Review article
Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR∗D) study

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MDD is a common condition

Major depressive disorder is a common, often chronic or episodic lifelong disorder that is associated with substantial disability and mortality. Although a range of effective treatments is available, a substantial proportion of patients do not respond adequately to treatment in those instances. Which treatments to use alone or in combination, and in what sequence they should be implemented, is not well-defined. As a result, current treatment guidelines rest substantially on open consecutive

Definition

Although the aim of treatment for depression is complete symptom remission and complete functional restoration [12], [30], [31], no single treatment is a panacea. The clearly preferred outcome is sustained clinical remission (ie, the absence of depressive symptoms) and full functional restoration. Based on randomized, placebo-controlled medication trials conducted for regulatory approval, about 50% to 60% of depressions respond to the first treatment, and about 35% to 40% achieve remission in

Evidence to define the next steps

Many treatments for depression have established efficacy in randomized controlled trials [1]. The actual acceptability, clinical benefit, and side effect burden of these treatments in populations representative of every day practice, however, is less well known. In addition, it remains unclear how to treat MDD that responds but does not remit with an initial antidepressant treatment. Response without full remission to antidepressant treatment is frequent [2], and is associated with continuing

Need for representative patients

Most efficacy studies have excluded participants with common general medical and psychiatric comorbidities. Generalization of even these tentative findings to representative populations is difficult. The proposed study has very broad inclusion criteria that allow enrollment of both adult and elderly patients, and clinically depressed patients with many other psychiatric comorbidities. General medical comorbidities are also allowed, as long as clinicians consider antidepressant treatment

Routine versus high-quality treatment

The implementation of treatments under evaluation in STAR∗D must be well enough conducted to ensure actual, not apparent, treatment resistance, yet must be representative of good practice. Treatments must also be tailored to individual participants with general medical, ethnic, and psychiatric diversity. This tension between generalizability and protocol adherence results in a need for a spectrum of clinically acceptable variations (ie, variations that do not profoundly affect outcomes or that

Domains of outcome

STAR∗D includes assessments of several domains: symptoms, function, quality of life, side effect burden, participant satisfaction, and health care utilization and cost.

Primary objectives

The STAR∗D uses a prospective design to determine the comparative effectiveness of different treatment options for MDD. It evaluates the comparative effectiveness of treatments when used either as augmenting treatments or as new treatments when remission is not attained with an initial SSRI CIT. STAR∗D provides several levels or steps in treatment following CIT failure. Assignment to multiple treatments at each level is randomized at all treatment levels (2, 2A, 3, and 4). Clinical outcomes

Equipoise versus forced randomization

From the 4000 participants who enter the STAR∗D treatment protocol, 2000 participants are expected not to have a satisfactory therapeutic response to CIT. These 2000 individuals are eligible for seven different treatment options at level 2. These options may be conceptualized as representing two overall treatment strategies: medication or psychotherapy switch, switching from CIT to another antidepressant medication or CT; and medication or psychotherapy augmentation, augmenting CIT with a

Tactical issues

The STAR∗D ensures that only participants who are treatment-resistant or intolerant enter each subsequent treatment level. It is essential that participants with merely “apparent treatment resistance” to inadequate treatment do not move to the next treatment level (ie, those without an adequate drug dose or an adequate duration of treatment at the prior level) [139]. The issues of dose and duration (for both medication and psychotherapy) are termed treatment tactics [32], [35], [140]. Current

Prediction of response or remission

The degree to which the type of initial treatment, type of depression (melancholic versus atypical), demographic parameters (eg, age, gender, or socioeconomic status), and coexisting axis I and III disorders affects the duration of an adequate trial, and the likelihood and timing of response must be ascertained.

Because STAR∗D strongly encourages 12 weeks of treatment with vigorous dosing at each level, it provides an opportunity to determine whether specific baseline features (patient, illness,

Prediction of relapse or recurrence

Very little is known about the long-term outcome of participants who successfully remit with an antidepressant, particularly if their remission follows nonresponse or partial response to a prior antidepressant trial. How long are they able to remain well? STAR∗D includes longitudinal, naturalistic 12-month follow-up of all participants who have a satisfactory response to any treatment option at any level. This population allows the investigation of possible clinical predictors of relapse or

Limitations of the protocol

The STAR∗D, although extensive, does not answer every question regarding the treatment of MDD. Only one form of psychotherapy is being evaluated (although other forms will be considered once the planned protocol is completed, if the National Institutes of Mental Health continues support). To ensure sufficient homogeneity and sample size, the authors had to begin with a single treatment at level 1, rather than several. The multiple roles or preferred positions in the randomization scheme for

Issues in dissemination of findings

Despite the high prevalence of MDD and the availability of effective treatments, underdiagnosis and undertreatment remain the norm. Only one third to one half of individuals with MDD is properly recognized by practitioners, and even of those who are, many do not receive adequate treatment [144]. In a study by Wells et al [13] from data across treatment settings, only 11% of mildly depressed patients received an antidepressant and 29% of patients of high severity received an antidepressant. Of

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    Supported in part by National Institutes of Mental Health Contract N01-MH-90003, the Betty Jo Hay Distinguished Chair in Mental Health, the Rosewood Corporation Chair in Biomedical Science, and the Sara M. and Charles E. Seay Center for Basic and Applied Research in Psychiatry.

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