Elsevier

Controlled Clinical Trials

Volume 25, Issue 1, February 2004, Pages 119-142
Controlled Clinical Trials

Design paper
Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design

https://doi.org/10.1016/S0197-2456(03)00112-0Get rights and content

Abstract

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18ā€“75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants without sufficient improvement are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Section snippets

Introduction and background

Major depressive disorder (MDD) is a common, typically recurrent, often chronic, and very disabling disorder, costing the United States over $44 billion/year in direct and indirect costs [1]. MDD has a lifetime prevalence of 4.9ā€“17.9% [2], [3]. Women are twice as likely to suffer MDD as men. MDD occurs more frequently among young adults and among those with general medical conditions (GMCs) [4]. Depressed adults have nearly twice the annual health care costs of those without depression [5].

MDD

Aims and treatment paradigm

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) aims to define prospectively which of several treatments are most effective for participants with MDD who experience an unsatisfactory clinical outcome following an initial and, if necessary, subsequent treatment(s). Eligible participants who consent to STAR*D are enrolled into the first level of STAR*D (level 1), which uses the selective serotonin reuptake inhibitor (SSRI) citalopram (CIT). Participants with an adequate clinical

Major endpoints

The primary outcome is depressive symptom severity, measured by the 17-item Hamilton Rating Scale for Depression (HRSD17) obtained at the end of each treatment level (levels 1ā€“4) by independent, telephone-based interviewers with no knowledge of treatment assignment [34], [35]. Treatment remission, for research purposes, is defined as an HRSD17 total score <8 upon exit from a treatment level. The 30-item Inventory of Depressive Symptomatologyā€”Clinician-Rated (IDS-C30), obtained by the same

Selection of protocol treatments

The specific treatments at each level were selected to balance safety while evaluating common practices and pharmacological reasoning. A detailed rationale for the treatments chosen at each level are reviewed elsewhere [39].

To illustrate, CIT was chosen to represent the SSRI class at level 1 since, as several SSRIs will shortly become generic, health care systems are likely to encourage use of an SSRI as a first agent. Thus, defining the ā€œnext bestā€ step following an ineffective SSRI has high

Organizational structure

The STAR*D infrastructure includes the NCC (Dallas), the data coordinating center (DCC) (Pittsburgh), and 14 regional centers (RCs), each of which oversees two to four primary and specialty care clinical sites (CSs). Each RC provides support, quality control, and coordination for the recruitment, retention, and safety of study participants and oversees the acquisition of clinical information from the CSs. STAR*D provides opportunities for ancillary studies relevant to improving the treatment of

Screening and clinical data

Table 2 summarizes the data collected during the screening process. Data collection forms can be ordered at www.star-d.org.

At all clinic visits, information is obtained to guide clinicians implementing study treatments (Table 3). Symptomatic status is measured by the QIDS-C16 [40], [41], [42]. The QIDS-C16 is used to gauge response because previous experiences suggest that global ratings may be insensitive to detecting residual symptoms [49], [50]. The QIDS-C16 rates all nine criterion symptoms

Anticipated analytic approaches

Data analyses from levels 2 and 3 are complicated by the fact that participants may accept or decline specific treatment strategies or substrategies (e.g., medication switch), in a so-called ā€œequipoise-stratified randomizedā€ design [68]. For level 2 analyses, data will be stratified by acceptability strata, and Mantel-Haenszel Ļ‡2 tests will be used to make pairwise comparisons among the treatment options within the medication switch substrategy and between-treatment options within the

Sample size, power, and effect size

Levels 2 through 4 of STAR*D are considered separate RCTs, addressing the question, ā€œWhat should be done next considering that the prior treatment(s) failed?ā€ Therefore, we have made efforts to maintain an overall type I error rate of 0.05 within each level.

Utilization and cost data analyses

Differences in utilization of services will also be calculated for each health outcome comparison among patients randomly assigned to treatment options within the same acceptability strata. Classifying care by type (depression-related, other mental, general medical) and setting (outpatient, emergency room, hospital), between-group differences from the censored and bimodal distributions often encountered with utilization data are tested separately by first comparing use versus no-use (e.g.,

Data monitoring and safety reporting

The data and safety monitoring board (DSMB) (three psychiatrists, one medical ethicist, one patient advocate, one statistician, and one physician/patient advocate) meets every 3 months to monitor various aspects of the study, including participant recruitment, protocol compliance, and adverse events. Adverse events are recorded by study clinicians or CRCs at each clinic visit, based on spontaneous reports and on a participant-completed side effects checklist. Serious adverse events (those that

Current status

As of June 1, 2003, 2555 subjects had been enrolled into level 1 at 41 CSs from 14 RCs. Of these, 771 had entered level 2, 164 had entered level 3, and 42 had entered level 4.

Conclusions

STAR*D uses a randomized, controlled design to evaluate both the theoretical principles and clinical beliefs that currently guide the management of treatment-resistant depression in terms of symptoms, function, satisfaction, side-effect burden, and health care utilization and cost estimates. Given the dearth of controlled data, results should have substantial public health and scientific significance, since they are obtained in representative participant groups/settings, using clinical

Acknowledgements

This project has been funded in part with federal funds from the National Institute of Health, National Institute of Mental Health under Contract N01-MH-90003. Additional funds were provided by the Betty Jo Hay Distinguished Chair in Mental Health, Rosewood Corporation Chair in Biomedical Science and the Sara M. and Charles E. Seay Center for Basic and Applied Research in Psychiatry (A.J.R.), and by MH-30915 (Mental Health Intervention Research Center) (M.E.T., D.J.K.). The following

References (73)

  • M.M Weissman et al.

    Affective disorders

  • R.C Kessler et al.

    Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey

    Arch Gen Psychiatry

    (1994)
  • Depression Guideline Panel

    Clinical practice guideline. Number 5. Depression in primary care: volume 1

    Detection and diagnosis

    (1993)
  • G.E Simon et al.

    Health care costs of primary care patients with recognized depression

    Arch Gen Psychiatry

    (1998)
  • M.B Keller et al.

    Treatment of chronic depression with sertraline or imipramine: preliminary blinded response rates and high rates of undertreatment in the community

    Psychopharmacol Bull

    (1995)
  • L.L Judd et al.

    A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders

    Arch Gen Psychiatry

    (1998)
  • M.E Thase et al.

    Refractory depression: relevance of psychosocial factors and therapies

    Psychiatr Ann

    (1994)
  • C.J Murray et al.

    Evidence-based health policyā€”lessons from the Global Burden of Disease Study

    Science

    (1996)
  • K.B Wells et al.

    The functioning and well-being of depressed patients: results from the Medical Outcomes Study

    JAMA

    (1989)
  • E Frank et al.

    Efficacy of treatments for major depression

    Psychopharmacol Bull

    (1993)
  • Depression Guideline Panel

    Clinical practice guideline. Number 5. Depression in primary care: volume 2

    Treatment of major depression

    (1993)
  • M.E Thase et al.

    Treatment-resistant depression

  • American Psychiatric Association

    Practice guideline for major depressive disorder in adults

    Am J Psychiatry

    (1993)
  • J.F Rosenbaum et al.

    Treatment-resistant mood disorders

  • R.B Jarrett et al.

    Short-term psychotherapy of depressive disorders: current status and future directions

    Psychiatry: Interpers Biol Process

    (1994)
  • E Frank et al.

    Conceptualization and rationale for consensus definitions of response, remission, recovery, relapse and recurrence in major depressive disorder

    Arch Gen Psychiatry

    (1991)
  • A.J Rush et al.

    Psychotherapies for depressive disorders: a review

  • I.W Miller et al.

    The treatment of chronic depression, Part 3: psychosocial functioning before and after treatment with sertraline or imipramine

    J Clin Psychiatry

    (1998)
  • L.L Judd et al.

    Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population

    Am J Psychiatry

    (1996)
  • L.L Judd

    The clinical course of unipolar major depressive disorders

    Arch Gen Psychiatry

    (1997)
  • A.J Rush et al.

    Treating depression to remission

    Psychiatr Ann

    (1995)
  • L Van Londen et al.

    Three- to 5-year prospective follow-up of outcome in major depression

    Psychol Med

    (1998)
  • H.A Sackeim et al.

    A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities

    Arch Gen Psychiatry

    (2000)
  • J.S McCombs et al.

    Pharmacy-enforced outpatient drug treatment protocols: a case study of Medi-Cal restrictions for cefaclor

    Ann Pharmacother

    (1993)
  • M.L Crismon et al.

    Texas Consensus Conference Panel: The Texas Medication Algorithm Project. Report of the Texas Consensus Conference Panel on medication treatment of major depressive disorder

    J Clin Psychiatry

    (1999)
  • D.A Gilbert et al.

    Texas Medication Algorithm Project: definitions, rationale and methods to develop medication algorithms

    J Clin Psychiatry

    (1998)
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    1

    See appendix for a complete listing and location of regional centers, regional center directors, and clinical sites.

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