between synaptic density and mGluR5 availability.

Enrollment: 90 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• General inclusion criteria:

18-80 years old English speaking

-Inclusion criteria for healthy controls: no current, or history of any DSM-5 diagnosis

• Inclusion criteria for MDD subjects clinical diagnosis of major depressive disorder
• Inclusion criteria for bipolar subjects clinical diagnosis of bipolar disorder

Exclusion criteria

• 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)

Trial design

90 participants in 3 patient groups

Healthy control

Description:

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

Treatment:

Radiation: [18F]FPEB

Radiation: [11C]APP311

MDD

Description:

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

Treatment:

Radiation: [18F]FPEB

Radiation: [11C]APP311

Bipolar

Description:

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

Treatment:

Radiation: [18F]FPEB

Radiation: [11C]APP311