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Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study Maurizio Fava, MD a , A. John Rush, MD b, * , Madhukar H. Trivedi, MD b , Andrew A. Nierenberg, MD a , Michael E. Thase, MD c,e , Harold A. Sackeim, PhD h,i,j , Frederic M. Quitkin, MD h,j , Steven Wisniewski, PhD c,d , Philip W. Lavori, PhD f,g , Jerrold F. Rosenbaum, MD a , David J. Kupfer, MD c,e , for the STAR*D Investigators Group a Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA b Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390–9086, USA c Department of Psychiatry, Graduate School of Public Health, University of Pittsburgh Medical Center, Pittsburgh, PA, USA d Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh Medical Center, Pittsburgh, PA, USA e Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA f Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA g Department of Veterans Affairs Cooperative Studies Program, Palo Alto VA, Palo Alto, CA, USA h Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY i Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY j New York State Psychiatric Institute, New York, NY, USA Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinical information gaps and to evaluate the Psychiatr Clin N Am 26 (2003) 457–494 Supported in part by National Institutes of Mental Health Contract N01-MH-90003, the Betty Jo Hay Distinguished Chair in Mental Health, the Rosewood Corporation Chair in Biomedical Science, and the Sara M. and Charles E. Seay Center for Basic and Applied Research in Psychiatry. * Corresponding author. E-mail address: [email protected] (A.J. Rush). 0193-953X/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0193-953X(02)00107-7
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Background and rationale for theSequenced Treatment Alternatives toRelieve Depression (STAR*D) study

Maurizio Fava, MDa, A. John Rush, MDb,*,Madhukar H. Trivedi, MDb,

Andrew A. Nierenberg, MDa, Michael E. Thase, MDc,e,Harold A. Sackeim, PhDh,i,j, Frederic M. Quitkin, MDh,j,Steven Wisniewski, PhDc,d, Philip W. Lavori, PhDf,g,

Jerrold F. Rosenbaum, MDa, David J. Kupfer, MDc,e,for the STAR*D Investigators Group

aDepartment of Psychiatry, Massachusetts General Hospital, Boston, MA, USAbDepartment of Psychiatry, University of Texas Southwestern Medical Center,

5323 Harry Hines Boulevard, Dallas, TX 75390–9086, USAcDepartment of Psychiatry, Graduate School of Public Health, University of Pittsburgh Medical

Center, Pittsburgh, PA, USAdDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh

Medical Center, Pittsburgh, PA, USAeWestern Psychiatric Institute and Clinic, Pittsburgh, PA, USA

fDepartment of Health Research and Policy, Stanford University School of Medicine,

Stanford, CA, USAgDepartment of Veterans Affairs Cooperative Studies Program, Palo Alto VA, Palo Alto, CA, USA

hDepartment of Psychiatry, Columbia University College of Physicians and Surgeons,

New York, NYiDepartment of Radiology, Columbia University College of Physicians and Surgeons,

New York, NYjNew York State Psychiatric Institute, New York, NY, USA

Sequenced Treatment Alternatives to Relieve Depression (STAR*D)attempts to fill in major clinical information gaps and to evaluate the

Psychiatr Clin N Am 26 (2003) 457–494

Supported in part by National Institutes of Mental Health Contract N01-MH-90003, the

Betty Jo Hay Distinguished Chair in Mental Health, the Rosewood Corporation Chair in

Biomedical Science, and the Sara M. and Charles E. Seay Center for Basic and Applied

Research in Psychiatry.

* Corresponding author.

E-mail address: [email protected] (A.J. Rush).

0193-953X/03/$ - see front matter � 2003, Elsevier Inc. All rights reserved.

doi:10.1016/S0193-953X(02)00107-7

theoretical principles and clinical beliefs that currently guide pharmaco-therapy of major depressive disorder (MDD). The study is conducted inrepresentative participant groups and settings, using clinical managementtools that can be applied easily in daily practice. Outcomes include clinicaloutcomes (eg, symptoms, function, side effect burden, and client satisfac-tion) and health care utilization and cost estimates. Research findingsshould be immediately applicable to, and easily implemented in, the dailyprimary and specialty care practices. This article provides the overallrationale for STAR*D and details the rationale for key design, measure-ment, and analytic features of the study.

Why study the treatment of MDD

MDD is a common condition

Major depressive disorder is a common, often chronic or episodic life-long disorder that is associated with substantial disability and mortality.Although a range of effective treatments is available, a substantial pro-portion of patients do not respond adequately to treatment in thoseinstances. Which treatments to use alone or in combination, and in whatsequence they should be implemented, is not well-defined. As a result,current treatment guidelines rest substantially on open consecutive caseseries or clinical opinions, especially when defining the next best step afterthe initial treatment is unsuccessful.

Many treatments (medication, psychotherapy, and electroconvulsivetherapy [ECT]) for MDD have established randomized controlled trialevidence of efficacy [1]. The actual acceptability, clinical benefit, and sideeffect burden of these efficacious treatments in populations in representativeclinical settings, however, is less well known. It is also unclear how toproceed when a depression responds but does not remit with an initialantidepressant treatment. Responses that fall short of complete symp-tomatic remission (sometimes called responses with residual symptoms) arefrequent [2], and are associated with continuing disability and a poorerprognosis than is complete remission [3].

Two large, community-based epidemiologic studies in the United States,the Epidemiologic Catchment Area Study [4] and the National ComorbiditySurvey [5], have reported 4.9% to 17.9% lifetime prevalence for MDD,with women about twice as likely as men to suffer from MDD. MDD wasmore frequent among youths and young adults, and among those withgeneral medical conditions (GMCs).

MDD typically has a chronic or recurrent course

For most people, MDD is a lifelong episodic disorder with multiplerecurrences, averaging one episode in every 5-year period [6,7]. Both the

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recurrence of episodes in some, and partial or nonresponse to treatment inothers, interact such that approximately 20% to 35% of persons with MDDexperience a chronic, unremitting course [7]. The Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, [8] Mood Disorders Field Trialfound that 79% of those with dysthymic disorder also met criteria fora lifetime diagnosis of MDD [9]. Furthermore, data reanalysis of the ECAStudy [6] found over only a 1-year period that 5% to 20% of persons withdysthymic disorder developed MDD (ie, exhibited the so-called doubledepression). Chronicity is a major issue, particularly among participantswith double depressions, and among depressed persons with poor inter-episode recovery from recurrent MDD. In fact, a study by Judd et al [10]found that 72% of individuals with double depression and 65% withrecurrent depression had chronic symptoms. Furthermore, there is a growingbody of evidence that the longer the depression lasts, the more difficult itmay be to treat [10,11].

MDD is very disabling

Studies have shown that MDD is very disabling [6,12]. The MedicalOutcomes Study [13] showed that patients who meet criteria for MDDfunction more poorly than other primary care outpatients in three domains:(1) limitations in physical activities, (2) limitations in occupational or roleresponsibilities, and (3) limitations in social activities because of healthproblems. In fact, a recent World Health Organization report [14] rankeddepression as the fourth most disabling medical condition worldwide basedon disability-adjusted life years, which expresses years of life lost to pre-mature death and years lived with a disability of specified severity andduration. They predicted that depression would be the second most dis-abling condition worldwide by 2020.

MDD is very costly

Major depressive disorder costs the United States over $40 billion peryear (both direct and indirect costs) [15]. Costs included the cost of inpatienthospital admissions; the cost of outpatient partial care programs; andproductivity lost as a result of depression-related morbidity, suicide, andother relevant parameters.

Depression represents a major economic burden to the health caresystem. Simon et al [16] used data from an HMO to identify primary carepatients with depressive disorders and other patients in the same settingwithout evidence of depressive illness. Depressed patients had almost twicethe annual health care costs of those lacking depression. Even more strikingwas that before the onset of their depressive illness, depressed patients hadhigher health costs, suggesting the possibility that prodromal symptoms ofdepression may lead to increased use of health resources. Other inter-pretations are possible. For example, depression may amplify the experience

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of pain and lead to greater use of health care services, or clinicians may bemore likely to pursue diagnostic evaluations in response to patients’ physicaland psychologic distress. Whatever the cause, depression entails substantialhealth care costs.

The aim of treatment is symptom remission, not just symptomreduction or response

That symptomatic response without remission is associated with con-tinuing functional disability [10,17–19] and with a worse prognosis [20], iswell established. The indirect economic cost of failure to attain remission toantidepressant treatment is likely to be significant.

For these reasons, acute-phase treatment aims at symptom remission,not just response. The management of depressed participants who do notrespond or who respond but do not attain remission with a treatment(treatment-resistant depression) is a major public health challenge, es-pecially because ongoing, chronic disability associated with treatment resis-tance accounts for a substantial portion of the overall costs involved in thetreatment of depression [21].

Multiple effective treatment options are available for MDD

The range of treatment options available for patients with MDD hasbeen outlined previously [12]. The Agency for Health Care Policy andResearch review and meta-analysis [6,12] and many others [1,2,22] revealthat about 50% of all nonpsychotic MDD outpatients initially exposedto either a time-limited psychotherapy targeted for depression or a singleantidepressant medication respond to treatment, which means that the otherhalf continue to be symptomatic and functionally impaired after this initialtreatment level.

Furthermore, of depressions that respond, only about 50% to 65% attainremission [23] (ie, they no longer present residual symptoms of depression).In shorter randomized controlled trials of medications lasting 6 to 8 weeks,symptomatic remissions occur in about 20% to 30% of all those initiallyrandomized to treatment; 20% to 30% respond (ie, have a 50% reduction intotal symptoms) but without remission (ie, their Hamilton Rating Scale forDepression [17-item] [HAM-D17] [24,25] score is >7); 10% to 15% partiallyrespond (ie, they have a �25% and <50% reduction in baseline symptomseverity); and 20% to 35% are nonresponders (ie, they have <25% re-duction in total symptoms) [2]. These numbers also seem to apply to time-limited depression-targeted psychotherapy [26,27].

It is unknown how to treat depressed patients for whom twoor more treatment attempts have been unsuccessful

A second major group of depressed persons with a substantial publichealth impact are those who have not responded to multiple trials of

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medications and psychotherapy. These individuals may account for 10% to30% of the total population with MDD. Because of the chronicity andseverity of their illness, they may use 40% to 50% of treatment resourcesover prolonged time periods. These individuals are also more likely tocommit suicide and are more likely to suffer greater morbidity or evenmortality from their GMCs [28,29]. These individuals also typically requirehigh medication costs (because they are often treated with polypharmacy),and in some instances multiple psychiatric admissions. One of the aims ofSTAR*D is to focus on the treatment of these types of participants.

Where psychotherapy fits in the treatment of MDD is unclear

Millions of people with MDD receive psychotherapy alone as the initialtreatment for their depression. This psychotherapy is often delivered undermanaged care circumstances (ie, for a short, time-limited, duration witha cap of 5, 7, or 10 sessions; limitations that are not supported by publishedscientific literature [27]). One cannot be certain that depressions that havenot responded to psychotherapy in a routine care setting have received anadequate course in terms of either the quantity or quality of the treatmentgiven.

Practice guidelines attempt to organize available treatment optionsin a logical, scientifically supportable sequence of care

As with the rest of medicine, psychiatry now faces the challenge ofrecommending a sequence of treatments for depressions that do not respondsatisfactorily to the initial treatment attempt. Psychotherapies, with efficacyestablished by randomized controlled trials, became available in the late1970s [27], Furthermore, only since 1988 have antidepressant agents otherthan tricyclic antidepressants (TCAs), trazodone, or monoamine oxidaseinhibitors (MAOIs) become available in the United States.

In the face of the paucity of data directing such recommendations, it isunderstandable that today’s evidence-based practice guidelines often donot recommend a specific sequence of treatment [6,12,30,31]. If specificsequences can be recommended based on better acceptability, efficacy, tol-erability, or cost, they should reduce unnecessary practice variation andimprove outcomes. Although expert consensus is a place to begin [32], suchrecommendations must be prospectively evaluated scientifically to deter-mine whether they are valid or simply current mythology.

Scientifically based recommendations regarding treatment sequences fordepression may well produce clinical, administrative, and potentially eco-nomic benefits [33–35]. Such guidelines must go beyond the initial nextlevel question for patients failing to respond to the first treatment becauseeven after two levels of treatment, at best only 75% of the initial group willhave responded (based on populations entering into randomized clinical

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trials) and less than 50% will have attained remission. Response andremission rates may be even lower in patients treated in routine care, givengreater psychiatric and general medical comorbidities and histories ofintolerance and nonresponse to prior treatments.

In addition to efficacy, a major factor in developing empirically basedtreatment recommendations is the acceptability of recommended treatmentsto persons who suffer from MDD. For example, a slightly less effective, butfar more widely acceptable treatment may be preferred over a somewhatmore effective, but highly unacceptable treatment in algorithms recom-mending treatment sequences. No studies have evaluated the acceptability ofdifferent treatment options in broadly defined participant groups treated indiverse care settings.

The longer-term treatment of MDD is not well defined

Another critical issue in the management of depressed patients is the highrisk of relapses (during continuation phase of treatments; <6 months afterremission) and recurrences (during maintenance phase of treatment; >6months after remission) [36,37] also referred to as depressive breakthrough.Broadly conceptualized, treatment resistance can apply not only to thosewho do not respond to initial treatment, but also to those whose symptomsreturn following response or remission to acute-phase treatment [38,39].

Multiple studies show that antidepressants confer about a fourfolddecrease in relapse or recurrence rates compared with placebo [36]. Never-theless, in clinical trials between 10% and 30% of those whose acute-phasetreatment is associated with a substantial response, or even remission, ex-perience depressive breakthroughs despite ongoing antidepressant treatment[36], with relapse rates up to 57% being reported in published clinical trials[40]. If only 50% initially achieve acute remission and, with the worst casescenario, 30% of these experience depressive breakthrough within 1 to 5years, or alternatively 70% stay well [36,41,42], then the proportion that getwell and stay well can be as low as 35% (50% acute remission � 70% whostay well). Furthermore, long-term outcomes may be substantially worsethan those found in clinical trials [7,14].

Treatment-resistant depression

Definition

Although the aim of treatment for depression is complete symptomremission and complete functional restoration [12,30,31], no single treat-ment is a panacea. The clearly preferred outcome is sustained clinicalremission (ie, the absence of depressive symptoms) and full functionalrestoration. Based on randomized, placebo-controlled medication trials con-ducted for regulatory approval, about 50% to 60% of depressions respond

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to the first treatment, and about 35% to 40% achieve remission in 8-weektrials.

Treatment resistance refers to the absence of an acceptable clinicaloutcome (ie, sustained remission), defined in terms of depressive symptomseverity or daily function, to one or more prior adequate (both in terms ofdose and duration) treatments.

For those unresponsive to the first treatment, a second medication (orpsychotherapy) apparently results in a 50% response rate (and perhapsa 30% remission rate) to the second treatment. About 75% of the originalpatient group should achieve response and 50% should achieve remissionwith two treatment trials. If a third treatment is implemented, the authorsbelieve about 25% to 35% respond to a third monotherapy step [43]. Afterthis point, more complicated medication combinations or ECT are ad-visable. Several schemas to stage the degree of treatment resistance areavailable [44,45].

Causes of treatment resistance

Treatment resistance may be apparent or actual. Apparent resistance iscaused by inadequate medication doses or trial durations. Often, clinicianstend to use inadequate drug doses [46–51]. For example, Kotin et al [52],Schatzberg et al [53], and Remick et al [54] found that at least half thepatients considered treatment-resistant and referred to specialists hadreceived inadequate medication doses, and they responded to increaseddoses.

The relevance of adequate dosing is emphasized by trials with TCAs orMAOIs that clearly support the relevance of dose [55]. Appropriately con-trolled studies indicate that 300 mg of imipramine (or its equivalent) isstatistically superior to 150 mg, and that 90 mg of phenelzine is superior to45 mg [56–59]. Studies of second-generation antidepressants (eg, selectiveserotonin reuptake inhibitors [SSRIs]) are less numerous and less convincingas to dose-response relationships. In general, studies have failed to showa statistically significant difference with higher doses of SSRIs [60–62]. Twostudies found that a proportion of patients unresponsive to a standard doseof fluoxetine (FLU) responded when a higher dose was used [63,64].Kelsey’s [65] review (1996) of several studies with venlafaxine (VEN) areconsistent with a dose-response curve because higher dose groups (ie, 150 to225 mg/d and 300 to 395 mg/d) demonstrated greater improvement thanlower dose groups (75 mg/d).

Actual treatment resistance should not be diagnosed unless an aggressivedose of the initial medication is used [12]., These data lead to all medicationtreatments in STAR*D being used at fixed-flexible doses with the aim ofprescribing a reasonably robust dose before the medication is consideredineffective. A fixed-flexible dosing regimen: (1) allows clinicians to delaydose increases if the participant is initially intolerant; (2) approximates

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clinical practice; (3) allows some initially intolerant participants to ac-commodate to a particular dose, subsequently permitting a dose increasewith an acceptable side effect burden; and (4) allows participants witha range of concurrent GMCs to be retained in the trial while also receivingadequate doses in a timely fashion.

Whether to use historical or prospective evidence of treatment resistance

Treatment resistance is commonly encountered in clinical practice. Theauthors had to decide whether to recruit subjects with established historicalevidence of treatment resistance or to prospectively treat those with non-resistant depression to determine who has a demonstrable case of treatmentresistance. The latter option was chosen for several reasons: (1) to eliminatethe risk of incorrect assessment of the degree of response caused by thepatients’ recall biases; (2) to prevent the misclassification as nonrespondersof patients who have relapsed after an initial response; (3) to establish thehistory of treatment resistance adequately in a specific patient requiressubstantial effort at documenting prior treatment attempts and their out-come, which may reduce the speed of enrollment; (4) some patients withactual treatment resistance are unable to produce sufficient documentation;(5) the types and degree of treatment resistance likely affect the outcomeof the next treatment provided by the research protocol (ie, case mixdetermines outcome in unspecified, if not unreplicable, ways); and (6) it isquite difficult to determine the adequacy of the antidepressant dose and ofthe duration of the failed trial.

Evidence to define the next steps

Many treatments for depression have established efficacy in randomizedcontrolled trials [1]. The actual acceptability, clinical benefit, and side effectburden of these treatments in populations representative of every daypractice, however, is less well known. In addition, it remains unclear how totreat MDD that responds but does not remit with an initial antidepressanttreatment. Response without full remission to antidepressant treatmentis frequent [2], and is associated with continuing functional disability[10,17–19] and with a worse prognosis [20].

Furthermore, clinical practice guidelines suggest different levels of carefor depressed patients [32]. The strength of the evidence for these recom-mendations is modest, even when MDD does not improve sufficientlyafter a trial of a single antidepressant. For example, lithium augmentationof TCAs or MAOIs has been evaluated [66], but the efficacy of lithiumcombined with newer agents is not as well established [64,67].

For MDD without remission to the first treatment, a next treatment stepis called for (eg, switching to a new treatment or augmenting the firsttreatment with a second). By prospectively comparing the effectiveness of

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different treatment options (used either as augmentation to the previoustreatment used or as a new switch treatment), STAR*D aims to provide anempirical basis for practice guidelines. Results also provide descriptiveinformation about selected tactics (eg, at what dose and for how long shoulda treatment be conducted before declaring failure and moving to the nextlevel of treatment?) and describe, in the study population, the rates at whichparticipants decline specific substrategy groups (eg, augmentation versusswitching to a new medication).

When depressed patients do not respond adequately to treatment with anantidepressant, clinicians may choose to switch to another antidepressant(switching strategy) or to keep the same antidepressant and to add anotheraugmenting compound. Such augmentation strategy involves the use ofa pharmacologic agent that is not considered to be a standard antidepres-sant but may boost or enhance the effect of an antidepressant. Alternatively,clinicians may choose to combine the antidepressant that did not produceadequate response with another antidepressant, typically of a different class.The latter approach is called combination strategy, and its popularity hasincreased over time with the introduction of newer antidepressants witha fairly benign side effect profile and with fewer concerns about drug-druginteractions. This section reviews the studies concerning the efficacy ofaugmentation strategies, combination strategies, and switching strategies.

Summary of augmentation studies

Over the past few decades, numerous compounds have been used asaugmenting agents of antidepressants. Although most of the studies of thistherapeutic approach are open-label, many investigations are also double-blind, often placebo-controlled. This certainly allows one to draw relativelyfirm conclusions on the efficacy of some of the augmenting agents, such aslithium and thyroid hormones. It seems that the improvement followingantidepressant augmentation tends to occur within 3 to 4 weeks, so it maybe too premature to decide in the first few days or couple of weeks whetheror not an augmentation strategy is working. Almost all the studies on theefficacy of these augmentation strategies have focused on the short-termoutcome, and very little is known about the minimum duration of theaugmentation trial in responders to such strategy. Although there are manyaugmentation strategies that have been studied or reported in the literature[66], the best studied augmentation strategies in resistant depression arelithium, thyroid hormone, and buspirone (BUS).

Lithium augmentationLithium augmentation is not as popular currently as in the 1980s,

although there are a lot of studies that have clearly shown that the additionof a dose of 600 mg or more a day of lithium, typically in divided doses, andwith reasonably good blood levels, leads to a robust increase in the chances

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of response in refractory patients who do not respond to TCAs, MAOIs,and SSRIs. Eleven double-blind controlled trials of lithium augmentation indepression have been published; of those, 10 actually reported the observedresponse rate, which averaged 52% for a total of 135 lithium-treatedpatients [64,68–78]. In several studies, however, lithium did not doparticularly well when added to SSRIs [64,74].

Thyroid hormone augmentationIn depression studies, L-triiodothyronine (T3) has been used in preference

to thyroxine (T4) because of its rapid onset and offset of action [79]. T3

augmentation, in doses of 25 to 50 lg/d, has been used successfully amongdepressed patients refractory to TCAs [80].

BUS augmentationBuspirone is typically a well-tolerated antianxiety drug, with serotonin

(5-HT-1a) partial agonist properties. Studies using 5 to 15 mg twice a day ofBUS have shown significant improvement in refractory patients [72,81–83].Although the first placebo-controlled study in refractory depression com-paring BUS against placebo augmentation did not find any statisticallysignificant difference in response rates between these two treatments (51%versus 47%, respectively) [84], a more recent double-blind study showed thatamong the SSRI-resistant patients with severe depression, BUS was moreeffective than placebo augmentation [85].

Summary of combination studies

Although there are numerous double-blind studies of augmentationstrategies, there are less than five double-blind studies of combinationstrategies, reflecting the need for further studies in this area. It seems that theimprovement following the combination of antidepressants tends to occurwithin 4 to 6 weeks, so it may be too premature to decide in the first fewdays or couple of weeks whether or not a combination strategy is working.Almost all the studies on the efficacy of these strategies have focused on theshort-term outcome, and very little is known about the minimum durationof the combination trial in responders to such strategy. A typical approachis to maintain the combination for 6 to 9 months after obtaining remissionand then to attempt a gradual discontinuation of one of the two anti-depressants.

Although the combination of TCAs with SSRIs has been the best studiedcombination in the literature, its efficacy has been put in question by a studythat showed that adding low-dose desipramine to FLU was less effectivethan raising the dose of FLU in patients who had not responded to 8 weeksof treatment with FLU, 20 mg/d [64]. The use of the combination ofbupropion (BUP) and SSRIs and of mirtazapine (MIRT) and SSRIs hasbeen considerably more promising.

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BUP and SSRIsBupropion sustained release (100 to 150 mg once or twice a day) com-

bined with SSRIs was the first strategy chosen by 400 psychiatrists surveyedby Fredman et al [86]. The evidence for this combination is primarily basedon anecdotal reports, case series, or small open trials [87–90].

MIRT and SSRIsMIRT is a dual-action antidepressant that increases both serotonergic and

noradrenergic activity by blocking the a2-adrenergic autoreceptors andheteroreceptors and blocks the serotonergic 5-HT2 and 5-HT3 receptors.MIRT (15 to 30mg qhs) combined with SSRIs has been reported to be helpfulin an open study of nonresponders to SSRIs [91], and to bemore effective thanplaceboplus SSRIs in a subsequent double-blind study of refractory depressedpatients [92]. A recent study by Debonnel et al [93] showed a significantlyhigher response rate to the combination of paroxetine (PAR) and MIRTthan monotherapy with either drug alone, and a 64% response rate to theswitch to combination therapy for patients not responding to monotherapy.

Cognitive therapy (CT) and medication

Recent evidence indicates that for those who respond but do not remit toa medication, CT not only removes residual symptoms, but is associatedwith an improved prognosis [94].

Summary of switch studies

Several theoretical principles commonly guide antidepressant pharma-cotherapy choices:

1. A switch from one agent that affects one neurotransmitter system(eg, from a serotonin reuptake blocker) to one that affects another(eg, selective norepinephrine reuptake blocker) is more effective than aswitch to another agent with a similar mechanism of action. This ra-tionale has become a common basis of clinical practice, although itsvalidity has not been studied in double-blind, controlled clinical trials [95].

2. Agents that affect more than one neurotransmitter system (eg, serotonin(5-HT) and norepinephrine (NE)) are more effective than more selectiveagents (eg, a selective norepinephrine agent) in those who have faileda more selective agent initially. For example, van Praag et al [96] havestated that effects of both NE and 5-HT are needed to optimize anti-depressant effects, a hypothesis indirectly supported by the DanishUniversity Antidepressant Group study [97], but which needs empiricalevaluation in representative outpatients.

3. A switch to an agent that produces changes in neuronal systems bydifferent mechanisms of action (eg, NE and 5-HT reuptake inhibi-tion plus postsynaptic receptor antagonism versus monoamine oxidase

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(MAD) inhibition) than the previously failed agent is more effectivethan a switch to agents with similar mechanisms of action as the failedprior agent (eg, switching from a TCA to a TCA is less effective thanswitching from a TCA to an MAOI). This hypothesis has beensupported by several studies [98–100], but it has not been investigated ina systematic fashion with the newer agents [101].

Based largely on studies of TCAs or MAOIs or on nonmasked,nonrandomized trials, recent reviews [44,45,102] suggest that a switch fromone medication class to another for those not responding to the first leadsto response rates of 50%. A switch within class, however, may be lesseffective. Response or remission rates for medication class switches inpatients who have responded, but not remitted, to the first medication arenot known.

Switching from one SSRI to anotherThree uncontrolled studies [103–105] found that participants who did

not respond to one SSRI had a 50% to 60% response rate to anotherSSRI. It has been suggested, however, that markedly lower response ratesto a switch within SSRIs would be observed when the failure to respond isdocumented prospectively, when medication doses were adjusted upwardfor the initial SSRI, and when only those who did not respond to (asopposed to those who were intolerant to) the first SSRI were included. Forthis reason, it is not surprising that a recent double-blind study [43] showedthat, among MDD patients with a history of resistance to two previousantidepressant treatments (mostly SSRIs) and a Clinical Global Impres-sions (CGI) [106] improvement score of 3 at the beginning of treatment,the response rate was 51.9% for VEN and 32.7% for PAR (P ¼ .044), anda remission was achieved in 42.3% of VEN-treated and 20% of PAR-treated patients (P ¼ .01). Similarly, a recent PAR survey by Fredman et al[86] of 400 US psychiatrists showed that the most common next step in themanagement of nonresponders to an SSRI was the switch to a non-SSRIantidepressant.

Switching from SSRIs to TCAsThe switch to TCAs has also been shown to be effective among SSRI

nonresponders in a large randomized and controlled study (n ¼ 117) of aswitch from sertraline (SER) to imipramine (IMI) (response rate, 44%)[107].

Switching to BUPEven though switching to BUP seems to be a very popular strategy among

psychiatrists [86], there is very little literature onwhich to base the decision. Aspointed out in a recent review [102], only small, uncontrolled studies havereported significant improvement on switching SSRI-treated patients to BUP.

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Switching to VENNierenberg et al [108] found a 30% to 33% response among 84 con-

secutive treatment-resistant depressed patients (who had failed at least threetrials). Another open study found that, among patients with MDD anda documented history of unsatisfactory improvement after a minimum of8 weeks of treatment with an adequate dose of an antidepressant, treatmentwith VEN was followed by a response (50% improvement from baseline) in58% of the patients [109].

Switching to MIRTA recent multicenter study [110] has shown a 48% response rate to MIRT

switch (15 to 45 mg/d) among 103 patients who had neither tolerated norresponded to SSRI treatment. The efficacy of MIRT was comparableamong SSRI nonresponders (n ¼ 76) and SSRI-intolerant patients (n ¼ 18).

Switching to MAOIsSwitching to MAOIs is a very effective strategy for refractory depression

that was popular in the 1970s and 1980s, but is now typically considered at theend of an algorithm, primarily because of the dietary restrictions and the riskof spontaneous and nonspontaneous hypertensive crises. Several studies haveexamined the efficacy ofMAOIs in the treatment of patients who had failed torespond to TCAs [102]. In a crossover study of patients with mood-reactive,nonmelancholic, depression, of 46 patients previously unresponsive toimipramine who completed phenelzine treatment, 31 (67%) responded tophenelzine, whereas of 22 patients previously unresponsive to phenelzine whocompleted imipramine treatment, 9 (41%) responded to IMI [99].

Alternative somatic treatments

The authors considered but did not include ECT or repetitive trans-cranial magnetic stimulation (rTMS) in STAR*D. At the time of protocoldevelopment, no information was available on vagus nerve stimulation(VNS). ECT was not included because (1) evidence for robust efficacy isalready available; (2) the authors did not expect to be able reliably to recruitsufficient sample size of highly refractory patients (who have not respondedto four or more consecutive treatments for depression); and (3) the authorscould not identify an equally acceptable alternative treatment easily.Repetitive transcranial magnetic stimulation was not included because (1)methods optimally to administer it have yet to be agreed on and (2) long-term use of rTMS in managing MDD once a response is obtained has notbeen established. Recently, suggestive (open trial) evidence of acute efficacyfor VNS has become available [20,111]. It is still, however, experimental innature (ie, not approved by the Food and Drug Administration fordepression). STAR*D includes no treatments that lack approval by theFood and Drug Administration for a mental illness.

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Issues in generalizability of participant population

Need for representative patients

Most efficacy studies have excluded participants with common generalmedical and psychiatric comorbidities. Generalization of even these ten-tative findings to representative populations is difficult. The proposed studyhas very broad inclusion criteria that allow enrollment of both adult andelderly patients, and clinically depressed patients with many other psy-chiatric comorbidities. General medical comorbidities are also allowed, aslong as clinicians consider antidepressant treatment appropriate. Thesedesign features increase the likelihood that the authors’ findings are asgeneralizable as possible.

Inclusion-exclusion criteria

In general, the inclusion-exclusion criteria of STAR*D are broad so as toacquire a sample representative of persons with MDD who would receivemedication or psychotherapy in practice. Patients with schizophrenia,schizoaffective disorder, anorexia, bulimia, or obsessive-compulsive disor-der as a primary diagnosis are excluded because they have a primarypsychiatric condition that requires a different initial treatment [6]. Patientswith currently active and clinically significant substance abuse are eligible,although their treating clinician should provide encouragement to partic-ipate in a substance abuse program. Those with substance dependence,defined clinically to require detoxification, are not eligible for reasons ofmedical safety.

Sources of patients

The STAR*D does not enroll patients through advertisement, butinstead prospectively enrolls patients in both primary and specialty carevenues, whether delivered by publicly or privately supported clinicians. Thisapproach tends to favor the recruitment of self-declared patients and toreduce the chance of recruiting symptomatic volunteers.

Issues in generalizability of treatment delivery

Routine versus high-quality treatment

The implementation of treatments under evaluation in STAR*D must bewell enough conducted to ensure actual, not apparent, treatment resistance,yet must be representative of good practice. Treatments must also betailored to individual participants with general medical, ethnic, and psy-chiatric diversity. This tension between generalizability and protocoladherence results in a need for a spectrum of clinically acceptable variations

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(ie, variations that do not profoundly affect outcomes or that affectoutcomes equally across all treatment options to be compared).

The STAR*D chooses not to accept routine practice as sufficientlydiligent and reliable for the purposes of this study. Instead, training andoversight are provided for both the pharmacotherapy and psychotherapy toensure reasonably high-quality care. The aim of this effort is to ensure thattreatment resistance is present before allowing the participant to proceed tothe next treatment level. This design (sometimes called a hybrid design) [112],engages representative patients and providers as participants, ensuringadequate care. Results are generalizable to reasonably well-delivered care tosuch patients.

Elements in high-quality treatment (time, dose, symptom,and side effect assessment)

The STAR*D strongly encourages 12 weeks of treatment with vigorousdosing at each of its four levels of treatment. STAR*D also providessystematic assessment of symptoms, function, and quality of life, to bestinform both clinicians and patients during treatment implementation. Out-come assessments are also obtained blind to treatment assignment bya team of independent research outcome assessors (ROAs). The importanceof adherence to protocol procedures is emphasized to patients with aneducational package that includes information about the nature of MDD;simple theories of mechanisms of action of antidepressants and of CT, withan emphasis on the importance of continued exposure of receptors forantidepressant medications; the importance of homework for those in CT;and clarification of reasonable expectations about the timing of therapeuticeffect. Further education focuses on early and longer-term medication sideeffects, noting that most side effects abate within a reasonable period oftime.

Medication side effects are major deterrents to adequate pharmaco-therapy. They are often the basis for changing doses or even classes ofantidepressants. They often limit doses possible for a particular patient. Itis, however, not simply the number, frequency, intensity, nor particular typesof side effects, but especially it is the burden of these side effects on patientdaily function that affects continuation or discontinuation of the treatment.To compare one treatment with another, STAR*D assesses the frequency,intensity, and day-to-day burden of the side effects of the antidepressanttreatments as defined by the patient, and also obtains these ratings at eachclinic visit to inform the providers whomust make dose adjustment decisions.

Adherence by clinicians

The implementation of the treatments to be evaluated must be wellconducted and representative of good practice, yet they must be tailored toindividual patients who are medically, ethnically, and demographically

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diverse. This tension between ecologic validity and protocol adherenceresults in a need for a spectrum of a clinically acceptable variation (ie,variation that does not profoundly affect outcomes or that affects outcomesequally across all treatment options to be compared). Protocol violations byclinicians are minimized by the use of start-up meetings with the inves-tigators followed by ongoing teleconferences to review the protocol imple-mentation. Each clinician is provided with a clinician procedures manualdetailing all clinical and relevant research procedures. Additionally,a checklist of inclusion and exclusion criteria is completed by the clinicalresearch coordinator (CRC) for each entering patient to ensure consistencywith the protocol.

Adherence by participants

A tension exists between (1) the goal of participant retention and (2) thegoal of maximizing the generalizability of the proposed study to hetero-geneous clinical settings, including those in which the resources for keepingparticipants in treatment are limited. In considering this tension, thisprotocol has emphasized ensuring that participants and clinicians makeevery reasonable effort to implement the treatments properly because themain objective is a comparison of different treatment strategies, substrat-egies, and options. It is of greater public health significance to compare well-implemented as opposed to poorly implemented treatments.

In the interests of representativeness and generalization, heroic orextreme efforts at both ensuring fidelity by clinicians and participation byparticipants cannot be implemented during the study (eg, large monetaryreimbursements to participants for attending each visit). Further, becausethere is a diversity of settings (primary and specialty clinicians in public andprivate care settings), it is very likely that there will be a wide variation inclinical procedures used to attend to participant adherence and attrition(eg, participant education and following up on missed appointments). Thiswide variation runs the risk of creating so much variation in adherence andattrition that comparisons of effectiveness may not be internally valid.

Implementing a set of reasonable clinical procedures to minimizeparticipant dropout is critical to the success of this study because it relieson good participant retention across the sequential treatment levels, in somecases extending over many months.

The STAR*D implements a program to train clinical staff to provide toparticipants (and family members or significant others) specific information,which is consistent across clinical sites, providers, and treatment levels. Thiseducational program is consistent with the practice guideline recommenda-tions [6,12,30,31]. In general, it provides a feasible, inexpensive set of con-sistent interactions, thereby reducing unneeded (and potentially scientificallydisadvantageous) procedural variations across sites and clinicians that couldlead to differential attrition.

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There are two types of nonadherence that could interfere with theconduct of this trial: treatment nonadherence (eg, not attending clinic visitsor not taking the treatment medication); and research nonadherence (eg, notparticipating in the research outcomes assessments). The following dis-cussion addresses both types of nonadherence.

Ideally, participants who do not remit with the initial treatment wish toproceed into one or more subsequent treatment levels until satisfactorybenefit has been attained. Thereafter, ideally they are then willing toparticipate in follow-up assessments aimed at further characterizing theextent and durability of those responses. To encourage sustained studyparticipation, the authors intend to pursue several strategies for all par-ticipants: (1) promoting study affiliation; (2) educating participants andfamilies about depression and its treatment; (3) ensuring timely follow-upfor and rescheduling of missed appointments; (4) compensating participantsfor the time and effort to participate in the research outcomes assessments(eg, 30 minutes with a telephone interview with the ROA and 30 minuteswith an interactive voice response [IVR] system [113] at study entry, at exitfrom each treatment level, and every 3 months in follow-up); and (5) pro-viding reminders (eg, letters) to alert participants to assessments.

Study affiliationStudy participants are provided printed brochures and a brief, in-

formational videotape (introduction to STAR*D) outlining the overarchingrationale, aims, and procedures entailed in STAR*D. It includes all relevantaspects of study design and a description of participating centers, andemphasizes the public health significance of STAR*D and the critical roleplayed by the participants. All participant information materials areapproved by the institutional review board at each regional center (RC).

In addition, participants receive a bimonthly newsletter (the STAR*DGram) to sustain interest. It features new information on depression, andselected updates on STAR*D and on any new ancillary studies, such asfamily-genetic studies. It also features members at each RC. The scope ofthese materials is limited so that they provide information relevant to studyparticipation but do not serve a broad didactic role about particulardepression treatments that might overlap with particular treatment options.These introductory materials and the newsletter are produced under theauspices of the communications committee.

EducationThere are several elements that are known to enhance participant

participation in and adherence to treatment. First and foremost is education(of both participants and significant others) [114]. In nearly every ran-domized trial comparing educated efforts versus none (or usual care), theeducated group had either greater adherence to the treatment procedures

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(whether measured by appointment keeping, medication counts, or bloodlevels), better outcomes, or both. For this reason, participant and familyeducation is recommended as part of the general clinical management ofdepressed participants in both primary [6,12] and specialty [30,31] care. Amultistep educational package is used. This educational package is providedto all participants.

Follow-upTimely follow-up and rescheduling of missed clinic visits is crucial in

ensuring adequate treatment and in minimizing dropouts. A schedule ofvisits is supplied to the CRCs by the Data Coordinating Center (Universityof Pittsburgh) as a participant enters a given level of treatment or entersfollow-up. A centralized system for tracking study appointments is set-up ateach RC (or clinical site) and a database with contact information for eachparticipant, which is updated at least every 3 months. The clinic staffcontacts participants on the day of the missed appointment, and againwithin 24 hours if there is no response. A letter signed by the participant’sclinician is sent out within 48 hours of the missed appointment if telephonecontact has not been established. This letter encourages prompt reschedul-ing of the missed appointment, and provides telephone numbers for theclinicians. It also ensures that participants are aware of other local mentalhealth resources in case of emergencies.

This level of follow-up for clinic visits is likely to be more aggressive thanthe usual care offered in some clinical settings. The authors believe, however,that it is justified to ensure participant retention, and to ensure the safety ofdepressed participants whose failure to keep an appointment may signalclinical deterioration and emergent safety concerns.

CompensationBecause many participants may suffer economic hardship by allocating

time to the research outcomes assessments (ROA) (especially hourly wageearners) and because of the authors’ and others’ experiences with reasonablecompensation for each research assessment, it is believed that a compensa-tion of $25 per assessment is reasonable (1 hour of participant time) ($15 foreach ROA and $10 for each IVR assessment).

RemindersSome clinical sites or RCs were already using a letter or telephone

reminder for clinic visits. Others were not. If missed clinic visits becomesignificant at particular clinical sites (eg, >15%), STAR*D implementsa letter reminder system before the next appointment. STAR*D uses a letterreminder system for all ROA calls.

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Guidelines for discontinuing participants from the randomized treatment studyThe following guidelines are used for discontinuing participants:

1. Participant request.2. Clinicians decide that to discontinue the study is in the best interest of

the participant.3. Participant becomes unable to attend clinic visits with STAR*D

clinicians, thereby precluding further clinical implementation of theprotocol.

4. Participant becomes unable to participate in ROA.

Training of staff, providers, and therapists

All ROAs and CRCs are trained on the study protocol, methods of datacollection, and data management. Training on the study protocol covers thescreening procedures, eligibility and exclusion criteria, data items to becollected, and the procedures for completing the data collection forms.Training on data management topics includes Web site access, data entryand management, correcting data, coding missing data, and runningreports. Certification is required for all CRCs, and recertification is doneannually through the study to ensure up-to-date knowledge of protocoladditions or changes over the course of the study. Throughout the course ofthe project retraining and training for new personnel is available. The testsused for certification are administered by the website, if necessary, and arerepeated at regular intervals for recertification. RC clinicians are trained atthe STAR*D START-UP meetings in Dallas, at which RC directors,associate directors, and CRCs are trained in the protocol. They, in turn,train the clinicians at their clinical sites. Ongoing teleconferences (weekly,biweekly, and monthly) are held over the first year of participant entrywith clinicians, CRCs, and the National Coordinating Center co-directorand clinical manager to check on and supervise protocol implementation.Each clinician is also provided with a clinical procedures manual detailingall clinical and relevant research procedures. All therapists involved inSTAR*D have been certified by the cognitive therapy training directorsat University of Pittsburgh. Throughout the study, they receive on-going supervision through conference calls and use the PsychotherapyManual, which specifies acceptable clinical variation in the use of cognitivetherapy.

Concurrent psychotropic medications

Adjunctive treatments are treatments used to manage transient associatedsymptoms (eg, insomnia) or transient or longer-term medication side effects(eg, sexual dysfunction). Adjunctive treatments cannot be ones aimed attreating depression or cannot be treatments that are used clinically asadjunctive treatments of antidepressants in treatment-resistant depression

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(eg, BUS or BUP). The overarching principles guiding adjunctive treatmentstry to balance the need to minimize the confounding effects of treatmentsthat may alter the effect sizes of treatments under study with the goals ofincreasing the feasibility of conducting a randomized treatment protocoland of increasing treatment adherence among participants. By allowingadjunctive treatments that are widely used in practice and that are ac-ceptable to participants, STAR*D enhances both generalizability andfeasibility.

At study entry and during the study, antipsychotic (eg, typical andatypical antipsychotic drugs) and mood stabilizing agents (eg, lithium,carbamazepine, valproate, lamotrigine, gabapentin, or other anticonvul-sants) are excluded. If participants have been taking inadequate doses ofantidepressants, these medications are tapered off and stopped, afterconsent but before beginning treatment. Baseline assessment for entry intothe study begins when citalopram (CIT) is started for treatment protocolparticipants who enter the treatment sequence. During protocol treatment,benzodiazepines and imidazopyridine hypnotics are allowed.

Concurrent nonpsychotropic medications

In general, participants can enter the study receiving any medications forconcurrent GMCs as long as there is no contraindication to use with anymedications in the STAR*D algorithm.

Concurrent psychotherapy

In general, participants can enter STAR*D receiving any psychotherapythat does not focus on depression, or that is non–cognitive-behavioral orinterpersonal.

Issues in outcome assessments

Domains of outcome

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

SymptomsResearch outcomes symptom measures used in STAR*D include the

HAM-D17 (primary) [24,25,115,116] and the 30-item Inventory of De-pressive Symptomatology–Clinician-Rated (IDS-C30) (secondary) [117,118].The IDS-C30 and the HAM-D17 are collected at entry into and exit fromeach treatment level, and every 3 months in follow-up. These measures arecollected by the ROAs. The 16-item Quick Inventory of DepressiveSymptomatology-Self-Report [34] is also collected by IVR to determine

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how this method performs compared with the previously mentioned twogold standards.

The primary outcome is a clinician rating of depressive symptoms(HAM-D17) administered at entry and exit from each treatment levelthrough telephone interviews by assessors masked to treatment assignments.Secondary outcomes include the IDS-C30 (by telephone-based interviewers)and self-reports of depressive symptoms, physical and mental function, sideeffect burden, client satisfaction, and health care utilization, all obtained byIVR telephone calls.

FunctionThe Short-Form Health Survey (12-item) (SF-12) [119] collected by IVR

is the primary functional outcome. Secondary functional outcome measuresare total scores on the six-item Work Productivity and Activity Impairment(WPAI) Questionnaire [120], and the five-item Work and Social AdjustmentScale (WSAS) [121], each collected by IVR.

There is no commonly agreed on gold standard for evaluating function inpersons with mental illnesses. The authors selected the SF-12 as a primaryfunction outcome measure because it is commonly used in mental healthservices research and in studies of general medical disorders. The SF-12 hastwo subscales: mental function and physical function, which closely ap-proximate those obtained with the longer SF-36 [122]. The SF-12 is collectedby IVR (4 minutes).

As a primary outcome measure for work function, the authors use thesix-item WPAI Questionnaire acquired by IVR (2.5 minutes). This measurefocuses on work and related function. As a secondary measure of overallwork and social function the authors use the WSAS (five items usinga Likert-type scale) acquired by IVR (2 minutes).2

Quality of lifeThe 16-item Quality of Life Enjoyment and Satisfaction Questionnaire

[123], collected by IVR, assesses quality of life (6 minutes). This ques-tionnaire is designed to measure satisfaction and enjoyment, as opposed tofunction per se, in various domains: physical health, mood, work, householdduties, school and course work, leisure time activities, social relations,and general activities. The short version has 16 items, and is obtained in6 minutes by IVR.

Side effect burdenThe primary side effect outcome measures are three global ratings: one

for side effect frequency; one for side effect intensity; and one for side effectburden. The Frequency and Intensity of Side Effect Rating (FISER) andGlobal Rating of Side Effect Burden (GRSEB) include global measures,each using a 7-point Likert-type scale rated 1 to 6, one rating anchored for

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frequency, another rating the intensity of side effects encountered in theprior week that the participant believes were caused by the antidepressanttreatment, and the third asking participants to estimate the overall burdenor degree of interference in day-to-day activities and function caused by theside effects attributable specifically to the antidepressant treatment. All arecollected by IVR.

Medication side effects are major deterrents to adequate pharmaco-therapy, and are often the bases for changing doses or even classes ofantidepressants. They often limit doses possible for a particular parti-cipant. It is, however, not simply the number, frequency, intensity, norparticular types of side effects, but especially it is the burden of these sideeffects on participant daily function that affects continuation or dis-continuation of the treatment. To compare one treatment with another, weassess the frequency and intensity (2-items), as well as the day-to-dayburden (1-item) of the side effects of the antidepressant treatment(s) asdefined by the participant (FISER and GRSEB), as part of the researchoutcomes assessments. Side effect questions are collected by IVR (1.5minutes).

Participant satisfactionA short (two-item) Patient Satisfaction Inventory (PSI) measures

satisfaction with the treatment and the treating personnel. At each researchoutcomes assessment, participant satisfaction is measured by two Likert-type questions using IVR (the PSI). These questions evaluate satisfactionwith the treatment and the clinical staff providing the treatment.

Health care utilization and costThe 15-item Modified Utilization and Cost Patient Questionnaire

(UAC-PQ) [124–129] gathers treatment information from the participantfor both mental and GMCs in the prior 3 months.

Estimates of participant use of both mental and general health care forthe entire sample are computed from participant responses to the ModifiedUAC-PQ-IVR. This system was derived from the Modified UAC-PQ asapplied in the Texas Medication Algorithm Project [110,130,131]. Partic-ipants are asked to dial a telephone number and record their use of careinformation by means of a touch-tone or voice-activated telephone.Structured questions ask participants if they have visited a medical doctor,psychologist, or social worker in an outpatient care clinic during the past 3months for their depressive disorder, for other mental health conditions, foraddiction disorders, and for general medical care. If so, participants areasked to describe how many visits they spent in each category. Participantsare also asked about visits to emergency rooms and days spent in thehospital. Of course, whenever possible, participant utilization information issupplemented by provider-based files.

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Overview of the STAR*D protocol

Primary objectives

The STAR*D uses a prospective design to determine the comparativeeffectiveness of different treatment options for MDD. It evaluates thecomparative effectiveness of treatments when used either as augmentingtreatments or as new treatments when remission is not attained with aninitial SSRI CIT. STAR*D provides several levels or steps in treatmentfollowing CIT failure. Assignment to multiple treatments at each level israndomized at all treatment levels (2, 2A, 3, and 4). Clinical outcomesinclude symptoms, function, side effect burden, quality of life, and par-ticipant satisfaction. These outcomes are evaluated by independent assessorsmasked to treatment assignments or by an IVR system [113].

The STAR*D results provide an empirical basis for practice guidelines,thereby reducing the reliance on clinical consensus. STAR*D follows-upthose with a satisfactory response to any treatment in a 12-monthnaturalistic follow-up. STAR*D determines the incidence, nature, andtiming of relapses (<6 months after remission) or recurrences (>6 monthsafter remission). Finally, STAR*D relates clinical outcomes and treatmentcosts and cost-offsets entailed in following the multistep treatment sequence.

The STAR*D is a multisite, prospective, sequentially randomized,clinical trial of outpatients with nonpsychotic MDD. The study comparesvarious treatment options for those who do not attain a satisfactoryresponse with the SSRI CIT. The study enrolls adults (ages 18 to 75) fromboth primary or specialty care practices who have not had either a priorinadequate response to a robust trial to any of the protocol treatments ora history of clear-cut intolerance to a protocol treatment during the currentmajor depressive episode.

After 4000 participants receive CIT (level 1), those without sufficientsymptomatic benefit are eligible for random assignment to level 2 treat-ments, which entail four switch options (SER, BUP, VEN, or CT [cognitivepsychotherapy]) and three CIT augment options (BUP, BUS, or CT). Thosewho receive CT (switch or augment options) at level 2 without sufficientimprovement are eligible for randomization to two level 2A switch options(VEN or BUP).

Level 2 or 2A participants not obtaining sufficient improvement afterat least two medications are eligible for level 3 random assignment to twoswitch options (MIRT or nortriptyline (NOR)) and to two augment options(lithium or T3) added to the primary antidepressant (CIT, BUP, SER, orVEN). Those without sufficient improvement at level 3 are eligible for level 4random assignment to one of two switch options (tranylcypromine orMIRT plus VEN).

The primary outcome is a clinician rating of depressive symptoms(HAM-D17) administered at entry and exit from each treatment level

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through telephone interviews by assessors masked to treatment assignments.Secondary outcomes include the IDS-C30 (by telephone-based interviewers)and self-reports of depressive symptoms, physical and mental function, sideeffect burden, client satisfaction, and health care utilization, all obtained byIVR telephone calls.

Participants with remission and those with a response who do not wish toproceed to the next level may enter the 12-month naturalistic continuationphase with brief monthly and more complete quarterly assessments.

Level 1Citalopram was chosen as a representative of the SSRI class. The authors

believed that patents will end during the lifetime of STAR*D on severalSSRIs, which in turn will likely lead to managed care and other systemsrecommending one of these SSRIs as a first-step agent. What is the next beststep following an unsatisfactory response to an SSRI is an importantquestion with high public health significance. Placement of CIT in specific,and SSRIs as a group, at level 1 should not imply that this is a preferredor endorsed practice. The selection was a research and scientific choicedesigned to answer one important question.

Citalopram (level 1) and SER (level 2) were selected from among theavailable SSRIs because of their minimal or modest effects on the cyto-chrome P-450 isoenzyme system (ie, minimizing drug-drug interactions),while also taking advantage of the minimal (CIT) or modest (SER) pro-clivity to have a discontinuation syndrome, which is more likely withshorter half-life SSRIs. Neither agent needs, in most cases, to be taperedwhen switching from it to another treatment. FLU also has minimaldiscontinuation problems. Its longer half-life, however, entails a study ofa combination of fluoxetine and the next switch agent (in level 2), which theauthors wished to avoid for scientific reasons.

Level 2Sertraline (see previously) was selected for level 2 to study the

effectiveness of an SSRI (CIT at level 1) to an SSRI (SER at level 2)switch. This common practice may or may not be as effective as switching‘‘out of class’’ to either BUP (which has no direct effect on the serotoninsystem) or to VEN (which has both NE and 5-HT effects), as suggested bya recent double-blind study [43]. Finally, the switch to CT is supported asa reasonable option following lack of efficacy with an antidepressant giventhe greater than 50% response rate to a variant of CT (Cognitive BehavioralAnalysis System of Psychotherapy) in patients with chronic MDD who hadnot responded satisfactorily to a 12-week trial of nefazodone [132]. Level 2switches test commonly held clinical beliefs and common clinical practices.In all cases, these beliefs and practices are supported only by open, non-comparative trials.

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The augmentation options for level 2 (BUS, BUP, or CT) are alsosupported by either open or double-blind studies [27,39]. The authors choseCT as opposed to interpersonal or behavioral therapy because CT has morerandomized trial evidence (acute phase) studies, and CT has been studied asa treatment for residual symptoms in two controlled trials [94,115]. Ideally,the authors would have liked to have studied more than one psychotherapyat level 2 or even compared it with an SSRI at level 1, but resource con-straints required a narrower scientific focus.

Finally, the authors wanted level 2 to entail treatments that could bedelivered in primary care settings. More complex medication regimens (eg,lithium augmentation, combining a TCA with CIT as an augmentingstrategy) were excluded from level 2.

Level 2ALevel 2A provides the same medications (as switch agents) as level 2 for

only those participants who had previously had only a single medicationtrial. The rationale is the same as for the level 2 medication choices. Thereasoning is that participants who enter level 3 should have had twoadequate antidepressant medication trials.

Level 3The selection of lithium or T3 as augmenting strategies at level 3, which in

most cases is delivered by specialists, is designed to compare these two well-established augmenting agents when used with newer antidepressants (ie,VEN, BUP, CIT, or SER). The switch options in level 3 compare a genericTCA (NOR) with another branded agent (MIRT) that works by a differentpharmacologic effect. Both of these agents affect both 5-HT and NEsystems. One (NOR) entails a greater safety risk (cardiovascular effects),however, in overdose. If the newer agent is as effective as the less expensivebut more medically risky agent, the newer agent is preferred in practice.Such a finding has high public health significance.

Level 4Level 4 participants have a relatively highly treatment-resistant de-

pression. They have been ill for at least 36 weeks while in the protocol (levels1, 2, and 3 are each 12 weeks in length). Some may also have had 12 to 14weeks of CT (ie, ill for up to 48 weeks while in the protocol). For theseparticipants, more complex, somewhat more medically risky interactions arejustified. The MAOI tranylcypromine is one of two switch options. MAOIsseem to be effective when dual action agents, such as the TCAs [44]. Theother switch option is a combination of two agents used in practice fortreatment-resistant depression (MIRT and VEN). An equivalent outcomelikely recommends against the MAOI, given the dietary and other re-quirements surrounding its use.

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In sum, the selection of the specific treatment options is an attemptto balance safety, common practice, and pharmacologic reasoning, whileempirically testing choices that can be implemented in routine primary care(levels 1 and 2) or specialty care (levels 1 to 4) practice. By randomization,assessment of symptomatic and functional outcomes, and client satisfactionand side effect burden informs specifically about the particular treatmentoptions under study. Simultaneously, post hoc analyses searching forpretreatment predictors of response shed light on whether particular groupsof participants or types of depression might especially benefit from one oranother of these options.

Issues in randomization and masking

Equipoise versus forced randomization

From the 4000 participants who enter the STAR*D treatment protocol,2000 participants are expected not to have a satisfactory therapeutic re-sponse to CIT. These 2000 individuals are eligible for seven differenttreatment options at level 2. These options may be conceptualized asrepresenting two overall treatment strategies: medication or psychotherapyswitch, switching from CIT to another antidepressant medication or CT;and medication or psychotherapy augmentation, augmenting CIT witha second medication or CT. Within level 2, multiple sets of treatmentoptions (substrategies) are compared, reflecting competing clinical ration-ales as to the types of medications to use for participants without a satis-factory response to an initial SSRI. Specifically, for those who switchtreatments at level 2, SER (a second SSRI), VEN (an antidepressant withboth noradrenergic and serotonergic effects), BUP (an antidepressant withboth noradrenergic and dopaminergic effects), or CT are available. Like-wise, within the medication or psychotherapy augmentation strategy, thethree treatments for augmenting CIT are BUP, BUS (an antianxietymedication), or CT. At treatment levels 2, 2A, 3, and 4, participants arerandomly assigned to all treatment groups and options found acceptable tothem.

Lavori et al [133] have described the methodologic approach used inSTAR*D, called ‘‘equipoise-stratified randomization.’’ For example, at level2, before randomization, participants indicate whether they wish to continueor discontinue the CIT from level 1. They are encouraged to accept bothpossibilities, but some may decide they do not wish to continue, whereasothers may insist only on continuing CIT. This first decision determines ifparticipants are eligible for either the medication or psychotherapy switch oraugmentation groups, or both. Secondly, participants are asked if they arewilling to accept CT as a treatment option at level 2. Those declining CTaltogether are assigned to either a medication switch or a medication

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augmentation group. Although all participants eligible for level 2 are askedto accept multiple strategies, they may continue in the protocol so long asa randomized assignment can be made among treatments found acceptable.Participants cannot select among specific medication treatment options (ie,they must accept both of the medication augmentation options or all threemedication switch options). Participants who do not accept randomizationto any option exit the study. When data are analyzed for level 2, thesubstrategies are defined by participant acceptability: (1) switching to a newtreatment (medication or psychotherapy switch); (2) augmenting with asecond treatment (medication or psychotherapy augmentation); (3) switch-ing, but only to a new medication (medication switch); (4) augmenting, butonly with medication (medication augmentation); (5) switching or augment-ing, but only with medication (medication augmentation or switch); or (6)switching to or augmenting with only CT (psychotherapy augmentation orpsychotherapy switch).

One of the imperatives guiding the development of STAR*D was topreserve the integral role participants typically play in negotiating treatmentdecisions in clinical settings. As medical practice has evolved and publicaccess to information regarding treatment of mental illness has grown,clinicians have increasingly recognized the value of patient participationwhen decisions need to be made. Among patients with mood disorders,efforts to foster patient involvement have been encouraged as a putativemeans to empower patients, strengthen the therapeutic alliance, optimizetreatment adherence, and improve outcome [114,134–136].

Given the range of options available to participants whose depressiondoes not respond to an initial course of treatment, a participant’s prefer-ence routinely yields a major influence over the selection of subsequenttreatments. In clinical trials, however, scope for implementing participantpreferences is usually limited. Potential participants who are reluctant toembark on or risk randomization to a particular course of treatmenttypically register their preference by declining enrollment. As a result,participant pools are liable to bias with respect to such variables as pasttreatment history, symptom characteristics, illness beliefs and attitudes, andlevel of depression severity [137,138]. More generally, samples enrolled inclinical trials are unlikely to represent adequately those many patients forwhom lack of influence over treatment decisions is unacceptable. To maxi-mize the generalizability of this study, the authors believe that provisionsmust be made to accommodate participant preferences when they emerge.

The STAR*D design helps achieve several major goals. By incorporatingacceptability, the protocol more closely represents decision making inclinical practice than does a more standard protocol that offers random-ization across all treatments as the only option. On the other hand,STAR*D preserves the power of randomization to the fullest extent feasiblefor each participant. It is expected that this design will facilitate recruitmentof a diverse, broadly representative participant population, including those

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individuals who might normally decline enrollment in clinical trials, and willimprove participant retention by offering greater flexibility.

Masking

Neither the study participants nor the study clinicians in STAR*D aremasked to treatments. Research outcomes are collected by telephoneinterview with ROAs who are masked to treatment and by an IVR systemusing push-button telephones.

Tactical issues

The STAR*D ensures that only participants who are treatment-resistantor intolerant enter each subsequent treatment level. It is essential thatparticipants with merely ‘‘apparent treatment resistance’’ to inadequatetreatment do not move to the next treatment level (ie, those without anadequate drug dose or an adequate duration of treatment at the prior level)[139]. The issues of dose and duration (for both medication and psycho-therapy) are termed treatment tactics [32,35,140]. Current recommendationsas to dose and duration have only modest empirical support [32,111,131,139,141–143] based on post hoc data analyses.

Duration

Questions about treatment tactics are addressed during the initial level 1treatment with CIT, and during subsequent levels. There is evidence fora biologically determined latency period that delays the onset of response toantidepressant treatment [142]. By ensuring an extensive (8 to 12 weeks), yetclinically practical, exposure to each treatment at each level, one candetermine when a treatment should be declared ineffective, and when itsmaximal benefit has been attained.

Prediction of response or remission

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

Because STAR*D strongly encourages 12 weeks of treatment withvigorous dosing at each level, it provides an opportunity to determinewhether specific baseline features (patient, illness, and care features) affectthe likelihood and timing of clinical benefits for each treatment option. Ifsample sizes are adequate, it will determine if there are interactions betweentype of treatment, the previously mentioned predictors, and response.

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Prediction of relapse or recurrence

Very little is known about the long-term outcome of participants whosuccessfully remit with an antidepressant, particularly if their remissionfollows nonresponse or partial response to a prior antidepressant trial. Howlong are they able to remain well? STAR*D includes longitudinal,naturalistic 12-month follow-up of all participants who have a satisfactoryresponse to any treatment option at any level. This population allows theinvestigation of possible clinical predictors of relapse or recurrence, becausemost participants who experience a relapse or recurrence during continuedantidepressant treatment do so within the first 6 to 12 months afterremission [36,37].

How common are relapses or recurrences during continued antidepres-sant treatment in real world clinical practice? Are there clinical predictors ofrelapse or recurrence? Are those with greater degrees of resistance morelikely to suffer more relapses or recurrences or have them earlier?

Limitations of the protocol

The STAR*D, although extensive, does not answer every questionregarding the treatment of MDD. Only one form of psychotherapy is beingevaluated (although other forms will be considered once the plannedprotocol is completed, if the National Institutes of Mental Health continuessupport). To ensure sufficient homogeneity and sample size, the authors hadto begin with a single treatment at level 1, rather than several. The multipleroles or preferred positions in the randomization scheme for psychotherapycould not all be evaluated scientifically at this time. Similarly, several otherpotential first-line medication classes or types could not be evaluated.

Issues in dissemination of findings

Despite the high prevalence of MDD and the availability of effectivetreatments, underdiagnosis and undertreatment remain the norm. Only onethird to one half of individuals with MDD is properly recognized bypractitioners, and even of those who are, many do not receive adequatetreatment [144]. In a study by Wells et al [13] from data across treatmentsettings, only 11% of mildly depressed patients received an antidepressantand 29% of patients of high severity received an antidepressant. Of thosewho were treated with an antidepressant, only 41% received an adequatedose. Other studies also show that most patients prescribed an antidepres-sant medication are not treated at an adequate dose or for a long enoughperiod of time. These findings indicate that there is insufficient applicationof research findings in the routine care of depressed patients. Finding aneffective dissemination method for empirically developed evidence continuesto be a great challenge [145–149].

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Despite tremendous resources invested in dissemination, results are oftenunderwhelming. Simply publishing treatment guidelines or algorithms orproviding them through continuing medical education programs is notespecially effective in changing practice [145]. Multiple interventions andmore immediate instruction or feedback on an ongoing basis have demon-strated a higher effect rate on the use of and compliance with new infor-mation and guidelines [150,151].

Medical practice has been lagging in its use of new technologies andcomputers to improve patient care. A recent review shows that computer-assisted decision support systems improve both clinical performance andpatient outcomes in most interventions from over 68 trials reviewed [152].To make treatment procedures more stable and predictable, health caredelivery systems in the private and public sectors are making major in-vestments in new information systems technology. These new technologieshelp translate the extensive, newly acquired knowledge into improvedmedical decisions at the time of service delivery.

In psychiatry, the last decade has witnessed a substantial growth in thenumber of medication alternatives with differing mechanisms of action,tolerability, and safety, and in some cases spectrum of action, for thetreatment of patients with severe and persistent mental illnesses [153,154].Results from STAR*D will provide evidence by which to inform sequentialtreatment algorithms, information that can then be disseminated with thisnew technology.

Computer technology not only provides assistance in the administrativeaspects of medicine, but has also begun to assist in clinical care. A com-puterized treatment algorithm is a viable solution to the obstacles con-fronting clinicians in busy clinical settings. This approach can assist theimplementing of ‘‘best practices’’ in various clinical environments, includingprimary care settings, which have significant time and resource constraints.Acceptable built-in alternatives increase adherence because this allowsclinicians some freedom of clinical input [155].

Education of both clinicians and patients is another beneficial factor insuccessful algorithm implementation [156–158]. Videos, demonstrations,and posters along with the traditional memos from administrators andin-service training were found to assist both clinicians and patients tounderstand the purpose of and to develop trust in the algorithm [159]. Asmultiple studies show, simply providing information, either by mailing,publication, or continuing medical education, does not have a significanteffect on clinician practice patterns. Stronger implementation tactics arenecessary.

The implementation of the algorithm is likely to have a positive effect onpatient care. Some patients may improve because of the increased attentionthey receive, especially initially, through following the algorithm. Overall,patients should improve secondary to the increased degree and quality ofcare provided, which in the long term should decrease cost.

486 M. Fava et al / Psychiatr Clin N Am 26 (2003) 457–494

The authors will begin the process of dissemination and assist inimplementation of STAR*D results as findings from the first two stagesbecome available.

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