Studies have shown that ketamine is very effective and has a quick onset in treatment of depression. Most of these studies used intravenous ketamine in an inpatient setting and there are no large trials examining its use in Post Stroke Depression (PSD). There have been only few studies that have used other routes of administration (i.e., oral, transmucosal, intranasal, intramuscular) of ketamine which provided symptom relief for depression. The purpose of this study is to assess the effectiveness and safety of use of transmucosal ketamine in treatment of PSD. We hypothesize that fast acting antidepressant effects can be achieved with tolerable side effects for translation into the general post-stroke population. To test our hypothesis, the specific aim is to: (1) demonstrate that transmucosal administration of ketamine is feasible within the post-stroke depression population and has tolerable side effects. Exploratory aims will include assessment if ketamine also produces fast acting antidepressant effects.

Inclusion Criteria:

• Men and women (18 years of age or older) of any ethnicity diagnosed with Major Depressive Disorder (DSM-V criteria), who have had failed to respond to prior therapy (as defined as at least one anti-depressant trial or patient was intolerant or noncompliant with anti-depressive medications).
• Willing to take the study drug ketamine on 2 separate occasions and comply with instructions for testing.
• Understands and willing to undergo risks associated with adverse effects of study medications.
• Willing to comply with restrictions and instructions disclosed in the consent form.

Exclusion Criteria:

• Patients with blood pressure over 150 systolic or heart rate over 110 on day of medication administration
• Patients with a diagnosis of epilepsy
• Patients with a significant history of high intraocular pressure.
• Patients with life threatening medical problems.
• Participant is pregnant or breastfeeding.
• Infants and children
• Patients who lack medical decision-making capacity
• Patients who would require medication adjustment during time in the study.
• Known hypersensitivity to the study drug (ketamine).
• Unwilling to undergo risks associated with adverse effects of study drugs.
• Unwilling to comply with restrictions and instructions disclosed in the consent form