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Acceptability of Second-Step Treatments to Depressed Outpatients: A STAR*D Report
Stephen R. Wisniewski, Ph.D.; Maurizio Fava, M.D.; Madhukar H. Trivedi, M.D.; Michael E. Thase, M.D.; Diane Warden, Ph.D., M.B.A.; George Niederehe, Ph.D.; Edward S. Friedman, M.D.; Melanie M. Biggs, Ph.D.; Harold A. Sackeim, Ph.D.; Kathy Shores-Wilson, Ph.D.; Patrick J. McGrath, M.D.; Philip W. Lavori, Ph.D.; Sachiko Miyahara, M.S.; A. John Rush, M.D.
Am J Psychiatry 2007;164:753-760. doi:10.1176/appi.ajp.164.5.753

Abstract

Objective: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients’ willingness to accept different second-step treatment approaches. Method: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. Results: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. Conclusions: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.

Abstract Teaser
Figures in this Article

No single treatment is a panacea for major depressive disorder. A wide variety of treatments are available, but many patients do not achieve a satisfactory outcome with an adequate implementation of their initial treatment, and a subsequent treatment is required. Second-step treatments take the form of either an augmentation strategy, in which a second treatment is added to the initial treatment, or a switch strategy, in which the initial treatment is discontinued and a different treatment is initiated. Various treatment guidelines (1) and algorithms (2, 3) have been formulated to assist clinicians in selecting, implementing, and changing (4) treatments. In addition, the relationship between patients’ treatment preferences and retention and symptomatic outcome has been studied (5), but little is known about what factors are associated with patients’ willingness to accept a given second-step treatment strategy for depression. The purpose of this study was to determine which sociodemographic and first-step treatment-related factors are associated with patients’ acceptance of second-step treatments for major depressive disorder.

This study was conducted as part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (6, 7). STAR*D was designed to define prospectively which of several treatments are most effective for participants with major depressive disorder who had an unsatisfactory clinical outcome after an initial treatment and, if necessary, subsequent treatments. The study used an equipoise-stratified randomized design (8) that allowed participants (with input from their clinicians) to select randomized assignment to any treatment within the following strategies for their second-step treatment: an augmentation strategy only (with or without cognitive therapy), a switch strategy only (with or without cognitive therapy), both augmentation and switch strategies (with or without cognitive therapy), or cognitive therapy only (including both switch and augmentation strategies).

Because STAR*D’s design incorporated participant choice, the trial offered a unique opportunity to identify factors associated with participants’ selections of second-step treatment. In this study, we addressed the following questions:

1. Do patients who are willing to receive cognitive therapy (as either a switch or augmentation treatment) differ from those who are not in terms of baseline clinical and demographic features, symptomatic response to citalopram in initial treatment, or side effect experience with citalopram?

2. Do those who will accept only a switch strategy (three medication treatment options or cognitive therapy) differ from those who will accept only an augmentation strategy (two medication treatment options or cognitive therapy) in terms of the same parameters?

3. Do those who will accept only a medication switch (three medication options) differ from those who will accept only a medication augmentation (two medication options) in terms of the same parameters?

The rationale and design of STAR*D have been detailed elsewhere (6, 7). A summary of the methods is presented below.

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Study Participants

From July 2001 to April 2004, STAR*D enrolled outpatients 18 to 75 years of age from 18 primary care and 21 psychiatric care practice settings across the United States. All enrollees had previously received a clinical diagnosis of nonpsychotic major depressive disorder, which was verified by a checklist based on DSM-IV criteria. Advertising for participants was proscribed to ensure that recruitment would produce a sample representative of patients seen in typical clinical practice. Written informed consent was obtained at study entry and again at enrollment in the second-step treatments.

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Inclusion and Exclusion Criteria

STAR*D used broad inclusion and minimal exclusion criteria (7) to ensure enrollment of a representative study sample. Inclusion criteria included a score ≥14 on the 17-item Hamilton Rating Scale for Depression (HAM-D) (9, 10). Patients with suicidal ideation were eligible if the treating clinicians deemed outpatient treatment to be safe for them. Patients with substance dependence were eligible if inpatient detoxification was not required. Exclusion criteria included a well-documented history of nonresponse to, or clear intolerance (in the current depressive episode) of, any of the treatments in the first two protocol treatment steps; a lifetime history of any bipolar or psychotic disorder; a primary diagnosis of obsessive-compulsive or eating disorder; or the presence of a general medical condition that contraindicated one or more protocol treatments. Women who were breastfeeding, pregnant, or intending to conceive in the 9 months following study entry were excluded, as were participants taking concomitant nonpsychotropic medications that contraindicated one or more protocol treatments and participants receiving targeted psychotherapy aimed at their depression (6, 7).

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Measures of Level 2 Baseline Characteristics

Baseline measures were collected by clinical research coordinators, by research outcome assessors through telephone interviews and by an interactive voice response system. Clinical research coordinators collected standard sociodemographic information, self-reported psychiatric history (including an assessment of suicidality), medical comorbidity as assessed with the Cumulative Illness Rating Scale (11, 12), and depressive symptom severity as assessed with the HAM-D, the 16-item Quick Inventory of Depressive Symptomatology—Clinician Rating (QIDS-C) (13–15), and the 30-item Inventory of Depressive Symptomatology—Clinician Rating (16–18). The Psychiatric Diagnostic Screening Questionnaire (19) was used to assess for the presence of 11 concurrent psychiatric disorders.

Research outcome assessors administered the HAM-D and the Inventory of Depressive Symptomatology. Anxious depression was defined on the basis of the anxiety/somatization factor of the HAM-D (20), and items from the Inventory of Depressive Symptomatology were used to establish the presence or absence of atypical features (21). The interactive voice response system was used to administer the self-report version of the QIDS (QIDS-SR) (13–15).

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Treatment With Citalopram (Level 1)

Citalopram, a selective serotonin reuptake inhibitor (SSRI), was used as the first treatment for all participants in Level 1 of STAR*D. The dosage was started at 20 mg/day for the first 4 weeks, raised to 40 mg/day for weeks 5–6, and raised to 60 mg/day for weeks 7–12. The protocol recommended that medication treatment visits be conducted at weeks 0, 2, 4, 6, 9, and 12 for all STAR*D medication treatments, although the visit schedule was flexible and extra visits could occur if clinically indicated. If participants had a response (defined as a reduction of ≥50% in baseline QIDS-C score) without remission (defined as a QIDS-C score ≤5) at week 12, they could continue treatment for an additional 2 weeks to determine whether that status was sustained. Symptom severity was assessed at each treatment visit with the QIDS-C and the QIDS-SR. The frequency, intensity, and burden of side effects were monitored with a scale developed for the STAR*D study (22).

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Moving to Level 2 or to Follow-Up

After Level 1 treatment, participants could decide to move to Level 2 (a randomized clinical trial comparing up to seven different treatments) or to the 12-month naturalistic follow-up phase. This decision was made by clinicians and participants on the basis of clinical judgment informed by side effect status and QIDS-C scores, which were obtained at treatment visits by researchers who did not have any knowledge of the primary research outcome measure (HAM-D score). Participants who did not achieve remission with citalopram or had a clear intolerance to the drug were encouraged to move to Level 2. Those who were in remission were enrolled in the follow-up phase. Those whose symptoms responded to treatment but without remitting were strongly encouraged to proceed to Level 2, although they could elect instead to enter the follow-up phase. Switching to another treatment required neither a tapering of citalopram nor a washout period.

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Level 2 Treatments

Level 2 treatments included four switch options (sustained-release bupropion, sertraline, extended-release venlafaxine, and cognitive therapy) and three augmentation options (citalopram plus sustained-release bupropion, buspirone, and cognitive therapy).

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Acceptability of Level 2 Treatments

An equipoise-stratified design (8) was used to approximate typical clinical decision making while retaining randomized comparisons. This design enhanced both study feasibility and generalizability by allowing participants to accept or reject certain treatment strategies, such as by specifying whether either or both the switch and augmentation strategies were acceptable, declining or accepting cognitive therapy within the strategies accepted, and declining all second-step medication changes to guarantee treatment with cognitive therapy either alone or as an augmentation to citalopram. Participants were eligible for inclusion in the instances where multiple treatment strategies were acceptable or a single treatment strategy with multiple treatment options (e.g., medication switch) was acceptable. For example, participants could decline all switch options and be randomly assigned to one of the three available augmentation options. However, participants could not select a specific medication. If participants accepted only one treatment option (e.g., only a switch to cognitive therapy), they exited the study because random assignment was not possible.

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Statistical Analyses

Analyses of the acceptability of cognitive therapy included all 1,439 participants who enrolled in Level 2. Analyses of the acceptability of either a switch strategy or an augmentation strategy included 1,273 participants after exclusion of the 166 participants willing to accept both strategies. Analyses of the acceptability of either a medication switch or an augmentation strategy included 1,013 participants after exclusion of the 259 participants willing to accept cognitive therapy as a switch or as an augmentation and the 166 participants willing to accept both an augmentation and a switch strategy.

For each subsample, a variety of sociodemographic and clinical factors were assessed for associations with acceptance of second-step treatment strategies. Sociodemographic variables included age, sex, race, ethnicity, marital status, insurance status, education, income, and number of people in household. Clinical variables included clinical setting (primary care or psychiatric practice), family history of depression or bipolar disorder, history of suicide attempt, atypical depression, anxious depression, age at onset of first major depressive episode, number of major depressive episodes, chronicity of depression, time since onset of first depressive episode, presence of comorbid general medical disorders, presence and number of comorbid psychiatric disorders (obsessive-compulsive, panic, social phobia, posttraumatic stress, alcohol abuse/dependence, drug abuse/dependence, somatoform, and generalized anxiety disorders, hypochondriasis, agoraphobia, and bulimia), and features of Level 1 citalopram treatment (side effect burden, duration of treatment, symptom severity, and percentage change in symptom severity after treatment).

Logistic regression models were used to estimate the association of these factors with willingness to accept cognitive therapy, independent of the effect of regional center, and odds ratios were generated. Logistic regression models were also used to estimate the magnitude of the association of these factors with willingness to accept a treatment switch (versus a treatment augmentation) and willingness to accept a medication switch (versus a medication augmentation), independent of the effects of side effect burden, relative improvement in symptom severity in Level 1 (as defined by the percentage reduction in QIDS-SR score), and regional center, and odds ratios were generated.

For the sake of brevity, we report only those characteristics that were statistically significant (p<0.05) in the adjusted analyses. Descriptive statistics for these characteristics, in the form of means and standard deviations for continuous variables and percentages for discrete variables, are presented separately for each subsample.

Of the 4,041 depressed outpatients who enrolled in STAR*D, 1,439 enrolled in Level 2 (Figure 1). Table 1 summarizes participants’ selections of treatments they would accept. Only 1% of participants (N=21) accepted all seven second-step treatments (stratum 1). Only 3% (N=44) ensured that they would receive cognitive therapy by excluding the medication treatment strategies (stratum 6), and 26% (N=369) were willing (and 74% not willing) to receive cognitive therapy as part of a switch and/or augmentation strategy (strata 1–10). Most participants accepted only a switch strategy (N=687; 48%) (strata 7 and 13) or an augmentation strategy (N=586; 41%) (strata 10 and 12).

Table 2 summarizes participants’ demographic and clinical characteristics. Table 3 presents the analysis of factors associated with the acceptability of treatment strategies.

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Willingness to Accept Cognitive Therapy

In this analysis, all Level 2 participants were classified as either willing to accept cognitive therapy (strata 1–10) (N=369) or unwilling (strata 11–13) (N=1,070).

As Table 3 shows, participants who were significantly more likely to accept cognitive therapy (independent of the effects of regional center) included those with greater education (see Figure 2), a family history of depression, a family history of a depression or bipolar disorder, or a greater amount of time in Level 1 treatment. Participants with panic disorder were significantly less likely to accept cognitive therapy than those without.

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Willingness to Accept a Switch Strategy Versus an Augmentation Strategy

Of the 1,439 participants enrolled in Level 2, a total of 1,273 selected either only switch strategies (strata 7 and 13) (N=687) or only augmentation strategies (strata 10 and 12) (N=586). Participants who accepted both switch and augmentation strategies (strata 1–6, 8, 9, and 11) (N=166) were excluded from these analyses. This subsample was similar to the full sample in presenting characteristics (Table 2).

Side effect burden with citalopram at exit from Level 1 treatment (Wald χ2=95.1, df=3, p<0.01) and percentage change in depressive symptom severity (Wald χ2=70.9, df=1, p<0.01) with citalopram were associated with participants’ acceptance of a switch strategy, independent of the effect of regional center. Participants who experienced greater reductions in symptom severity with citalopram in Level 1 were less likely to accept a switch (odds ratio=0.90 for a 5% increment in symptom severity). The likelihood that participants would accept a switch increased as side effect burden with citalopram at exit from Level 1 increased (minimal or mild side effects versus no side effects, odds ratio=1.51; moderate to marked side effects versus no side effects, odds ratio=3.36; severe side effects to inability to function because of side effects versus no side effects, odds ratio=8.69).

After controlling for the effects of side effect burden, relative change in symptom severity during Level 1, and regional center, participants with concurrent drug abuse were less likely to accept a switch in treatment (odds ratio=0.40, p<0.01), as were those with recurrent major depressive disorder (odds ratio=0.66, p=0.01) or a greater amount of time in Level 1 treatment (odds ratio=0.96, p<0.01). Participants who were treated in a primary care setting were more likely to select switch strategies (odds ratio=1.66, p<0.01) (Table 3).

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Willingness to Accept a Medication Switch Versus a Medication Augmentation

Of the 1,273 participants who elected to receive switch or augmentation strategies, 1,013 were willing to receive only a medication switch strategy (stratum 13) (N=583) or only a medication augmentation strategy (stratum 12) (N=430). The 260 participants who were excluded were willing to accept either all augmentation therapies (including cognitive therapy [stratum 10]) (N=156) or all switch therapies (including cognitive therapy [stratum 7]) (N=104) (Table 2).

Significant associations were observed for relative change in symptom severity with citalopram (Wald χ2=57.6, df=3, p<0.01) and side effect burden (Wald χ2=61.5, df=1, p<0.01), independent of the effect of regional center. Participants who experienced greater reductions in symptom severity with citalopram treatment in Level 1 were less likely to accept a medication switch (odds ratio=0.89 for a 5% decrement in symptom severity) (Table 3). The likelihood that participants would accept a switch increased as side effect burden with citalopram at exit from Level 1 increased (minimal or mild side effects versus no side effects, odds ratio=1.39; moderate to marked side effects versus no side effects, odds ratio=2.84; severe side effects to inability to function because of side effects versus no side effects, odds ratio=6.32).

After controlling for side effect burden, relative change in symptom severity, and regional center, participants with comorbid drug abuse were less likely to accept a medication switch (odds ratio=0.42, p<0.01), as were those with a greater amount of time in Level 1 treatment (odds ratio=0.96, p<0.01) (Table 3).

This study is the first to quantify the association of sociodemographic and clinical factors with the acceptability of second-step treatments for major depressive disorder after an unsuccessful first treatment step. The study design allowed participants to exclude treatment strategies while remaining eligible for the study, so long as random assignment to acceptable treatments was possible.

Several key findings emerged. First, few participants were willing to accept all possible second-step treatments. This result highlights the importance of equipoise-stratified randomization and calls into question the generalizability of findings from randomized clinical trials that use a complete randomization design, especially when the randomly assigned treatments involve radically different forms of treatment, such as pharmacotherapy and psychotherapy.

Second, acceptance of cognitive therapy was associated primarily with sociodemographic characteristics (education level and a family history of mood disorder) and was unrelated to the degree of improvement patients experienced with citalopram or whether they were intolerant to the drug. Thus, participants’ acceptance of cognitive therapy was not related to the course of the first treatment step. No association was observed between acceptance of cognitive therapy and insurance availability and type (i.e., private, public, or none). However, programs were reimbursed for the cost of therapy if patients did not have insurance, which to some extent decoupled acceptability and affordability.

Third, only 29% of participants were willing to accept cognitive therapy as a second-step treatment. This proportion was substantially lower than anticipated, and if it is generalizable to settings outside of those of STAR*D, it may suggest a limited potential utility for psychotherapy as a treatment alternative for patients who do not respond to antidepressants. However, the acceptance rate of cognitive therapy may have been diminished by the study design, which required that participants accept medication as a first-step treatment. In another study, Schatzberg and colleagues (23) found that nearly 90% of patients who initially consented to random assignment to pharmacotherapy or a form of cognitive behavior therapy, either singly or in combination, were willing to switch from pharmacotherapy to psychotherapy. Logistical issues (e.g., off-site location of therapists and, for patients with insurance, responsibility for copayments) also may have made cognitive therapy less attractive than a second course of pharmacotherapy to some participants.

Fourth, the acceptance of a switch strategy versus an augmentation strategy was primarily driven by participants’ experience in the initial treatment. As one might expect, participants who experienced only a modest reduction in depressive symptoms or a greater side effect burden with the initial treatment were more likely to prefer discontinuing that treatment and switching to a new one. Participants in primary care settings were also more likely to prefer a treatment switch, independent of side effect burden and degree of reduction of depressive symptoms. This finding may be attributable to a preference among primary care physicians for avoiding polypharmacy.

Finally, factors associated with preferring a medication switch to a medication augmentation were consistent with those related to preferences for switching or augmenting when cognitive therapy was among the options. This finding can be attributed to the large overlap in the two cohorts. In some instances, the differences in statistical significance can be attributed to a reduction in sample size.

Despite the utility of STAR*D’s innovative study design, several limitations should be noted. Because the design grouped three medication switch options into one strategy and two medication augmentation options into another, the acceptability of individual treatments could not be assessed. The study also did not assess the processes by which consensus was reached on treatment acceptability within the participant-clinician dyad; the specific preferences of participants and clinicians were not recorded—only the resulting consensus preferences.

Future studies with a similar design using SSRIs other than citalopram as the first-step treatment for major depressive disorder may further enhance our understanding of the factors associated with patients’ preferences in selecting second-step treatment strategies. We might also benefit from research on factors associated with patients’ acceptance of individual second-step treatments.

+Received June 16, 2006; revision received Sept. 5, 2006; accepted Sept. 28, 2006. From the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh, Pittsburgh; Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston; Department of Psychiatry, University of Pittsburgh Medical Centers, Pittsburgh; National Institute of Mental Health, Bethesda, Md.; New York State Psychiatric Institute, New York; Columbia College of Physicians and Surgeons, New York; VA Cooperative Studies Program, Palo Alto VA, Palo Alto, Calif.; and the Department of Health Research and Policy, Stanford University, Stanford. Address correspondence and reprint requests to Dr. Wisniewski, Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh, 127 Parran Hall, 130 DeSoto St., Pittsburgh, PA 15261; wisniew@edc.pitt.edu (e-mail).

+Dr. Wisniewski has provided consultation to Bristol-Myers Squibb, Cyberonics, and ImaRx Therapeutics and has received research support from NIMH. Dr. Fava has received research support from, served in an advisory or consulting capacity to, or received speakers honoraria from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals, BrainCells, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, Compellis, Cypress Pharmaceuticals, DOV Pharmaceuticals, Eli Lilly, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Grunenthal GmbH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Neuronetics, Novartis, Nutrition 21, Organon, PamLab, Pfizer, PharmaStar, Pharmavite, Roche, Sanofi-Synthelabo, Sepracor, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, and Wyeth-Ayerst Laboratories. He has equity holdings with Compellis and MedAvante. Dr. Trivedi has received research support from, served in an advisory or consulting capacity to, or received speakers honoraria from Abbott Laboratories, Akzo (Organon Pharmaceuticals), Bayer, Bristol-Myers Squibb, Cephalon, Corcept Therapeutics, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica Products LP, Johnson & Johnson PRD, Eli Lilly, Meade Johnson, Merck, NIMH, National Alliance for Research in Schizophrenia and Depression, Novartis, Parke-Davis Pharmaceuticals, Pfizer, Pharmacia & Upjohn, Predix Pharmaceuticals, Sepracor, Solvay Pharmaceuticals, and Wyeth-Ayerst Laboratories. Dr. Thase has served in an advisory or consulting capacity to or received speakers honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutica, MedAvante, Neuronetics, Novartis, Organon, Sanofi-Aventis, Sepracor, Shire US, and Wyeth Pharmaceuticals and has equity holdings in MedAvante. Dr. Warden owns shares of Pfizer stock and has owned shares of Bristol-Myers Squibb stock. Dr. Friedman has received research support from, served in an advisory or consulting capacity to, or received speakers honoraria from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Specialty Sales, GlaxoSmithKline, Roerig Division of Pfizer, Sanofi-Aventis, and Wyeth-Ayerst Laboratories, and he owns shares of Cephalon stock. Dr. Biggs has received honoraria for consultations to Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, and Pfizer. Dr. Sackeim has received research support from Cyberonics, Forest Pharmaceuticals, Magstim, MECTA Corp., Neuronetics, Pfizer, and Wyeth-Ayerst Laboratories and has received honoraria from Cyberonics and MECTA Corp. He has provided consultation to Cyberonics, Eli Lilly, Forest Pharmaceuticals, Givey, Magstim, MECTA Corp., Neuronetics, Pfizer, and Wyeth-Ayerst Laboratories. Dr. McGrath has received research support from or served in an advisory or consulting capacity to GlaxoSmithKline, NIMH, National Institute on Alcohol Abuse and Alcoholism, New York State Department of Mental Hygiene, Research Foundation for Mental Hygiene (New York State), GlaxoSmithKline, Eli Lilly, Organon, Lipha Pharmaceuticals, and Somerset Pharmaceuticals. Dr. Lavori has served in an advisory or consulting capacity to Bristol-Myers Squibb, Celera Diagnostics, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Leaf Cabrezer Hyman and Bernstein, and Neuronetics and has received research support from the National Institutes of Health and the Department of Veterans Affairs. Dr. Rush has received research support from, served in an advisory or consulting capacity to, or received speakers honoraria from Advanced Neuromodulation Systems, AstraZeneca, Best Practice Project Management, Bristol-Myers Squibb, Cyberonics, Forest Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, Jazz Pharmaceuticals, Eli Lilly, Merck, NIMH, Neuronetics, Ono Pharmaceutical, Organon USA, PamLab, Personality Disorder Research Corp., Pfizer, Robert Wood Johnson Foundation, Stanley Foundation, Urban Institute, and Wyeth-Ayerst Laboratories. He has received royalties from Guilford Press and Health Technology Systems, and he owns shares of Pfizer stock. Drs. Niederehe and Shores-Wilson and Ms. Miyahara report no competing interests.

+The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study is supported by federal funds from NIMH under contract N01 MH-90003 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.

+The authors thank Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, King Pharmaceuticals, Organon, Pfizer, and Wyeth-Ayerst Laboratories for providing medications at no cost for this trial. The authors acknowledge editorial support from Jon Kilner, M.S., M.A., and secretarial support from Fast Word Information Processing, Inc.

+Additional information about this study may be found in a data supplement that accompanies the online version of the article (ajp.psychiatryonline.org).

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19.Zimmerman M, Mattia JI: The reliability and validity of a screening questionnaire for 13 DSM-IV axis I disorders (the Psychiatric Diagnostic Screening Questionnaire) in psychiatric outpatients. J Clin Psychiatry 1999; 60:677–683
 
20.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
 
21.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
 
22.Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA: Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 2006; 12:71–79
 
23.Schatzberg AF, Rush AJ, Arnow BA, Banks PL, Blalock JA, Borian FE, Howland R, Klein DN, Kocsis JH, Kornstein SG, Manber R, Markowitz JC, Miller I, Ninan PT, Rothbaum BO, Thase ME, Trivedi MH, Keller MB: Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry 2005; 62:513–520
 
 
Figure 1. STAR*D Participant Flow and Acceptance of Level 2 Treatment Strategies
 
Figure 2. Proportion of STAR*D Level 2 Participants (N=1,429) Who Accepted Cognitive Therapy, by Education Level

Figure 1. STAR*D Participant Flow and Acceptance of Level 2 Treatment Strategies

Figure 2. Proportion of STAR*D Level 2 Participants (N=1,429) Who Accepted Cognitive Therapy, by Education Level
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References

1.Depression Guideline Panel: Depression in Primary Care, vol 2: Treatment of Major Depression. Clinical Practice Guideline No 5. AHCPR Publication No 93-0551. Rockville, Md, US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993
 
2.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
 
3.Rush AJ: Algorithmusgestützte Behandlung, in Akute und Therapieresistente Depressionen—2: Auflage. Edited by Bauer M, Berghöfer A, Adli M. Heidelberg, Springer Medizin Verlag, 2005, pp 459–476
 
4.Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Key T, Biggs MM, Shores-Wilson K, Witte B, Suppes T, Miller AL, Altshuler KZ, Shon SP: Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry 2004; 61:669–680
 
5.van Schaik DJ, Klijn AF, van Hout HP, van Marwijk HW, Beekman AT, de Haan M, van Dyck R: Patients’ preferences in the treatment of depressive disorder in primary care. Gen Hosp Psychiatry 2004; 26:184–189
 
6.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
 
7.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
 
8.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
 
9.Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62
 
10.Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278–296
 
11.Linn BS, Linn MW, Gurel L: Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 16:622–626
 
12.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
 
13.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
 
14.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
 
15.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
 
16.Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C: The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18:65–87
 
17.Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH: The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26:477–486
 
18.Rush AJ, Carmody T, 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; 9:45–59
 
19.Zimmerman M, Mattia JI: The reliability and validity of a screening questionnaire for 13 DSM-IV axis I disorders (the Psychiatric Diagnostic Screening Questionnaire) in psychiatric outpatients. J Clin Psychiatry 1999; 60:677–683
 
20.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
 
21.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
 
22.Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA: Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 2006; 12:71–79
 
23.Schatzberg AF, Rush AJ, Arnow BA, Banks PL, Blalock JA, Borian FE, Howland R, Klein DN, Kocsis JH, Kornstein SG, Manber R, Markowitz JC, Miller I, Ninan PT, Rothbaum BO, Thase ME, Trivedi MH, Keller MB: Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry 2005; 62:513–520
 
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