Ketamine for the Treatment of Depression in Parkinson's Disease (KET-PD)

Ketamine for the Treatment of Depression in Parkinson's Disease (KET-PD)

The main purpose of this study is to examine the efficacy and safety of a repeated dosing ketamine infusion paradigm compared to placebo in individuals with PD.

A subset of participants in each arm will undergo baseline and post-treatment PET and fMRI scans, to examine whether changes in synaptic density and reorganization of functional networks underlie ketamine's putative antidepressant effects in PD.

Study Overview

• Status: Recruiting
• Conditions: Depression; Parkinson's Disease
• Intervention / Treatment: Drug: Ketamine Infusion; Other: Placebo - Saline Infusion

Detailed Description

This study will assess the efficacy of ketamine for the treatment of depression in Parkinson's disease (PD), in a parallel, double-blind, placebo controlled randomized clinical trial (RCT). Imaging will be used to examine the mechanistic effects of ketamine treatment. Specifically, the investigators will use positron emission tomography (PET) to measure synaptic density and functional magnetic resonance imaging (fMRI) to measure functional connectivity. The investigators hypothesize that a course of ketamine treatment will result in a significant reduction in depression severity compared to placebo. Mechanistically, ketamine will result in a reorganization of functional networks and an increase in synaptic density.

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gerard Sanacora, MD; Phone Number: 203-974-7560; Email: Gerard.sanacora@yale.edu
• Study Contact Backup: Name: Sophie E. Holmes, PhD; Phone Number: 203-685-4066; Email: sophie.holmes@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale New Haven Hospital
      • Contact: Sophie Holmes, PhD; Email: sophie.holmes@yale.edu
      • Principal Investigator: Sophie Holmes, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female ages 40-80 years, inclusive
2. Clinical diagnosis of Parkinson's disease, stage 1, 2 or 3 as determined by the Hoehn and Yahr Scale
3. Meet criteria for major depressive disorder (MDD) as determined by the Mini-International Neuropsychiatric Interview (MINI), and at least 15 on the MADRS, which has shown maximum discrimination between depressed and non-depressed PD patients.
4. For women of reproductive potential, use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation, as well as a negative pregnancy test at screening.
5. Abstinence from drugs of abuse, other than alcohol, cannabis, nicotine and caffeine for the duration of the study.
6. Stated willingness to comply with all study procedures and availability for the duration of the study.
7. Provision of signed and dated informed consent form.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Presence of Dementia and a Montreal Cognitive Assessment (MoCA) score of less than 18.
2. A primary psychiatric disorder (as determined by the MINI) except for MDD
3. Active suicidal ideation with intent
4. History of substance dependence in the last 2 years
5. Current substance use disorder, except tobacco use disorder
6. Prior clinical psychiatric treatment with ketamine or prior recreational use of ketamine
7. A history of or current significant medical (e.g. cardiovascular, renal), or neurological (e.g. cerebrovascular, seizure, traumatic brain injury) illness other than PD that is unstable and significantly increase their risk and/or might affect the study objectives, as determined by study physicians
8. Uncontrolled hypertension, defined as average blood pressure greater than or equal to 140 mmHg or an average diastolic blood pressure greater than or equal to 90 mmHg among those patients who have hypertension.
9. Orthostatic hypotension (OH) that presents with symptoms sustained longer than a few minutes (e.g., light-headedness, blurred vision, dizziness, weakness, fatigue) or with syncope. OH is defined by a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within 3 minutes of standing compared with blood pressure from the sitting position.
10. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines.

11. Any condition or finding that in the judgement of the PI significantly increases risk or significantly reduces the likelihood of benefit from participation in the study.

    For participation in the PET/fMRI only:

12. Prior radiation exposure for research purposes within such that participation in this study would place them over FDA limits for annual radiation exposure (5 rem per yr)
13. Contraindications to MRI scanning.
14. Presence of a bleeding disorder as determined by the PT/INR (Prothrombin time and international normalized ratio) test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine Infusion; 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	Drug: Ketamine Infusion; 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
Placebo Comparator: Saline Infusion; Participants will receive 6 infusions of placebo (saline IV), administered over 40 minutes while on continuous cardiac monitoring and oximetry	Other: Placebo - Saline Infusion; Participants will receive 6 infusions of saline administered over 40 minutes while on continuous cardiac monitoring and oximetry

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Depression Severity	The primary outcome of depression severity post-treatment will be compared between groups using a linear mixed model with group (ketamine, placebo) included as a between-subjects factor and time (baseline, weeks 1, 2, 3) included as a within-subjects factor. The scale used to measure depression severity is called The Montgomery-Åsberg Depression Rating Scale (MADRS). The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. The overall score ranges from 0 to 60, higher MADRS score indicates more severe depression.	Baseline, Week 1, Week 2, and Week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Blood pressure: systolic	Changes in systolic and diastolic blood pressure determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in Blood pressure: diastolic	Changes in systolic and diastolic blood pressure determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in Heart rate	Changes in heart rate determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in Respiration	Changes in respiration determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in O2 saturation	Changes in O2 saturation determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in ECG	Changes in ECG indicating a cardiac event such as an arrhythmia or ischemia determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in CBC with differential	Changes in CBD with differential determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in complete metabolic panel	Changes in complete metabolic panel determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in TFTs	Changes in TFTs determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Change in routine urinalysis	Changes in routine urinalysis determined as clinically significant by the Investigator	Baseline and up to 19 days after last administration of study intervention
Adverse events	Assessed by CTCAE v5.0 and the abbreviated version of the SAFTEE-GI and -SI to assess all body systems	Baseline and up to 32 days after last administration of study intervention
Change in synaptic density	The change in synaptic (SV2A) density (measured using [11C]UCB-J PET) between baseline and post-intervention scans will be measured across regions of interest	Baseline, Week 3
Change in network function	The change in network function will be measured by comparing fMRI functional connectivity between baseline and post-intervention scans	Baseline, Week 3

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Fox (Michael J.) Foundation for Parkinson's Research
• Investigators: Principal Investigator: Sophie E. Holmes, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: June 22, 2021
• First Posted (Actual): June 29, 2021

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Ketamine Treatment
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mood Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Depression; Depressive Disorder; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 2000030394; DO NOT RELEASE (Other Identifier: CB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes