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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].
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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.
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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
Quick Inventory of Depressive
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
Quick Inventory of Depressive
SymptomatologyClinician Rating (16-item)
3 Interview CRC/clinician
Quick Inventory of Depressive
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)
Quick Inventory of Depressive
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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