PCORI Comparative Effectiveness Study-Esketamine (Spravato) Vs. Ketamine-Equivalence Study

Inclusion Criteria:

• Provision of signed and dated informed consent form

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

• Adults ages 18 or older

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

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

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

• A female participant must be: a. Not of childbearing potential*, OR b. Of childbearing potential and practicing ahighly effective method of contraception (failure rate of <1% per year when usedconsistently and correctly) and agrees to remain on a highly effective method whilereceiving study intervention and until 1 week after last dose - the end of relevantsystemic exposure. The investigator will evaluate the potential for contraceptivemethod failure (e.g., noncompliance, recently initiated) in relationship to thefirst dose of drug. Acceptable methods of contraception are: i. combined (estrogenand progestogen containing) hormonal or progestogen-only hormonal contraceptionassociated 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 withdocumented aspermia or a bilateral orchiectomy vi. male or female condom withspermicide, diaphragm, or sponge with spermicide (Note: Use of condom as the solemethod of contraception is not considered to be a highly effective method ofcontraception).

• A female participant must agree not to donate eggs (ova, oocytes) or freeze forfuture use for the purposes of assisted reproduction during the study * We willconsider women to be of childbearing potential if they are within 2 years ofmenopause (within 3 years since last menstrual period) and have not had ahysterectomy, 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 thepredominant 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 participationswill result in more than 8 lifetime exposures to ketamine (e.g., prior exposure toketamine, prior recreational use with ketamine)

• 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 anincreased risk related to ketamine or esketamine administration (includingspace-occupying CNS lesions). This includes those prospective participants whoundergo EKG and are shown to have an abnormality that would put them at increasedrisk 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 areprescribed (i.e., benzodiazepines, stimulants). Given the extended length of timebetween exposure and negative toxicology screen, a positive screen for THC will notbe exclusionary unless the pattern of use and clinical evaluation are indicative ofcannabis 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 treatmentsession; patients who are unwilling to refrain from driving and operating machineryon treatment days until the next day following sleep will be excluded.