The purpose of this study is to assess the effects of simultaneous administration of oral aspirin and oral ketamine as a therapeutic for those with Treatment Resistant Depression.

The objective of the study is to evaluate the effect of simultaneous administration of oral aspirin and oral ketamine, formulated for partial release in the oral cavity and partially swallowed, as an adjunct to the oral antidepressant on depressive symptoms in patients suffering from Treatment Resistant Depression (TRD) in outpatient Psychiatric Clinic. Investigators will evaluate the effects of simultaneous administration of oral aspirin and oral ketamine, on depressive symptoms.

This is a prospective open-label, proof of concept clinical trial of simultaneous administration of proprietary formulations of oral aspirin and ketamine in medically stable adult patients with a diagnosis of Treatment Resistant Depression. All eligible participants will commit to three visits. The first two visits are in-person at the clinic for administration of oral ketamine and oral aspirin. Participants will be under observation for at least two hours. Study participant's vital signs will be monitored, periodically. The last visit will be conducted remotely.

Adult patients 18 years of age and older, with a diagnosis of TRD presenting to the psychiatric clinic will be screened for enrollment by study team.

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Inclusion Criteria:

• Adult patients with Treatment Resistant Depression with Montgomery-Asberg Depression Rating Scale score >22 upon presentation to the clinic
• Treatment Resistant Depression is defined as Major Depressive Disorder that does not cease after at least 6 week trial of another class of antidepressants
• Unipolar Depression

Exclusion Criteria:

• Adult patients with recent or current suicidal ideation with an intent to act, homicidal ideations with an intent to act
• History of Bipolar Disorder, Obsessive Compulsive Disorder, antisocial personality disorder, borderline personality disorder, and congestive cardiac failure
• Uncontrolled hypertension (BP >140 mm Hg systolic and/or >90 mm Hg diastolic on two separate readings at the time of screening) or on 2 medications for hypertension
• Patients with unstable vital signs (systolic blood pressure <90 or>160 mm Hg, pulse rate <50 or >150 beats/min, and respiration rate <10 or >30 breaths/min),
• History of Gastrointestinal hemorrhage, renal and hepatic insufficiency
• Allergy to Ketamine or Aspirin
• Active Substance Abuse Disorder
• Active psychosis
• Active Peptic Ulcer Disease
• Lithium Therapy
• Swallowing difficulty
• Consumption of Aspirin or NSAID's within 6 hours of arrival to the site
• Previous participation in this study; a patient may not re-enroll in another study while in this study
• Pregnant or breastfeeding