# A feasibility trial of esketamine plus cognitive behavioral therapy for patients with major depressive disorder who are hospitalized for suicidal ideation

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $575,520

## Abstract

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 s...

## Key facts

- **NIH application ID:** 10264145
- **Project number:** 5R01MH125205-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SAMUEL WILKINSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,520
- **Award type:** 5
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264145

## Citation

> US National Institutes of Health, RePORTER application 10264145, A feasibility trial of esketamine plus cognitive behavioral therapy for patients with major depressive disorder who are hospitalized for suicidal ideation (5R01MH125205-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10264145. Licensed CC0.

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