Ketamine for the Treatment of Depression in Parkinson's Disease

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 theHoehn and Yahr Scale

3. Meet criteria for major depressive disorder (MDD) as determined by theMini-International Neuropsychiatric Interview (MINI), and at least 15 on the MADRS,which has shown maximum discrimination between depressed and non-depressed PDpatients.

4. For women of reproductive potential, use of highly effective contraception for atleast 1 month prior to screening and agreement to use such a method during studyparticipation, as well as a negative pregnancy test at screening.

5. Abstinence from drugs of abuse, other than alcohol, cannabis, nicotine and caffeinefor the duration of the study.

6. Stated willingness to comply with all study procedures and availability for theduration 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

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

4. Active suicidal ideation with intent

5. History of substance dependence in the last 2 years

6. Current substance use disorder, except tobacco use disorder

7. Prior clinical psychiatric treatment with ketamine or prior recreational use ofketamine

8. A history of or current significant medical (e.g. cardiovascular, renal), orneurological (e.g. cerebrovascular, seizure, traumatic brain injury) illness otherthan PD that is unstable and significantly increase their risk and/or might affectthe study objectives, as determined by study physicians

9. Uncontrolled hypertension, defined as average blood pressure greater than or equalto 140 mmHg or an average diastolic blood pressure greater than or equal to 90 mmHgamong those patients who have hypertension.

10. Orthostatic hypotension (OH) that presents with symptoms sustained longer than a fewminutes (e.g., light-headedness, blurred vision, dizziness, weakness, fatigue) orwith syncope. OH is defined by a decrease in systolic blood pressure of 20 mm Hg ora decrease in diastolic blood pressure of 10 mm Hg within 3 minutes of standingcompared with blood pressure from the sitting position.

11. Inability to provide written informed consent according to the Yale HumanInvestigation Committee (HIC) guidelines.

12. Any condition or finding that in the judgement of the PI significantly increasesrisk or significantly reduces the likelihood of benefit from participation in thestudy. For participation in the PET/fMRI only:

13. Prior radiation exposure for research purposes within such that participation inthis study would place them over FDA limits for annual radiation exposure (5 rem peryr)

14. Contraindications to MRI scanning.

15. Presence of a bleeding disorder as determined by the PT/INR (Prothrombin time andinternational normalized ratio) test