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Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report
A. John Rush, M.D.; Madhukar H. Trivedi, M.D.; Stephen R. Wisniewski, Ph.D.; Andrew A. Nierenberg, M.D.; Jonathan W. Stewart, M.D.; Diane Warden, Ph.D., M.B.A.; George Niederehe, Ph.D.; Michael E. Thase, M.D.; Philip W. Lavori, Ph.D.; Barry D. Lebowitz, Ph.D.; Patrick J. McGrath, M.D.; Jerrold F. Rosenbaum, M.D.; Harold A. Sackeim, Ph.D.; David J. Kupfer, M.D.; James Luther, M.A.; Maurizio Fava, M.D.
Am J Psychiatry 2006;163:1905-1917. doi:10.1176/appi.ajp.163.11.1905
Abstract

Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD17]) defined remission; a QIDS-SR16 total score of ≥11 (HRSD17≥14) defined relapse. Results: The QIDS-SR16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. Conclusions: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Abstract Teaser
Figures in this Article

Symptom remission is the desired goal of treatment for depression, given its implications for better daily functioning and better longer-term prognosis (1–6). Since no treatment is a panacea, several sequential treatment steps are often needed to obtain remission with a tolerated treatment (7, 8). If a trial does not result in remission, it is an unsuccessful trial, whether due to lack of efficacy (i.e., lack of remission) or intolerable side effects, as long as the treatment is vigorously dosed to tolerance and provided for a sufficient duration to achieve remission. The number of treatment steps needed to achieve an adequate benefit is typically used to gauge the degree of treatment resistance (9–13), usually with a focus on acute outcomes without reference to longer-term outcomes. Two small studies have suggested that lower acute response rates may be anticipated if patients have greater levels of treatment resistance (14, 15). We do not know, however, whether patients who require more treatment steps (i.e., are more treatment resistant) are different than patients who require fewer steps, nor do we know whether those who require more steps have lower remission rates, take longer to achieve remission, or have poorer longer-term outcomes.

This report builds upon data from four steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (16, 17) (www.star-d.org). The STAR*D trial employed one or more acute treatment steps aimed to achieve symptom remission delivered by using measurement-based care methods (18, 19) to ensure appropriately vigorous and timely dose adjustments and timely changes in treatment when remission was not attained at a tolerable dose. This report describes the patient groups and the acute and longer-term outcomes for each acute treatment step.

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Study Overview

The STAR*D protocol provided a series of randomized controlled treatment trials in a broadly representative group of outpatients with nonpsychotic major depressive disorder who were candidates for medication as a first treatment step. If patients did not achieve remission or could not tolerate a treatment step, they were encouraged to proceed to the next acute treatment step. Those who achieved remission and tolerated acute treatment could enter a longer-term (12-month) naturalistic follow-up phase, as could those with at least a meaningful improvement and acceptable tolerability.

The organization and methods of the STAR*D trial are detailed elsewhere (16, 17). The study was conducted at 41 clinical sites providing primary (N=18) or psychiatric (N=23) care. Clinical sites were identified by availability of depressed outpatients, clinicians, administrative support, and large numbers of minorities. STAR*D was approved and monitored by the institutional review boards at each participating institution, a National Coordinating Center, a Data Coordinating Center, and the Data Safety and Monitoring Board at the National Institute of Mental Health.

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Participants

All participants provided written informed consent at study entry and at entry into each level and the follow-up phase. Only outpatients seeking medical care were eligible (i.e., symptomatic volunteers were excluded). Participants met DSM-IV criteria for nonpsychotic major depressive disorder at study entry as determined by clinical diagnosis and confirmed with a DSM-IV checklist by the clinical research coordinator. Participants were 18–75 years of age, not pregnant, not breastfeeding, and not previously exposed to an adequate trial of any protocol treatment within the first two treatment steps of the study. Exclusion criteria were minimal. Patients with bipolar or psychotic disorders, those with a primary diagnosis of obsessive-compulsive disorder or an eating disorder, those with general medical conditions that contraindicated protocol medications in the first two treatment steps, and participants with substance abuse/dependence that required inpatient detoxification were excluded, as were suicidal patients who required immediate hospitalization.

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Assessments

Baseline and outcome measures were collected by offsite, treatment-masked research outcome assessors via telephone, clinical research coordinators, and an interactive voice response system (20, 21). The research outcome assessors administered the 17-item Hamilton Rating Scale of Depression (HRSD17) and the clinician-rated 30-item Inventory of Depressive Symptomatology (IDS-C30) (22–24) both at baseline and exit from each acute treatment level and every 3 months during the follow-up phase. Baseline HRSD17 ratings were used to ascribe anxious features (25), while Inventory of Depressive Symptomatology ratings ascribed melancholic (26) and atypical (27) features.

The clinical research coordinators at each site collected baseline sociodemographic information and self-reported psychiatric history information (personal and familial). They also administered a baseline HRSD17 to determine study eligibility and the 14-item Cumulative Illness Rating Scale (28, 29) to gauge the number, severity, and overall burden of general medical conditions based on different organ systems. The Cumulative Illness Rating Scale identified the number of 14 possible comorbid general medical conditions (categories endorsed), the average severity score of the categories endorsed (severity index), and total severity score (the sum of severity scores across the categories endorsed). The clinical research coordinators also completed the 16-item, clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16) (23, 24, 30) at each clinic visit to assess symptoms over the prior week.

Patients completed the Psychiatric Diagnostic Screening Questionnaire, which estimated the presence of 11 different concurrent axis I disorders using a threshold of ≥90% specificity for each disorder (31). Patients also completed the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) (23, 24, 30) and the Frequency, Intensity, and Burden of Side Effects Rating (17, 32) at each clinic visit. To equate HRSD17 total scores indicating no depression (score=0–7), mild depression (score=8–13), moderate depression (score=14–19), severe depression (score=20–25), and very severe depression (score=26+) with QIDS-SR16 total scores, a conversion table (30) was used to provide equivalent QIDS-SR16 ratings (no depression: score=0–5; mild: score=6–10; moderate: score=11–15; severe: score=16–20; very severe: score=21+).

The interactive voice response system collected measures of functioning and quality of life at baseline, 6 weeks, and exit from each acute treatment trial and at monthly intervals during the 12-month naturalistic follow-up phase. Interactive voice response ratings included physical and mental health functioning assessed with the 12-item Short Form Health Survey (SF-12), the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire, and the 5-item Work and Social Adjustment Scale. During the 12-month naturalistic follow-up phase, the interactive voice response also collected monthly QIDS-SR16 scores. The QIDS-SR16 total scores obtained through the interactive voice response system correspond very closely to both the paper-and-pencil QIDS-SR16 and the QIDS-C16(33).

The SF-12, a 12-item self-report, assesses perceived mental and physical health status. Two subscales (a physical health factor score and a mental health factor score) range from 0 to 100—higher scores indicate better functioning. The population norm for each score is 50 (34).

The Quality of Life Enjoyment and Satisfaction Questionnaire assesses several domains (e.g., physical health, feelings, work, household duties, school/house work). The 16-item short version was used. We summed the first 14 items to globally rate satisfaction, each of which is scored on a 5-point Likert scale to indicate the degree of enjoyment or satisfaction during the past week (1=very poor, 5=very good), and divided by the total possible score and multiplied by 100. Higher scores (range=0–100) represent greater life enjoyment and satisfaction.

The Work and Social Adjustment Scale, a 5-item self-report, assessed the ability to work, to manage affairs at home and socially, and to form and maintain close relationships. Each item is rated on a 0 to 8 Likert scale (0=no impairment at all, 8=very severe impairment; range=0–40). Scores between 10 and 20 are associated with significant functional impairment, while scores above 20 suggest at least moderately severe functional impairment.

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Acute Treatment

A measurement-based care treatment approach (19, 35) entailed the routine use of the QIDS-C16 (obtained by clinical research coordinators) and the Frequency, Intensity, and Burden of Side Effects Rating at each acute treatment visit to guide treatment as specified in a treatment manual (www.star-d.org). All acute treatment trials aimed to achieve symptom remission (QIDS-C16 score ≤5). Those with an adequate benefit (preferably remission) per clinician judgment after any acute treatment step could enter the 12-month naturalistic follow-up phase. All patients, however, who did not reach remission were strongly encouraged to proceed to the next treatment step.

In Level 1, participants received citalopram as their first treatment step. Level 2 and 3 treatments were randomly assigned using an equipoise stratified randomized design (16, 17, 36, 37). Level 2 provided seven possible treatments involving four switch treatments (citalopram was stopped and new treatment initiated with sustained-release bupropion, cognitive therapy, sertraline, or extended-release venlafaxine) and three augmentation options (citalopram plus bupropion, buspirone, or cognitive therapy).

The equipoise stratified randomized design (36) allowed patients to exercise choices over which switch or augmentation strategies were acceptable at Levels 2 and 3. For example, participants entering Level 2 could decline all three augmentation options, decline all four switch options, decline either or both cognitive therapy cells (i.e., cognitive therapy alone or cognitive therapy plus citalopram), or decline all treatments except for the two cognitive therapy cells (to ensure that they would receive cognitive therapy) (37). This design was used to mimic clinical practice as opposed to mandating randomization to all seven treatments (at Level 2) or all four treatments (at Level 3) (38).

Participants who accepted the switch strategies in the second step (Level 2) differed from participants who accepted the second step augmentation strategies. As a group, they tended to be more severely ill and to have experienced more side effects with citalopram (39). Only 21 of 1,439 Level 2 participants accepted randomization to all seven treatments.

For the most part, patients who had not achieved remission or were unable to tolerate their assigned second step (Level 2) treatment could subsequently enter Level 3 directly. Level 3 included two medication switch strategies (mirtazapine or nortriptyline) or two medication augmentation strategies (lithium or T3 [25 mg]). Once again, many Level 3 participants elected either the augmentation or switch strategy, although both strategies were encouraged.

Level 4 entailed only a single randomization to either tranylcypromine or extended-release venlafaxine plus mirtazapine. For most patients, the third and fourth treatment steps corresponded to Levels 3 and 4.

For those who received cognitive therapy alone or combined with citalopram in Level 2, however, the third treatment step was a special Level 2A, required only for participants who did not achieve remission or were unable to tolerate either cognitive therapy alone or cognitive therapy plus citalopram in Level 2. Level 2A, which involved random assignment to either bupropion or venlafaxine, was included to ensure that all participants who entered Level 3 had not adequately benefited from two different medication trials. Consequently, for this subgroup, the fourth treatment step (when needed) consisted of Level 3 treatments. A few patients (N=3) received cognitive therapy or cognitive therapy plus citalopram at Level 2, then Level 2A, and then Level 3, before progressing to a fifth treatment step (i.e., Level 4). We will not report on this group.

The multistep protocol allowed all eligible and consenting Level 1 enrollees to enter Level 2 (or subsequent levels) if they were not in remission or could not tolerate citalopram (or subsequent treatments). All Level 1 enrollees had to score ≥14 on the HRSD17 as rated by the clinical research coordinator. Some of these patients did not have an HRSD17 obtained by the research outcome assessor at entry into Level 1. Nevertheless, these participants could and did enter Level 2. Participants who entered Levels 2, 2A, 3, or 4 were not required to meet criteria for a major depressive episode at that time since some could have experienced significant symptom reduction that fell short of remission.

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Naturalistic Follow-Up Phase

Protocol-recommended treatment visits during the follow-up phase were to occur every 2 months. In the follow-up phase, the protocol strongly recommended that participants continue the previously effective acute treatment medication(s) at the doses used in acute treatment but that any psychotherapy, medication, or medication dose change could be used. Medication management was based on clinician judgment, typically without clinical research coordinator support.

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Definition of Outcomes

We used the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) as the primary measure to define outcomes for acute and follow-up phases because 1) QIDS-SR16 ratings were available for all participants at each acute treatment clinic visit, 2) QIDS-SR16 and HRSD17 outcomes are highly related (19, 30, 37δ2), 3) the QIDS-SR16 was not used to make treatment decisions, which minimizes the potential for clinician bias, and 4) the QIDS-SR16 scores obtained from the interactive voice response system, the main follow-up outcome measure, and the paper-and-pencil QIDS-SR16 are virtually interchangeable (33), which allows us to use a similar metric to summarize the acute and follow-up phase results. Response was defined as at least a 50% reduction from treatment step entry in QIDS-SR16 score. Remission was defined as a QIDS-SR16 score ≤5 (corresponding to an HRSD17 score of ≤7) (33, 41). Relapse was declared when the QIDS-SR16 score collected by the interactive voice response system during the follow-up phase was ≥11 (corresponding to an HRSD17 ≥14) (30). Time to remission for those who remitted was defined as the time (in weeks) from initiating a treatment at the relevant treatment step to the first occasion at which the QIDS-SR16 score was ≤5.

Patients were defined as treatment intolerant if they left the relevant acute treatment step prior to 4 weeks of treatment for any reason, or if the reason for leaving was not obtained (which was the case for the vast majority of patients), or if they left the step after 4 weeks and the treatment step exit form indicated intolerance.

For this report, we created successive subsets of the study sample, including those participants who entered each treatment step, and grouped participants by the number of treatment steps they had taken. Since a patient could have entered one or more of the several treatment steps, these subsets are not mutually exclusive. We describe the clinical and demographic features of each subset to characterize those patients who entered each treatment step. We then report the overall acute symptom outcomes (e.g., remission rates) associated with each acute treatment step and describe the longer-term outcomes of the 12-month naturalistic follow-up phase for each group. Finally, we assess the relationship between remission at follow-up entry and the likelihood of relapse following each treatment step.

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Analyses

Summary statistics are presented as means and standard deviations for continuous variables and percentages for discrete variables. Analysis of variance was used to compare QIDS-SR16 scores at entry to follow-up across treatment steps. Chi-square tests were used to compare the percentage of patients in remission at entry into the follow-up phase across treatment steps as well as relapse rates in follow-up across treatment steps. Kaplan-Meier curves and log-rank tests were used to compare the cumulative proportion not experiencing relapse across treatment steps, overall, and stratified by remission status at entry to follow-up. For significant findings, post hoc tests were conducted by making pairwise comparisons of treatment steps with Bonferroni corrections.

The overall acute treatment findings based on the protocol-defined level of treatment are reported elsewhere (19, 37–40, 42). The remission rate per QIDS-SR16 score was 32.9% for the evaluable Level 1 patient group (19). For the intent-to-treat group, the remission rates per QIDS-SR16 score were 30.6% for Level 2, 13.6% for Level 3, and 14.7% for Level 4.

For this report, we combined the patients who enrolled in the various protocol-defined treatment levels into groups defined by the number of prior treatment steps (Figure 1). Overall, 4,041 participants were enrolled in the STAR*D study. All participants had to have scores ≥14 on the HRSD17 as obtained by the clinical research coordinator at study entry. We excluded 370 of these participants because they did not return for a postbaseline assessment in Level 1, leaving 3,671 participants. (Note: this sample includes the 2,876 reported in Trivedi et al. [19] plus those patients whose HRSD17 score per research outcome assessor was <14 at entry and who had at least one postbaseline visit. These latter participants were excluded from Trivedi et al.) Overall, 1,439 participants entered the second step, and 390 had a third treatment step, either Level 3 treatment (N=359) or Level 2A (N=31). Only 123 participants had a fourth treatment step (105 of whom entered Level 4, and 18 of whom entered Level 3).

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Acute Treatment Outcomes Associated With the Various Acute Treatment Steps

Table 1 and Table 2 describe the demographic and clinical features of the successive subsets of participants who entered treatment steps 1, 2, 3, and 4. As can be seen, participants who required more treatment steps tended to have greater depressive illness burden and more concurrent psychiatric and general medical disorders. Table 3 shows the status at entry and exit for each acute treatment step. The earlier treatment steps were associated with higher remission rates. For those who achieved remission at each step, the times to remission were 5.4 to 7.4 weeks across the four treatment steps. In addition, rates of intolerance seemed to be greater in the later steps. To determine whether remission rates might differ depending on prior treatment history before study entry, we compared the remission rates in the first and second treatment steps between those who had and had not received treatment for their current major depressive episode before study entry (we did not obtain prior treatment history other than for the current episode). For step 1, those not previously treated for their current episode (N=614) had a 42.7% remission rate compared with a 35.6% remission rate in those who had been treated (N=3,057). For the second step, the remission rates were comparable for those not treated (N=185) and those who were treated (N=1,254) for their current major depressive episode (remission rates of 30.7% and 30.3%, respectively).

Table 4 shows the overall entry and outcome values for participants in each treatment step and by the type of treatment used in each step. Of note, those in Level 2A (having received cognitive therapy alone or combined with citalopram at Level 2) had very modest remission rates with venlafaxine or bupropion. Note that one cannot compare the remission rates with augmentation versus switch at either steps 2 or 3, since these are not randomized samples (i.e., largely different patient groups received switch or augmentation).

The cumulative remission rate can be estimated by assuming that 100 patients begin citalopram treatment. Overall, 36.8 will achieve remission in step 1, leaving 63 to proceed to the next step. In step 2, 30.6% (N=19) will remit (.306×63 = 19). In the third step, 13.7% or N=6 will remit (.137 x [100–37-19]). In the fourth step, 13.0% or N=5 will remit. The theoretical cumulative remission rate is 67% (37+19+6+5). Note that this estimate assumes no dropouts, and it assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol.

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Longer-Term Outcomes Associated With Each Treatment Step

Table 5 shows that at follow-up entry, participants from the later treatment steps were less likely to be in remission (p<0.0001), and they had higher QIDS-SR16 scores (p<0.0001) at entry into follow-up. Relapse rates were higher for those who entered follow-up after more treatment steps (p<0.0001).

To further explore these follow-up findings, we evaluated the probability of relapse (QIDS-SR16 score obtained by interactive voice response ≥11) using survival analyses (Figure 2). Overall, relapse rates were higher for those who entered follow-up after more treatment steps. Recall that participants could enter the follow-up phase if they reached remission or had adequately benefited but had not reached remission. In this context, the higher relapse rates found in patients with more acute treatment steps could be due to the greater nonremission rates among those who required more treatment steps. To address this issue, we divided participants into those who had and had not reached remission at follow-up entry (Figure 3 and Figure 4). Once again, for participants who either had or had not achieved remission at follow-up entry, we found higher relapse rates among those who required more treatment steps.

This report summarizes the acute and longer-term STAR*D trial findings based on the number of acute treatment steps needed to achieve an adequate benefit as defined by clinicians using a measurement-based care approach (19) in a large, representative group of depressed adult outpatients with nonpsychotic major depressive disorder. The acute remission rates (per QIDS-SR16 score) were substantial for the first two treatment steps (which correspond to the first two protocol levels): 36.8% for step 1 and 30.6% for step 2. The latter steps (3 and 4) were each associated with lower QIDS-SR16 remission rates (13.7% and 13.0%, respectively). Theoretically, had all the patients stayed in treatment and had those who exited the study had remission rates similar to those who stayed in protocol treatments, the overall cumulative remission rate would approach 70% after four steps (if needed). The time to remission in those who did remit seems to have been slightly greater for those who required more treatment steps. These prospective data provide a benchmark (at least with the treatments studied) for practitioners.

In addition, the acute treatment step findings highlight the importance of retaining patients in treatment. Despite the availability of the clinical research coordinator, free treatment, and diligent care, the percent of patients exiting after each step was clinically meaningful (20.9% after step 1, 29.7% after step 2, 42.3% after step 3).

What might explain the substantial numbers of patients who did not achieve remission in acute treatment? There may be some kinds of depression for which our treatments (at least the ones under study) cannot produce remission (independent of the chronicity and comorbid conditions that were present). Conversely, the presence of comorbid general medical or psychiatric disorders may be associated with or induce biological changes that render our otherwise useful treatments ineffective. Perhaps these patients would have benefited from earlier application of different treatment approaches (e.g., ECT, vagus nerve stimulation, repeated transcranial magnetic stimulation, augmentation with atypical antipsychotic medication, etc.). Alternatively, perhaps those with more chronic depression, had they been treated earlier in the course of their illness (i.e., before chronicity had developed), might have remitted with the treatments used in this study (43). The present data cannot determine which of these explanations is valid. These data do suggest that clinicians need to attend especially to those with more chronic depression, combined with more concurrent general medical and psychiatric disorders.

The follow-up results revealed 1) remission at entry into follow-up was associated with a better prognosis than was simple improvement without remission, 2) relapse rates were higher for participants who entered follow-up after more versus fewer acute treatment steps regardless of remission status at follow-up entry, and 3) the mean time to relapse for those who did relapse was shorter for those who required two or more steps. Whether a particular treatment in each treatment step is associated with a different longer-term outcome and whether baseline clinical features predict longer-term outcomes will be reported subsequently.

The clinical implications of these findings are profound. Remission is the accepted goal of acute treatment (6, 7, 16, 17, 44ε7) because remission is associated with better day-to-day function (1) and a better prognosis (2–5). These conclusions, however, are based largely on depressed patients who have responded or remitted after only one treatment step. The present findings indicate that remission is associated with a better prognosis even if remission is reached after several treatments. In addition, the chance of attaining remission was lower when more acute treatments were needed (at least with the treatments and treatment sequences used in this study). Thus, in terms of acute treatment, clinicians must weigh the benefit already achieved with the initial (or subsequent) acute treatments against their estimates of the probability of reaching remission and the potential side-effect burden associated with undertaking the next treatment step for each patient. Specifically, clinicians (with patients) must decide when remission (given our current treatments) is sufficiently unlikely that subsequent alternative treatments should be considered.

Second, the present results indicate that even following antidepressant response or remission, diligent follow-up treatment is called for, particularly in the first several months and especially for patients who enter follow-up treatment not in remission, since the risk of relapse in this time period is high, especially for those who have received three or four acute treatment steps.

These results also have provocative theoretical implications. The findings are suggestive that major depressive disorder is biologically heterogeneous such that different treatments differ in the likelihood of achieving remission in different patients. However, without a placebo control at each step and without substantial differences in remission rates among treatments in the same step, such a notion remains to be fully established. It does appear that those with a more prolonged or chronic illness course (i.e., overall length of illness and length of the current episode), and those with more concurrent general medical and psychiatric comorbidity may be less likely to achieve remission with acute treatment. The present results serve to highlight the need for more effective short- and longer-term treatments to both achieve and sustain remission in more depressed patients sooner in the treatment sequence.

Study limitations in this report include reliance on a self-report (the QIDS-SR16) as the primary outcome, although the high correlation between the QIDS-SR16 and the HRSD17(19, 33, 37, 39, 41) mitigates this concern. Second, neither clinicians nor participants were blind to the treatments or to the results achieved with each treatment step. On the one hand, this open treatment design likely encouraged vigorous dosing of medications, enhanced safety, and mimicked practice. On the other hand, while the doses in this study do represent high quality of care, they likely exceed the doses commonly used in practice. Finally, a placebo control was not used in any step. Consequently, we cannot rule out the possibility that the passage of time alone might not have produced similar results.

The generalizability of our findings can also be questioned. The broadly representative study group provides results for a broadly defined cohort of patients. Better (or worse) outcomes might be achieved with particular subgroups (e.g., less chronically ill, only insured and employed patients, etc.). Furthermore, these findings were obtained in the context of a series of randomized controlled trials that required participants to provide written informed consent at entry into each acute treatment step and into the follow-up phase, which might limit generalizability.

Many participants did choose to exit the study rather than electing to take the next protocol treatment step. Whether these patients would have had similar results had they remained in the study is unknown, although most of them were in need of additional treatment because most who exited were not in remission (approximately 80%) at the time of study exit. Third, despite the 12–14 week duration of each acute treatment step, one might also argue that at least some patients would have achieved remission had they been treated longer. Such patients, it can be argued, should not have moved to the next step. That is, even longer acute trial durations than used in this study might have increased the remission rates associated with each step. We will subsequently report on the follow-up outcomes for those patients who entered the follow-up phase without having remitted to determine what proportion ultimately remitted. Finally, high quality of care was delivered (measurement-based care) (19) with additional support from the clinical research coordinator. Consequently, the outcomes in this report may exceed those that are presently obtained in daily practice wherein neither symptoms nor side effects are consistently measured and wherein practitioners vary greatly in the timing and level of dosing.

After two treatment steps, it appears that over 50% of patients will achieve remission if they stay in treatment (i.e., 36.8% step 1 plus 30.6% of the remaining 63.2% of patients). Thereafter, the chances of subsequent remission are much lower. The theoretical cumulative remission rate after four acute treatment steps was 67%. Greater illness burden (i.e., depression chronicity, psychiatric or general medical comorbidity) was characteristic of those who required more treatment steps. At entry into the follow-up phase, remission, as opposed to improvement without remission, was associated with a better prognosis. Unfortunately, poorer longer-term outcomes were found with participants who required more treatment steps independent of whether or not they were in remission at entry into the follow-up phase. Studies to identify the best multistep treatment sequence for individual patients are needed, as is the development of more broadly effective treatments.

+Received June 15, 2006; revision received Aug. 2, 2006; accepted Aug. 7, 2006. From the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the University of Pittsburgh Department of Epidemiology and Department of Psychiatry, Pittsburgh; the Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York; the National Institute of Mental Health, Bethesda, Md.; VA Cooperative Studies Program and Stanford University, Palo Alto, Calif.; and the Sam and Rose Stein Institute for Research on Aging, University of California San Diego School of Medicine, San Diego. Address correspondence and reprint requests to Dr. Rush, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9086; john.rush@utsouthwestern.edu (e-mail).Dr. Rush has served as an advisor, consultant, or speaker for or received research support from Advanced Neuromodulation Systems, Inc.; Best Practice Project Management, Inc.; Bristol-Myers Squibb Company; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals, Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems, Inc.; Jazz Pharmaceuticals; Merck & Co., Inc.; the National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Personality Disorder Research Corp.; Pfizer Inc.; the Robert Wood Johnson Foundation; the Stanley Medical Research Institute; the Urban Institute; and Wyeth-Ayerst Laboratories Inc. He has equity holdings in Pfizer Inc and receives royalty/patent income from Guilford Publications and Healthcare Technology Systems, Inc. Dr. Trivedi has served as an advisor, consultant, or speaker for or received research support from Abbott Laboratories, Inc.; Akzo (Organon Pharmaceuticals Inc.); Bayer; Bristol-Myers Squibb Company; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica; Johnson & Johnson PRD; Meade Johnson; the National Institute of Mental Health; the National Alliance for Research in Schizophrenia and Depression; Novartis; Parke-Davis Pharmaceuticals, Inc.; Pfizer Inc; Pharmacia & Upjohn; Predix Pharmaceuticals; Sepracor; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. Dr. Wisniewski has received research support from the National Institute of Mental Health and served as an advisor/consultant for Cyberonics, Inc. Dr. Nierenberg has served as an advisor, consultant, or speaker for or received research support from Bristol-Myers Squibb Company; Cederroth; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals Inc.; Genaissance; GlaxoSmithKline; Innapharma; Janssen Pharmaceutica; Lichtwer Pharma; the National Institute of Mental Health; the National Alliance for Research in Schizophrenia and Depression; Neuronetics; Organon, Inc.; Pfizer Inc; Sepracor; Shire; Stanley Foundation; and Wyeth-Ayerst Laboratories. Dr. Stewart has served as an advisor, consultant, or speaker for or received research support from Eli Lilly & Company; GlaxoSmithKline; Organon USA Inc.; Shire; and Somerset. Dr. Warden has received research support from the National Institute of Mental Health and has equity holdings in Bristol-Myers Squibb Company and Pfizer, Inc. Dr. Thase has served as an advisor, consultant, or speaker for AstraZeneca; Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Laboratories, Inc.; GlaxoSmithKline; Janssen Pharmaceutica; Eli Lilly & Company; Novartis; Organon, Inc.; Pfizer Pharmaceutical; Sanofi Aventis; Sepracor, Inc.; Shire US Inc.; and Wyeth Pharmaceuticals. Dr. Lavori has served as an advisor, consultant, or speaker for or received research support from Bristol-Myers Squibb Company; Celera Diagnostics Inc; Cyberonics, Inc.; the Department of Veterans Affairs; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Leaf Cabrezer Hyman and Bernstein; the National Institutes of Health; and Neuronetics, Inc. Dr. McGrath has served as an advisor, consultant, or speaker for or received research support from Eli Lilly & Company; GlaxoSmithKline; Lipha Pharmaceuticals; the National Institute of Mental Health; the National Institute on Alcohol Abuse and Alcoholism; New York State Department of Mental Hygiene; Organon, Inc.; Research Foundation for Mental Hygiene (New York State); and Somerset Pharmaceuticals. Dr. Rosenbaum has served as an advisor, consultant, or speaker for or received research support from Astra-Zeneca; Boehringer-Ingelheim; Bristol-Myers Squibb Company; Cephalon; Compellis; Cyberonics; EPIX; Forest; GlaxoSmithKline; Janssen; Lilly; MedAvante; Neuronetics; Novartis; Orexigen; Organon; Pfizer, Inc; Roche Diagnostics; Sanofi; Schwartz; Somaxon; Somerset; Sepracor; Shire; Supernus; and Wyeth. He has equity holdings in Compellis, Medavante, and Somaxon. Dr. Sackeim has served as an advisor, consultant, or speaker for or received research support from Cyberonics, Inc.; Eli Lilly & Company; Magstim Ltd.; MECTA Corporation; Neurocrine Biosciences Inc.; Neuronetics Inc.; NeuroPace Inc.; and Pfizer Inc. Dr. Kupfer has served as an advisor, consultant, or speaker for or received research support from Amersham; the Commonwealth of Pennsylvania; Corcept Corporated; Eli Lilly & Company; F. Hoffmann-La Roche Ltd.; Forest Pharmaceuticals; Lundbeck; the National Institute of Mental Health; Novartis; Pfizer, Inc; Servier Amerique; and Solvay/Wyeth. He has equity holdings in Body Media and Med Avante and receives royalty income from Oxford University Press. Dr. Fava has served as an advisor, consultant, or speaker for or received research support from Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Bayer AG; Biovail Pharmaceuticals, Inc.; BrainCells, Inc.; Bristol-Myers Squibb Company; Cephalon; Compellis; Cypress Pharmaceuticals; Dov Pharmaceuticals; Eli Lilly & Company; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Grunenthal GmBH; J & J Pharmaceuticals; Janssen Pharmaceutica; Jazz Pharmaceuticals; Knoll Pharmaceutical Company; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck; MedAvante, Inc.; Novartis; Nutrition 21; Organon Inc.; PamLab, LLC; Pfizer, Inc; PharmaStar; Pharmavite; Roche; Sanofi/Synthelabo; Sepracor; Solvay Pharmaceuticals, Inc.; Somerset Pharmaceuticals; and Wyeth-Ayerst Laboratories. He has equity holdings in Compellis and MedAvante. Dr. Niederehe, Dr. Lebowitz, and Mr. Luther report no competing interests.This project was funded by the National Institute of Mental Health under contract N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (A.J. Rush, principal investigator). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, King Pharmaceuticals, Organon, Pfizer, and Wyeth provided medications at no cost for this trial.Additional information about the STAR*D study accompanies the online version of this article.

1.Miller IW, Keitner GI, Schatzberg AF, Klein DN, Thase ME, Rush AJ, Markowitz JC, Schlager DS, Kornstein SG, Davis SM, Harrison WM, Keller MB: The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry 1998; 59:608–619
 
2.Judd LL: The clinical course of unipolar major depressive disorders. Arch Gen Psychiatry 1997; 54:989–991
 
3.Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A: Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180
 
4.Rush AJ, Trivedi MH: Treating depression to remission. Psychiatr Ann 1995; 25704–25705, 25709
 
5.Van Londen L, Molenaar RP, Goekoop JG, Zwinderman AH, Rooijmans HG: Three- to 5-year prospective follow-up of outcome in major depression. Psychol Med 1998; 28:731–735
 
6.Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, Ninan PT, Thase ME, Gelenberg AJ, Kupfer DJ, Regier DA, Rosenbaum JF, Ray O, Schatzberg AF: Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder. Neuropsychopharmacology 2006; advance online publication, 21. June 2006; doi:10.1038/sj.npp. 1301131
 
7.Crismon ML, Trivedi M, Pigott TA, Rush AJ, Hirschfeld RM, Kahn DA, DeBattista C, Nelson JC, Nierenberg AA, Sackeim HA, Thase ME: The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142–156
 
8.Adli M, Bauer M, Rush AJ: Algorithms and collaborative-care systems for depression: are they effective and why? A systematic review. Biol Psychiatry 2006; 59:1029–1038
 
9.Fava M: Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649–659
 
10.Thase ME, Rush AJ: When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58(suppl 13):23–29
 
11.Sackeim HA: The definition and meaning of treatment-resistant depression. J Clin Psychiatry 2001; 62(suppl 16):10–17
 
12.Fava M, Davidson KG: Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996; 19:179–200
 
13.Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz J: Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999; 9(1–2):83–91
 
14.Barbee JG, Jamhour NJ: Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002; 63737–63741
 
15.Barbee JG, Conrad EJ, Jamhour NJ: The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 2004; 65:975–981
 
16.Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ: Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am 2003; 26:457–494
 
17.Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G: Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials 2004; 25:119–142
 
18.Trivedi MH, Rush AJ, Gaynes BN, Stewart JW, Wisniewski SR, Warden D, Ritz L, Luther J, Stegman D, DeVeaugh-Geiss J, Howland RH: Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR*D measurement-based care. Neuropsychopharmacology (in press)
 
19.Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M: Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28–40
 
20.Mundt JC: Interactive voice response systems in clinical research and treatment. Psychiatr Serv 1997; 48611–48612
 
21.Kobak KA, Greist JH, Jefferson JW, Mundt JC, Katzelnick DJ: Computerized assessment of depression and anxiety over the telephone using interactive voice response. MD Comput 1999; 16:63–68
 
22.Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH: The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26:477–486
 
23.Rush AJ, Carmody TJ, Reimitz PE: The Inventory of Depressive Symptomatology (IDS): clinician (IDS-C) and self-report (IDS-SR) ratings of depressive symptoms. Int J Methods Psychiatr Res 2000; 945–959
 
24.Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, Crismon ML, Shores-Wilson K, Toprac MG, Dennehy EB, Witte B, Kashner TM: The Inventory of Depressive Symptomatology, clinician rating (IDS-C) and self-report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, clinician rating (QIDS-C) and self-report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med 2004; 34:73–82
 
25.Fava M, Alpert JE, Carmin CN, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K, Morgan D, Schwartz T, Balasubramani GK, Rush AJ: Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D. Psychol Med 2004; 34:1299–1308
 
26.Khan AY, Carrithers J, Preskorn SH, Wisniewski SR, Lear R, Rush AJ, Stegman D, Kelley C, Kreiner K, Nierenberg AA, Fava M: Clinical and demographic factors associated with DSM-IV melancholic depression. Ann Clin Psychiatry 2006; 18:91–98
 
27.Novick JS, Stewart JW, Wisniewski SR, Cook IA, Manev R, Nierenberg AA, Rosenbaum JF, Shores-Wilson K, Balasubramani GK, Biggs MM, Zisook S, Rush AJ: Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STAR*D. J Clin Psychiatry 2005; 66:1002–1011
 
28.Linn BS, Linn MW, Gurel L: Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 16:622–626
 
29.Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF III: Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:237–248
 
30.Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB: 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; 54:573–583 (erratum, p 585)
 
31.Rush AJ, Zimmerman M, Wisniewski SR, Fava M, Hollon SD, Warden D, Biggs MM, Shores-Wilson K, Shelton RC, Luther JF, Thomas B, Trivedi MH: Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features. J Affect Disord 2005; 87:43–55
 
32.Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA, for the STAR*D Investigators: Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 2006; 1271–1279
 
33.Rush AJ, Bernstein IH, Trivedi MH, Carmody TJ, Wisniewski S, Mundt JC, Shores-Wilson K, Biggs MM, Woo A, Nierenberg AA, Fava M: An evaluation of the Quick Inventory of Depressive Symptomatology and the Hamilton Rating Scale for Depression: a Sequenced Treatment Alternatives to Relieve Depression trial report. Biol Psychiatry 2006; 59:493–501
 
34.Gandek B, Ware JE, Aaronson NK, Apolone G, Bjorner JB, Brazier JE, Bullinger M, Kaasa S, Leplege A, Prieto L, Sullivan M: Cross-validation of item selection and scoring for the SF-12 Health Survey in nine countries: results from the IQOLA project. J Clin Epidemiol 1998; 51:1171–1178
 
35.Rush AJ: Strategies and tactics in the management of maintenance treatment for depressed patients. J Clin Psychiatry 1999; 60(suppl 14):21–26
 
36.Lavori PW, Rush AJ, Wisniewski SR, Alpert J, Fava M, Kupfer DJ, Nierenberg A, Quitkin FM, Sackeim HA, Thase ME, Trivedi M: Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 2001; 50:792–801
 
37.Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M: Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242
 
38.Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH: A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163:1161–1172
 
39.Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ: Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252
 
40.McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ, for the STAR*D Trial Team: Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medications trials for depression: a STAR*D report. Am J Psychiatry 2006; 163:1531–1541
 
41.Rush AJ, Trivedi MH, Carmody TJ, Ibrahim HM, Markowitz JC, Keitner GI, Kornstein SG, Arnow B, Klein DN, Manber R, Dunner DL, Gelenberg AJ, Kocsis JH, Nemeroff CB, Fawcett J, Thase ME, Russell JM, Jody DN, Borian FE, Keller MB: Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients. Neuropsychopharmacology 2005; 30:405–416
 
42.Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ: A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163:1519–1530
 
43.Post RM: Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms? Epilepsy Res 2002; 50(1–2):203–219
 
44.Rush AJ, Ryan ND: Current and emerging therapeutics for depression, in Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Davis KL, Charney D, Coyle JT, Nemeroff C. Philadelphia, Lippincott Williams & Wilkins, 2002, pp 1081–1095
 
45.Altshuler LL, Cohen LS, Moline ML, Kahn DA, Carpenter D, Docherty JP: The Expert Consensus Guideline Series: treatment of depression in women. Postgrad Med 2001; March, pp 1–107
 
46.American Academy of Child and Adolescent Psychiatry: Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 1998; 37(suppl 10):63S–83S
 
47.American Psychiatric Association: Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000; 157(Apr suppl):1–45
 
48.Anderson IM, Nutt DJ, Deakin JFW: Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 1993 British Association for Psychopharmacology guidelines. J Psychopharmacol 2000; 14:3–20
 
49.Ballenger JC: Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psychiatry 1999; 60(suppl 22):29–34
 
50.Bauer MS, Whybrow PC, Angst F, Versiani M, Moller HJ: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry 2002; 369–386
 
51.Bauer MS, Whybrow PC, Angst F, Versiani M, Moller HJ: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: Acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 2002; 35–43
 
52.Canadian Psychiatric Association Network for Mood and Anxiety Treatments: Clinical Guidelines for the Treatment of Depressive Disorders. Can J Psychiatry 2001; 46(suppl 1): 5S–90S
 
53.Depression Guideline Panel: Clinical Practice Guideline, number 5: Depression in Primary Care: Volume 2. Treatment of Major Depression. Rockville, Md, US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993
 
54.Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F, Endicott J, Froom J, Goldstein M, Gorman JM, Marek RG, Maurer TA, Meyer R, Phillips K, Ross J, Schwenk TL, Sharfstein SS, Thase ME, Wyatt RJ: The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277:333–340
 
55.Reesal RT, Lam RW, CANMAT Depression Work Group: Clinical guidelines for the treatment of depressive disorders, II: principles of management. Can J Psychiatry 2001; 46(suppl 1):21S–28S
 
56.Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Trivedi MH, Suppes T, Miller AL, Biggs MM, Shores-Wilson K, Witte BP, Shon SP, Rago WV, Altshuler KZ: Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003; 64:357–369
 
57.Trivedi MH, DeBattista C, Fawcett J, Nelson C, Osser DN, Stein D, Jobson K: Developing treatment algorithms for unipolar depression in cyberspace: International Psychopharmacology Algorithm Project (IPAP). Psychopharmacol Bull 1998; 34355–34359
 
 
Figure 1. Overall STAR*D Participant Flow

aNine participants entered step 2 without a step 1 postbaseline visit being recorded.

bOnly possible for participants who received cognitive therapy alone or cognitive therapy plus citalopram at step 2.

 
Figure 2. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for All STAR*D Participantsa

aSignificant overall difference among steps (χ2=69, df=3, p<0.0001). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2 and steps 1 and 3.

 
Figure 3. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for STAR*D Participants Who Entered Follow-Up Phase in Remissiona

aSignificant overall difference among steps (χ2=23, df=3, p<0.0001). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2.

 
Figure 4. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for STAR*D Participants Who Entered Follow-Up Phase Not in Remissiona

aSignificant overall difference among steps (χ2=13, df=3, p<0.005). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2.

Figure 1. Overall STAR*D Participant Flow

aNine participants entered step 2 without a step 1 postbaseline visit being recorded.

bOnly possible for participants who received cognitive therapy alone or cognitive therapy plus citalopram at step 2.

Figure 2. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for All STAR*D Participantsa

aSignificant overall difference among steps (χ2=69, df=3, p<0.0001). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2 and steps 1 and 3.

Figure 3. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for STAR*D Participants Who Entered Follow-Up Phase in Remissiona

aSignificant overall difference among steps (χ2=23, df=3, p<0.0001). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2.

Figure 4. Relapse During Follow-Up Phase by Number of Acute Treatment Steps for STAR*D Participants Who Entered Follow-Up Phase Not in Remissiona

aSignificant overall difference among steps (χ2=13, df=3, p<0.005). Significant post-hoc comparisons with Bonferroni corrections revealed significant differences between steps 1 and 2.

+

References

1.Miller IW, Keitner GI, Schatzberg AF, Klein DN, Thase ME, Rush AJ, Markowitz JC, Schlager DS, Kornstein SG, Davis SM, Harrison WM, Keller MB: The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry 1998; 59:608–619
 
2.Judd LL: The clinical course of unipolar major depressive disorders. Arch Gen Psychiatry 1997; 54:989–991
 
3.Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A: Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180
 
4.Rush AJ, Trivedi MH: Treating depression to remission. Psychiatr Ann 1995; 25704–25705, 25709
 
5.Van Londen L, Molenaar RP, Goekoop JG, Zwinderman AH, Rooijmans HG: Three- to 5-year prospective follow-up of outcome in major depression. Psychol Med 1998; 28:731–735
 
6.Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, Ninan PT, Thase ME, Gelenberg AJ, Kupfer DJ, Regier DA, Rosenbaum JF, Ray O, Schatzberg AF: Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder. Neuropsychopharmacology 2006; advance online publication, 21. June 2006; doi:10.1038/sj.npp. 1301131
 
7.Crismon ML, Trivedi M, Pigott TA, Rush AJ, Hirschfeld RM, Kahn DA, DeBattista C, Nelson JC, Nierenberg AA, Sackeim HA, Thase ME: The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142–156
 
8.Adli M, Bauer M, Rush AJ: Algorithms and collaborative-care systems for depression: are they effective and why? A systematic review. Biol Psychiatry 2006; 59:1029–1038
 
9.Fava M: Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649–659
 
10.Thase ME, Rush AJ: When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58(suppl 13):23–29
 
11.Sackeim HA: The definition and meaning of treatment-resistant depression. J Clin Psychiatry 2001; 62(suppl 16):10–17
 
12.Fava M, Davidson KG: Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996; 19:179–200
 
13.Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz J: Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999; 9(1–2):83–91
 
14.Barbee JG, Jamhour NJ: Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002; 63737–63741
 
15.Barbee JG, Conrad EJ, Jamhour NJ: The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 2004; 65:975–981
 
16.Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ: Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am 2003; 26:457–494
 
17.Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G: Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials 2004; 25:119–142
 
18.Trivedi MH, Rush AJ, Gaynes BN, Stewart JW, Wisniewski SR, Warden D, Ritz L, Luther J, Stegman D, DeVeaugh-Geiss J, Howland RH: Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR*D measurement-based care. Neuropsychopharmacology (in press)
 
19.Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M: Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28–40
 
20.Mundt JC: Interactive voice response systems in clinical research and treatment. Psychiatr Serv 1997; 48611–48612
 
21.Kobak KA, Greist JH, Jefferson JW, Mundt JC, Katzelnick DJ: Computerized assessment of depression and anxiety over the telephone using interactive voice response. MD Comput 1999; 16:63–68
 
22.Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH: The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26:477–486
 
23.Rush AJ, Carmody TJ, Reimitz PE: The Inventory of Depressive Symptomatology (IDS): clinician (IDS-C) and self-report (IDS-SR) ratings of depressive symptoms. Int J Methods Psychiatr Res 2000; 945–959
 
24.Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, Crismon ML, Shores-Wilson K, Toprac MG, Dennehy EB, Witte B, Kashner TM: The Inventory of Depressive Symptomatology, clinician rating (IDS-C) and self-report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, clinician rating (QIDS-C) and self-report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med 2004; 34:73–82
 
25.Fava M, Alpert JE, Carmin CN, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K, Morgan D, Schwartz T, Balasubramani GK, Rush AJ: Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D. Psychol Med 2004; 34:1299–1308
 
26.Khan AY, Carrithers J, Preskorn SH, Wisniewski SR, Lear R, Rush AJ, Stegman D, Kelley C, Kreiner K, Nierenberg AA, Fava M: Clinical and demographic factors associated with DSM-IV melancholic depression. Ann Clin Psychiatry 2006; 18:91–98
 
27.Novick JS, Stewart JW, Wisniewski SR, Cook IA, Manev R, Nierenberg AA, Rosenbaum JF, Shores-Wilson K, Balasubramani GK, Biggs MM, Zisook S, Rush AJ: Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STAR*D. J Clin Psychiatry 2005; 66:1002–1011
 
28.Linn BS, Linn MW, Gurel L: Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 16:622–626
 
29.Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF III: Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:237–248
 
30.Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB: 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; 54:573–583 (erratum, p 585)
 
31.Rush AJ, Zimmerman M, Wisniewski SR, Fava M, Hollon SD, Warden D, Biggs MM, Shores-Wilson K, Shelton RC, Luther JF, Thomas B, Trivedi MH: Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features. J Affect Disord 2005; 87:43–55
 
32.Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA, for the STAR*D Investigators: Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 2006; 1271–1279
 
33.Rush AJ, Bernstein IH, Trivedi MH, Carmody TJ, Wisniewski S, Mundt JC, Shores-Wilson K, Biggs MM, Woo A, Nierenberg AA, Fava M: An evaluation of the Quick Inventory of Depressive Symptomatology and the Hamilton Rating Scale for Depression: a Sequenced Treatment Alternatives to Relieve Depression trial report. Biol Psychiatry 2006; 59:493–501
 
34.Gandek B, Ware JE, Aaronson NK, Apolone G, Bjorner JB, Brazier JE, Bullinger M, Kaasa S, Leplege A, Prieto L, Sullivan M: Cross-validation of item selection and scoring for the SF-12 Health Survey in nine countries: results from the IQOLA project. J Clin Epidemiol 1998; 51:1171–1178
 
35.Rush AJ: Strategies and tactics in the management of maintenance treatment for depressed patients. J Clin Psychiatry 1999; 60(suppl 14):21–26
 
36.Lavori PW, Rush AJ, Wisniewski SR, Alpert J, Fava M, Kupfer DJ, Nierenberg A, Quitkin FM, Sackeim HA, Thase ME, Trivedi M: Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 2001; 50:792–801
 
37.Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M: Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242
 
38.Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH: A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163:1161–1172
 
39.Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ: Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252
 
40.McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ, for the STAR*D Trial Team: Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medications trials for depression: a STAR*D report. Am J Psychiatry 2006; 163:1531–1541
 
41.Rush AJ, Trivedi MH, Carmody TJ, Ibrahim HM, Markowitz JC, Keitner GI, Kornstein SG, Arnow B, Klein DN, Manber R, Dunner DL, Gelenberg AJ, Kocsis JH, Nemeroff CB, Fawcett J, Thase ME, Russell JM, Jody DN, Borian FE, Keller MB: Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients. Neuropsychopharmacology 2005; 30:405–416
 
42.Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ: A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163:1519–1530
 
43.Post RM: Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms? Epilepsy Res 2002; 50(1–2):203–219
 
44.Rush AJ, Ryan ND: Current and emerging therapeutics for depression, in Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Davis KL, Charney D, Coyle JT, Nemeroff C. Philadelphia, Lippincott Williams & Wilkins, 2002, pp 1081–1095
 
45.Altshuler LL, Cohen LS, Moline ML, Kahn DA, Carpenter D, Docherty JP: The Expert Consensus Guideline Series: treatment of depression in women. Postgrad Med 2001; March, pp 1–107
 
46.American Academy of Child and Adolescent Psychiatry: Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 1998; 37(suppl 10):63S–83S
 
47.American Psychiatric Association: Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000; 157(Apr suppl):1–45
 
48.Anderson IM, Nutt DJ, Deakin JFW: Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 1993 British Association for Psychopharmacology guidelines. J Psychopharmacol 2000; 14:3–20
 
49.Ballenger JC: Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psychiatry 1999; 60(suppl 22):29–34
 
50.Bauer MS, Whybrow PC, Angst F, Versiani M, Moller HJ: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry 2002; 369–386
 
51.Bauer MS, Whybrow PC, Angst F, Versiani M, Moller HJ: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: Acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 2002; 35–43
 
52.Canadian Psychiatric Association Network for Mood and Anxiety Treatments: Clinical Guidelines for the Treatment of Depressive Disorders. Can J Psychiatry 2001; 46(suppl 1): 5S–90S
 
53.Depression Guideline Panel: Clinical Practice Guideline, number 5: Depression in Primary Care: Volume 2. Treatment of Major Depression. Rockville, Md, US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993
 
54.Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F, Endicott J, Froom J, Goldstein M, Gorman JM, Marek RG, Maurer TA, Meyer R, Phillips K, Ross J, Schwenk TL, Sharfstein SS, Thase ME, Wyatt RJ: The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277:333–340
 
55.Reesal RT, Lam RW, CANMAT Depression Work Group: Clinical guidelines for the treatment of depressive disorders, II: principles of management. Can J Psychiatry 2001; 46(suppl 1):21S–28S
 
56.Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Trivedi MH, Suppes T, Miller AL, Biggs MM, Shores-Wilson K, Witte BP, Shon SP, Rago WV, Altshuler KZ: Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003; 64:357–369
 
57.Trivedi MH, DeBattista C, Fawcett J, Nelson C, Osser DN, Stein D, Jobson K: Developing treatment algorithms for unipolar depression in cyberspace: International Psychopharmacology Algorithm Project (IPAP). Psychopharmacol Bull 1998; 34355–34359
 
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