Ketamine for Depression in Parkinson's Disease

(KPD Trial)

Overseen By Kimberly Sakai, BA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Benzodiazepines, Sedative-hypnotics, MAOIs, others

Disqualifiers: Schizophrenia, Bipolar, Dementia, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 25

Duration: 1 day

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ketamine, administered through an IV, can alleviate depression in Veterans with Parkinson's disease. Researchers aim to determine if ketamine not only eases depression but also enhances brain adaptability and reduces inflammation. Participants will receive either ketamine or a placebo to compare effects. Veterans with Parkinson's who have persistent depression despite trying antidepressants may be suitable for this study. As a Phase 2 trial, this research measures ketamine's effectiveness in an initial, smaller group, offering participants a chance to potentially benefit from a new treatment approach.

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

You need to be on a stable medication regimen for at least 2 months before joining the trial and cannot change medications during the study. Some medications that might interfere with ketamine or increase risks must be stopped for a certain period before and during the trial, if it's safe to do so.

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

Research has shown that low doses of ketamine are generally safe and well-tolerated for people with treatment-resistant depression. Studies have found that low-dose ketamine infusions can be safely used in clinical trials for treating depression. This is important because the current trial tests ketamine for depression in people with Parkinson's disease.

Although ketamine is often used for other conditions, it is not yet approved specifically for depression in Parkinson's disease. However, previous research suggests it is safe. Reported side effects in these studies are usually mild and temporary, such as dizziness or feeling a bit strange for a short time after the infusion.

In summary, ketamine has been studied for safety in similar situations and is generally well-tolerated. This makes it a promising option for people considering joining this trial for depression related to Parkinson's disease. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for depression in Parkinson's Disease, which often involve medications like SSRIs or SNRIs, ketamine offers a new approach by targeting the NMDA receptors in the brain. This mechanism is different from traditional antidepressants and could potentially work much faster, providing relief in just hours or days instead of weeks. Researchers are excited about ketamine because it not only has the potential for rapid symptom improvement but also may help patients who haven't responded well to other medications.

What evidence suggests that ketamine might be an effective treatment for depression in Parkinson's disease?

Research shows that ketamine, which participants in this trial may receive, may help treat depression, especially in people with Parkinson's disease (PD). Studies have found that ketamine can quickly reduce depression symptoms, often within 24 hours. This is particularly important for people with PD, as depression significantly affects their quality of life. In animal studies, ketamine not only improved depression but also helped the brain adapt better and reduced inflammation. These findings suggest that ketamine could be an effective treatment option for depression in PD. ^{2 4 6 7 8}

Who Is on the Research Team?

Ellen R Bradley, MD

Principal Investigator

San Francisco VA Medical Center, San Francisco, CA

Are You a Good Fit for This Trial?

This trial is for Veterans with Parkinson's Disease who are experiencing depression. It aims to test if ketamine, known for its rapid antidepressant effects, can improve their condition and quality of life.

Inclusion Criteria

Commit to attend all in-person and remote study visits and participate in all data collection procedures

Is a United States Veteran

I can understand and provide written consent.

Exclusion Criteria

I have an autoimmune or cancer-related disorder.

I've been on a stable dose of medication for inflammation for at least 2 months.

I am not taking medications that increase seizure risk, or I can stop them before the trial.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of intravenous ketamine or remimazolam and are assessed for changes in depression, neuroplasticity, and inflammation

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, tolerability, and changes in depression and other symptoms

7 days

Multiple assessments at 24 hours, Day 3, Day 5, and Day 7

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine

Trial Overview

The study is testing the effectiveness of intravenous (IV) ketamine compared to a placebo in treating depression in Veterans with Parkinson's Disease. It will also explore how ketamine may affect brain adaptability and inflammation.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

intravenous ketamine infusion 0.5 mg/kg

Group II: Remimazolam Placebo Group 1 Intervention

intravenous remimazolam infusion 0.25 mg/kg

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?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

A 65-year-old male cancer patient experienced significant improvement in depression symptoms and achieved remission within 7 days after receiving subcutaneous esketamine, indicating its rapid antidepressant effect.

Subcutaneous administration of esketamine appears to be a safe and effective option for managing both pain and depression in palliative care, suggesting it could be a valuable alternative to traditional intravenous methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. Barbosa, MG., Delfino, RS., Sarin, LM., et al.[2021]

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 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]

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]

In a study using male Wistar rats with Parkinson's disease-like symptoms, ketamine effectively reversed both memory impairment and depressive-like behaviors, suggesting its potential as a treatment for these non-motor symptoms in Parkinson's patients.

All tested doses of ketamine improved short-term memory and reduced depressive behaviors, indicating a promising therapeutic profile for ketamine in addressing the cognitive and emotional challenges faced by individuals with Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine reversed short-term memory impairment and depressive-like behavior in animal model of Parkinson's disease. Vecchia, DD., Kanazawa, LKS., Wendler, E., et al.[2022]

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 series of 5 case studies, low-dose subanesthetic intravenous ketamine infusion demonstrated long-lasting benefits in Parkinson's disease patients, including reduced l-DOPA-induced dyskinesia, improved on time, and decreased depression.

The findings suggest that low-dose ketamine may work by desynchronizing abnormal brain activity, similar to deep brain stimulation, indicating its potential as a safe and effective treatment that warrants further investigation in controlled clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Reports Showing a Long-Term Effect of Subanesthetic Ketamine Infusion in Reducing l-DOPA-Induced Dyskinesias. Sherman, SJ., Estevez, M., Magill, AB., et al.[2020]

A Phase I study involving 32 patients showed that esketamine (0.5 mg/kg) is generally safe and well-tolerated for use in painless gastroscopy, with no serious adverse events reported.

Esketamine resulted in a shorter recovery time compared to racemic ketamine (9 minutes vs. 13 minutes), making it a potentially more efficient option for anesthesia without gender differences affecting its pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Wang, J., Huang, J., Yang, S., et al.[2022]

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]

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Using Ketamine to Treat Depression in Parkinson's Disease

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Positive results in this study could lead to new novel treatments for dyskinesia and further development for other PD symptoms such as depression and pain.

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Ketamine for Veterans With Parkinson's Disease

The investigators hypothesize that ketamine will have a strong safety and tolerability profile and improve depressive symptoms within 24 hours ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10154013/

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Regarding side effects, more patients had positive outcomes than negative outcomes at all time points, and all side effects were psychiatric (disorientation, ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4728020/

Long-term effect of sub-anesthetic ketamine in reducing L ...

Recent publications also showed that low-dose ketamine infusion paradigms are safe and well tolerated in clinical trials for treatment-resistant depression [4–7] ...

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sciencedirect.com

sciencedirect.com/science/article/pii/S0014488620302442

Preclinical evidence in support of repurposing sub ...

We show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity.

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39721099/

Safety outcomes of ketamine for treatment-resistant ...

Naturalistic data gives an estimate of frequency of ketamine SEs within session, between sessions and at follow-up. The KSET-R has improved feasibility and ...