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

Trial Summary

What is the purpose of this trial?

This study is designed to examine SV2A density in MDD and PTSD as a correlate of synaptic density, and to determine whether ketamine administration will reverse the synaptic loss in vivo in human subjects. To our knowledge, this is the first human study to examine SV2A in vivo in MDD and PTSD and to use the first known drug (ketamine) that rapidly reverses synaptic loss to determine whether ketamine administration could restore some of the structural changes associated with depression and PTSD. After a screening process to determine eligibility, all subjects will participate in an MRI, and 2-3 PET scans with the administration of ketamine for one of the scans. Cognitive testing and a stress test may also be done on scan days.

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.

What data supports the effectiveness of the drug ketamine for mood disorders?

Research shows that ketamine can quickly and effectively reduce symptoms of depression, including treatment-resistant depression, when administered in various forms such as oral, intravenous, and subcutaneous. It is also suggested that combining ketamine with psychotherapy may enhance its benefits for reducing depression and anxiety. ^{1 2 3 4 5}

Is ketamine safe for use in humans?

Ketamine is generally safe for use in humans, but common side effects include dissociation (feeling detached from reality) and increased blood pressure. These effects are usually temporary, and different formulations or ways of taking ketamine might help reduce them. ^{4 6 7 8 9}

How is the drug ketamine unique in treating mood disorders?

Ketamine is unique because it acts rapidly, often within hours, to relieve symptoms of depression and other mood disorders, unlike traditional antidepressants that can take weeks to work. It is also the only legal psychedelic medicine used in mental health, and its effects can be enhanced when combined with psychotherapy, offering a novel approach to treatment. ^{3 5 10 11 12}

Research Team

Irina Esterlis, PhD

Principal Investigator

Yale University

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker. [2023]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

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

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

8. England 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. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Ketamine in neuropsychiatric disorders: an update. [2023]

11. Germany 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. [2020]

12. United States 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). [2019]