Glutamate Imaging and Cognitive Testing for Depression

Recruiting in Palo Alto (17 mi)

Overseen by Irina Esterlis, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Waitlist Available

Sponsor: Yale University

No Placebo Group

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

The trial requires participants to be medication-free for at least 2 weeks or to be on a permissible medication. The protocol does not specify which medications are permissible, so you may need to discuss your current medications with the study team.

What data supports the idea that Glutamate Imaging and Cognitive Testing for Depression is an effective drug?

The available research shows that ketamine, a drug used in Glutamate Imaging and Cognitive Testing for Depression, can rapidly reduce symptoms in people with severe depression who haven't responded to other treatments. Studies have found that ketamine can quickly improve mood and decrease suicidal thoughts. For example, one study showed that ketamine led to changes in brain areas related to mood and reward, which are important for feeling better. Another study found that ketamine increased certain brain chemicals linked to feeling less depressed. These findings suggest that ketamine can be an effective option for people with treatment-resistant depression. ^{1 2 3 4 5}

What safety data exists for ketamine treatment in depression?

Ketamine has been shown to be safe in short-term use for depression, with rapid antidepressant effects demonstrated in several studies. However, its long-term safety profile is not well-established. Known side effects include psychiatric, cardiovascular, neurologic, and genitourinary effects, as well as potential for abuse. While ketamine is safe in sub-anesthetic doses administered once or a few times, prolonged use safety data is lacking. ^{3 5 6 7 8}

Is the drug Ketamine, used with MRI and PET scans, a promising treatment for depression?

Yes, Ketamine is a promising drug for treating depression, especially for those who don't respond to traditional treatments. It works quickly and can help understand how depression affects the brain. MRI and PET scans can help doctors see how Ketamine changes brain activity, which can improve treatment strategies. ^{1 9 10 11 12}

Research Team

Irina Esterlis, PhD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults aged 18-65 with certain psychiatric conditions like depression, bipolar disorder, or PTSD. It's also open to healthy individuals without any DSM-5 diagnosis. Participants must be English-speaking and medication-free or on approved meds for at least two weeks.

Inclusion Criteria

I haven't taken any medication for the last 2 weeks or only allowed medications for depression.

I haven't taken any medication in the last 2 weeks or only allowed medications for PTSD.

Subjects must be English speaking

Exclusion Criteria

Have given a blood donation within eight weeks of the start of the study

I have a bleeding disorder or am on blood thinners like Coumadin.

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

Treatment Details

Interventions

• Cognitive Testing (Behavioral Intervention)
• MRI (Other)
• PET (Other)

Trial Overview The study examines the glutamate system in mental health by using PET scans, MRI imaging, and cognitive tests over 1-2 months. The goal is to understand how this system differs among those with psychiatric disorders compared to healthy controls.

Participant Groups

Group I: Cognitive Testing Experimental Treatment 1 Intervention

Cognitive assessments

Group II: Magnetic Resonance Imaging Active Control 1 Intervention

All subjects will have one MRI with a possibility of one functional MRI (fmri).

Group III: Positron Emission Tomography Active Control 1 Intervention

All subjects will have PET scan using FPEB or ABP688.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

PET Center New Haven, CT

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1963

Patients Recruited

3,046,000+

VA Office of Research and Development

Collaborator

Trials

1691

Patients Recruited

3,759,000+

Findings from Research

Ketamine, used at subanesthetic doses, shows promise for rapidly treating treatment-resistant depression, which is a challenging form of major depressive disorder (MDD).

Neuroimaging studies highlight key brain areas affected by ketamine, such as the subgenual anterior cingulate cortex, and suggest that it may alter self-monitoring and enhance reward processing, although further research is needed to fully understand its antidepressant mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Ionescu, DF., Felicione, JM., Gosai, A., et al.[2023]

In a small study of 7 patients with treatment-resistant depression, a single IV ketamine infusion was associated with increased GABA levels in the anterior cingulate cortex, which correlated with improvements in depression symptoms the next day.

These findings suggest that GABA neurotransmission may play a key role in ketamine's antidepressant effects, highlighting the potential for developing GABA-related biomarkers to predict treatment response in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration. Singh, B., Port, JD., Voort, JLV., et al.[2021]

In a study of 98 adults with unipolar depression who had not responded to previous antidepressants, a single infusion of intravenous ketamine significantly enhanced neuroplasticity within 24 hours, as measured by changes in gray matter microstructure using diffusion tensor imaging (DTI).

Greater neuroplasticity, indicated by a decrease in DTI mean diffusivity (DTI-MD), was associated with larger improvements in depression scores, particularly in the left BA10 and left amygdala regions, suggesting that ketamine's rapid antidepressant effects may be linked to its ability to promote neuroplastic changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. Kopelman, J., Keller, TA., Panny, B., et al.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine. Zavaliangos-Petropulu, A., Al-Sharif, NB., Taraku, B., et al.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structural connectivity and response to ketamine therapy in major depression: A preliminary study. Vasavada, MM., Leaver, AM., Espinoza, RT., et al.[2018]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. Howland, RH.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy: Ketamine and Esketamine. Feeney, A., Papakostas, GI.[2023]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Has psychiatry tamed the "ketamine tiger?" Considerations on its use for depression and anxiety. Rasmussen, KG.[2015]

Major depression is linked to diffuse neuromodulatory mechanisms rather than permanent changes in brain connectivity, with significant effects on mood and behavior stemming from the fronto-striatal regions of the brain.

In older patients, major depression is associated with structural brain abnormalities and cognitive impairments, particularly in memory, which are reflected in reduced blood flow to frontal, temporal, and parietal brain areas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. Goodwin, GM.[2022]

Neuroimaging studies reveal that depression is linked to structural and functional abnormalities in specific brain regions, such as the frontal lobe, temporal lobe, and limbic system, which may help explain the psychological symptoms and behavioral deficits associated with the disorder.

Magnetic resonance imaging (MRI) could become a crucial tool for psychiatrists in diagnosing depression early and accurately, as well as in identifying tailored treatment targets to improve clinical outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain structural and functional changes in patients with major depressive disorder: a literature review. Dai, L., Zhou, H., Xu, X., et al.[2020]

Excessive glutamate release is linked to stress and neurodegenerative diseases, and abnormalities in glutamatergic neurotransmission are significant in major psychiatric disorders like schizophrenia and depression.

Ketamine, an NMDA antagonist, shows rapid antidepressant effects for treatment-resistant depression, highlighting the potential of new antidepressants targeting the glutamate system, as supported by recent human studies using advanced imaging techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. Li, CT., Yang, KC., Lin, WC.[2020]

Structural neuroimaging studies have consistently shown that individuals with major depressive disorder have reduced volumes in key brain areas such as the prefrontal lobe, hippocampus, and amygdala, which may contribute to the disorder's symptoms.

Functional imaging reveals decreased activation in the dorsolateral prefrontal cortex and increased activity in the amygdala and other regions during depressive episodes, suggesting that these brain areas are crucial for emotion regulation and that successful treatment can normalize these abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The anatomy of depression in light of evidence from neuroimaging studies]. Jaracz, J.[2009]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Structural connectivity and response to ketamine therapy in major depression: A preliminary study. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Pharmacotherapy: Ketamine and Esketamine. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Has psychiatry tamed the "ketamine tiger?" Considerations on its use for depression and anxiety. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Brain structural and functional changes in patients with major depressive disorder: a literature review. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. [2020]

12. Poland pubmed.ncbi.nlm.nih.gov

[The anatomy of depression in light of evidence from neuroimaging studies]. [2009]