Ketamine Imaging for Mood Disorders

Overseen By Sarah B, MA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must be taking: Ketamine

Must not be taking: Anticoagulants

Disqualifiers: Neurologic abnormality, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

130 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ketamine can reverse brain changes linked to depression and PTSD (post-traumatic stress disorder). Researchers will use advanced brain scans to examine synaptic density (connections between neurons) before and after ketamine treatment. The study aims to determine if ketamine can restore some of the brain's structure affected by these conditions. Individuals diagnosed with major depression or PTSD who are receiving ketamine treatment might be suitable candidates for this trial. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research on ketamine's potential benefits for mental health.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team to get a clear answer.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine is generally safe. In past studies, even when individuals accidentally received more than the usual dose, they tolerated it well. Ketamine has treated various conditions, and many reports confirm its safety for humans. Some individuals might experience side effects, but these are usually mild. Importantly, the FDA has already approved ketamine for other uses, supporting its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about ketamine for mood disorders because it works much faster than traditional antidepressants, which can take weeks to show effects. Unlike most standard treatments that target serotonin or norepinephrine pathways, ketamine acts on the NMDA receptor, a part of the brain's glutamate system, offering a novel mechanism of action. This unique approach has the potential to provide rapid relief from depressive symptoms, making it a promising option for those who don't respond to conventional therapies.

What evidence suggests that ketamine might be an effective treatment for mood disorders?

Research has shown that ketamine, which participants in this trial may receive, can quickly and strongly reduce symptoms of depression. One study found that people felt much better immediately after receiving ketamine, with positive effects lasting up to a month. Studies also indicate that ketamine can rapidly repair brain connections damaged by depression and PTSD. This suggests that ketamine could effectively treat mood disorders by addressing changes in the brain. ^{5 6 7 8 9}

Who Is on the Research Team?

Irina Esterlis, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with Major Depressive Disorder (MDD) or Post-Traumatic Stress Disorder (PTSD), who understand the study's research nature. Healthy individuals without any DSM-5 diagnosis can also participate. Exclusions include neurological issues, low IQ, substance abuse, certain medical conditions, and contraindications to MRI or PET scans like claustrophobia.

Inclusion Criteria

Healthy controls must have no current or history of any DSM-5 diagnosis

Depressed subjects must meet DSM-5 diagnostic criteria for Major Depressive Disorder and for a current depressive episode, and understand that the study is for research purposes only

PTSD subjects must have current Post Traumatic Stress Disorder

Exclusion Criteria

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

History of significant medical illness that would contraindicate study participation based on above criteria and PI/MD history review

Contraindication to MRI scanning including claustrophobia and presence of a ferromagnetic object, including orthodontic braces

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Imaging

Participants undergo baseline MRI and PET scans to assess SV2A density

1 week

1-2 visits (in-person)

Ketamine Administration and Imaging

Participants receive ketamine and undergo additional PET scans to assess changes in SV2A density

2-3 weeks

2-3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1-2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cognitive Testing
• Ketamine
• MRI
• PET

Trial Overview

The study investigates how ketamine affects synaptic density in people with MDD and PTSD using imaging techniques like MRI and PET scans. Participants will undergo cognitive tests and a stress test on scan days to see if ketamine can reverse changes associated with these disorders.

How Is the Trial Designed?

Group I: PET scans for subjects undergoing ketamine treatment Active Control 1 Intervention

For subjects currently undergoing treatment with ketamine. Subjects will participate in 1-3 PET scans (up to 4 if cancelations occur) on the High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available, or the HR+ will be used to image subjects. Vital signs (blood pressure and pulse) will be obtained before and after radiotracer administration. Venous catheter(s) will be used for IV administration of the radiotracer and for venous blood sampling. An arterial catheter will be inserted by an experienced physician before the PET scan. Baseline scan will occur prior to initiation of ketamine treatment. Subsequent scans will occur after several treatments with ketamine and after completion of treatment. Bipolar subjects will not participate in any ketamine arms.

Group II: PET scans and ketamine administration Active Control 1 Intervention

Subjects will participate in 2-3 PET scans (up to 4 if cancelations occur) on the High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available, or the HR+ will be used to image subjects. Vital signs (blood pressure and pulse) will be obtained before and after radiotracer administration. Venous catheter(s) will be used for IV administration of the radiotracer and for venous blood sampling. An arterial catheter will be inserted by an experienced physician before the PET scan. After a baseline scan, subjects will be administered a low dose of ketamine for the second scan. Bipolar subjects will not participate in any ketamine arms.

Group III: Single PET scan Active Control 1 Intervention

Subjects will participate in 1 PET scan (up to 2 if cancelations occur) on the High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available, or the HR+ will be used to image subjects. Vital signs (blood pressure and pulse) will be obtained before and after radiotracer administration. Venous catheter(s) will be used for IV administration of the radiotracer and for venous blood sampling. An arterial catheter will be inserted by an experienced physician before the PET scan.

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

VA Office of Research and Development

Collaborator

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

The study evaluated the PET tracer [18F]PK-209 in 10 healthy humans, focusing on its test-retest reproducibility and binding specificity after administering S-ketamine, but found that it was not a reliable imaging agent for NMDA receptors due to insufficient reproducibility and specificity.

Despite showing high affinity for the NMDA receptor site, [18F]PK-209 did not demonstrate consistent changes in PET parameters after ketamine administration, suggesting that endogenous processes may complicate its use in quantifying NMDA receptor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First in human evaluation of [18F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors. van der Aart, J., Golla, SSV., van der Pluijm, M., et al.[2020]

The study used PET imaging to investigate how the two enantiomers of ketamine bind to different brain regions in Rhesus monkeys, showing that both enantiomers have specific binding properties that can be blocked by their respective unlabelled forms.

The (S)-enantiomer of ketamine demonstrated selective binding in the striatum and cortical areas, which can be displaced by the (R)-enantiomer, indicating that the two forms of ketamine interact differently with NMDA receptors in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain kinetics of (R)- and (S)-[N-methyl-11C]ketamine in the rhesus monkey studied by positron emission tomography (PET). Hartvig, P., Valtysson, J., Antoni, G., et al.[2019]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

In a study of 24 patients with major depressive disorder, activity in the pregenual anterior cingulate cortex (pgACC) was found to predict how well patients would respond to ketamine treatment, suggesting its importance in personalizing depression therapy.

The study also revealed that increased pgACC activity was linked to higher levels of glutamate 24 hours after ketamine infusion, which correlated with better clinical outcomes, indicating a potential biomarker for early treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker. Weigand, A., Gärtner, M., Scheidegger, M., et al.[2023]

A review of 41 treatment arms from 21 studies found that ketamine formulations that maximize first pass metabolism and delay the time to peak concentration (Tmax) are associated with better safety and tolerability, particularly in reducing side effects like dissociation and increased blood pressure.

The study revealed strong correlations between the ketamine:norketamine ratio and both dissociation ratings and blood pressure changes, suggesting that careful formulation can help minimize adverse effects while maintaining the antidepressant efficacy of ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. Glue, P., Russell, B., Medlicott, NJ.[2021]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

A systematic review of 19 studies involving 1006 patients found that combining psychotherapy with ketamine treatment for psychiatric disorders generally leads to positive outcomes, particularly for conditions like substance use disorders and treatment-resistant depression.

Despite the promising results, the significant variability in psychotherapy types and ketamine protocols across studies means that more standardized and larger randomized controlled trials are needed to determine the best ways to integrate these treatments effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. Kew, BM., Porter, RJ., Douglas, KM., et al.[2023]

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

Ketamine Assisted Psychotherapy (KAP) is an effective treatment for reducing depression and anxiety, particularly in older patients and those with severe symptoms, based on data from 235 patients.

Unlike traditional intravenous ketamine treatments that view its psychedelic effects as side effects, KAP utilizes these effects in a therapeutic context, making it suitable for office and supervised at-home use due to ketamine's proven safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. Dore, J., Turnipseed, B., Dwyer, S., et al.[2020]

Ketamine and its (S)-enantiomer, esketamine, have been shown to provide rapid antidepressant effects within hours or days, making them promising treatments for various neuropsychiatric disorders, including depression and anxiety.

The review highlights the different mechanisms of action between racemic ketamine, its enantiomers, and its metabolites, suggesting that these differences may influence their efficacy and therapeutic applications in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine in neuropsychiatric disorders: an update. Johnston, JN., Kadriu, B., Kraus, C., et al.[2023]

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

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