The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations
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
References (68)
- et al.
Principles of effectiveness trials and their implementation in VA Cooperative Study #430:’‘Reducing the efficacy-effectiveness gap in bipolar disorder’
Journal of affective disorders
(2001) - et al.
Development and validation of a brief screening version of the Childhood Trauma Questionnaire
Child Abus. Negl.
(2003) - et al.
Implementing practice guidelines for depression: applying a new framework to an old problem
Gen. Hosp. Psychiatry
(2002) GBD 2010: understanding disease, injury, and risk
Lancet
(2012)- et al.
Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. Introduction
J. Affect. Disord.
(2009) - et al.
Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale
Psychiatry Res.
(1992) - et al.
Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: a meta-analysis of individual patient data from 10 double-blind, randomized clinical trials
J. Psychiatr. Res.
(2008) - et al.
The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression
Biol. Psychiatry
(2003) - et al.
Novel antipsychotics and new onset diabetes
Biol. Psychiatry
(1998) - et al.
Use of bupropion in combination with serotonin reuptake inhibitors
Biol. Psychiatry
(2006)
Antipsychotic-induced weight gain: a review of the literature
J. Clin. Psychiatry
Antipsychotic-induced weight gain: a comprehensive research synthesis
Am. J. Psychiatry
Practice guidelines for the psychiatric evaluation of adults
A rating scale for drug-induced akathisia
Br. J. Psychiatry
Outcomes on the pharmacopsychometric triangle in bupropion-SR vs. buspirone augmentation of citalopram in the STAR*D trial
Acta Psychiatr. Scand.
An inventory for measuring clinical anxiety: psychometric properties
J. Consult. Clin. Psychol.
The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study
J. Clin. Psychiatry
A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction
The Journal of clinical psychiatry
The Texas medication algorithm project: report of the Texas consensus conference panel on medication treatment of major depressive disorder
J. Clin. Psychiatry
Utility of atypical antipsychotics in the treatment of resistant unipolar depression
CNS Drugs
Clinical trials: bridging the gap between efficacy and effectiveness
Int. Rev. Psychiatry
Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure
Psychopharmacol. Bull.
Antidepressant drug effects and depression severity: a patient-level meta-analysis
ECDEU assessment manual for psychopharmacology-revised. U.S. Department of Health, Education, and Welfare. Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration
A rating scale for depression
J. Neurol. Neurosurg. Psychiatry
A sharper Bonferroni procedure for multiple tests of significance
Biometrika
Does the presence of an open-label antidepressant treatment period influence study outcome in clinical trials examining augmentation/combination strategies in treatment partial responders/nonresponders with major depressive disorder?
J. Clin. Psychiatry
The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder
J. Affect. Disord.
Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness?
Am. J. Psychiatry
Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine
Arch. Gen. Psychiatry
Body weight and leptin plasma levels during treatment with antipsychotic drugs
Am. J. Psychiatry
The PHQ-9: validity of a brief depression severity measure
J. Gen. Intern. Med.
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia
N. Engl. J. Med.
Off-label use of antipsychotic medications in the department of veterans affairs health care system
Psychiatr. Serv.
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