This is a double-blind active placebo controlled clinical trial for individuals with moderate to severe depression. The purpose of this study is to assess if nebulized ketamine can reduce depressive symptoms.

The objective of this study is to evaluate the effect of ketamine formalized to be dispensed via inhalation, as an adjunct to concomitant medications and therapies on those with moderate to severe depression currently in an inpatient psychiatric unit. Investigators will examine the effects of nebulized ketamine on depressive symptoms.

This is a prospective double-blind placebo controlled study in which an active placebo, Midazolam, will be used. Participants will commit to either 4 visits or 5 visits depending on which treatment arm they are randomized into. All visits can be done remotely, however, days in which the participant will be dosed will have to be in person. During dosing days, the participant will be monitored for a minimum of two hours. Study participant's vitals will be collected at regular intervals during the observation period.

Adult psychiatry inpatients who are 18 years and older with a diagnosis of moderate to severe depression will be screened for enrollment by the study.

Inclusion Criteria:

• All individuals 18 years and older with a Montgomery-Asberg Depression Rating Scale score (MADRS) ≥ 20
• Must have a diagnosis of moderate to severe Major Depressive Disorder (MDD)
• Structured Clinical Interview for DSM-5 (SCID-5) will be performed to confirm MDD diagnosis

Exclusion Criteria:

• Adult patients with an allergy to Ketamine
• Adult patients with an allergy to Midazolam
• Individuals with a history of mania/hypomania or diagnosis of bipolar disorder
• Patients on lithium and/or lamotrigine therapy
• Recent or current homicidal ideation with an intent to act
• MDD with psychotic features or current or past diagnosis of a psychotic disorder
• No substance use disorder in the preceding 3 months except nicotine or caffeine or a positive urine screen for substances (except cannabis)
• Diagnosis of obsessive-compulsive disorder, antisocial personality disorder, borderline personality disorder, posttraumatic stress disorder, intellectual disability, altered mental status, pregnant or breastfeeding patients,
• Patients on > 2 medications for hypertension
• Patients with uncontrolled hypertension (BP >140 mm Hg systolic and/or >90 mm Hg diastolic on two separate readings at the time of screening)
• Body weight of > 150kg
• Patients with history of congestive cardiac failure
• Day of presentation, 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)
• Consumption of opioids within 24 hours of drug administration
• Acutely intoxicated patients will also be excluded