Ketamine for the Treatment of Depression in Parkinson's Disease

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.

Inclusion Criteria:

1. Male or female ages 40-70 years, inclusive
2. Clinical diagnosis of Parkinson's disease, stage 1 or 2 as determined by the Hoehn and Yahr Scale
3. Meet criteria for major depressive disorder (MDD) as determined by the Structured Clinical Interview for DSM-5 (SCID-575), and at least 15 on the MADRS, which has shown maximum discrimination between depressed and non-depressed PD patients.
4. Physically healthy by medical history, physical, ECG and laboratory examinations.
5. 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.
6. Abstinence from drugs of abuse, other than alcohol, cannabis, nicotine and caffeine for the duration of the study.
7. Stated willingness to comply with all study procedures and availability for the duration of the study.
8. 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 (Montreal Cognitive Assessment (MoCA) score < 21)
2. A significant DSM-5 psychiatric disorder except for MDD
3. Active suicidal ideation with intent
4. History of substance dependence
5. Current DSM-5 substance use disorder, except tobacco use disorder
6. Prior participation in a ketamine study, prior clinical psychiatric treatment with ketamine, or prior recreational use of ketamine
7. A history of significant medical (e.g. cardiovascular, renal), or neurological (e.g. cerebrovascular, seizure, traumatic brain injury) illness other than PD that is unstable and/or might affect the study objectives
8. History of 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 in English.

For participation in the PET/fMRI only:

1. 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)
2. Contraindications to MRI scanning.
3. Presence of a bleeding disorder as determined by the PT/INR (Prothrombin time and international normalized ratio) test