Inclusion Criteria:

• Age 18 years to 99 years.
• Male or female sex.
• Admitted to the Mayo Clinic Florida ICU for 6 or more days.
• Diagnosis of depression with clinical signs and symptoms confirmed by PHQ-9 score of 10 or higher.
• Participation in IRB 22-004767.

Exclusion Criteria: 

• Poor vital sign stability hypoxia: O2 < 95%, hypotension: SBP < 90 hypertension: SBP > 180
• Heart rate: < 50 or >. 120, or Respiratory Rate: < 10 or > 30
• Altered mental status.
• Patient is unwilling to participate or provide informed consent.
• Any allergy to ketamine or diphenhydramine.
• Patient is female of child-bearing age and unwilling to provide urine or blood for HCG analysis.
• Pregnant, post-partum (within 2 months), or breast feeding.
• Presence of intracranial mass or vascular lesion.
• Presence of a history of psychosis or hallucinations (as assessed by electronic chart review).
• Weight greater than 115 kg or less than 45kg.
• History of increased intracranial pressure/hypertensive hydrocephalus or increased intraocular pressure.
• Patient is acutely psychotic.
• Patient with psychiatric diagnosis including dissociative disorder, primary psychotic disorders (i.e., schizophrenia, schizoaffective disorders, mania with psychosis, etc.), pervasive development disorder, cognitive disorder, or anorexia nervosa.
• Provider feels that patient currently or likely will require chemical and/or physical restraints.
• History of prolonged QT-interval.
• Current treatment includes any medication known to affect the N‐methyl‐D‐aspartate receptor system (e.g., lamotrigine, acamprosate, memantine, riluzole, or lithium).
• Patient receiving aminophylline or theophylline.
• Patient in withdrawal from substance abuse or who have used hallucinogens (including cannabis) in the last month for any indication, as determined by the clinical interview and urine drug screening.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/15/23. Questions regarding updates should be directed to the study team contact.