The purpose of this study is to compare the relative effectiveness, acceptability, and side effects of ketamine delivered through an IV (a drip into the arm) which is not currently FDA approved for use in the treatment of treatment-resistant depression (TRD) and Esketamine (Spravato®), taken as a nasal spray which has received FDA approval for use in the treatment of treatment-resistant depression (TRD) in the treatment of patients with treatment-resistant depression (TRD). The study will look at the following:

• How well the treatment helps with symptoms of depression (effectiveness),
• How comfortable and willing people are to use the treatment (acceptability), and
• How well people can deal with any side effects from the treatment (tolerability).

The study will also examine factors that may predict which treatment works better for certain patients.

This non-inferiority, multi-site, comparative effectiveness study will utilize a randomized design. Individuals with treatment resistant depression (TRD) will be randomized (1:1) to Spravato® or IV ketamine. This 5-year multisite comparative effectiveness study will enroll 400 total patients (~200 per group).

Inclusion Criteria:

• Provision of signed and dated informed consent form

• Stated willingness to comply with all study procedures and availability for the duration of the study

• Adults ages 18 or older

• Diagnosis of major depressive disorder that is refractory to two or more antidepressant trials

• Moderate or severe depression based on an initial MADRS score ≥ 25

• Judged appropriate for ketamine or esketamine by clinician, independent of potential study participation

• A female participant must be:

  a. Not of childbearing potential*, OR b. Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until 1 week after last dose - the end of relevant systemic exposure. The investigator will evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of drug. Acceptable methods of contraception are: i. combined (estrogen and progestogen containing) hormonal or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, transdermal, or intravaginal) ii. intrauterine device (IUD) iii. intrauterine hormone-releasing system (IUS) iv. bilateral tubal occlusion/ligation v. male partner with a bilateral vasectomy with documented aspermia or a bilateral orchiectomy vi. male or female condom with spermicide, diaphragm, or sponge with spermicide (Note: Use of condom as the sole method of contraception is not considered to be a highly effective method of contraception).

• A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study * We will consider women to be of childbearing potential if they are within 2 years of menopause (within 3 years since last menstrual period) and have not had a hysterectomy, bilateral oophorectomy, or other definitive surgical intervention.

Exclusion Criteria:

• Diagnosis of bipolar disorder or psychotic disorder (i.e., schizophrenia, schizoaffective disorder)
• Other psychiatric comorbidities are permitted so long as depression is the predominant diagnosis
• Active or recent (within 12 months) substance use disorder (other than nicotine)
• Pregnant or lactating women
• Intracerebral hemorrhage or aneurysmal vascular disease
• Hypersensitivity to ketamine, esketamine or any of the excipients
• Known family history of ketamine use disorder
• Prior known ketamine use disorder as well as subjects for whom study participations will result in more than 8 lifetime exposures to ketamine (e.g., prior exposure to ketamine, prior recreational use with ketamine). Prior esketamine exposure is also exclusionary.
• Uncontrolled hypertension, as demonstrated by a blood pressure of greater than 145 / 90 at screening visit. (Pre-treatment blood pressure will be permitted to be 150 / 95 to allow for "whitecoat" hypertension on treatment visits 1-8.)
• Known cardiovascular and cerebrovascular conditions that are associated with an increased risk related to ketamine or esketamine administration (including space-occupying CNS lesions). This includes those prospective participants who undergo EKG and are shown to have an abnormality that would put them at increased risk related to treatment.
• Known condition for which an acute rise in blood pressure would pose a serious risk.
• Arteriovenous malformation
• Positive urine toxicology at screening visit, except for substances that are prescribed (i.e., benzodiazepines, stimulants). Given the extended length of time between exposure and negative toxicology screen, a positive screen for THC will not be exclusionary unless the pattern of use and clinical evaluation are indicative of cannabis use disorder. Cannabis used within 24 hours of dosing is exclusionary.
• Positive alcohol breathalyzer at screening or clinical signs of intoxication
• The patient is unable to arrange for someone to drive them home after each treatment session; patients who are unwilling to refrain from driving and operating machinery on treatment days until the next day following sleep will be excluded.