This is a rater-blinded, randomized controlled trial. All patients will receive esketamine for treatment of Major Depression with Suicidal Ideation (MDSI). Subjects will be randomized (1:1) to receive CBT (computer-assisted) or TAU alone following esketamine.

Specific Aim 1: To determine the feasibility and safety of performing a larger study examining the effectiveness and mechanism of action of CBT to improve the longer-term outcomes following esketamine treatment in patients hospitalized for suicidal ideation or suicide attempt.

Specific Aim 2: To evaluate the appropriateness and utility of the proposed tests of cognitive control measures in exploring the mechanisms underlying the effects on depression of esketamine and the combination of esketamine+CBT.

Specific Aim 3: To examine the efficacy of esketamine+CBT combination compared to esketamine+TAU in reducing suicidal ideation.

In August 2022, the targeted enrollment was expanded to include outpatient participants, the anticipated enrollment was increased from 60 to 100 participants as a result.

Inclusion Criteria:

• Participants are eligible for the study if they meet all the following criteria:

  1. Written informed consent before any study procedures are performed
  2. Meeting criteria for inpatient admission for suicidal ideation or attempt at one of the study sites
  3. Recommended by a physician for esketamine treatment
  4. Males or females ages 18 through 65 years of age
  5. Diagnosis of major depressive disorder as confirmed by the MINI (inpatient) or the HAM-D-17 (outpatient)
  6. Willing to adhere to a reliable form of contraception throughout the trial and for one month following completion of the trial (for subjects who are sexually active)
  7. In the opinion of the investigator, the patient is willing and able to comply with scheduled visits, treatment plan, and other trial procedures for the duration of the study

Exclusion Criteria:

• Participants are excluded if they meet any of the following criteria:

  1. Active substance use disorder (except tobacco) within 6 months of screening date

  2. Meets DSM-5 criteria for bipolar disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, or pervasive development disorder

  3. Dementia or other cognitive disorder or intellectual disability that would impair the subject's ability to meaningfully engage in CBT (per investigator judgment)

  4. Any other medical or psychiatric comorbidity that the investigator judges would put the participant at additional undue risk due to study participation or would impair subject's ability to participate in the study.

  5. Current or planned participation in a formal CBT program defined by the following characteristics, each session has an agenda, a homework assignment is given at each session, and the homework assignment from the previous session is reviewed at the following appointment.

  6. Previous Esketamine or ketamine treatment that did not produce a clinical response as outlined below.

     • 6 treatments with Esketamine at a dose of 56 mg or more with no clinical response
     • 6 treatments of IV ketamine at a dose between 0.4 mg/kg and 0.7mg /kg with no clinical response Patients must not have received Esketamine or ketamine treatment within the past 12 weeks of time of enrollment.

  7. The patient is pregnant or breastfeeding

  8. Unable to give informed consent

  9. Was previously enrolled/randomized into the trial

  10. Patients who have a contraindication to receiving Esketamine including any of the following:

      • aneurysmal vascular disease
      • arteriovenous malformation
      • history of intracerebral hemorrhage
      • hypersensitivity to esketamine or ketamine

Rater blinded