Major Depressive DisorderNCT03898297
Imaging mGluR5 and Synaptic Density in Psychiatric Disorders
An observational study of Major Depressive Disorder and Bipolar Disorder, run by Yale University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Major Depressive Disorder, Bipolar Disorder, Healthy
- What is being tested?
- [18F]FPEB and [11C]APP311
- Type of treatment
- Surgery or procedure
- How many people
- 79 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Jan 2017to 8 Oct 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Adult, Older adult
Study population: 60 psychiatrically-healthy controls 30 MDD 30 bipolar
Who may be able to join
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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 locations and contacts
1 site in 1 country.
United States1 site
Yale University PET Center
New Haven, Connecticut, 06519
About this study
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.
Read the detailed 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.
- Conditions
- Major Depressive Disorder, Bipolar Disorder, Healthy
- Being tested
- [18F]FPEB, [11C]APP311
- Keywords
- Depression, Bipolar, Mood disorder, PET, mGluR5, glutamate system, MRI
- Medical subject headings
- Depressive Disorder, Major, Bipolar Disorder, Depression, Mood Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
[18F]FPEBRadiation
Radiotracer: [18F]FPEB
[11C]APP311Radiation
Also called [11C]UCB-J
Radiotracer: [11C]APP311, [11C]UCB-J
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: Radiation: [18F]FPEB; Radiation: [11C]APP311 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Through study completion date: 5 years
Secondary outcomes (2)
glutamate cycling using MRS
alterations in glutamate cycling in individuals with mood disorders compared to healthy controls using [1H]MRS and [13C]MRS
[1H]MRS: proton Magnetic Resonance Spectroscopy (MRS) [13C]MRS: baseline spectra obtained then [13C]glucose administered at a rate to raise the fractional 13C enrichment of the plasma glucose quickly to 60% and maintain it constant for 120 minutes, with a plasma glucose concentration between 150 and 200 mg/dl. The 13C MRS measurements will continue throughout the infusion of glucose. These data will be analyzed using a metabolic model to derive the rates of oxidative glucose metabolism and glutamate neurotransmitter cycling.
Measured: Through study completion date: 5 years
Cognitive Functioning Assessed with CogState Software
relationship between cognitive functioning and mGluR5 availability in individuals with mood disorders compared to healthy controls.
Cognitive functioning: the way people think, remember, and process information. Utilizing CogState software.
Measured: Through study completion date: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Apr 2019
- Study start11 Jan 2017
- Primary completion8 Oct 2024
- Study completion8 Oct 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 79 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA)
- Responsible party
- Sponsor
- Investigators
- Irina Esterlis, PhD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03898297
- Sponsor's protocol ID
- 2000020186
- Other IDs
- 1R01MH116657-01A1, 1K23DA045957-01
- Status last verified
- Aug 2026
- First submitted
- 21 Dec 2018
- Last updated
- 3 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Imaging mGluR5 and Synaptic Density in Psychiatric Disorders
- ClinicalTrials.gov ID
- NCT03898297
- Acronym / sponsor ID
- 2000020186
- Conditions
- Major Depressive Disorder, Bipolar Disorder, Healthy
- Keywords
- Depression, Bipolar, Mood disorder, PET, mGluR5, glutamate system, MRI
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 79 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA)
- Study start
- 11 Jan 2017 (actual)
- Primary completion
- 8 Oct 2024 (actual)
- Study completion
- 8 Oct 2024 (actual)
- First posted
- 1 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Healthy control | – | Radiation: [18F]FPEB, Radiation: [11C]APP31160 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 |
| MDD | – | Radiation: [18F]FPEB, Radiation: [11C]APP31130 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 |
| Bipolar | – | Radiation: [18F]FPEB, Radiation: [11C]APP31130 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 |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- 60 psychiatrically-healthy controls 30 MDD 30 bipolar
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| [18F]FPEBRadiotracer: [18F]FPEB | Radiation | Bipolar, Healthy control, MDD |
| [11C]APP311Also: [11C]UCB-JRadiotracer: [11C]APP311, [11C]UCB-J | Radiation | Bipolar, Healthy control, MDD |
Primary outcome
mGluR5 availability using [18F]FPEB
Time frame: Through study completion date: 5 years
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.
Synaptic density using [11C]APP311
Time frame: Through study completion date: 5 years
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.
2 secondary outcomes
glutamate cycling using MRS
Time frame: Through study completion date: 5 years
Cognitive Functioning Assessed with CogState Software
Time frame: Through study completion date: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Irina Esterlis, PhD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Major Depressive Disorder and Bipolar Disorder, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
mGluR5 availability using [18F]FPEB (time frame: Through study completion date: 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2026.