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Yale Researcher Awarded $40 Million to Lead New VA Study to Evaluate Esketamine for Treatment Resistant Depression

April 27, 2023

Somaia Mohamed, MD, PhD, associate professor of psychiatry, is lead co-investigator of a Department of Veterans Affairs (VA) study that has been awarded $40 million to evaluate the effectiveness of a novel antidepressant medicine, esketamine, for veterans and others with treatment resistant depression (TRD).

The VA Aripiprazole vs. Esketamine for Treatment Resistant Depression (VAST-D II) is a multisite study that will compare the effectiveness of two medications approved by the U.S. Food and Drug Administration (FDA) used to enhance the effect of standard antidepressants esketamine (Spravato®) and aripiprazole.

Patients with TRD, a form of depression that has not responded to multiple previous treatments, are at highest risk to become chronically ill, attempt suicide, or both.

“Esketamine represents the only currently FDA-approved approach that holds the promise of being a breakthrough,” said Mohamed, associate director of VA’s Northeast Program Evaluation Center (NEPEC) and principal co-chair of the study. “If it produces greater remission rates, has more sustained benefits with fewer side effects, and lower health-related costs, the benefit to thousands of veterans and millions of other patients would be substantial.”

Co-chairs for the study are Dr. Michael Thase, from the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, and Dr. James Murrough, from the James J. Peters VA Medical Center in the Bronx, N.Y.

The study is the first to evaluate the comparative effectiveness and cost-effectiveness of esketamine as compared to aripiprazole, according to Mohamed. The researchers suggest that participants who receive an intranasal dose of esketamine to enhance the effect of standard antidepressants will be significantly more likely to achieve remission for their depression after six weeks of treatment, than those adding aripiprazole.

In 2019, the FDA reviewed intranasal esketamine as a new treatment that can lead to a rapid reduction in symptoms of TRD. The safety and efficacy of esketamine was evaluated as compared to placebo in a series of phase III studies that ultimately led to its approval by the FDA for treatment in adults, but did not compare it with other effective treatment strategies.

The newly funded study will be a randomized clinical trial in which more than 900 veterans across 25 VA sites will receive either intranasal esketamine or oral aripiprazole for up to six months of treatment. This study will assess the efficacy, safety, and acceptability of esketamine in direct comparison to aripiprazole for TRD.

Depressive symptoms will be assessed by using the Quick Inventory of Depressive Symptomatology clinician rating tool, which is well-validated tool and is easily translated across other depression inventory scales.

In a previous multisite VA study, Mohamed and colleagues showed the addition of aripiprazole resulted in a significantly greater likelihood of depression remission, compared to switching to bupropion. Later analyses demonstrated that the benefit of using adjunctive aripiprazole among 12-week remitters was sustained for up to six additional months of therapy and was evident whether patients had co-occurring PTSD or not. This was the first study to show one strategy of TRD treatment had some advantage over another, but the gains were small in magnitude and left room for improvement.

“If esketamine produces greater remission rates, the results of this research may provide an empirical basis for revising current practice guidelines for TRD,” Mohamed said.

Funding for the study is provided by the U.S. Department of Veterans Affairs.

Submitted by Christopher Gardner on April 27, 2023