star-d 1 - desenho do estudo

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Design paper

Sequenced treatment alternatives to relieve depression

(STAR*D): rationale and design

A. John Rusha,*, Maurizio Favab, Stephen R. Wisniewskic, Philip W. Lavorid,Madhukar H. Trivedia, Harold A. Sackeime, Michael E. Thase f,

Andrew A. Nierenbergb

, Frederic M. Quitkinf

, T. Michael Kashnerg

,David J. Kupferf, Jerrold F. Rosenbaumb, Jonathan Alpertb,Jonathan W. Stewarte, Patrick J. McGrathe, Melanie M. Biggsa,

Kathy Shores-Wilsona, Barry D. Lebowitzh, Louise Ritzh, George Niedereheh,for the STAR*D Investigators Group

1

aDepartment of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USAbClinical Psychopharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

cDepartment of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAdDepartment of Veterans Affairs Cooperative Studies Program and Stanford University, Palo Alto, California, USA

eNew York State Psychiatric Institute and the Department of Psychiatry,

College of Physicians and Surgeons of Columbia University, New York, New York, USAfDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

gHealth Services Research and Development Service, Department of Veterans Affairs, and Department of Psychiatry,

University of Texas Southwestern Medical Center, Dallas, Texas, USAhNational Institute of Mental Health, Bethesda, Maryland, USA

Received 24 September 2001; accepted 8 August 2003

Abstract

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic

major depressive disorder. The study compares various treatment options for those who do not attain asatisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls

4000 adults (ages 18 75) from both primary and specialty care practices who have not had either a prior

inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major

depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are

0197-2456/$ - see front matterD 2004 Elsevier Inc. All rights reserved.doi:10.1016/S0197-2456(03)00112-0

* Corresponding author. Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines

Boulevard, Dallas, TX 75390-9086. Tel.: +1-214-648-4600; fax: +1-214-648-4612.

E-mail address: [email protected] (A.J. Rush).1 See appendix for a complete listing and location of regional centers, regional center directors, and clinical sites.

www.elsevier.com/locate/conclintrial

Controlled Clinical Trials 25 (2004) 119142


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eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion,

venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy).

Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are

eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2Aparticipants without sufficient improvement are eligible for random assignment to two switch options

(mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary

antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement

at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the

combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton

Rating Scale for Depression, administered at entry and exit from each treatment level through telephone

interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive

symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and

cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase

with brief monthly and more complete quarterly assessments.

D

2004 Elsevier Inc. All rights reserved.

Keywords: Major depressive disorder; Antidepressants; Cognitive therapy; Randomized clinical trial; Multistep multicenter

clinical trial; Utilization and costs

1. Introduction and background

Major depressive disorder (MDD) is a common, typically recurrent, often chronic, and very disabling

disorder, costing the United States over $44 billion/year in direct and indirect costs [1]. MDD has a

lifetime prevalence of 4.9 17.9% [2,3]. Women are twice as likely to suffer MDD as men. MDD occ urs

more frequently among young adults and among those with general medical conditions (GMCs) [4].Depressed adults have nearly twice the annual health care costs of those without depression [5].

MDD is usually an episodic disorder with an average of one episode every 5 years [4,6]. Of persons with

MDD, 2035% experience a chronic, unremitting course [4,6,7]. A similarly sized (and partly over-

lapping) group has early-onset dysthymia, a condition involving milder but chronic depressive symptoms,

which precede the onset of major depressive episodes. Relapses and recurrent episodes are most likely

among patients with antecedent dysthymia or incomplete interepisode recovery (i.e., those with residual

interepisode symptoms). Longer major depressive episodes appear to be more difficult to treat [8,9].

Depression is the fourth most disabling medical condition worldwide based on disability-adjusted life-

years (years of life lost due to premature death and years lived with a disability of specified severity and

duration) [10]. Depression is predicted worldwide to be second only to ischemic heart disease with regardto disability by the year 2020 [10]. Patients with MDD function more poorly than other outpatients with a

variety of GMCs in terms of physical activity and occupational and social role responsibilities [11].

As established by randomized controlled trials (RCTs), many medications and several depression-

targeted psychotherapies have efficacy [1216]. Since most of these efficacy studies exclude many

patients with general medical and psychiatric comorbidities, generalizability is limited. Thus, the

effectiveness of established treatments in more representative clinical populations is not well established.

About 50% of outpatients with nonpsychotic MDD initially treated with either a time-limited,

depression-targeted psychotherapy or a single antidepressant medication respond (i.e., have z50%

reduction in baseline symptom severity) to treatment in efficacy trials [4,12,13,17,18].

A.J. Rush et al. / Controlled Clinical Trials 25 (2004) 119142120


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In acute phase RCTs with medications lasting 6 8 weeks, about 20 30% attain symptomatic

remission, while 2030% respond but have residual symptoms (i.e., have a z50% reduction in total

symptom severity without remission). Thus, only about 5070% of those who respond attain remission

[17,19].2 Similar outcomes are found with time-limited, depression-targeted psychotherapies [20,21].Symptomatic response with residual symptoms is associated with continuing functional disability [8,22

24] and a worse prognosis [2527].

The management of patients with treatment-resistant depression (i.e., lacking remission to one or

more adequate trials of treatment) is a major public health challenge [28]. RCTs that compare treatments

for depressions that have not remitted after an initial antidepressant treatment are rare. Thus, clinical

practice guidelines that suggest different second or third treatment steps rest largely on clinical

consensus or on open uncontrolled trials [14,29,30]. In fact, mostpractice guidelines do not recommend

specific next-step treatments or specific treatment sequences [4,13,15]. Scientific evidence to define

the most specific, effective next-step treatment options for treatment-resistant MDD should improve

clinical outcomes and may reduce the cost of care [3133].

2. Aims and treatment paradigm

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) aims to define prospectively

which of several treatments are most effective for participants with MDD who experience an

unsatisfactory clinical outcome following an initial and, if necessary, subsequent treatment(s). Eligible

participants who consent to STAR*D are enrolled into the first level of STAR*D (level 1), which uses the

selective serotonin reuptake inhibitor (SSRI) citalopram (CIT). Participants with an adequate clinical

response with level 1 (as defined by the clinician, who is informed by a brief clinical ratingsee below)

enter a 12-month, naturalistic, follow-up phase.Participants without a satisfactory clinical outcome to CIT are eligible to enter a series of randomized

clinical trials. The first trial (level 2) compares the effectiveness of seven different treatments including

four switch options (venlafaxine [VEN], sertraline [SER], bupropion [BUP], and cognitive therapy [CT])

and three augment options (CT, BUP, or buspirone [BUS] added to CIT) ( Fig. 1). Thus, STAR*D

evaluates the comparative effectiveness of different treatment strategies, such as switch of treatment

(switch) versus augmentation of the initial treatment (augment) at level 2. It also compares the

effectiveness of individual treatment options within and across these two strategies (switch versus

augment). Those with a satisfactory therapeutic response in level 2 enter the 12-month naturalistic follow-

up phase.

Participants without a satisfactory therapeutic response to both CIT (level 1) and to CT (level 2),whether used as a switch or augment option, enter level 2A, an RCT comparing the effectiveness of two

2 According to Frank et al. [19], response is a clinically significant reduction in depressive symptoms (e.g., z50% reduction

in baseline symptom severity). Remission is the complete absence of depressive symptoms, defined for this protocol as total 17-

item Hamilton Rating Scale for Depression (HRSD17) score of


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pharmacological switch options (BUP or VEN),3 which ensures that all participants who enter level 3

have not responded to two different antidepressant medication treatments. Those with a satisfactory

response to level 2A enter the 12-month follow-up, while those without such a response enter level 3.

Level 3 is an RCT that compares the relative effectiveness of two switch options (mirtazapine [MRT]

or nortriptyline [NTP]) and two augment options (lithium [Li] or thyroid hormone [THY]). Those with a

satisfactory therapeutic response to level 3 enter the 12-month naturalistic follow-up phase. The

remaining participants may enter level 4, an RCT comparing the effectiveness of two treatment switch

options (tranylcypromine [TCP] or the combination of MRT+VEN). Those with an adequate response to

level 4 enter the 12-month naturalistic follow-up, while the remaining participants exit the study and are

treated as clinically indicated.

3. Major endpoints

The primary outcome is depressive symptom severity, measured by the 17-item Hamilton Rating

Scale for Depression (HRSD17) obtained at the end of each treatment level (levels 1 4) by

3 Level 2A did not include SER because we viewed this as an unlikely clinical choice, given the out of class switch

entailed with CIT (i.e., a return to the original class would be clinically redundant). Second, with two as opposed to three cells at

level 2A, the potential for adequate sample sizes was increased.

Fig. 1. Treatment strategies/substrategies and options.



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independent, telephone-based interviewers with no knowledge of treatment assignment [34,35].

Treatment remission, for research purposes, is defined as an HRSD17 total score


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response without remission is a z50% reduction in baseline QIDS-C16 score but a QIDS-C16 score > 5

at exit from a treatment level (as long as exit is not due to intolerance).

The decision to move to the next level is made by the clinician based on symptom severity (assessed

by clinical judgment and informed by the QIDS-C16 total score) and by side-effect status. Participantswith clear intolerance or minimal reduction in baseline symptom severity (e.g.,


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audiotapes from 20% of study sessions are reviewed; if therapists experience significant adherence

problems, additional supervision is provided. Therapists unable to adhere to CT methods are not

permitted to continue to see study patients.

4.4. Concurrent treatments

Across all levels, adjunctive treatments for associated symptoms (e.g., insomnia) or medication side

effects (e.g., sexual dysfunction) are allowed, thereby mirroring common practice, but antipsychotic

(e.g., risperidone or olanzapine) and mood-stabilizing agents (e.g., valproic acid or lamotrigine) other

than Li as one of the randomized augment options at level 3 are prohibited. Participants may receive

treatment for concurrent GMCs, as long as these medications do not contraindicate the use of level 1 and

all level 2 treatments.

Participants may not be receiving any psychotherapy that is aimed at the treatment of depression other

than CT as prescribed in the protocol. Any antidepressant medications taken at study entry must bediscontinued (after consent) before beginning CIT. The discontinuation is guided by clinical judgment

without the formal requirement of a washout period.

Table 1

Inclusion/exclusion criteria for study entry

Inclusion criteria

1. Age 1875

2. Written informed consent obtained

3. Score z14 on the HRSD174. Meets DSM-IV* criteria for single or recurrent nonpsychotic MDD

a. At least one of the symptoms is either depressed mood or loss of interest and pleasure and

b. Five or more symptoms have been present simultaneously during at least the past 2 weeks and represent a change from

previous functioning

Exclusion criteria

1. History of bipolar disorder (I, II, not otherwise specified) (lifetime)

2. History of schizophrenia, schizoaffective disorder, or psychosis not otherwise specified (lifetime)

3. Current anorexia or bulimia

4. Current primary obsessive compulsive disorder

5. History of clear-cut intolerability to, or lack of effect with, an adequate trial (e.g., 60 mg of fluoxetine for 6 weeks) of at

least one protocol medication in the current episode of MDD

6. Lack of response to an adequate trial of an SSRI (CIT, FLU, paroxetine, and SER) in the current episode of MDD (e.g.,

adequate trial with CIT is at least 40 mg/d for 6 weeks or 60 mg/d for the last 2 weeks of a 6-week trial)7. Currently taking CIT and has been taking it for more than 7 days

8. Did not respond to 16 or more sessions of CT in the current episode of MDD

9. Did not respond to seven or more sessions of electroconvulsive therapy in the current episode of MDD

10. Has general medical condition that contraindicates any level 1 or 2 treatment option

11. Is taking any concomitant medication that contraindicates any level 1 or 2 treatment option

12. Requires immediate hospitalization for substance/alcohol detoxification or treatment

13. Requires immediate hospitalization or day treatment for psychiatric disorder(s)

14. Requires antipsychotic medication or mood stabilizers

15. If female, is pregnant

*DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition [45].

A.J. Rush et al. / Controlled Clinical Trials 25 (2004) 119142 125


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4.5. Follow-up

STAR*D also aims to describe the incidence, nature, and course of symptoms and function for those

entering the 12-month naturalistic follow-up.This follow-up phase is available to all participants with at least a response to any treatment. Clinic

visits are held every 23 months. All participants are encouraged to continue the same type and dose of

medication found successful in acute treatment.

4.6. Study participants

The broad inclusion and minimal exclusion criteria (Table 1) were chosen to include outpatients with

nonpsychotic MDD who would typically receive medication or psychotherapy in most clinical settings.

Those over age 75 were excluded because concomitant GMCs or medications may complicate treatment

with a number of protocol medications, while adolescents/children were excluded because the efficacyand safety of most study medications have not been established and the delivery of CT would have

required separate training/specific experience in this population.

The study protocol was developed according to the principles of the Declaration of Helsinki [46]. All

risks, benefits, and adverse events associated with each treatment within the randomized treatments are

explained to study participants, who provide written informed consent prior to study entry and again

prior to entry into each new level of treatment or into follow-up.

5. Study organization

5.1. Organizational structure

The STAR*D infrastructure includes the NCC (Dallas), the data coordinating center (DCC)

(Pittsburgh), and 14 regional centers (RCs), each of which oversees two to four primary and specialty

care clinical sites (CSs). Each RC provides support, quality control, and coordination for the recruitment,

retention, and safety of study participants and oversees the acquisition of clinical information from the

CSs. STAR*D provides opportunities for ancillary studies relevant to improving the treatment of

treatment-resistant depression that otherwise do not impede the conduct of the main protocol.

5.2. Site selection/training/recruitment

Applications from potential RCs were reviewed, site visits were conducted at those that ranked highly,

and RCs were selected based on the likelihood that CSs in either the public or private sector overseen by the

RC could meet recruitment goals, ensure adequate overall minority representation, and provide adequate

and safe protocol adherence. CSs largely include practices not typically engaged in efficacy RCTs.

CRCs at each RC are trained and certified in protocol implementation and data collection methods.

CRCs work very closely with the participants and clinicians, administer some of the clinician-rated

instruments, ensure that all self-rated instruments are properly filled out, and function as study

coordinators, providing a liaison among CSs, the RC, and the DCC. The CRCs minimize research

burdens for clinicians.



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5.3. Enrollment/randomization

Eligible and consenting outpatients are screened and enrolled in protocol-defined treatment at the

CSs. The CRC then calls the IVR system and enters a patient identification number. Consentingparticipants undergo randomization at levels 2, 2A, 3, and 4. Treatment assignment using randomization

occurs via a blocked randomization scheme, stratified by CSs, and by the treatment options that are

acceptable to the participant at that particular level (levels 2 and 3).

To account for differences in participants acceptance of the various treatment strategies (e.g.,

augment or switch) or substrategies (e.g., augment exclusively with one of the two medications), we

have created specific acceptability strata for levels 2 and 3. Participants are stratified according to

their acceptance of the seven treatment options at level 2 and of the four treatment options at level 3.

Participants are randomized among the treatment options included in the strategies (or substrategies)

that they accept. Level 2 has two strategies (augment or switch) and four substrategies (medication

switch, medication augment, CT switch, and CT augment), while level 3 has two strategies (switch andaugment). A patient must accept all treatment options within a substrategy (levels 2 and 3). In analyses

comparing strategies or particular sets of substrategies, outcome data will be restricted to all

participants assigned to those treatment options under conditions of potential randomization to any

of them.

Uniform random number generation is used to randomize participants among treatment options within

each level, with an equal chance of receiving any option. Randomization was blocked with the block size

equal to the number of treatment options within the preferred strata.

The randomization process for the next treatment level is initiated upon exiting the current treatment

level, following participant written consent to proceed. The CRC notifies the IVR system that the

participant is exiting the current level and entering the next treatment level and presents the participants

treatment preferences. The IVR system identifies the next treatment option in the appropriate stratum andimmediately responds to the CRC.

6. Data collection

6.1. Screening and clinical data

Table 2 summarizes the data collected during the screening process. Data collection forms can be

ordered at www.star-d.org.

At all clinic visits, information is obtained to guide clinicians implementing study treatments (Table3). Symptomatic status is measured by the QIDS-C16 [4042]. The QIDS-C16 is used to gauge

response because previous experiences suggest that global ratings may be insensitive to detecting

residual symptoms [49,50]. The QIDS-C16 rates all nine criterion symptoms of MDD, is easily

administered, and is distinct from the primary symptom measure (the HRSD17). The self-rated form of

the QIDS (QIDS-SR16) is also administered at all visits [41]. The clinical record form records the

Clinician Global ImpressionImprovement scale [51], the Patient-Rated Inventory of Side Effects,

and global ratings according to the Frequency and Intensity of Side Effects Rating (FISER), and

Global Rating of Side-Effect Burden (GRSEB), which are seven-point Likert scales developed for this

study.

http://%20http//www.star-d.orghttp://%20http//www.star-d.org


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6.2. Research outcomes

Research outcomes (Table 4) are collected by IVR and by telephone interviews conducted by

Research Outcomes Assessors (ROAs), independent of and masked to treatment. ROAs collect the

HRSD17, the IDS-C30, and the five-item Income and Public Assistance Questionnaire measuring the

participants monthly income by source (employment, assistance and welfare, unemployment

Table 2

Data collection at screeninga

Domain Measure Time

(minutes)

Method Occasion Administrator Location

Consent Consent 20 Interview At intake CRC Clinic

Characteristics Clinical/demographic features 3 Interview At intake CRC Clinic

Eligibility Inclusion/exclusion 5 Interview At intake CRC Clinic

Concurrent psychiatric

diagnosis(es)

Psychiatric Diagnostic

Screening Questionnaire [47]

2030 Self-report At intake Participant Clinic

Symptoms Hamilton Rating Scale

for Depression (17-item) [34,36]/

Quick Inventory of Depressive

SymptomatologyClinician

Rating (16-item) [4042]

15 Interview At intake CRC Clinic


SymptomatologySelf-Report(16-item) [4042]

4 Self-report At intake Patient Clinic

General medical

conditions

Cumulative Illness Rating Scale [48] 5 Interview At intake CRC Clinic

aScreening and baseline research outcomes assessments are obtained on all participants (anticipated n = 4000).

Table 3

Data collection at clinical visitsa

Domain Measure Time (minutes) Method Administrator

Symptoms Clinical Global

ImpressionImprovement (1-item)

0.5 Interview Clinician


SymptomatologyClinician Rating (16-item)

3 Interview CRC/clinician


SymptomatologySelf-Report (16-item)

4 Self-report Patient

Side effects Frequency and Intensity of Side Effect

Rating/Global Rating of Side-Effect

Burden (3-item)

1.5 Self-report Patient

Patient-Rated Inventory of Side Effects (8-item) 3 Self-report Patient

Medication Clinical record form 3 Self-report Clinician

Medication

compliance

Medication adherence questionnaire 3 Self-report Participant

aThese measures are used to provide consistent information to the clinicians who use this information in the protocol and are

recorded on the CRF. These measures are collected at clinic visits for participants in protocol treatment. They are not collected

at clinic visits for participants seen in follow-up.



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benefits, and unearned income including retirement benefits, interest, royalties, and leases). The IVR

collects the QIDS-SR16 and ratings of function, quality of life, side effects, and health care

utilization.

The IVR method was chosen because self-reporting of symptomatic and functional outcomes innonpsychotic, depressed outpatients reliably corresponds to observer ratings obtained through standard

clinical interviews [38,62,63]. IVR has the advantages of: (1) high participant acceptance and

convenience, (2) high interrater reliability with well-standardized measures, (3) high correspondence

with clinical interview data, (4) high sensitivity to change over time, and (5) equivalent capacity to

distinguish symptomatic outcomes between treatment groups when compared to standard clinician

ratings in depressive and other psychiatric disorders [63].

Research outcomes are collected at pretreatment, at exit from each treatment level, and at months 3, 6,

9, and 12 in follow-up. Interim research outcomes (QIDS-SR16, five-item Work and Social Adjustment

Scale [WSAS], six-item Work and Productive Activity Impairment Questionnaire [WPAI], and FISER/

GRSEB) are also collected by IVR, at week 6 in each treatment level and at months 1, 2, 4, 5, 7, 8, 10,and 11 in follow-up.

6.3. Utilization/cost data

STAR*D gathers information on participant use of health services, measured in both physical units and

costs by type (depression-related, other psychiatric or mental health care, general medical care) and setting

(outpatient clinic, emergency room, inpatient care). Indirect costs include changes in market produc-

tivity measured in terms of employment status, hours worked, and earned income (wages, salaries, tips,

commissions, and earnings from self-employment) [6467]. Changes in both market work and household

Table 4

Research outcomesa

Domain Measure Time (minutes) Method

Symptoms Hamilton Rating Scale for Depression

(17-item)/Inventory of Depressive

SymptomatologyClinician-rated (30-item)

20 25 Telephone (ROA)


SymptomatologySelf-Report (16-item)

6 Telephone (IVR)

Function Short-Form Health Survey (12-item) [52] 4 Telephone (IVR)

Work and Social Adjustment Scale (5-item) [53] 2 Telephone (IVR)

Work and Productive Activity Impairment

Questionnaire (6-item) [54]

2.5 Telephone (IVR)

Quality of life Quality of Life Enjoyment and Satisfaction

Questionnaire [55]

6 Telephone (IVR)

Side effects Frequency and Intensity of Side Effect

Rating/Global Rating of Side-Effect Burden (3-item)

1.5 Telephone (IVR)

Patient satisfaction Patient Satisfaction Inventory (2-item) 1 Telephone (IVR)

Utilization and cost Utilization and Cost Patient Questionnaire

(15-item) [5661]

5 Telephone (IVR)

Income Income and Public Assistance Questionnaire (5-item) 3 Telephone (ROA)

Current treatment Current Treatment Questionnaire (5-item) 2 Telephone (ROA)aResearch outcomes are obtained at entry and exit from each treatment level and in follow-up at months 3, 6, 9, and 12.



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management functioning due to depression symptoms (WSAS) and health status (WPAI) are also

measured. Indirect costs also include the administrative costs associated with welfare transfer payments.

6.4. Data management

Data are collected on paper forms, through an IVR system, and through direct electronic transfer from

CS administrative databases. The paper data collection forms are faxed to the DCC. The fax

transmissions are sent directly to a microcomputer where the forms are scanned using optical character

recognition software, and data are immediately transferred into an ACCESS database on a secure server.

The data are verified and pass through an editing process to check for logical inconsistencies within the

data. Any discrepancies are e-mailed to the appropriate CRC for resolution. The resolutions are e-mailed

back to the DCC for inclusion in the database.

IVR data are transferred routinely from Health Technology Systems, Inc. (Madison, WI) to the DCC,

where they are appended to the other study data.Reports are available to study personnel via the study website for monitoring data quality, recruitment,

and treatment adherence. These reports are updated three times a week to assure the most recent data are

being assessed.

Data abstracted from the CS administrative databases are used solely for the economic analyses and as

a check to determine patient protocol adherence.

All data collection forms and data reports include only the subjects study identification number (ten

alpha-numeric characters). The first two characters indicate the RC, the third and fourth indicate the CS,

the fifth through seventh indicate the sequential recruitment of the subject at that CS, and the last three

characters indicate the subjects name code (first three letters of the last name). No names or personal

identification information are sent to the DCC or stored in the STAR*D database.

6.5. Statistical considerations

Each level of treatment past level 1 is considered to be a unique RCT. The primary analyses make no

attempt to control for prior treatments, assuming that the random treatment assignment will balance the

prior treatments across the treatment groups. Secondary analyses may be conducted to determine if there

is a prior treatment effect, especially if there is an imbalance of the prior treatments across the treatment

groups.

7. Anticipated analytic approaches

Data analyses from levels 2 and 3 are complicated by the fact that participants may accept or decline

specific treatment strategies or substrategies (e.g., medication switch), in a so-called equipoise-stratified

randomized design [68]. For level 2 analyses, data will be stratified by acceptability strata, and Mantel-

Haenszel v2 tests will be used to make pairwise comparisons among the treatment options within the

medication switch substrategy and between-treatment options within the medication augment substrategy.

A satisfactory outcome for research purposes is defined as an HRSD17


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used at the next level of testing. For example, if the pairwise comparisons of the medication switch show

that SER is the most effective of the switch options, only the SER data will be used to represent the

medication switch substrategy in comparisons with the other substrategies (i.e., medication augment,

psychotherapy switch, or psychotherapy augment). If the pairwise comparisons of the medication switchoption show that no one medication switch is more effective than the others, then all the data on

medication switch options will be pooled when comparing this substrategy with other substrategies (i.e.,

medication augment, psychotherapy switch, or psychotherapy augment).

Next, all pairwise comparisons will be made between the medication switch, medication augment,

psychotherapy switch, and psychotherapy augment strategies. All comparisons will be made from

contrasts among outcomes for participants randomly assigned to all elements of the contrast. For

example, the comparison of medication switch to medication augment would include only those who

had included both medication switch and medication augment as acceptable substrategies [68].

The analytic approach for level 3 is the same as the analytic approach for the medication switch and

medication augment substrategies in level 2.The analyses of binary secondary endpoints will be conducted using the same analytic approach as

used for the primary endpoints. Continuous secondary endpoints will be analyzed by a standard F-test

for treatment effect applied to the two-way layout of strata and group.

Exploratory analyses are planned of the naturalistic follow-up data outcomes and utilization of health

care services during the 12-month follow-up period, including descriptive analyses of symptom severity,

daily function, and the likelihood of time to relapse. Logistic regression and time-to-event (e.g., Cox

proportional hazards) models will be used to assess the effect of factors associated with relapse and time

to relapse, respectively.

8. Sample size, power, and effect size

Levels 2 through 4 of STAR*D are considered separate RCTs, addressing the question, What should

be done next considering that the prior treatment(s) failed? Therefore, we have made efforts to maintain

an overall type I error rate of 0.05 within each level.

8.1. Level 2

The original National Institute of Mental Health Request for Application capped the total at 4000

participants. Given this studys design and previous reports in the literature and an expected response

rate to CIT (level 1) of 50%, it was estimated that 2000 participants would enter level 2.To estimate the sample size of each pairwise comparison at level 2, one needs to first make

assumptions about acceptability strata. Fig. 2 shows the mutually exclusive acceptability strata for the

level 2 treatments that we anticipate. The number of participants in each stratum (in parentheses) is also

included. For example, those entering stratum 1.1 have declined the medication switching substrategy

altogether but are willing to accept randomization to medication augment or to psychotherapy either as a

switch or augment substrategy.

The numbers shown in each stratum are only estimates, since such an experiment has not been

previously conducted. We arrived at these estimates using independent estimates by three experienced

practitioners/clinical investigators (Drs. Fava, Rush, and Thase) with surprisingly close interrater



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agreement. These estimates were derived largely from inferences based on the results of published

efficacy trials [13,16].

To determine the detectable effect size (v/N), consider the seven treatment options in level 2 [69]. We

propose a step up procedure, taking advantage of the fact that there are two substrategies (medication

switch and medication augment) where we can organize outcomes (response proportions): pVEN, pSER,

pBUP for the three medication switch strategies and pCIT+BUP and pCIT+BUS for the two medication

augment strategies. In addition, there are the response proportions from psychotherapy switch (pCT) and

psychotherapy augment (pCIT+CT). First, we will test the null hypotheses of the equality of treatmentoptions within the medication switch substrategy pVEN pSER;pSER pBUP and medicationaugment substrategy pCITBUP pCITBUS, at level aH3 (two-sided). This is test 1.

The next test, test 2, will compare the four substrategies (medication switch, medication augment,

psychotherapy switch, psychotherapy augment) (4 3H2 6 pairwise comparisons). If any of thethree null hypotheses from test 1 are rejected, then the treatment option with the superior outcome will

be used to represent the treatment substrategy. If the null hypotheses from test 1 are not rejected, then the

data within the medication switch and medication augment substrategies will be pooled.

It is possible that within test 1, a null hypothesis would be rejected for one of the substrategies (e.g.,

medication switch) but not within the other substrategy (e.g., medication augment). In this situation, the

Fig. 2. Mutually exclusive level 2 acceptability stratum-specific randomizations.



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data within the substrategy that did not reject a null hypothesis would be pooled. Within the substrategy

with a null hypothesis rejected, the treatment option with the superior outcome will be used to represent

the treatment substrategy.

Ifa = 0.025 for test 1 and test 2, the overall rate is


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For example, if we look at the comparison of the medication switch strategy to the medication

augment strategy, patients from acceptability strata where both medication switch and medication

augment are acceptable are included in the analyses. This would include the following acceptability

strata: 0, 1.3, 1.4, and 2.3. The estimate of the number of patients assigned to each treatment option inthe medication switch and medication augment strategies (n = 132) is obtained by summing the expected

number of patients per option across the pertinent acceptability strata from Fig. 2 (stratum 0: 24 (168/

7)+stratum 1.3: 4 (22/6)+stratum 1.4: 4 (22/6)+stratum 2.3: 100 (500/5) = 132). If the results of test 1

indicate that differences exist in the treatment options within the medication switch strategy and within

the medication augment strategy, then only one treatment option for each strategy will be used in test 2.

Thus, only 132 subjects in each treatment option would be used for test 2 (those assigned to the best

treatment option within each treatment strategy). In this case, the detectable effect size would be 0.228.

However, if no differences are detected within either strategy, then the patients within each strategy

will be pooled. The medication switch strategy would then have 396 patients (three medication augment

treatment strategies132 patients per treatment strategy) and the medication augment strategy wouldhave 264 patients (two medication augment treatment strategies132 patients per treatment strategy). Inthis case, the minimum detectable effect size would be 0.131.

8.2. Level 3

The analytic approach for level 3 will be similar to that for level 2. For level 3, the number of

acceptability strata and the number of comparisons are smaller. A total of 698 participants are expected

to enter level 3. We assume that 25% will choose a switch strategy, 25% will choose an augment

strategy, and 50% will be willing to accept all possible treatments. There will be only one test (e.g., test

1) in each of the strategies to determine if there is a more effective treatment in the switch strategy and in

the augment strategy. A type I error rate of 0.025H2 will be used for each of these tests. Given thisinformation, the sample size per treatment option for the test within each strategy would be 174

participants and the detectable effect size would be 0.253. The next step will be to compare the two

treatment strategies, using the test 2 approach as described above, with a type I error rate of 0.025. The

detectable effect sizes for this comparison are 0.234 for the nonpooled results and 0.165 for the pooled

results. This error rate is larger than the error rate used for test 2 in level 2 due to the fact that there are

fewer acceptability strata and fewer treatment comparisons involved in level 3.

8.3. Level 4

Assuming a sample size of 292 (146 per group), a type I error rate of 0.05, 80% power, and a two-sided alternative hypothesis, an effect size of 0.164 can be detected among the response rates of the two

treatment groups.

Generally, an effect size of 0.2 is considered small, while 0.5 is considered moderate [68]. Therefore,

at levels 2, 2A, 3, and 4, the study has the necessary power to detect small to moderate effects.

Sample size and thus power will depend on the acceptability of strategies (e.g., switch versus

augment) or substrategies (e.g., medication switch, psychotherapy switch, medication augment,

psychotherapy augment). If we have underestimated the acceptability of certain substrategies, then

power to compare them to other strategies or substrategies is obviously increased (i.e., more participants

than anticipated will be more widely accepting of more treatment substrategies). If we overestimated the



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acceptability of certain substrategies, then the power of comparisons involving them, and of treatment

option comparisons within them, is reduced. Even if our estimates are overstated by 50%, however,

nearly every substrategy still contains a sufficient sample to detect clinically meaningful differences in

effectiveness. Furthermore, if some substrategies (e.g., medication augment) are rarely accepted, studyresources will then be appropriately focused on comparing those treatments that have a good chance of

acceptance in representative participant populations.

9. Utilization and cost data analyses

Differences in utilization of services will also be calculated for each health outcome comparison

among patients randomly assigned to treatment options within the same acceptability strata. Classifying

care by type (depression-related, other mental, general medical) and setting (outpatient, emergency

room, hospital), between-group differences from the censored and bimodal distributions oftenencountered with utilization data are tested separately by first comparing use versus no-use (e.g.,

logistic regression) and then volume-of-use among users [7072]. Differences are computed from two-

level hierarchical models that account for timed observations nested within patient. The skewed volume

distributions are normalized with a log, square root, or other appropriate transformation. Cost subtotals

are computed for each care type and setting by multiplying the expected probability of use by the

predicted volume among users, and then by a schedule of unit-costs representing market-rates computed

from national transaction charges. Total costs are computed by summing the type and setting subtotals.

Sensitivity analyses are applied to contrast findings from different unit-cost schedules (e.g., Medicare

fees, Department of Veterans Affairs Reasonable Charges). Confidence intervals are computed by

bootstrapping samples.

10. Data monitoring and safety reporting

The data and safety monitoring board (DSMB) (three psychiatrists, one medical ethicist, one patient

advocate, one statistician, and one physician/patient advocate) meets every 3 months to monitor various

aspects of the study, including participant recruitment, protocol compliance, and adverse events. Adverse

events are recorded by study clinicians or CRCs at each clinic visit, based on spontaneous reports and on

a participant-completed side effects checklist. Serious adverse events (those that result in hospitalization,

prolongation of hospitalization, persistent disability, congenital anomaly, death, or that are life-

threatening) are reported verbally and in writing to the RC director, the STAR*D safety officer, theDSMB, the RC institutional review board, the Food and Drug Administration, and the manufacturer of

the medication. Interim analyses were initially proposed but not requested by the DSMB so they were

not included in the final design.

11. Current status

As of June 1, 2003, 2555 subjects had been enrolled into level 1 at 41 CSs from 14 RCs. Of these, 771

had entered level 2, 164 had entered level 3, and 42 had entered level 4.



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12. Conclusions

STAR*D uses a randomized, controlled design to evaluate both the theoretical principles and clinical

beliefs that currently guide the management of treatment-resistant depression in terms of symptoms,function, satisfaction, side-effect burden, and health care utilization and cost estimates. Given the dearth

of controlled data, results should have substantial public health and scientific significance, since they are

obtained in representative participant groups/settings, using clinical management tools that can easily be

applied in daily practice.

To ensure that treatment resistance is present before allowing participants to proceed to the next

treatment level, we provide training and oversight for both the pharmacotherapy and psychotherapy to

ensure reasonably high-quality care. This design (sometimes called a hybrid design) engages

representative patients and providers as participants, while ensuring adequate care [73].

STAR*D entails several innovations in study design and methods as compared to classical

efficacy trials in MDD (i.e., broad inclusion criteria to increase generalizability of results,involvement of both primary and specialty care settings, outcome measures to assess multiple

domains, the routine clinical use of symptom ratings to inform clinical decisions, and the concurrent

use of two [ROAs and IVR] independent methods of evaluation). One of the most innovative

aspects of the study is the flexible approach to randomizations at levels 2 and 3, where participants

are randomized only to those treatment substrategies that they find acceptablethe equipoise-

stratified randomized design [68]. Because of these unique design features, the results of the study

will be generalizable to a large set of patients.

Acknowledgements

This project has been funded in part with federal funds from the National Institute of Health,

National Institute of Mental Health under Contract N01-MH-90003. Additional funds were

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

Chair in Biomedical Science and the Sara M. and Charles E. Seay Center for Basic and

Applied Research in Psychiatry (A.J.R.), and by MH-30915 (Mental Health Intervention

Research Center) (M.E.T., D.J.K.). The following pharmaceutical companies are providing

medication for STAR*D participants: Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline,

King Pharma, Novartis, Organon, Pfizer, and Wyeth-Ayerst. The authors appreciate the

contributions of the NIMH STAR*D Scientific Advisory Group, the NIMH Protocol Oversight

Committee, the thoughtful consultation by Health Technology Systems, Inc., and the guidance of

the NIMH Data and Safety Monitoring Board. We appreciate the provision of educational

materials by the Texas Department of Mental Health and Mental Retardation. The authors appreciate the

secretarial support of Fast Word Information Processing Inc. (Dallas, Texas) and David Savage, and the

administrative support of Kenneth Z. Altshuler, M.D., Stanton Sharp Distinguished Chair (past Chairman)

and Eric Nestler, M.D., Ph.D., Lou and Ellen McGinley Distinguished Professor and Chairman,

Department of Psychiatry, University of Texas Southwestern Medical Center. 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.



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AppendixA.Participatin

gregionalcentersandclinica

lsites



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