Ketamine for Depression in Parkinson's Disease
(KET-PD Trial)
Recruiting in Palo Alto (17 mi)
Overseen bySophie E. Holmes, PhD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Yale University
Disqualifiers: Dementia, Suicidal ideation, Substance dependence, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing if ketamine can help reduce depression in people with Parkinson's disease. The study will use brain scans to see if ketamine changes brain activity and increases connections between brain cells. Researchers hope that these changes will lead to less severe depression symptoms. Ketamine has been studied for its potential effects on depression and other symptoms in Parkinson's disease.
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.
What data supports the effectiveness of the drug Ketamine Infusion for depression in Parkinson's Disease?
Research shows that low-dose ketamine infusions can reduce depression and improve symptoms in Parkinson's disease patients, as well as in those with treatment-resistant depression. Additionally, animal studies suggest ketamine can reverse depressive-like behaviors and memory issues in Parkinson's models.
12345Is ketamine safe for treating depression in Parkinson's disease?
Ketamine has a known safety profile and is generally well tolerated when administered by trained professionals, with mild side effects like brief changes in blood pressure, heart rate, or respiratory rate. Long-term safety is not fully understood, but even extended use has not been associated with significant adverse effects, and it has been used safely for depression and pain in various forms.
46789How does the drug ketamine differ from other treatments for depression in Parkinson's disease?
Ketamine is unique because it is administered as a low-dose infusion and acts quickly to reduce depression and improve motor symptoms in Parkinson's disease by desynchronizing abnormal brain activity, unlike traditional antidepressants that may take weeks to show effects.
45101112Eligibility Criteria
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.
+4 more
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
+11 more
Trial Timeline
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)
Participant Groups
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.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Ketamine InfusionExperimental Treatment1 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 InfusionPlacebo Group1 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:
πΊπΈ Approved in United States as Ketalar for:
- Anesthesia
- Pain management
- Depression (off-label)
πͺπΊ Approved in European Union as Ketanest for:
- Anesthesia
- Pain management
π¨π¦ Approved in Canada as Ketamine for:
- Anesthesia
- Pain management
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Yale New Haven HospitalNew Haven, CT
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Who Is Running the Clinical Trial?
Yale UniversityLead Sponsor
Fox (Michael J.) Foundation for Parkinson's ResearchCollaborator
References
Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review. [2021]Major Depressive Disorder (MDD) is a common psychiatric disorder with major implications for healthcare system and socioeconomic burden. For chronic and treatment-resistant depression, Ketamine has emerged as a possible treatment option. This systematic review explores the evidence for the effectiveness and tolerability of Ketamine in patients with MDD. This systematic review was conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. Eight electronic databases were searched by using search terms: (ketamine) AND (trial OR RCT OR clinical-trial) AND (depressive OR depression OR "depressive-disorder"). After a rigorous screening process against the predetermined eligibility criteria, 35 randomized controlled trials (RCTs) were included. Quality assessment of included studies was done by using the Cochrane risk-of-bias tool for RCTs. Thirty-five RCTs are included in this review article with majority of studies from United States, Iran, and China. Intravenous (IV) Ketamine was effective in 70% (21/30) of the included studies whereas oral and Intranasal (IN) Ketamine were effective in two and three studies, respectively. The majority of studies (6/8) using Ketamine as anesthetic agent during electroconvulsive therapy (ECT) failed to show an improvement compared to the participants receiving ECT and placebo. The most common reported side effects were nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, hallucinations, and confusion. Ketamine is an effective treatment option for patients with MDD with undesirable effects when administered via oral, IV and IN routes. Ketamine agumentation of ECT requires further exploration in well-designed studies with adequate sample size. The short-lived antidepressant effect of Ketamine is a potential limitation, therefore, further studies administering multiple infusions for acute treatment and maintenance are necessary.
An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis. [2021]Intravenous Ketamine has shown robust antidepressant efficacy although other routes of administration are currently needed. We conducted a systematic review and meta-analysis of studies evaluating the efficacy and tolerability of oral ketamine for depression.
Ketamine augmentation for major depressive disorder and suicidal ideation: Preliminary experience in an inpatient psychiatry setting. [2022]Ketamine is known to rapidly reduce depressive symptoms and suicidal ideation (SI) in patients with major depressive disorder (MDD), but evidence is limited for its acceptability and effectiveness in "real-world" settings. This case series examines serial ketamine infusions in reducing SI and depression scores in adults with MDD admitted to a tertiary care hospital.
Case Reports Showing a Long-Term Effect of Subanesthetic Ketamine Infusion in Reducing l-DOPA-Induced Dyskinesias. [2020]Ketamine is an FDA-approved drug with a known safety profile. Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states. We report on low-dose subanesthetic intravenous ketamine infusion treatment in Parkinson's disease (PD) patients by 5 case studies and show a long-lasting therapeutic benefit to reduce l-DOPA-induced dyskinesia (LID), improve on time, and reduce depression. Based on the literature we hypothesize that low-dose ketamine may act as a 'chemical deep brain stimulation', by desynchronizing hypersynchronous oscillatory brain activity, including in the basal ganglia and the motor cortex. The presented PD case reports indicate tolerability, safety and long-term beneficial effects of low-dose ketamine infusion that should be further investigated in a properly controlled prospective clinical trial for treatment of LID, as well as the prevalent nonmotor features pain and depression in PD patients.
Ketamine reversed short-term memory impairment and depressive-like behavior in animal model of Parkinson's disease. [2022]The most common features of Parkinson's disease (PD) are motor impairments, but many patients also present depression and memory impairment. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to be effective in patients with treatment-resistant major depression. Thus, the present study evaluated the action of ketamine on memory impairment and depressive-like behavior in an animal model of PD. Male Wistar rats received a bilateral infusion of 6 ΞΌg/side 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNc). Short-term memory was evaluated by the social recognition test, and depressive-like behaviors were evaluated by the sucrose preference and forced swimming tests (FST). Drug treatments included vehicle (i.p., once a week); ketamine (5, 10 and 15 mg/kg, i.p., once a week); and imipramine (20 mg/kg, i.p., daily). The treatments were administered 21 days after the SNc lesion and lasted for 28 days. The SNc lesion impaired short-term social memory, and all ketamine doses reversed the memory impairment and anhedonia (reduction of sucrose preference) induced by 6-OHDA. In the FST, 6-OHDA increased immobility, and all doses of ketamine and imipramine reversed this effect. The anti-immobility effect of ketamine was associated with an increase in swimming but not in climbing, suggesting a serotonergic effect. Ketamine and imipramine did not reverse the 6-OHDA-induced reduction in tyrosine hydroxylase immunohistochemistry in the SNc. In conclusion, ketamine reversed depressive-like behaviors and short-term memory impairment in rats with SNc bilateral lesions, indicating a promising profile for its use in PD patients.
Ketamine for depression: where do we go from here? [2021]Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.
Ketamine as treatment for depression. [2018]Ketamine infusions administered intravenously 1 to 3 times per week are the quickest and most effective treatment for depression. Short-course ketamine medication is established treatment both for unipolar depression and depressive episodes of bipolar affective disorder. Ketamine is suitable for initiating the treatment for treatment-resistant depression, alleviation of suicidal tendencies, and treatment of depressive patients suffering from simultaneous pain. The safety of prolonged treatment with ketamine is not known to sufficient degree. However, even long periods (up to 1.5 years) of ketamine treatment have not been associated with adverse effects. It would be appropriate to use short-course ketamine treatment more often than is currently done.
Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. [2019]Clinical evidence is accumulating to support the use of ketamine as a powerful, quick-acting intervention for depression. Ketamine has been administered by oral, sublingual, transmucosal, intravenous, intramuscular, subcutaneous, intranasal, and even rectal routes. Whereas intravenous ketamine is the best studied approach, common sense dictates that oral ketamine is the most practical. The bioavailability of oral ketamine and interindividual variations thereof have been poorly studied; possibly only 20%-25% of an oral dose reaches the bloodstream. This is not necessarily a limitation because, as with other drugs that have poor oral bioavailability, compensation is possible by administering an appropriately higher dose, and interindividual variations can be addressed through individualized dose up-titration. A quarter- century of experience supports the use of oral ketamine for treating acute and chronic pain in children and adults. Case reports, case series, chart reviews, and 3 recent randomized controlled trials (RCTs) show that oral ketamine is effective in treating severe depression, depression with suicidal ideation, and treatment-resistant depression; that oral ketamine, used as an augmentation agent, improves outcomes in patients receiving a conventional antidepressant; and that oral ketamine reduces depression in patients with chronic pain. Doses of oral ketamine have ranged from 0.25 to 7 mg/kg and from 50 mg per occasion to 300 mg per occasion in multiple daily dosing, daily dosing, and intermittent dosing schedules. Oral ketamine was well tolerated in all studies; dropout and reasons for dropout were similar in ketamine and control arms in the 3 RCTs. These findings suggest that if ketamine is to find a place as an off-label treatment for depression and suicidality in mainstream psychiatry, researchers should study the safety, efficacy, and optimization of oral ketamine. Intravenous and intranasal routes may be monetarily more promising, but the oral route could be of greatest service.
Ketamine for Treatment-Resistant Mood Disorders. [2023]Strong evidence supports the rapid, although temporary, antidepressant effects of a single intravenous ketamine infusion for treatment-resistant major depressive disorder (MDD) and bipolar depression. Although ketamine has diverse effects on brain neurotransmitters, current theories have implicated N-methyl-d-aspartate antagonist effects at the presynaptic interneuron in mediating its antidepressant effects. Intravenous ketamine administration for treatment-resistant depression (TRD) is generally safe and well tolerated when administered by trained professionals. Repeated intravenous ketamine infusions as an off-label treatment for TRD are increasingly available for clinical use, although their safety and effectiveness are not well characterized. Intranasal administration of esketamine-the (S)-enantiomer of racemic ketamine-recently completed phase 3 multicenter trials; a Food and Drug Administration application for its use in TRD is expected. Relatively little is known about the longer term side effects of ketamine for TRD. Concerns have been raised about its dissociative side effects, risk of abuse, and potential excitotoxic neuronal injury at higher doses and with repeated use. Treatment guidelines are needed to standardize ketamine use in psychiatric disorders. Ketamine research is transforming our understanding of the pathophysiology of mood disorders and leading the way toward developing new, rapid-acting interventions for TRD.
Subcutaneous Ketamine in Depression: A Systematic Review. [2021]Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434.
Oral ketamine for the treatment of pain and treatment-resistant depressionβ . [2022]Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.
Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. [2023]Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.