VA Augmentation and Switching Treatments for Improving Depression Outcomes

NCT01421342 | Completed Phase 3 Results DMC

• 1 other identifier: 576
• Study Type: interventional
• Target: 1,522
• Locations: 1 country
• Sites: 35

Brief Summary

The overall purpose is to determine research based 'next-steps' for outpatients with major depressive disorder who have not had satisfactory outcomes to standard 'first-step' treatments. The primary objective is to compare the acute (up to 12 weeks) treatment effectiveness of augmenting an antidepressant with aripiprazole or with bupropion-slow release (SR) vs. switching treatment to bupropion-SR monotherapy on symptom remission in Veterans with Major Depressive Disorder (MDD) who have not achieved optimal response after an adequate trial on antidepressant (a selective serotonin reuptake inhibitor \[SSRI\] or serotonin and norepinephrine reuptake inhibitor \[SNRI\] or mirtazapine) monotherapy. The secondary objectives are to compare the acute (up to 12 weeks) and long term (up to 36 weeks) efficacy, safety, effects on functioning, suicidality, quality of life, anxiety and other associated symptoms, costs and cost-effectiveness of each of the three treatments.

Conditions

Major Depressive Disorder

Keywords

Mood Disorder; Depression; Depressive Disorder; Depressive Disorder, Major; Bupropion; Aripiprazole; Remission; Relapse; Cost-Effectiveness; Atypical Antipsychotic; Antidepressant; Augmentation; Veterans; Mental Health

Outcome Measures

Primary Outcomes (1)

• Rate of Protocol Remission of Symptoms of Major Depressive Disorder

  Remission of symptoms of major depression during the acute treatment phase (12 weeks) defined as a sustained clinician-rated Quick Inventory of Depressive Symptoms (QIDS-C16) of \<= 5 for two consecutive visits.

  During acute phase (12 weeks)

Secondary Outcomes (3)

• Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase

  Within 36 weeks after randomization (initiation of treatment)

• Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C)

  During acute phase (up to 12 weeks)

• Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale

  During acute phase (up to 12 weeks)

Study Arms (3)

Switching: Bupropion-SR

ACTIVE COMPARATOR

Switching: Bupropion-SR

Drug: Switching: Bupropion-SR

Augmenting: Antidepressant + Bupropion-SR

ACTIVE COMPARATOR

Augmenting: Antidepressant + Bupropion-SR

Drug: Augmenting: Antidepressant + Bupropion-SR

Augmenting: Antidepressant + Aripiprazole

ACTIVE COMPARATOR

Augmenting: Antidepressant + Aripiprazole

Drug: Augmenting: Antidepressant + Aripiprazole

Interventions

Switching: Bupropion-SR DRUG

Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

Switching: Bupropion-SR

Augmenting: Antidepressant + Bupropion-SR DRUG

Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

Augmenting: Antidepressant + Bupropion-SR

Augmenting: Antidepressant + Aripiprazole DRUG

Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

Augmenting: Antidepressant + Aripiprazole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• DSM-IV diagnosis of single or recurrent, non-psychotic, major depressive disorder
• Currently taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine for major depressive disorder
• Need for "next-step" treatment based on documented suboptimal outcome from current antidepressant treatment for major depressive episode (at least 6 weeks treatment with a QIDS-C16 \>= 16 or at least 8 weeks with a QIDS-C16 \>= 11; and at least 3 weeks at a stable "optimal" dose
• Age: 18 years of age or older

You may not qualify if:

• Prior inadequate response after an adequate treatment trial or clear cut intolerance to either of the study medications (aripiprazole or bupropion)
• Current treatment with bupropion, aripiprazole or any other antipsychotic agent
• Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis not otherwise specified
• Current diagnosis of Dementia
• Current diagnosis of an eating disorder or a seizure disorder
• High suicide risk currently requiring acute intervention (other than outpatient treatment of depression)
• Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care
• Requiring immediate hospitalization for psychiatric disorders
• Taking any concomitant medication that contraindicates any of treatment options or augmenting agents known to have an antidepressant effect
• Concurrent or recent participation (within the last 30 days) in another conflicting clinical trial with a mental health, investigational drug, or medical device intervention
• Female - pregnant or lactating or planning to become pregnant
• Patient was not able or willing to provide informed consent; or changed mind about participating prior to randomization
• Patient was not referred to the study

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (35)

Tuscaloosa VA Medical Center, Tuscaloosa, AL

Tuscaloosa, Alabama, 35404, United States

Location

Phoenix VA Health Care System, Phoenix, AZ

Phoenix, Arizona, 85012, United States

Location

Southern Arizona VA Health Care System, Tucson

Tucson, Arizona, 85723, United States

Location

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, 92357, United States

Location

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, 90822, United States

Location

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, 94304-1290, United States

Location

VA San Diego Healthcare System, San Diego, CA

San Diego, California, 92161, United States

Location

San Francisco VA Medical Center, San Francisco, CA

San Francisco, California, 94121, United States

Location

VA Eastern Colorado Health Care System, Denver, CO

Denver, Colorado, 80220, United States

Location

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, 06516, United States

Location

Washington DC VA Medical Center, Washington, DC

Washington D.C., District of Columbia, 20422, United States

Location

Miami VA Healthcare System, Miami, FL

Miami, Florida, 33125, United States

Location

James A. Haley Veterans' Hospital, Tampa, FL

Tampa, Florida, 33612, United States

Location

Atlanta VA Medical and Rehab Center, Decatur, GA

Decatur, Georgia, 30033, United States

Location

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, 60141-5000, United States

Location

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Indianapolis, Indiana, 46202-2884, United States

Location

Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD

Baltimore, Maryland, 21201, United States

Location

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, 55417, United States

Location

Kansas City VA Medical Center, Kansas City, MO

Kansas City, Missouri, 64128, United States

Location

St. Louis VA Medical Center John Cochran Division, St. Louis, MO

St Louis, Missouri, 63106, United States

Location

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Omaha, Nebraska, 68105-1873, United States

Location

New Mexico VA Health Care System, Albuquerque, NM

Albuquerque, New Mexico, 87108-5153, United States

Location

Asheville VA Medical Center, Asheville, NC

Asheville, North Carolina, 28805, United States

Location

Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC

Salisbury, North Carolina, 28144, United States

Location

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, 45220, United States

Location

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, 44106, United States

Location

Philadelphia VA Medical Center, Philadelphia, PA

Philadelphia, Pennsylvania, 19104, United States

Location

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

Memphis VA Medical Center, Memphis, TN

Memphis, Tennessee, 38104, United States

Location

Central Texas Veterans Health Care System, Temple, TX

Temple, Texas, 76504, United States

Location

Salem VA Medical Center, Salem, VA

Salem, Virginia, 24153, United States

Location

VA Puget Sound Health Care System American Lake Division, Tacoma, WA

Tacoma, Washington, 98493, United States

Location

Clarksburg Louis A. Johnson VA Medical Center, Clarksburg, WV

Clarksburg, West Virginia, 26301, United States

Location

William S. Middleton Memorial Veterans Hospital, Madison, WI

Madison, Wisconsin, 53705, United States

Location

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, 53295-1000, United States

Location

Related Publications (9)

• Mohamed S, Johnson GR, Vertrees JE, Guarino PD, Weingart K, Young IT, Yoon J, Gleason TC, Kirkwood KA, Kilbourne AM, Gerrity M, Marder S, Biswas K, Hicks P, Davis LL, Chen P, Kelada A, Huang GD, Lawrence DD, LeGwin M, Zisook S. The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations. Psychiatry Res. 2015 Oct 30;229(3):760-70. doi: 10.1016/j.psychres.2015.08.005. Epub 2015 Aug 6.

  PMID: 26279130 BACKGROUND

• Zisook S, Tal I, Weingart K, Hicks P, Davis LL, Chen P, Yoon J, Johnson GR, Vertrees JE, Rao S, Pilkinton PD, Wilcox JA, Sapra M, Iranmanesh A, Huang GD, Mohamed S. Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report. J Affect Disord. 2016 Dec;206:232-240. doi: 10.1016/j.jad.2016.07.023. Epub 2016 Jul 26.

  PMID: 27479536 RESULT

• Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, Gleason TC, Vertrees JE, Weingart K, Tal I, Scrymgeour A, Lawrence DD, Planeta B, Thase ME, Huang GD, Zisook S; and the VAST-D Investigators; Rao SD, Pilkinton PD, Wilcox JA, Iranmanesh A, Sapra M, Jurjus G, Michalets JP, Aslam M, Beresford T, Anderson KD, Fernando R, Ramaswamy S, Kasckow J, Westermeyer J, Yoon G, D'Souza DC, Larson G, Anderson WG, Klatt M, Fareed A, Thompson SI, Carrera CJ, Williams SS, Juergens TM, Albers LJ, Nasdahl CS, Villarreal G, Winston JL, Nogues CA, Connolly KR, Tapp A, Jones KA, Khatkhate G, Marri S, Suppes T, LaMotte J, Hurley R, Mayeda AR, Niculescu AB 3rd, Fischer BA, Loreck DJ, Rosenlicht N, Lieske S, Finkel MS, Little JT. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017 Jul 11;318(2):132-145. doi: 10.1001/jama.2017.8036.

  PMID: 28697253 RESULT

• Zisook S, Johnson GR, Planeta B, Mohamed S. How Does Positive Mental Health Affect Next-Step Treatment Outcomes in Treatment-Resistant Depression? A VAST-D Report. J Clin Psychopharmacol. 2025 Sep-Oct 01;45(5):421-431. doi: 10.1097/JCP.0000000000002051. Epub 2025 Jul 31.

  PMID: 40742171 DERIVED

• Zisook S, Planeta B, Hicks PB, Chen P, Davis LL, Villarreal G, Sapra M, Johnson GR, Mohamed S. Childhood adversity and adulthood major depressive disorder. Gen Hosp Psychiatry. 2022 May-Jun;76:36-44. doi: 10.1016/j.genhosppsych.2022.03.008. Epub 2022 Mar 24.

  PMID: 35366613 DERIVED

• Zisook S, Johnson GR, Hicks P, Chen P, Beresford T, Michalets JP, Rao S, Thase ME, Wilcox J, Sevilimedu V, Mohamed S. Continuation phase treatment outcomes for switching, combining, or augmenting strategies for treatment-resistant major depressive disorder: A VAST-D report. Depress Anxiety. 2021 Feb;38(2):185-195. doi: 10.1002/da.23114. Epub 2020 Nov 22.

  PMID: 33225492 DERIVED

• Mohamed S, Johnson GR, Sevilimedu V, Rao SD, Hicks PB, Chen P, Lauro K, Jurjus G, Pilkinton P, Davis L, Wilcox JA, Iranmanesh A, Sapra M, Aslam M, Michalets J, Thase M, Zisook S; CSP#576 VAST-D Investigators. Impact of Concurrent Posttraumatic Stress Disorder on Outcomes of Antipsychotic Augmentation for Major Depressive Disorder With a Prior Failed Treatment: VAST-D Randomized Clinical Trial. J Clin Psychiatry. 2020 Jun 23;81(4):19m13038. doi: 10.4088/JCP.19m13038.

  PMID: 32603560 DERIVED

• Zisook S, Johnson GR, Tal I, Hicks P, Chen P, Davis L, Thase M, Zhao Y, Vertrees J, Mohamed S. General Predictors and Moderators of Depression Remission: A VAST-D Report. Am J Psychiatry. 2019 May 1;176(5):348-357. doi: 10.1176/appi.ajp.2018.18091079. Epub 2019 Apr 5.

  PMID: 30947531 DERIVED

• Yoon J, Zisook S, Park A, Johnson GR, Scrymgeour A, Mohamed S. Comparing Cost-Effectiveness of Aripiprazole Augmentation With Other "Next-Step" Depression Treatment Strategies: A Randomized Clinical Trial. J Clin Psychiatry. 2018 Dec 18;80(1):18m12294. doi: 10.4088/JCP.18m12294.

  PMID: 30695291 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Mood Disorders; Depression; Depressive Disorder; Recurrence; Psychological Well-Being

Interventions

Aripiprazole

Condition Hierarchy (Ancestors)

Mental Disorders; Behavioral Symptoms; Behavior; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Personal Satisfaction

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Gary R. Johnson, MS
• Organization: VA Cooperative Studies Program Coordinating Center, West Haven, CT

gary.johnson4@va.gov

(203) 932-5711

Study Officials

• Somaia Mohamed, PhD

  VA Connecticut Healthcare System West Haven Campus, West Haven, CT

  STUDY CHAIR

• Sidney Zisook, MD

  VA San Diego Healthcare System, San Diego, CA

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2011
• First Posted: August 22, 2011
• Study Start: December 1, 2012
• Primary Completion: August 1, 2015
• Study Completion: June 1, 2016
• Last Updated: May 29, 2018
• Results First Posted: May 29, 2018

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (35)