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

Trial Summary

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.

What evidence supports the effectiveness of the drug ketamine for depression in Parkinson's disease?

Research shows that low-dose ketamine can reduce depression and improve motor symptoms in Parkinson's disease patients. It has also been effective in treating depression and memory issues in animal models of Parkinson's disease, suggesting potential benefits for human patients. ^{1 2 3 4 5}

Is ketamine generally safe for use in humans?

Ketamine has been studied for its use in treating depression and is generally considered safe, though it can cause temporary side effects like a sense of detachment from reality and increased blood pressure. It has been used in various forms and routes, with safety monitoring being an important part of its clinical use. ^{3 6 7 8 9}

How does the drug ketamine differ from other treatments for depression in Parkinson's disease?

Ketamine is unique because it acts quickly to relieve depression and can be administered in various ways, including intravenously and subcutaneously, which may be more convenient and cost-effective. It also has a potential long-term benefit in reducing movement issues caused by Parkinson's medication, acting like 'chemical deep brain stimulation' by altering brain activity. ^{1 3 10 11 12}

What is the purpose of this trial?

Parkinson's disease (PD) is a devastating illness that has a growing impact on Veterans. One of the most disabling symptoms is depression, which is common in PD and linked to poor quality of life and higher risk of suicide. Unfortunately, there is a lack of effective treatments for depression in PD. Ketamine, which has rapid and potent antidepressant effects, is a potential option but has not been tested in Veterans with PD. Studies in rodents show that ketamine may not only improve depression in PD, it may target two of the underlying drivers of the disease: (1) reduced neuroplasticity, or the brain's ability to adapt and remodel itself; and (2) elevated inflammation. The investigators are conducting a randomized, placebo-controlled study to examine if a dose of intravenous (IV) ketamine improves depression in Veterans with PD. The investigators will also examine ketamine's effects on neuroplasticity and inflammation, which will help us understand how ketamine works in PD and if it can be a useful treatment for Veterans with the disease. This study will lay groundwork for a larger clinical trial across multiple VA sites.

Research Team

Ellen R Bradley, MD

Principal Investigator

San Francisco VA Medical Center, San Francisco, CA

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Case Reports Showing a Long-Term Effect of Subanesthetic Ketamine Infusion in Reducing l-DOPA-Induced Dyskinesias. [2020]

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

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Ketamine reversed short-term memory impairment and depressive-like behavior in animal model of Parkinson's disease. [2022]

5. India pubmed.ncbi.nlm.nih.gov

Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson's disease. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

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

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

8. New Zealand 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. [2022]

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

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

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

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

11. England pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Where ketamine and dopamine collide. [2021]