ABSTRACT Suicide is a public health crisis, with rising rates of suicide death over the last 20 years. Esketamine has generated considerable excitement as the first FDA-approved rapid-acting antidepressant. Recent positive results from Phase 3 trials in patients hospitalized for risk of suicide are also encouraging. However, there are legitimate concerns about longer-term outcomes given that the protocols for these Phase 3 trials stopped esketamine treatment within a few weeks following hospitalization, a period of extremely high risk. We propose a two-site safety and feasibility trial of cognitive behavior therapy (CBT) to sustain esketamine’s antidepressant effects in individuals with major depressive disorder who are hospitalized for suicidal ideation or attempt. This proposal is in response to RFA-MH-20-345 seeking to test “interventions that include pharmacological, psychosocial/behavioral … approaches … alone or in combination.” There is significant evidence that esketamine has short-term efficacy in the treatment of depressive symptoms in individuals with mood disorders and suicidal ideation. Moreover, there is also strong evidence that CBT 1) is effective in depression relapse prevention; 2) has an enduring effect even following discontinuation of therapy; and 3) has been shown to reduce rates of suicide attempts over long-term follow-up periods in patients at high-risk. Further rationale for using the combination of esketamine and CBT derives from esketamine’s ability to induce neuroplasticity and the potential of CBT to harness such a state to produce lasting positive changes in neuro-circuitry that may be associated with recovery from depressive symptoms, including suicidal ideation. We have collected pilot data that strongly suggests that CBT can sustain the antidepressant effects in patients with treatment-resistant depression. This pilot data also suggests, in line with our hypotheses, that changes in cognitive functioning may be related to remission following ketamine. The proposed study will enroll 60 patients with major depressive disorder who are hospitalized for suicidal ideation or attempt. These patients will be treated (open-label) with esketamine for 4 weeks (in line with prior protocols of phase 3 trials in this patient population). At week 2, patients will be randomly assigned to receive treatment as usual (TAU) or TAU plus CBT. The CBT will be a computer-assisted modality of CBT that has been shown to be non-inferior to traditional CBT in NIH-funded trials and can be more readily implemented than traditional CBT. The primary aim of this project, in keeping with the explicit purpose of the RFA, is to evaluate the safety and feasibility of this trial to allow for the planning of a subsequent larger, well-powered clinical trial. Other aims will investigate efficacy of the treatment combination and the cognitive mechanisms by which the esketamine + CBT treatment may work. Strengths of the proposal include the use of two sites to test the feasibility of a multisite approach, the recruitment of patients hospitalized for suicide risk, and our experience and pilot data from implementing similar protocols in TRD.

Narrative Two positive Phase 3 trials make the regulatory approval of esketamine very likely for the treatment of individuals with major depressive disorder with suicidal ideation with intent who need hospitalization. However, the proposed treatment paradigm only includes 4 weeks of treatment, leaving the strong possibility of relapse and a rebound of suicide risk following hospitalization, a period of extremely high risk. We propose a two-site, randomized safety and feasibility trial of esketamine plus cognitive behavioral therapy to rapidly reduce and sustain the risk for suicide in patients with major depressive disorder who are hospitalized for suicidal ideation.