Clinical trial NCT01421342: VA Augmentation and Switching Treatments for Improving Depression Outcomes
Official title: CSP #576 - VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2011-08-22
Enrollment: 1522
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* 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

Primary outcomes:
measure: Rate of Protocol Remission of Symptoms of Major Depressive Disorder
timeFrame: During acute phase (12 weeks)
Secondary outcomes:
measure: Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase
timeFrame: Within 36 weeks after randomization (initiation of treatment)
measure: Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C)
timeFrame: During acute phase (up to 12 weeks)
measure: Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale
timeFrame: During acute phase (up to 12 weeks)
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: Tuscaloosa VA Medical Center, Tuscaloosa, AL
state: Alabama
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson
state: Arizona
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver, CO
state: Colorado
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Washington
country: United States
facility: Washington DC VA Medical Center, Washington, DC
state: District of Columbia
city: Miami
country: United States
facility: Miami VA Healthcare System, Miami, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Indianapolis
country: United States
facility: Richard L. Roudebush VA Medical Center, Indianapolis, IN
state: Indiana
city: Baltimore
country: United States
facility: Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
state: Maryland
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque, NM
state: New Mexico
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Philadelphia
country: United States
facility: Philadelphia VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Temple
country: United States
facility: Central Texas Veterans Health Care System, Temple, TX
state: Texas
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
city: Tacoma
country: United States
facility: VA Puget Sound Health Care System American Lake Division, Tacoma, WA
state: Washington
city: Clarksburg
country: United States
facility: Clarksburg Louis A. Johnson VA Medical Center, Clarksburg, WV
state: West Virginia
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
Study officials:
affiliation: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
name: Somaia Mohamed, PhD
role: STUDY_CHAIR
affiliation: VA San Diego Healthcare System, San Diego, CA
name: Sidney Zisook, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.