Elsevier

Psychiatry Research

Volume 229, Issue 3, 30 October 2015, Pages 760-770
Psychiatry Research

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations

https://doi.org/10.1016/j.psychres.2015.08.005Get rights and content

Highlights

  • Over 2/3s of Major Depressive Disorder cases do not achieve remission on initial treatment.

  • Urgent need to identify effective next step treatments for MDD.

  • Switching to bupropion-SR vs. augmenting with bupropion-SR or aripiprazole.

  • Compare 12-week remission and relapse for up to 6 months after remission.

  • Seven methodological issues to balance efficacy and effectiveness.

Abstract

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three “next-step” strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed “efficacy-effectiveness” trial.

Introduction

Major Depressive Disorder (MDD) is a painful, chronic, highly debilitating and sometimes fatal disorder that accounts for 4.4% of the entire global burden of disease and over half of all disability attributable to mental illness (Horton, 2012). Although many effective treatments are available, less than one-third of patients with MDD achieve remission in the first trial of antidepressant therapy (Trivedi et al., 2006b). Thus, the identification of the most effective and safe “next-step” strategy for the remaining two-thirds is a public health priority of global importance.

The current “best practice” of pharmacotherapy when the initial antidepressant medication fails is either to switch to another antidepressant or to augment with a second treatment. Because there are no studies to inform prescribers whether, or under what circumstances, to switch or augment, or which agent is most effective and safe for either purpose, decisions are at present based on trial and error efforts that can involve months of delay of significant relief from disabling and potentially life threatening depressive symptoms (Rush et al., 2003). Although treatment guidelines may help, most of these guidelines rely on expert opinion rather than empirically based research (American Psychiatric Association, 2006, Yager et al., 2014).

Considerable emphasis has been placed, in recent years, on comparative effectiveness trials or pragmatic trials that compare FDA approved treatments against each other – treatments whose superiority to placebo has already been established (Rush, 2007; Lieberman et al., 2005; Wang et al., 2009). The largest and most comprehensive study of this type that evaluated treatments for MDD, thus far, was the National Institute on Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D), which was itself designed to determine best “next-step” treatments for depressed patients who did not respond satisfactorily to their initial treatment. STAR*D confirmed the need for "next-step" treatments for the majority of patients and provided many useful guidelines for clinical care (Rush, 2007). However, the study did not meet its overriding objective of identifying optimally effective “next-step” treatments (Rush et al., 2009). In addition, atypical antipsychotics were first approved by the FDA for augmentation of depression treatments in 2007, after STAR*D was complete, and have been frequently used for this purpose even prior to FDA approval (Leslie et al., 2009, Mohamed et al., 2009). Thus two of the important questions that were left unanswered are: (1) for which patients, under what circumstances, is switching to vs. augmenting with other antidepressants the most effective “next-step” strategy? and (2) how does augmentation with atypical antipsychotics compare to either switching or augmenting with antidepressants?

The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, a Veterans Affairs (VA) Cooperative Study (VA CSP#576) is the first to systematically compare benefits and risks of three commonly used switch and augmentation strategies for patients with MDD who have not remitted after an initial adequate antidepressant trial. A planning committee of experts in the fields of depression and psychiatry research and methodology (Appendix B) was assembled in order to address the various decisions/issues involved in designing a study of this magnitude. This paper describes a series of study design decisions made in attempting to answer the two primary study questions: (1) is switching or augmenting more effective “next-step” strategy in real-world practice?; and (2) does augmentation with atypical antipsychotics improve outcomes compared to augmenting with another antidepressant? First we present the final study design and then review key considerations that led to it, articulating methodological design principles that guided critical decisions and solutions.

Section snippets

Summary of study design

VAST-D is a multi-site, prospective, randomized, “next-step” clinical trial of outpatients with nonpsychotic MDD. VAST-D's planned enrollment is 1518 total Veterans (approximately 50 participants at each of 30–35 participating VA Medical Centers) including both genders and all ethnic/racial and socioeconomic backgrounds. All participants were intended to meet DSM-IV-TR criteria for nonpsychotic MDD. The diagnostic criteria for eligibility are established by clinical interview by qualified site

Design considerations

Randomized clinical trials have been described along a continuum from effectiveness to efficacy studies, recognizing that aspects of both are usually present in what have been called “hybrid trials” (Bauer et al., 2001). The goal of a pure efficacy trial is to determine what treatment works best under ideal “laboratory” circumstances, maximizing internal validity by controlling all extrinsic factors that can contribute variability to treatment effects. Essential features of the efficacy study

Summary and conclusions

In this paper, we have highlighted some of the key design decisions we faced as we finalized the VAST-D protocol. VAST-D is a multi-site, randomized, controlled treatment trial designed to compare three commonly used, “next-step” strategies for outpatients with nonpsychotic MDD who have not had acceptable outcomes to their prescribed antidepressants: switching to bupropion-SR or augmenting with either bupropion-SR or aripiprazole. VAST-D is designed to address questions left unanswered by

Limitations

Although VAST-D is the largest and most comprehensive VA trial ever attempted for the treatment of major depression, it cannot answer every important question regarding the treatment of MDD after an initial antidepressant trial fails to achieve a satisfactory outcome, nor should it. While there are certainly other options that could also have been considered, none are routinely available in most practice settings, especially primary care settings. Alternative agents that were considered include

Funding

This study is supported and conducted by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, Washington, DC, USA as CSP #576, VA augmentation and switching treatments for improving depression outcomes (VAST-D)

ClinicalTrials.gov Identifier: NCT01421342

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