Major Depressive DisorderPhase 3VAST-DNCT01421342
VA Augmentation and Switching Treatments for Improving Depression Outcomes
A Phase 3 study testing Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR and Augmenting: Antidepressant + Aripiprazole in people with Major Depressive Disorder, run by VA Office of Research and Development at 35 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR and Augmenting: Antidepressant + Aripiprazole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,522 participants
- Where
- 35 sitesUnited States
- Study dates
- Dec 2012to Jun 2016
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 14Show fewer
- Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care
- Requiring immediate hospitalization for psychiatric disorders
- Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion criteria)
- 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
Trial locations and contacts
35 sites in 1 country.
35 sites in 1 country
United States35 sites
New Mexico VA Health Care System, Albuquerque, NM
Albuquerque, New Mexico, 87108-5153
Asheville VA Medical Center, Asheville, NC
Asheville, North Carolina, 28805
Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
Baltimore, Maryland, 21201
Cincinnati VA Medical Center, Cincinnati, OH
Cincinnati, Ohio, 45220
Clarksburg Louis A. Johnson VA Medical Center, Clarksburg, WV
Clarksburg, West Virginia, 26301
Louis Stokes VA Medical Center, Cleveland, OH
Cleveland, Ohio, 44106
Atlanta VA Medical and Rehab Center, Decatur, GA
Decatur, Georgia, 30033
VA Eastern Colorado Health Care System, Denver, CO
Denver, Colorado, 80220
Edward Hines Jr. VA Hospital, Hines, IL
Hines, Illinois, 60141-5000
Richard L. Roudebush VA Medical Center, Indianapolis, IN
Indianapolis, Indiana, 46202-2884
Kansas City VA Medical Center, Kansas City, MO
Kansas City, Missouri, 64128
VA Loma Linda Healthcare System, Loma Linda, CA
Loma Linda, California, 92357
VA Long Beach Healthcare System, Long Beach, CA
Long Beach, California, 90822
William S. Middleton Memorial Veterans Hospital, Madison, WI
Madison, Wisconsin, 53705
Memphis VA Medical Center, Memphis, TN
Memphis, Tennessee, 38104
Miami VA Healthcare System, Miami, FL
Miami, Florida, 33125
Clement J. Zablocki VA Medical Center, Milwaukee, WI
Milwaukee, Wisconsin, 53295-1000
Minneapolis VA Health Care System, Minneapolis, MN
Minneapolis, Minnesota, 55417
Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
Omaha, Nebraska, 68105-1873
VA Palo Alto Health Care System, Palo Alto, CA
Palo Alto, California, 94304-1290
Philadelphia VA Medical Center, Philadelphia, PA
Philadelphia, Pennsylvania, 19104
Phoenix VA Health Care System, Phoenix, AZ
Phoenix, Arizona, 85012
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, 15240
Salem VA Medical Center, Salem, VA
Salem, Virginia, 24153
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
Salisbury, North Carolina, 28144
VA San Diego Healthcare System, San Diego, CA
San Diego, California, 92161
San Francisco VA Medical Center, San Francisco, CA
San Francisco, California, 94121
St. Louis VA Medical Center John Cochran Division, St. Louis, MO
St Louis, Missouri, 63106
VA Puget Sound Health Care System American Lake Division, Tacoma, WA
Tacoma, Washington, 98493
James A. Haley Veterans' Hospital, Tampa, FL
Tampa, Florida, 33612
Central Texas Veterans Health Care System, Temple, TX
Temple, Texas, 76504
Southern Arizona VA Health Care System, Tucson
Tucson, Arizona, 85723
Tuscaloosa VA Medical Center, Tuscaloosa, AL
Tuscaloosa, Alabama, 35404
Washington DC VA Medical Center, Washington, DC
Washington D.C., District of Columbia, 20422
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, 06516
About this study
Official title: CSP #576 - VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
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.
Read the detailed description
The overall aim of VAST-D is to enhance treatment outcomes for representative outpatients diagnosed with nonpsychotic major depressive disorder (MDD) and treated in primary or psychiatric VA care settings. In particular, VAST-D is designed to determine the comparative effectiveness of different treatment options for participants with MDD who fail to have a satisfactory outcome to treatment with their initial antidepressants.
These options may be conceptualized as representing two overall treatment strategies: 1) Medication Switch - switching from the initial antidepressant to another antidepressant medication, specifically bupropion-SR and 2) Medication Augmentation - augmenting the initial antidepressant with a second antidepressant, specifically bupropion-SR or a second generation antipsychotic, specifically aripiprazole. VAST-D's primary goal is to determine which of these 3 treatment strategies is most likely to lead to remission. Other key objectives include comparisons of response, time to remission, time to response, relapse, anxiety symptoms, suicidal ideation and behaviors, side effects, tolerability, quality of life, health related costs and satisfaction with participation in the study.
VAST-D will enroll 1518 total patients of both genders and all ethnic/racial and socioeconomic backgrounds. All patients will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR (text revised) criteria for nonpsychotic MDD. The diagnostic criteria for eligibility will be established by clinical interview supplemented with the 9-item Patient Health Questionnaire (PHQ-9). Final determination for eligibility will be made by the study clinician. Only participants with a suboptimal outcome to a well documented, adequately delivered (dose and duration), trial with selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) or mirtazapine will be eligible for the study. Failure to achieve an adequate outcome will be ascertained by a score on the 16-item Quick Inventory of Depressive Symptomatology - Clinician rated (QIDS-C16) scale >= 16 (considered severe depression) after at least 6 weeks of treatment or QIDS-C16 >= 11 (considered moderately severe depression) after at least 8 weeks of treatment. Otherwise, the inclusion criteria are broad and the exclusion criteria are few; participants with most comorbid general medical or psychiatric disorders are generally included to provide a broadly representative sample.
Participants will be randomized (1:1:1 ratio) to switch to bupropion-SR alone (n=506), current antidepressant plus bupropion-SR (n=506), or current antidepressant plus aripiprazole (n=506). Treatment will be guided by clinician-rated symptom measures (the PHQ-9) and global side effects measures (the Frequency, Intensity, and Burden of Side Effects Rating or FIBSER) obtained at each treatment visit. Acute treatment visits will occur at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 to ensure delivery of appropriate and yet vigorous and tolerable pharmacotherapy. Participants who tolerate the acute treatment and achieve adequate response at 12 weeks will enter the 24-week Continuation Treatment phase, during which the initial treatment will continue and visits will occur every four weeks subsequently until patients have been followed for 36 weeks post-randomization. The QIDS-C16 will be administered at baseline and at each follow-up visit by an independent evaluator (who will be blinded to treatment assignment) to measure symptoms of depression for the study outcomes of remission, response and relapse. Neither the participant nor the treating clinician will be blinded to treatment.
Primary hypotheses:
Primary hypothesis 1.a: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) compared to those switched to bupropion-SR monotherapy.
Primary Hypothesis 1.b: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to those switched to bupropion-SR monotherapy.
Secondary hypotheses:
Secondary Hypothesis 2.a: Remission rate will be greater in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those augmented with aripiprazole (antidepressant + aripiprazole).
Secondary Hypothesis 2.b: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose antidepressant is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those whose antidepressant is switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.c: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) vs. those switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.d: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in patients whose treatment was augmented with aripiprazole (antidepressant + aripiprazole).
Secondary Hypothesis 2.e: The proportion of patients who develop akathisia, other akathisia-like side effects (e.g., tremor, irritability, motor restlessness) and extrapyramidal side effects will be greater in the patients whose antidepressant treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR), or switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.f: The relative costs (direct and indirect) of augmenting an antidepressant with aripiprazole (antidepressant + aripiprazole) will be greater than the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR), and the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR) will be greater than the costs of switching to bupropion-SR monotherapy, and augmentation and monotherapy with bupropion-SR will be more cost-effective than aripiprazole augmentation.
- Conditions
- Major Depressive Disorder
- Being tested
- Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
- Keywords
- Mood Disorder, Depression, Depressive Disorder, Depressive Disorder, Major, Bupropion, Aripiprazole, Remission, Relapse, Cost-Effectiveness, Atypical Antipsychotic, Antidepressant, Augmentation, Veterans, Mental Health
- Medical subject headings
- Depressive Disorder, Major, Mood Disorders, Depression, Depressive Disorder, Recurrence, Psychological Well-Being
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Switching: Bupropion-SRDrug
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-SRDrug
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 + AripiprazoleDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Switching: Bupropion-SR | Active comparator | Switching: Bupropion-SR Receives: Drug: Switching: Bupropion-SR |
| Augmenting: Antidepressant + Bupropion-SR | Active comparator | Augmenting: Antidepressant + Bupropion-SR Receives: Drug: Augmenting: Antidepressant + Bupropion-SR |
| Augmenting: Antidepressant + Aripiprazole | Active comparator | Augmenting: Antidepressant + Aripiprazole Receives: Drug: Augmenting: Antidepressant + Aripiprazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: During acute phase (12 weeks)
Secondary outcomes (3)
Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase
Relapse in symptoms of major depression defined as a QIDS-C16 => 11 among those achieving remission in the acute phase.
Measured: Within 36 weeks after randomization (initiation of treatment)
Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C)
Response measured as reduction in symptom score for major depression defined as: 1. a reduction in QIDS-C16 of 50% or greater
Measured: During acute phase (up to 12 weeks)
Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale
Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976). A secondary outcome measure of response was defined as achieving a score of 2 (much improved) or 1 (very much improved).
Measured: During acute phase (up to 12 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2011 (estimated)
- Study startDec 2012
- Primary completionAug 2015
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 1,522 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Somaia Mohamed, PhD, Study chair, VA Connecticut Healthcare System West Haven Campus, West Haven, CTSidney Zisook, MD, Study chair, VA San Diego Healthcare System, San Diego, CA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01421342
- Sponsor's protocol ID
- 576
- Acronym
- VAST-D
- Status last verified
- Apr 2018
- First submitted
- 5 Aug 2011
- Last updated
- 29 May 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 26279130Zisook 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.
PubMed 27479536Mohamed 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.
PubMed 28697253Zisook 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.
PubMed 40742171Zisook S, Moutier CY, Rush AJ, Johnson GR, Tal I, Chen PJ, Davis LL, Hicks PB, Wilcox J, Planeta B, Lauro KW, Scrymgeour AA, Kasckow J, Mohamed S. Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial. Psychol Med. 2024 Apr;54(6):1172-1183. doi: 10.1017/S0033291723003008. Epub 2023 Oct 20.
PubMed 37859623Zisook 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.
PubMed 35366613Zisook 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.
PubMed 33225492Mohamed 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.
PubMed 32603560Zisook 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.
PubMed 30947531Yoon 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.
PubMed 30695291
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CSP #576 - VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
- ClinicalTrials.gov ID
- NCT01421342
- Acronym / sponsor ID
- VAST-D / 576
- Conditions
- Major Depressive Disorder
- Keywords
- Mood Disorder, Depression, Depressive Disorder, Depressive Disorder, Major, Bupropion, Aripiprazole, Remission, Relapse
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,522 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- Dec 2012
- Primary completion
- Aug 2015 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 22 Aug 2011 (estimated)
- Results
- Posted 29 May 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The overall aim of VAST-D is to enhance treatment outcomes for representative outpatients diagnosed with nonpsychotic major depressive disorder (MDD) and treated in primary or psychiatric VA care settings. In particular, VAST-D is designed to determine the comparative effectiveness of different treatment options for participants with MDD who fail to have a satisfactory outcome to treatment with their initial antidepressants.
These options may be conceptualized as representing two overall treatment strategies: 1) Medication Switch - switching from the initial antidepressant to another antidepressant medication, specifically bupropion-SR and 2) Medication Augmentation - augmenting the initial antidepressant with a second antidepressant, specifically bupropion-SR or a second generation antipsychotic, specifically aripiprazole. VAST-D's primary goal is to determine which of these 3 treatment strategies is most likely to lead to remission. Other key objectives include comparisons of response, time to remission, time to response, relapse, anxiety symptoms, suicidal ideation and behaviors, side effects, tolerability, quality of life, health related costs and satisfaction with participation in the study.
VAST-D will enroll 1518 total patients of both genders and all ethnic/racial and socioeconomic backgrounds. All patients will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR (text revised) criteria for nonpsychotic MDD. The diagnostic criteria for eligibility will be established by clinical interview supplemented with the 9-item Patient Health Questionnaire (PHQ-9). Final determination for eligibility will be made by the study clinician. Only participants with a suboptimal outcome to a well documented, adequately delivered (dose and duration), trial with selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) or mirtazapine will be eligible for the study. Failure to achieve an adequate outcome will be ascertained by a score on the 16-item Quick Inventory of Depressive Symptomatology - Clinician rated (QIDS-C16) scale >= 16 (considered severe depression) after at least 6 weeks of treatment or QIDS-C16 >= 11 (considered moderately severe depression) after at least 8 weeks of treatment. Otherwise, the inclusion criteria are broad and the exclusion criteria are few; participants with most comorbid general medical or psychiatric disorders are generally included to provide a broadly representative sample.
Participants will be randomized (1:1:1 ratio) to switch to bupropion-SR alone (n=506), current antidepressant plus bupropion-SR (n=506), or current antidepressant plus aripiprazole (n=506). Treatment will be guided by clinician-rated symptom measures (the PHQ-9) and global side effects measures (the Frequency, Intensity, and Burden of Side Effects Rating or FIBSER) obtained at each treatment visit. Acute treatment visits will occur at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 to ensure delivery of appropriate and yet vigorous and tolerable pharmacotherapy. Participants who tolerate the acute treatment and achieve adequate response at 12 weeks will enter the 24-week Continuation Treatment phase, during which the initial treatment will continue and visits will occur every four weeks subsequently until patients have been followed for 36 weeks post-randomization. The QIDS-C16 will be administered at baseline and at each follow-up visit by an independent evaluator (who will be blinded to treatment assignment) to measure symptoms of depression for the study outcomes of remission, response and relapse. Neither the participant nor the treating clinician will be blinded to treatment.
Primary hypotheses:
Primary hypothesis 1.a: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) compared to those switched to bupropion-SR monotherapy.
Primary Hypothesis 1.b: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to those switched to bupropion-SR monotherapy.
Secondary hypotheses:
Secondary Hypothesis 2.a: Remission rate will be greater in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those augmented with aripiprazole (antidepressant + aripiprazole).
Secondary Hypothesis 2.b: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose antidepressant is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those whose antidepressant is switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.c: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) vs. those switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.d: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in patients whose treatment was augmented with aripiprazole (antidepressant + aripiprazole).
Secondary Hypothesis 2.e: The proportion of patients who develop akathisia, other akathisia-like side effects (e.g., tremor, irritability, motor restlessness) and extrapyramidal side effects will be greater in the patients whose antidepressant treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR), or switched to bupropion-SR monotherapy.
Secondary Hypothesis 2.f: The relative costs (direct and indirect) of augmenting an antidepressant with aripiprazole (antidepressant + aripiprazole) will be greater than the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR), and the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR) will be greater than the costs of switching to bupropion-SR monotherapy, and augmentation and monotherapy with bupropion-SR will be more cost-effective than aripiprazole augmentation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Switching: Bupropion-SR | Active comparator | Drug: Switching: Bupropion-SRSwitching: Bupropion-SR |
| Augmenting: Antidepressant + Bupropion-SR | Active comparator | Drug: Augmenting: Antidepressant + Bupropion-SRAugmenting: Antidepressant + Bupropion-SR |
| Augmenting: Antidepressant + Aripiprazole | Active comparator | Drug: Augmenting: Antidepressant + AripiprazoleAugmenting: Antidepressant + Aripiprazole |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Switching: Bupropion-SRBupropion-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. | Drug | Switching: Bupropion-SR |
| Augmenting: Antidepressant + Bupropion-SRCurrent 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. | Drug | Augmenting: Antidepressant + Bupropion-SR |
| Augmenting: Antidepressant + AripiprazoleCurrent 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. | Drug | Augmenting: Antidepressant + Aripiprazole |
Primary outcome
Rate of Protocol Remission of Symptoms of Major Depressive Disorder
Time frame: During acute phase (12 weeks)
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.
3 secondary outcomes
Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase
Time frame: Within 36 weeks after randomization (initiation of treatment)
Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C)
Time frame: During acute phase (up to 12 weeks)
Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale
Time frame: During acute phase (up to 12 weeks)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26279130Mohamed 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.
- Results publication: PubMed 27479536Zisook 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.
- Results publication: PubMed 28697253Mohamed 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.
- Derived from this study: PubMed 40742171Zisook 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.
- Derived from this study: PubMed 37859623Zisook S, Moutier CY, Rush AJ, Johnson GR, Tal I, Chen PJ, Davis LL, Hicks PB, Wilcox J, Planeta B, Lauro KW, Scrymgeour AA, Kasckow J, Mohamed S. Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial. Psychol Med. 2024 Apr;54(6):1172-1183. doi: 10.1017/S0033291723003008. Epub 2023 Oct 20.
- Derived from this study: PubMed 35366613Zisook 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.
- Derived from this study: PubMed 33225492Zisook 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.
- Derived from this study: PubMed 32603560Mohamed 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.
- Derived from this study: PubMed 30947531Zisook 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.
- Derived from this study: PubMed 30695291Yoon 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Somaia Mohamed, PhD study chair
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Sidney Zisook, MD study chair
VA San Diego Healthcare System, San Diego, CA
35 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR and Augmenting: Antidepressant + Aripiprazole in people with Major Depressive Disorder, run by VA Office of Research and Development at 35 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 May 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of Protocol Remission of Symptoms of Major Depressive Disorder (time frame: During acute phase (12 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01421342, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2018.