Ketamine for Depression in Parkinson's Disease

(KET-PD Trial)

Overseen By Gerard Sanacora, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Disqualifiers: Dementia, Suicidal ideation, Substance dependence, others

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

Compensation: Varies

Number of Visits: 8

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of ketamine infusions for easing depression in people with Parkinson's disease. Participants will receive either ketamine, an anesthetic, or a placebo, a harmless saline solution, to compare results. Some participants will undergo brain scans to observe potential changes in brain activity related to depression. Suitable candidates include those diagnosed with Parkinson’s disease and major depressive disorder (MDD). As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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 based on your specific situation.

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

Research shows that ketamine infusions are generally safe and well-tolerated for treating depression. Studies have found that low doses of ketamine can lead to lasting improvements in depression and chronic pain. It is particularly safe for people with Parkinson's disease.

Ketamine's use in other medical treatments means its safety profile is well understood. Although some unknowns remain about its use specifically for Parkinson's disease, current research is encouraging. In past studies, researchers closely monitored participants, regularly checking heart and oxygen levels during treatment. This careful monitoring helps ensure safety and manage any possible side effects.

Overall, while more research is needed, ketamine is considered a safe option for many people with depression. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression in Parkinson's disease?

Unlike the standard treatments for Parkinson's disease-related depression, which primarily include antidepressants like SSRIs and SNRIs, ketamine offers a novel approach by acting on the NMDA receptors in the brain. Researchers are excited about ketamine because it can potentially deliver rapid antidepressant effects, sometimes within hours, compared to the weeks it often takes for traditional antidepressants to work. Additionally, ketamine's infusion method allows for controlled dosing and monitoring, which is particularly important given the complex needs of Parkinson's disease patients. This unique mechanism and delivery could offer new hope for a population that often struggles with conventional treatment options.

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

Research has shown that ketamine can reduce depression symptoms in people with Parkinson's disease (PD). Studies have found that low doses of ketamine, administered through infusions, can lead to long-lasting improvements in treatment-resistant depression. In this trial, participants will receive either ketamine infusions or placebo saline infusions. Ketamine may also help by altering brain function, which could benefit depression related to PD. Some animal research suggests that ketamine might address two key issues in Parkinson's, potentially offering additional benefits. Overall, strong evidence supports the effectiveness of ketamine in treating depression in PD. ^{1 3 6 7 8}

Who Is on the Research Team?

Sophie E. Holmes, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for people aged 40-80 with Parkinson's Disease (stages 1-3) and major depression, who don't have dementia or other serious medical conditions. Participants must not use drugs of abuse, agree to contraception if applicable, and be willing to follow the study plan.

Inclusion Criteria

Stated willingness to comply with all study procedures and availability for the duration of the study

I have been diagnosed with major depression and scored at least 15 on a depression scale.

I have Parkinson's disease at stage 1, 2, or 3.

Exclusion Criteria

A primary psychiatric disorder (as determined by the MINI) except for MDD

My blood pressure is not controlled and is often 140/90 mmHg or higher.

Contraindications to MRI scanning

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 6 infusions of ketamine or placebo over 3 weeks, with continuous cardiac monitoring and oximetry

3 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in depression severity and various physiological measures

4-5 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine Infusion
• Placebo - Saline Infusion

Trial Overview The trial tests repeated doses of ketamine infusion against a saline placebo in those with Parkinson's Disease to see if it helps with depression. Some participants will also get brain scans before and after treatment to look at changes related to ketamine's effects.

How Is the Trial Designed?

Group I: Ketamine Infusion Experimental Treatment 1 Intervention

Participants will receive 6 infusions of ketamine (0.5 mg/kg IV, up to 60 mg total) , administered over 40 minutes while on continuous cardiac monitoring and oximetry

Group II: Saline Infusion Placebo Group 1 Intervention

Participants will receive 6 infusions of placebo (saline IV), administered over 40 minutes while on continuous cardiac monitoring and oximetry

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

Approved in United States as Ketalar for:

• Anesthesia
• Pain management
• Depression (off-label)

Approved in European Union as Ketanest for:

• Anesthesia
• Pain management

Approved in Canada as Ketamine for:

• Anesthesia
• Pain management

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Fox (Michael J.) Foundation for Parkinson's Research

Collaborator

Trials

2

Recruited

100+

Published Research Related to This Trial

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]

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]

Oral ketamine shows a significant antidepressant effect in patients with major depressive disorder, with a standardized mean difference of -0.75 based on a meta-analysis of 3 randomized controlled trials involving 161 participants.

The study found no significant increase in side effects when comparing oral ketamine to placebo, suggesting it is well-tolerated, but the remission and response rates were only marginally better than placebo, indicating the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis. Nuñez, NA., Joseph, B., Pahwa, M., 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]

A single intravenous infusion of ketamine has been shown to provide rapid but temporary relief from symptoms of treatment-resistant major depressive disorder (MDD) and bipolar depression, indicating its potential as a quick intervention for severe cases.

While generally safe and well tolerated when administered by trained professionals, concerns exist regarding the long-term side effects, including dissociative symptoms and risk of abuse, highlighting the need for standardized treatment guidelines for ketamine use in psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for Treatment-Resistant Mood Disorders. Park, LT., Falodun, TB., Zarate, CA.[2023]

A systematic review of 35 randomized controlled trials found that intravenous (IV) Ketamine is effective in treating Major Depressive Disorder (MDD) in 70% of studies, while oral and intranasal forms showed limited effectiveness.

Common side effects of Ketamine include nausea, dizziness, and hallucinations, highlighting the need for careful monitoring; further research is needed to explore its use in combination with electroconvulsive therapy (ECT) and to determine optimal dosing strategies for sustained effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review. Memon, RI., Naveed, S., Faquih, AE., et al.[2021]

In a case series of five inpatients with major depressive disorder and suicidal ideation, six infusions of ketamine led to an impressive 84% reduction in suicidal ideation scores and a 47% reduction in depression scores over approximately 12 days.

The study suggests that serial ketamine infusions are safe and feasible for reducing suicidal thoughts and depressive symptoms, although the small sample size highlights the need for larger randomized controlled trials to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine augmentation for major depressive disorder and suicidal ideation: Preliminary experience in an inpatient psychiatry setting. Sinyor, M., Williams, M., Belo, S., et al.[2022]

Oral ketamine appears to be well tolerated for treating treatment-resistant depression, especially when administered over longer periods, although the overall quality of studies on its antidepressant effects is low.

Current research suggests that while intravenous ketamine shows short-term success in major depressive disorder, more rigorous studies are needed to evaluate the long-term effects and side effects of all ketamine administration routes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral ketamine for the treatment of pain and treatment-resistant depression†. Schoevers, RA., Chaves, TV., Balukova, SM., et al.[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]

Ketamine infusions, given 1 to 3 times a week, are the fastest and most effective treatment for both unipolar and bipolar depression, making it a strong option for those with treatment-resistant depression and suicidal tendencies.

While the long-term safety of ketamine treatment is not fully established, studies show that even up to 1.5 years of use have not resulted in significant adverse effects, suggesting it could be used more frequently in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine as treatment for depression. Taiminen, T.[2018]

Ketamine has shown rapid antidepressant effects in patients with treatment-resistant depression, with response rates ranging from 25% to 85% at 24 hours post-infusion, indicating its potential as a treatment option for severe mood disorders.

While ketamine is generally safe with mild adverse effects, its administration requires hospitalization and further research is needed due to the limited number of randomized controlled trials and concerns about long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for depression: where do we go from here? Aan Het Rot, M., Zarate, CA., Charney, DS., et al.[2021]

In a study of 66 patients with treatment-resistant bipolar depression, repeated intravenous ketamine infusions led to significant reductions in depressive symptoms, with an average decrease of 6.08 points on the Quick Inventory for Depression Symptomatology-Self Report-16 scale after four infusions.

The treatment was generally well tolerated, with only 4.5% of patients experiencing treatment-emergent hypomania, and no cases of mania or psychosis, indicating a favorable safety profile for ketamine in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Fancy, F., Rodrigues, NB., Di Vincenzo, JD., et al.[2023]

Citations

1. michaeljfox.org michaeljfox.org/grant/using-ketamine-treat-depression-parkinsons-disease

Using Ketamine to Treat Depression in Parkinson's Disease We hypothesize that, compared to a placebo, a course of ketamine treatment will result in a significant decrease in symptoms of depression in PD. We further ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4899651/

Case Reports Showing a Long-Term Effect of ... Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states.

3. medicine.yale.edu medicine.yale.edu/psychiatry/research/clinics-and-programs/psychiatric-symptoms/pd-ketamine-trial/

The PD Ketamine Trial < Psychiatry - Yale School of Medicine Ketamine hold significant potential for effectively treating depression in Parkinson's disease. We will test this for the first time in a controlled, clinical ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06021756

Phase I Open-label Study of Low-dose Ketamine Infusion ... 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.

5. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06231563

Ketamine for Veterans With Parkinson's Disease 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) ...

6. beta.clinicaltrials.gov beta.clinicaltrials.gov/study/NCT04944017

Ketamine for the Treatment of Depression in Parkinson's ... It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...

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

Efficacy and safety of ketamine for the treatment ... Although ketamine is generally safe and potentially useful, its efficacy in palliative care settings remains unclear.

8. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04944017/ketamine-for-the-treatment-of-depression-in-parkinsons-disease

Ketamine for the Treatment of Depression in Parkinson's ... The main purpose of this study is to examine the efficacy and safety of a repeated dosing ketamine infusion paradigm compared to placebo in ...