# VA Aripiprazole vs. Esketamine for Treatment of Depression VAST-D II

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2021 · —

## Abstract

Project Summary/Abstract
Among all medical, mental health and substance related disorders, Major Depressive Disorder (MDD) is the
leading cause disease burden worldwide; MDD is a major cause of suffering and disability for those receiving
their care from the Veterans Health Administration (VHA). Current treatments have limited effectiveness as
only about 30% of patients achieve remission with the first antidepressant treatment. By regulatory convention,
the term treatment-resistant depression (TRD) is used when a depressed patient has not responded to two or
more adequate treatment trials in the current episode. So defined, patients with TRD account for a
disproportionately large share of treatment resources and, despite such efforts, are at the highest risk to
become chronically ill, develop a complicating substance abuse disorder and/or die by suicide. The CSP 576,
VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D), showed that
adjunctive aripiprazole resulted in a significantly greater likelihood of remission as compared to switching to
bupropion. Secondary analyses of VAST-D demonstrated that the advantage of adjunctive aripiprazole among
12-week remitters was sustained across up to six months of therapy and was evident whether or not patients
had co-occurring PTSD. In 2019 the U.S. Food and Drug Administration (FDA) reviewed intranasal esketamine
as a new therapy for treatment of TRD. The safety and efficacy of esketamine was evaluated in a series of
phase III studies that ultimately led to the FDA approval of esketamine (Spravato) for the treatment of TRD in
adults. The proposed study will be an open-label, parallel-group, randomized clinical trial of up to 6 months
treatment of adjunctive intranasal esketamine vs. adjunctive aripiprazole in Veterans with TRD. This study will
assess the efficacy, safety, and acceptability of adjunctive intranasal esketamine in direct comparison to
adjunctive aripiprazole for therapy of TRD. The primary hypothesis is that participants receiving adjunctive
intranasal esketamine will be significantly more likely to achieve remission after six weeks of treatment as
compared to those who receive adjunctive aripiprazole. Depressive symptoms will be assessed by
independent evaluators without knowledge of treatment assignment using the Quick Inventory of Depressive
Symptomatology clinician rating (QIDS-C), which is a well-validated tool that commonly and is easily translated
across other depression inventory scales. The study is powered to be able to detect an absolute difference in
remission rates of 10% or larger at 6 weeks. Secondary outcomes of interest include symptom reduction
across 6 months of randomized therapy, side effects and other tolerability indices, suicidality, and measures of
quality of life and cost-effectiveness.

## Key facts

- **NIH application ID:** 10123121
- **Project number:** 1I01CX002191-01
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** SOMAIA MOHAMED
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123121

## Citation

> US National Institutes of Health, RePORTER application 10123121, VA Aripiprazole vs. Esketamine for Treatment of Depression VAST-D II (1I01CX002191-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123121. Licensed CC0.

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