Abstract

Back to table of contents Previous article Next article Special Section on the Implications of STAR*DFull AccessWhat Did STAR*D Teach Us? Results From a Large-Scale, Practical, Clinical Trial for Patients With DepressionBradley N. Gaynes M.D., M.P.H.Diane Warden Ph.D., M.B.A.Madhukar H. Trivedi M.D.Stephen R. Wisniewski Ph.D.Maurizio Fava M.D.A. John Rush M.D.Bradley N. Gaynes M.D., M.P.H.Search for more papers by this authorDiane Warden Ph.D., M.B.A.Search for more papers by this authorMadhukar H. Trivedi M.D.Search for more papers by this authorStephen R. Wisniewski Ph.D.Search for more papers by this authorMaurizio Fava M.D.Search for more papers by this authorA. John Rush M.D.Search for more papers by this authorPublished Online:1 Nov 2009https://doi.org/10.1176/ps.2009.60.11.1439AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Depression affects one in eight persons in the United States ( 1 ) and is projected to become the second leading cause of disability in the world by the year 2020 ( 2 ). However, generalizable evidence from clinical trials to inform treatment selection and sequencing is quite limited. Most clinical trial participants are recruited by advertisement rather than from representative practice settings. Eligibility criteria often exclude persons who have coexisting general medical or psychiatric disorders or who are taking medication other than antidepressants ( 3 , 4 ). Those with chronic depression or current suicidal ideation are also excluded ( 1 , 5 ). Consequently, the available "evidence" from clinical trials involves a largely "pure," uncomplicated population of depressed patients that is rarely seen by most practicing clinicians ( 6 ). In addition, the care delivered in these efficacy trials, which involves using interviewer-administered measures and frequent and time-intensive follow-up interviews, blinding patients and physicians to treatment, and employing fixed dosing strategies, does not reflect what is and can be done in real-world practices. The available evidence may not translate to the care provided by practicing psychiatrists and primary care physicians ( 7 ). Further, the bulk of the evidence base is for patients who have yet to experience treatment failure in their current episode of depression, even though only about a third of patients achieve remission after a single treatment ( 8 ). Management of most patients after one or more failed treatments is not evidence based. To address these knowledge deficits, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a large-scale clinical trial funded by the National Institutes of Health, aimed to develop and evaluate feasible treatment strategies to improve clinical outcomes for more representative, "real-world" outpatients with one or more prior failed treatments. The study created its own prospectively defined sample of treatment-resistant patients from a pool of patients currently experiencing a major depressive episode for subsequent inclusion in a series of up to five prospective treatments. Specifically, STAR*D aimed to determine which of several treatments are the most effective "next-step" treatments for patients whose symptoms do not remit or who cannot tolerate the initial treatment and, if needed, ensuing treatments. This article provides an overview of the design, methods, and results of STAR*D, with attention to the implications and limitations of the trial. The rationale and design of STAR*DDesign The rationale and design of the study have been fully described elsewhere ( 3 , 4 , 9 ). STAR*D is the largest prospective clinical trial of major depressive disorder ever conducted. It was a multicenter, nationwide association of 14 university-based regional centers, which oversaw a total of 23 participating psychiatric clinics and 18 primary care clinics. Enrollment began in 2000, with follow-up completed in 2004. All enrolled patients began on a single selective serotonin reuptake inhibitor (SSRI) (citalopram) and were managed by clinic physicians, who followed an algorithm-guided acute phase treatment through five visits over a 12-week course. Dosing was aggressive and focused on maximizing the tolerable dose; if patients who were tolerating a medication had not achieved remission (that is, complete recovery from the depressive episode) by any of the critical decision points (weeks 4, 6, and 9), the algorithm recommended increasing the dose. Patients whose depression did not remit after this initial treatment were able to participate in a sequence of up to three randomized clinical trials or levels. For example, at the end of level 1, patients whose depression had not fully recovered were eligible to participate in level 2 ( Figure 1 ). Figure 1 STAR*D treatment levels Treatment assignments were made using an equipoise stratified randomized design ( 10 ). To reflect treatment decisions in clinical practice, patients were allowed to choose among acceptable options (for example, to switch to a different treatment or augment the current treatment with an additional treatment). Participants could opt out of certain strategies as long as there were at least two possible options to which they might be randomly assigned. Participants Study entry criteria were broadly defined and inclusive. Patients had to have nonpsychotic major depressive disorder identified by clinicians and confirmed with a symptom checklist based on DSM-IV-TR ( 11 ), for which antidepressant treatment is recommended. Patients, whose ages ranged from 18 to 75, had to score of ≥14 on the 17-item Hamilton Rating Scale for Depression (HAM-D) ( 12 ) and could not have a primary diagnosis of bipolar disorder, obsessive-compulsive disorder, or an eating disorder or have a history of a seizure disorder. A total of 4,041 patients were enrolled in the first level of treatment, making STAR*D the largest prospective clinical trial of depression ever conducted. SettingBoth primary and specialty care sites that provided care to public- and private-sector patients were selected on the basis of having sufficient numbers of patients, sufficient numbers of clinicians, sufficient administrative support, and sufficient numbers of patients from racial-ethnic minority groups to ensure that the study population would mirror the U.S. census data and that results would be widely generalizable. The median number of clinicians was 14 at the 18 primary care sites and 12 at the 23 specialty sites. Three-quarters of the facilities were privately owned, and approximately two-thirds were freestanding (not hospital based).Measures The primary research outcome was the standard definition of remission as measured by the HAM-D ( 13 ). Assessments were conducted by treatment-blinded raters at exit from each treatment level. A secondary instrument, the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), was administered at each clinic visit, and remission was measured as a score of ≤5. Because the QIDS-SR was most often successfully collected at a time point closer to when a patient exited a level, the QIDS-SR provided more frequent assessment points during the acute phase and may have been a slightly better reflection of actual remission. The group of patients who improved but whose symptoms did not completely remit was defined as those who showed a ≥50% reduction in QIDS-SR score from baseline to the last assessment in the level. Intervention A systematic approach to treatment called measurement-based care was used that can be easily implemented in busy primary care or psychiatric settings ( 14 , 15 ). Measurement-based care involves the routine use of symptom and side-effect measurement, with guidance on when and how to modify medication dosages at critical decision points. STAR*D resultsLevel 1 outcomesA total of 2,876 individuals with analyzable data completed level 1 treatment. Measurement-based care was feasible and led to an average citalopram dosage of greater than 40 mg per day, indicating that high-quality care was delivered in these real-world settings. Remission rates were 27% as measured by HAM-D and 33% as measured by QIDS-SR, and response rates were 47% as measured by QIDS-SR. For those whose symptoms remitted, the mean time to remission was approximately 47 days. Factors that increased the chance of remission included being Caucasian, female, and employed and having more years of education and income. Factors associated with lower remission rates were greater chronicity of the current episode, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), greater degree of general medical comorbidity, and lower levels of functioning and quality of life at baseline. On average, patients required nearly seven weeks of measurement-based care to achieve remission. Notably, approximately half of the patients who ultimately remitted did so after six weeks, and 40% of those who achieved remission required eight or more weeks to do so ( 15 ). Level 2 outcomes After consideration of patient preference, 727 patients were randomly assigned to the switch strategy option in level 2. Nearly one-quarter of patients achieved remission when switched to measurement-based care-guided treatment with sertraline (a "within class" SSRI switch), venlafaxine-XR (a serotonin-norepinephrine reuptake inhibitor), or bupropion-SR (a norepinephrine and dopamine reuptake inhibitor) ( 16 ). Remission rates for bupropion-SR (21% by HAM-D and 26% by QIDS-SR), sertraline (18% and 27%), and venlafaxine-XR (25% for both) were neither statistically nor clinically different by either measure. Mean daily dosage at the final visit for bupropion-SR was 282.7 mg, for sertraline it was 135.5 mg, and for venlafaxine-XR was it 193.6 mg. Of note, the dosage of venlafaxine was less likely to approach the protocol-recommended maximum than that of either of the other two drugs. The overall side effect burden and the rate of serious adverse events did not differ significantly among the three medications. Moderators of remission were also studied but offered little help in the selection of antidepressants after an initial treatment failure. Neither clinical symptom patterns (including anxious, atypical, and melancholic features) nor standard demographic measures were of clear value in recommending any particular medication for a second step treatment ( 17 ). Augmentation strategy. After consideration of patient preference, 565 patients were randomly assigned to the augmentation strategy option in level 2. Augmentation of citalopram with bupropion-SR or buspirone led to similar rates of remission as measured by the HAM-D (30% and 30%, respectively) and by the QIDS-SR (39% and 33%, respectively) ( 18 ). However, on an alternative outcome measure, bupropion-SR was associated with a greater total reduction in QIDS-SR scores than buspirone (25% compared with 17%, p75% in this study), the fact that only about half the patients reached remission after two treatments, and the poor long-term outcomes for patients when two or more acute treatments failed all suggest the need for more evidence to guide the effective treatment of treatment-resistant depression.Conclusions STAR*D was a seminal, large-scale, practical clinical trial that provided a great deal of data for clinicians, researchers, and policy makers. The findings are still being actively discussed, analyzed, and disseminated, and the acute-treatment data set is now available in the public domain to allow further analysis. The research infrastructure, which continues as the Depression Trials Network ( www.DTN.com ), has completed enrollment for two separate clinical trials whose design was guided, in part, by the findings of STAR*D. Acknowledgments and disclosuresThis project was funded by the National Institute of Mental Health (NIMH) under contract N01MH90003 to the University of Texas Southwestern Medical Center at Dallas. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NIMH approved the design of the overall study and reviewed its conduct but performed no role in the col