Clinical TrialTreatment-Resistant Depression (TRD)EsketamineWithdrawn

VA Aripiprazole vs Esketamine for Treatment Resistant Depression (VAST-D II)

Open-label, parallel-group, randomised trial (withdrawn; ACTUAL n=0) comparing adjunctive intranasal esketamine versus adjunctive aripiprazole in veterans with treatment-resistant depression over up to 6 months; primary endpoint remission at 6 weeks.

Target Enrollment
Not specified
Study Type
Phase IV interventional
Design
Randomized, single Blind

Detailed Description

VAST-D II was designed as a multicenter, randomised, open-label, parallel-group study to compare adjunctive intranasal esketamine with adjunctive oral aripiprazole in veterans with unipolar treatment-resistant depression; primary outcome was remission at six weeks assessed by blinded central raters using QIDS-C16.

The trial planned 940 participants across approximately 25 VA medical centres with follow-up visits at weeks 1,2,3,4,6,8,10,12,18 and 24 to assess symptom change, tolerability, attrition, quality of life, and cost-effectiveness; the registry records actual enrolment of 0 and the study was withdrawn.

Study Arms & Interventions

Esketamine

experimental

Adjunctive intranasal esketamine (Spravato) administered per Spravato schedule: twice weekly for first 4 weeks, then once weekly until week 12, with clinician-determined dosing up to 6 months.

Interventions

  • Esketamine
    via Inhalation• Twice weekly (weeks 1–4), then once weekly (weeks 5–12); ongoing per clinician

    Intranasal spray; dose per product label/clinician.

Aripiprazole

active comparator

Adjunctive oral aripiprazole per treating clinician

Interventions

  • Compound
    via Oral

    Adjunctive oral aripiprazole; dose per treating clinician.

Participants

Ages
18 – 74
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • DSM-5 diagnosis of current episode of major depressive disorder (MDE, single or recurrent, non-psychotic) by MINI
  • TRD defined as at least 2 failed trials of antidepressants (adequate dose and duration) including the current episode and another during last 2 years
  • Current QIDS-C16 score of > 14
  • Currently on an antidepressant medication at stable dose for at least 6 weeks without adequate improvement
  • Ages 18-74 years old at the time of randomization

Exclusion Criteria

  • Exclusion Criteria:
  • Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or other psychotic disorder
  • Presence of psychotic features in the current MDE
  • Lifetime history of major neurocognitive disorder or any diagnosed neurodegenerative or neurodevelopmental disorder
  • Current evidence of cognitive dysfunction based on MoCA score < 24
  • Hypersensitivity to ESK or ketamine
  • History of aneurysmal vascular disease or arteriovenous malformation
  • History of intracerebral hemorrhage
  • Uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg, unless cleared by the patient's primary care physician)
  • History of significant cardiovascular disease, including recent myocardial infarction (within last 12 months), unstable angina, or chronic heart failure
  • History of interstitial or ulcerative cystitis
  • Any current unstable medical condition that in the opinion of the investigator would place the patient at increased risk, including hepatic, respiratory, immunological, cardiovascular, endocrine, or renal disease
  • Imminent need for psychiatric hospitalization
  • History of moderate or severe SUD in last 6 months will be excluded, not including cannabis, tobacco, and caffeine
  • Women who are pregnant, lactating, or planning to become pregnant or those of childbearing potential who are sexually active but unwilling to use a contraceptive
  • Unable to provide informed consent
  • Current treatment with any antipsychotic
  • Prior antidepressant treatment with ketamine or ESK within the current episode/past two years
  • Prior antidepressant treatment with ARI at an FDA-approved dose for at least 6 weeks within the past 2 years
  • Lifetime history of ketamine use disorder
  • History of drug induced leukopenia

Study Details

Locations

Tuscaloosa VA Medical Center, Tuscaloosa, AL — Tuscaloosa, Alabama, United States
Phoenix VA Health Care System, Phoenix, AZ — Phoenix, Arizona, United States
Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR — Little Rock, Arkansas, United States
VA Long Beach Healthcare System, Long Beach, CA — Long Beach, California, United States
VA Palo Alto Health Care System, Palo Alto, CA — Palo Alto, California, United States
VA San Diego Healthcare System, San Diego, CA — San Diego, California, United States
Rocky Mountain Regional VA Medical Center, Aurora, CO — Aurora, Colorado, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT — West Haven, Connecticut, United States
CERC (VISN1, West Haven, CT) — West Haven, Connecticut, United States
Atlanta VA Medical and Rehab Center, Decatur, GA — Decatur, Georgia, United States
Edward Hines Jr. VA Hospital, Hines, IL — Hines, Illinois, United States
Richard L. Roudebush VA Medical Center, Indianapolis, IN — Indianapolis, Indiana, United States
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA — Boston, Massachusetts, United States
Minneapolis VA Health Care System, Minneapolis, MN — Minneapolis, Minnesota, United States
Kansas City VA Medical Center, Kansas City, MO — Kansas City, Missouri, United States
New Mexico VA Health Care System, Albuquerque, NM — Albuquerque, New Mexico, United States
Asheville VA Medical Center, Asheville, NC — Asheville, North Carolina, United States
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC — Salisbury, North Carolina, United States
Cincinnati VA Medical Center, Cincinnati, OH — Cincinnati, Ohio, United States
Louis Stokes VA Medical Center, Cleveland, OH — Cleveland, Ohio, United States
Jackson C. Montgomery VA Medical Center, Muskogee, OK — Muskogee, Oklahoma, United States
Philadelphia MultiService Center, Philadelphia, PA — Philadelphia, Pennsylvania, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA — Pittsburgh, Pennsylvania, United States
Michael E. DeBakey VA Medical Center, Houston, TX — Houston, Texas, United States
Salem VA Medical Center, Salem, VA — Salem, Virginia, United States
William S. Middleton Memorial Veterans Hospital, Madison, WI — Madison, Wisconsin, United States

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