Prim Care Clin Office Pract

34 (2007) 505–519

Navigating the Sequenced Treatment

Alternatives to Relieve Depression
(STAR*D) Study: Practical Outcomes
and Implications for Depression
Treatment in Primary Care
Robert A. Cain, MD*
Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue,
Cleveland, OH 44195, USA

Depression is a common medical illness with enormous personal and so-

cietal impact. The lifetime prevalence of depressive illness is 15% to 20% [1].
Approximately one third of women will experience depression in their life-
times. For perspective, that is more common than blond hair with blue
eyes for women in the United States.
The global public health implications are staggering. Depressive illness
constitutes 4% of the worldwide disease burden [2] and affects some 121 mil-
lion people worldwide [3]. The World Health Organization estimates that by
2020 unipolar depression will be second only to ischemic heart disease as
a cause of illness burden worldwide, and will be the leading cause of disabil-
ity in the world [3]. There is substantial comorbidity associated with depres-
sion coexisting with other serious health problems [4–6].
Similarly, the economic impact is astronomical. Recent estimates calcu-
late a cost of at least $44 billion dollars in related direct expenses and pro-
ductivity loss associated with depression in the United States [7–11]. The
need for better understanding of the disease process and improved treatment
is undeniable.
In the primary care of adults and adolescents, treatment of depression is
an often complex daily concern. The challenge is made even more daunting

* Cleveland Clinic Brunswick Family Health Center, 3724 Center Road Suite 100,
Brunswick, OH 44212, USA.
E-mail address: cainr@ccf.org

0095-4543/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.pop.2007.05.006 primarycare.theclinics.com
506 CAIN

by the paucity of real-world treatment data to guide the physician through

clinical decisions.
Most traditional depression studies have been of the ‘‘clinical efficacy tri-
als’’ variety, in which generally healthy (ie, few or no comorbid health prob-
lems, no substance abuse, age less than 65, no other psychiatric disorders)
recruited volunteers who have depression are treated with either drug or pla-
cebo for a relatively short time. These blinded, randomized studies (often
funded by the pharmaceutical industry) compare response rates of the con-
trol and treatment groups. From this, inferences must be made regarding
which treatments are most appropriate for real-world primary care patients.
Such information, however, does not often translate well into real-world
practice, where patients often have substantial comorbidities, and where life-
long remission, rather than short-term response, is the ultimate goal of
therapy.
The need for practical clinical trials in psychiatry is made even more ob-
vious as evidence-based practice becomes the standard. Such studies de-
scribe research that is focused upon answering questions that will inform
those making patient care decisions [12]. These practical studies are designed
to be conducted in clinical practice settings (rather than solely in specialized
or academic centers), and to be replicable under best-practice clinical condi-
tions [12].
The National Institute of Mental Health (NIMH) addressed this pressing
need with the funding of three large practical clinical trials. The most ambi-
tious of these was the Sequenced Treatment Alternatives to Relieve Depres-
sion (STAR*D) study, the largest study ever conducted with depressed
patients. The other trials in this NIMH series are Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) [13], and Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE) [14] which focus
on bipolar disorder and psychosis and Alzheimer’s disease, respectively.

Sequenced Treatment Alternatives to Relieve Depression study design

STAR*D, initially funded in 1998, was a 7-year, $35 million, multicenter,
prospective, sequentially randomized controlled trial of outpatients who had
nonpsychotic unipolar depression. The study used randomization at multi-
ple levels (Box 1) via the unique equipoise-stratified randomization strategy
[15] to compare switching medications or medication augmentation strate-
gies that were deemed either to be in common use or based on distinct phar-
macological properties [16,17]. Equipoise randomization implies that all
available randomization choices are equally favorable to the clinician. The
STAR*D protocol takes this into the real world, where patients or clinicians
may rank, or stratify, available options as ‘‘more ‘‘or ‘‘less’’ favorable. The
resultant design, equipoise-stratified randomization, allows patients to be
randomized to available treatment options based on patient preference for
 NAVIGATING STAR*D 507

Box 1. Multiple-level randomization of depression treatment

Level 1
 CIT
Level 2
 Switch: BUP, CT, SER, VEN
 Augment: BUP, BUS, CT
Level 3
 Switch: NOR, MIR
 Augment: LI, THY
Level 4
 Switch: TCP, VEN + MIR

Abbreviations: BUP, bupropion SR; BUS, buspirone; CIT, citalopram; CT, cog-
nitive therapy; LI, lithium; MIR, mirtazapine; NOR, nortriptyline; SER, sertraline;
TCP, tranylcypromine; THY, triiodothyronine; VEN, venlafaxine XR.

mode of therapy. In STAR*D trials, patients could opt for medication

switching, augmentation, cognitive therapy, and so forth, and then were
subsequently randomized to acceptable arms of the study. This mimics
real-world clinical decision-making, in which the patient is an active partic-
ipant in this decision process. Results obtained in this way have particular
clinical relevance for this reason.
Over 120 physicians were involved in the care of the enrollees, with 23
psychiatry and 18 primary care facilities used. The inclusion of substantial
numbers of primary care clinicians in the study is an important consider-
ation, because most patients who have depression are initially seen in the
primary care setting [18].
Broad inclusion criteria ensured a real-world patient population (Box 2).
Exclusions were limited to patients who had psychosis, bipolar disorder,
substance abuse likely to need inpatient detoxification or treatment, and
pregnant or lactating women. Patients who had other concurrent psychiatric
diagnoses were not excluded otherwise (in fact, 61% of enrollees had one or
more such diagnoses). Significant comorbid medical problems (such as com-
plicated diabetes, coronary artery disease, hypertension, rheumatologic dis-
orders, chronic obstructive pulmonary disease, and so forth) were not
excluded unless these conditions contraindicated the use of the study’s pro-
tocol medications. It is noteworthy that there were not substantial differ-
ences in severity of illness, demographics, or comorbidities between those
seen in the primary care setting and those seen in the psychiatry setting [19].
Patients were not recruited for this study, unlike the design for most ef-
ficacy trials. Only patients presenting for medical care at one of the study
508 CAIN

Box 2. STAR*D study overview

 4041 patients
 Nonpsychotic depression
 Few comorbidities excluded
 Specialty and primary care populations
 Equipoise-stratified randomization
 12 weeks per treatment level
 Up to four treatment levels
 1 year follow-up upon exit

Data from Trivedi MH, Stegman D, Rush AJ, et al. STAR*D clinical proce-
dures manual. July 31, 2002. Available at: www.edc.pitt.edu/stard/public/study_
manuals.html. Accessed February 15, 2007.

clinical centers were considered for participation. Those 18 to 75 years old

with a baseline score of at least 14 on the Hamilton Depression Rating Scale
(HAM-D) were then eligible if antidepressant therapy was deemed safe and
indicated by a clinician. The treatment protocol included recommended
visits at 2, 4, 6, 9, and 12 weeks, with an optional visit at week 14 at the cli-
nician’s discretion. Citalopram was dosed at 20 mg/day initially, and dosing
guidelines called for adjustments up to 60 mg total daily dose based on re-
sponse and time on each dose between adjustments. After an optimal trial,
responders and remitters could enter a 12-month follow-up phase, but all re-
sponders who did not reach and sustain full remission of their symptoms
were encouraged to enter the subsequent randomized level of the study.
The study size was determined by statistical projections of the number of
patients needed at each treatment level, in order to ensure sufficient power to
discriminate between the effectiveness of the different treatment options. An
initial pool of approximately 5000 patients was expected, with 4000 partic-
ipants anticipated to enter the treatment phase at level 1 [20]. About half of
these were expected to have insufficient response to level 1 treatment, and
thus progress to subsequent levels. At all treatment levels after level 1, par-
ticipants were randomized to all treatment groups and options they deemed
acceptable to them via the equipoise-stratified randomization protocol.
STAR*D relied on measurement-based care protocols that included
a treatment manual (with protocols and procedures) [21], didactic instruc-
tion, the use of structured evaluation of symptoms and side effects at each
visit, and a centralized treatment monitoring and feedback system. The clin-
ical decision system relied on measurement of depression symptoms with the
16-item Quick Inventory of Depressive Symptomatology (QIDS), QIDS Cli-
nician Rating (QIDS-C), and QIDS Self-Report (QIDS-SR); side effects
with the Frequency and Intensity of Side Effect Rating (FISER) and Global
Rating of Side Effect Burden (GRSEB); and exit scores on HAM-D scales.
 NAVIGATING STAR*D 509

The goal of treatment was remission. This is an important consideration,

because many clinical trials focus on response rather than remission as the
outcome. Remission was the treatment goal because it is associated with
better long-term prognosis and functionality than response (ie, reduction
of O50% in baseline symptoms) [16]. The investigators defined remission as
the virtual absence of symptoms, as measured by a HAM-D score less than
or equal to 7, or a last-observed QIDS-SR score of less than or equal to 5.
The grand scale of the study allowed investigators the rare opportunity
to also meaningfully evaluate moderators of symptom remission based on
demographic features (age, rare, sex, ethnicity), social features (education,
employment, income, marital status, insurance coverage), and clinical
features of their depression and medical disorders.
All patients entering level 1 were placed on citalopram (Celexa) and dosed
according to treatment protocols guided by measured outcomes. Patients
were treated for up to 12 weeks (with visits at 2, 4, 6, 9, and 12 weeks) or until
intolerance or remission was evident. All those who did not achieve remission,
including those with significant measured response, were encouraged to enter
level 2 of treatment. Those who reached remission were followed regularly for
up to 12 months. The treatment algorithm is summarized in Fig. 1.
In level 2, seven treatment options were available after equipoise random-
ization, including four medication switch options and three augmentation
options. The switch options were sertraline (Zoloft), sustained-release bupro-
pion (Wellbutrin SR), extended-release venlafaxine (Effexor XR), or cognitive
therapy. Augmentation strategies included sustained-release bupropion,
buspirone (Buspar), or cognitive therapy [17]. Patients were again followed
for up to 12 weeks, depending on degree of improvement and tolerability of
treatments. Those who received only cognitive therapy as their switch or
augmentation option and did not reach remission were then randomized again

LEVEL
1
Initial Treatment: citalopram

SWITCH TO: bupropion, cognitive therapy,

LEVEL sertraline, venlafaxine
2 OR AUGMENT WITH: bupropion, buspirone,
cognitive therapy
(Only for those receiving cognitive therapy in
LEVEL Level 2) SWITCH TO: bupropion or venlafaxine (if
2a
exiting Level 2a)

LEVEL SWITCH TO: mirtazapine or nortriptyline

3 OR AUGMENT WITH: lithium or
triiodothyronine

LEVEL SWITCH TO: tranylcypromine or mirtazapine

4 combined with venlafaxine

Fig. 1. STAR*D treatment algorithm.

510 CAIN

to receive either bupropion SR or venlafaxine XR. This would ensure that no

patient would enter level 3 without at least two drug failures.
Patients progressing to level 3 were re-randomized to receive either a med-
ication switch or augmentation. This was a rare look at responses by truly
treatment-resistant depressed patients. Participants in the switch arm of
the study received either mirtazapine (Remeron) at up to 60 mg/day or nor-
triptyline (Pamelor) at up to 150 mg/day. Those in the augmentation arm
were given either lithium (450–900 mg/day) or triiodothyronine (T3) at
50 mcg/day.
Nonremitters were then rerandomized before level 4 treatment, which
consisted of the monoamine oxidase inhibitor (MAOI) tranylcypromine
(Parnate), maximum 60 mg/day, or the combination of venlafaxine XR
(300 mg/day maximum) with mirtazapine (45 mg/day maximum). Patients
were again followed for up to 12 weeks in this level of the study.

Results
Outcomes from level 1 were reported in January 2006 [19]. Of the 4041
study-eligible patients, 3671 had a subsequent visit, and 2876 of those
were deemed eligible for citalopram therapy. With citalopram and close fol-
low-up over a 12-week period (an optional 14-week visit was available for
those responding at 12 weeks, but who had not yet attained remission),
about 30% of patients achieved the goal of remission of symptoms
(32.9% as measured by QIDS-SR, 27.5% by HAM-D) [21]. Remission rates
and medication dosages were similar in the primary care and psychiatry
settings [19]. The mean dose of citalopram was 41.8 mg, and mean duration
of treatment was 47 days. Higher rates of remission were associated
with: female, Caucasian, higher education level, marriage or cohabitation,
employed, insured, shorter current episode, and fewer concurrent general
medical or psychiatric disorders [19].
Of particular note, 33.5% of those reaching remission in level 1 were sub-
sequently felt to have relapsed during the follow-up period. Thus, for some
70% of patients, it appears that citalopram alone is insufficient to sustain
long-term remission from depression symptoms.
The demographic analysis of the STAR*D participants provides substan-
tial insight into depression in the United States. For more than 75% of these
patients, depression was recurrent, with a greater than 16-year average
duration of illness. A mean of seven lifetime depressive episodes was seen.
Sixty-one percent had a concurrent psychiatric diagnosis [19]. Trivedi and
colleagues [19], concluded that the level 1 results ‘‘should be generalized to
routine clinical practice because this is the largest ecologically valid ‘real
world’ study of outpatients with non-psychotic major depressive disorder.’’
Level 2 results were published in March 2006 [22,23]. No previous study
had attempted to prove the effectiveness of switching among several antide-
pressant options after initial unsuccessful selective serotonin reuptake
 NAVIGATING STAR*D 511

inhibitor (SSRI) therapy. Level 2 would also attempt to determine efficacy

of the common practice of medication augmentation in a controlled, ran-
domized study. The investigators used the equipoise-stratified randomiza-
tion design to assign 565 patients to the augmentation arm, and 727
patients to switch medications after an initial unsatisfactory response to cit-
alopram therapy in level 1.
Here, the somewhat unexpected results of the unique study design were
revealed (Fig. 2). Because patients were allowed to choose which therapies
they could be randomized to (amongst augmentation, switching, or cogni-
tive therapy), disparate proportions entered each treatment combination.
Only 21 of 1439 patients (1.5%) accepted complete randomization to any
of the seven level 2 treatments. Only 25.6% (369 of 1439) allowed cognitive
therapy to be included amongst acceptable treatments. Some form of drug
therapy was requested by 76.3% (1098 of 1439) of patients.
Because most patients chose to have their medication either augmented
or switched, and few chose to do both options, it was not possible to validly
compare the outcomes of augmentation strategies with switching strategies.
The reasons for the patient choices were not defined by the study design.
The cohort groups in the level 2 study were distinctly different in their
outcomes with citalopram treatment. Patients in the switching arm of level
2 had greater intolerance and less benefit from citalopram than did the
patients in the augmentation arm of the study.
In the medication switch groups, approximately 25% of patients switch-
ing to any of the three study medications (bupropion-SR, sertraline, or ven-
lafaxine-XR) achieved remission. There were no significant differences in

Results of Level 2 Equipoise Stratified Randomization

1439 patients
Eligible

Patients choose acceptable

Options and are
Randomized

Switch Augment Any Drug Any CT Any Any Any Any Drug Drug
Only Only switch or (Cognitive Treatment Treatment Treatment Treatment Switch or Augment
Augment Therapy) Except CT (Full Except Except CT Or
Switch or Alone Random- Augment Switch Augment CT Switch
Augment ization) Only
687 586 57 44 27 21 7 7 4 1

Fig. 2. Results of level 2 equipoise-stratified randomization.

512 CAIN

remission rates, tolerability, or side-effect burden among these medications.

A notable finding with significant clinical implication was the revelation that
intolerance to one SSRI, citalopram, did not portend intolerance to another
SSRI (sertraline). Whereas 56% of patients entering the switch portion of
level 2 had intolerance to citalopram at one of the study doses, sertraline
was as well-tolerated as the non-SSRI bupropion-SR. Because approxi-
mately 17.6% of patients given sertraline in level 2 reached remission, it
can be concluded that intolerance or lack of efficacy of one SSRI does
not seem to imply the same response to another SSRI [22].
In the augmentation phase, approximately 30% of patients treated with
either bupropion-SR or buspirone in addition to their citalopram achieved
remission. The study authors concluded that augmentation with bupropion-
SR was preferred because of greater reduction in measured depression
symptoms from baseline and fewer overall side effects [23].
Long-term relapse rates (as defined by relapse at any time during study
participation after having achieved remission) for level 2 responders (from
any group) totaled an alarming 47.4%. The rate was higher for patients
who improved, but did not achieve remission. Intolerance to therapy was
demonstrated in 19.5% of patients in level 2.
Level 3 results were published in July 2006 [24] for the switching phase
and September 2006 [25] for the augmentation phase of the study. Patients
could agree to augment only, switch only, or be randomized to either. A to-
tal of 142 patients entered level 3 augmentation treatment with lithium or
T3; 15.9% of lithium-treated patients and 24.7% of T3 treated patients
achieved remission. These rates were not felt to be significantly different
[25]. The study authors slightly favored T3 treatment over lithium, primarily
because of slight advantages in effectiveness and tolerability, and lack of
need for blood level monitoring; however, only 56.5% of patients who re-
ceived lithium augmentation actually had their lithium blood levels checked.
The median lithium blood level was 0.6 meq/liter. Improved response and
tolerability may have been attainable with more widely employed lithium
blood level monitoring.
The switch phase of level 3 treatment studied 235 patients, who were
given either mirtazapine or nortriptyline. Remission rates did not differ sig-
nificantly for these two medications (12.3% for mirtazapine and 19.8% for
nortriptyline). There was no difference in tolerability or adverse events.
There was no clear advantage to either one of these medications, and the
study authors suggest there may be only limited utility to three sequential
monotherapies for depression treatment [24].
A total of 13.7% of level 3 patients achieved remission. Total relapse rate
for all successful level 3 therapies was 42.9%. Additionally, 25.6% of all pa-
tients experienced intolerance to their assigned therapy.
Level 4 looked at additional treatment options (MAOI or combination
therapy) for multiple-treatment–resistant patients. This was the first report
of a randomized treatment trial with prospectively observed patients failing
 NAVIGATING STAR*D 513

to remit with three antecedent medication trials. McGrath and colleagues

[26], published their findings in September 2006. The HAM-D average score
for level 4 entrants was 20, indicating moderate to severe depression, and
showed only minimal improvement from their level 1 baseline score of
23.4. The comorbidity burden was high, with 64.2% of entrants having at
least one general medical condition. Some 76% had at least one additional
Axis I comorbid condition, and over 19% had at least four.
Randomization here produced two potentially influential findings: more
of the group assigned to combination therapy had already failed mirtaza-
pine therapy in level 3, and the proportion of patients exiting level 3 because
of side effects was greater in the tranylcypromine group. The study authors,
however, reported there were no differences in outcomes based on level 3
intolerance.
Remission rates as measured by HAM-D scores were paltry in both groups,
with only 6.9% of patients in the tranylcypromine group and 13.7% of the
venlafaxine-XR and mirtazapine group achieving remission. These were not
statistically different. The overall remission rate was 13.0%, but 50% of these
remitters subsequently relapsed. Intolerance was experienced by 34.1% of
level 4 participants. Patients taking the MAOI tranylcypromine were more
likely to exit the study because of side effects. Patients who had atypical symp-
toms did not have significantly different remission rates when treated with
MAOI therapy compared with those without such features.
No significant difference in remission or symptom relief was observed be-
tween treatment groups. Low remission rates suggested that switching anti-
depressant medication after failure to achieve remission with three previous
medication trials provides only a limited chance for success. The study au-
thors concluded that a more tolerable side effect burden and the lack of di-
etary interactions favor combination therapy with venlafaxine-XR and
mirtazapine for highly treatment-resistant depression patients who have
failed multiple other management strategies [26].
Overall remission, relapse, and intolerance rates are summarized in Table 1.

Study limitations
The very nature of the equipoise-stratified randomization design can lead
to unexpected results. Patients have opinions, and statistical projections

Table 1
Remission, intolerance and relapse rate for 4041 STAR*D enrollees by level
Number entering Remission Relapse Intolerance
treatment rate (%) rate (%) experienced (%)
Level 1 3671 36.8 33.5 16.3
Level 2 1439 30.6 47.4 19.5
Level 3 390 13.7 42.9 25.6
Level 4 123 13.0 50.0 30.1
514 CAIN

(however prescient) may not fully account for these. The participants’ pref-
erences were not well-anticipated by the study’s designers, and this led to
disparate number assignments in level 2 treatments and beyond. For exam-
ple only 21 of 1439 patients (1.5%) in level 2 agreed to randomization of all
treatment choices (see Fig. 2). The study’s ability to detect small and mod-
erate response effects was thus compromised in levels 3 and 4. For example,
the initial study design anticipated that 698 participants would enter level 3.
The actual number was 377. It was also assumed that 25% would choose
a switch strategy, 25% would choose an augmentation strategy, and 50%
would be willing to accept all possible treatments [20]. In the actual study,
127 patients (33.7%) accepted augmentation only, 221 (58.6%) chose
switching strategies only, and a mere 29 (7.7%) accepted all possible treat-
ments. Subsequent estimates of effect sizes were not applicable at the as-
sumed Type I error rate and desired 80% power. Comparison among
treatment strategies was limited by this lack of traditional randomization.
Therefore, a conclusion cannot be made regarding whether switching or
augmentation is superior with any acceptable degree of confidence.
The study design did not account for unexpected patient preferences, and
did not provide any means of delineating the reasons why patients chose the
treatment options they selected. Further investigation of this is warranted to
help in the design of future practical outcome trials in psychiatry (and med-
icine in general).
The lack of placebo controls made it difficult to account for nonspecific
treatment effects, which can be substantial in depression studies [27]. Adding
placebo controls in level 2 and beyond was an ethical concern for the
STAR*D investigators because some patients with significant improvement
(responders who did not reach remission) would have been assigned to pla-
cebo only therapy in subsequent levels. The very frank possibility of adverse
outcome (suicide, need for hospitalization, adverse effects on functioning,
and the like) cannot be overlooked.
The use of a single agent (citalopram) at level 1 limits the generalization
of this portion of the study to other medications. Further study is needed
with other medications following these practical clinical outcomes trial for-
mat to adopt such generalizations.
The STAR*D protocols were not blinded to patients or clinicians (but in-
terviewers and other nonclinical personnel participating in informational ca-
pacities were blinded to treatment choices). This fosters inherent participant
and observer bias. Well-designed treatment protocol manuals and patient
self-reports of symptoms and side effects helped to limit clinician bias. Pri-
mary outcomes were determined by measurements of the HAM-D scores,
which minimize patient bias to treatment at any given intervention. The
reliance on self-reports (QIDS-SR) as secondary outcome measures may
be less than ideal.
The longer duration of therapy (12 weeks per level) may be a primary
determining factor for success rather than the mechanism of action on
 NAVIGATING STAR*D 515

a psychopharmacological level. Allowing an extended amount of time for

a medication to reach full effectiveness, with generous dosing adjustments
as appropriate, is a strategy with obvious clinical implications for treating
physicians. This may help explain similar remission rates in the level 2 switch
phase for treatments with three different mechanisms of action. By contrast,
most traditional clinical efficacy trials stop after 8 weeks of therapy.
Although the STAR*D trials are far from perfect in their construct, the
primary care practice world is far from a perfect world. Concessions to
study design constraints were made to most closely replicate real-world out-
comes and enhance patient retention through the entire study. It is this ‘‘real
world’’ focus that makes STAR*D a landmark study. As Dr. Thomas R.
Insel [28], Director of NIMH stated, ‘‘There has been a gulf between re-
search and practice. This has led to the unfortunate current state where
too many research studies have little immediate relevance to practice, and
too little practice is based on research evidence. NIMH has developed sev-
eral practical trials such as STAR*D to bridge this gap between research
and practice by studying patients in real-world settings and asking questions
with practical relevance.’’

Lessons learned
Because much of the STAR*D study was conducted in primary care of-
fices with patients highly representative of such settings, the results have di-
rect clinical implications for primary care physicians. Several of these salient
features deserve further attention (Box 3).
STAR*D demonstrates emphatically and conclusively that meaningful
practical outcomes data can be obtained in the primary care setting. Inves-
tigators conducted treatment in primary care offices for 1091 of the 2358
(37.9% of the total patients) who entered the treatment phase with citalo-
pram in level 1 [19]. It is noteworthy that there were no significant differ-
ences in outcomes (ie, response or remission rates, dosages prescribed) in
the two settings. The use of convenient, reliable self-monitoring tools for
symptoms (HAM-D, QIDS-SR) and side effects (FISER) can easily be
adopted into any clinician’s routine as an important facet of depressive dis-
ease management, analogous to home glucose monitoring and self-measure-
ment of blood pressure. Additionally, many of these measurement tools can
be conducted and coordinated by nonclinical personnel. The STAR*D
Study team used such personnel as well as a voice-activated interactive
phone recording system to conduct follow-up interviews and complete
self-assessment questionnaires.
The overall results suggest that it may be prudent to consider a longer
course of treatment for patients initially failing to respond to a prescribed
therapy. The 12- week duration (optionally extended to 14 weeks for pa-
tients showing late, incomplete response) of each STAR*D Level may
have contributed to some of the surprising findings, including a relatively
516 CAIN

Box 3. STAR*D study highlights

 Measurement-based outcomes are crucial in the management
of depression. Achieving good results depends on appropriate
use of measurement tools, in the same way that the
sphygmomanometer is used in hypertension management, or
home glucose monitoring and hemoglobin A1c determination
is vital to adequate diabetes control.
 Application of evidence-based care with measured outcomes
and systematically applied treatment guidelines will result in
improved symptom relief for the nonremitted depressed
patient.
 Primary care providers who apply such treatment guidelines
and functional monitoring measurements can achieve results
equivalent to specialty care clinicians in the treatment of
depression in the outpatient setting.
 A longer trial of any drug therapy for depression can yield
improved response rates. The 12-week protocols in STAR*D
may have helped to bolster clinical success without
compromising patient safety.
 Equipoise randomization applied to practical trials validates
a clinical process in which patients and clinicians form
a therapeutic alliance to choose rational treatment strategies.
 Application of the STAR*D treatment algorithm does not
invalidate the value of evidence-based psychotherapies at all
levels of pharmacological intervention.
 Remission, rather than response, should be the goal of
antidepressant therapy.

robust response rate to sertraline (equal to the other switch options of level 2)
after initial failure of another SSRI. Longer course of treatment also permit-
ted aggressive dosing protocols for the antidepressants in the study. Self-
measurement of side effect burden promoted the safety and utility of this
practice.
Conversely, lithium dosing did not exceed 900 mg per day, and blood
level monitoring (with a mean level of 0.6 meq/l) was done in only 56.5%
of these patients in level 3. This may have curtailed the remission rates of
this augmentation strategy.
Irrespective of the treatment pathway chosen, it appears clear that little
additional benefit is to be garnered by switching to another medication after
the failure of two consecutive monotherapies.
Remission, rather than response, should be the goal of antidepressant
therapy [29,30]. In this study over 70% of patients did not attain sustained
 NAVIGATING STAR*D 517

remission with citalopram alone, and fewer than half of all patients achieved
sustained remission after four treatment levels [31]. Because it is clear that
patients who reach remission with their therapy have better functional out-
comes than those who do not [30,32], it appears that most patients treated
with an SSRI will ultimately require additional or alternate forms of treat-
ment to reap maximum benefit from therapeutic intervention. Many pa-
tients will be treatment-resistant if we are using sustained-remission as the
gold standard of therapy. STAR*D does not guide us to the most appropri-
ate next treatment steps, because study limitations did not enable meaning-
ful comparison of all options at each level. Because no other form of therapy
except the SSRI citalopram was offered at level 1, the effectiveness of this
approach as the best available starting point was not addressed.
STAR*D elegantly enumerated and detailed treatment-resistant depres-
sion on a scale not previously attempted, but it will be up to further practical
outcomes studies to delineate optimum treatment of these patients.

Summary
The ambitious STAR*D study attempted to answer many clinically-
relevant issues regarding the treatment of depressed outpatients. The unique
study design used an equipoise-stratified randomization scheme that en-
hanced the real-world expediency of the treatment options studied. Because
patients who had significant comorbid medical and psychiatric problems
were included, and care was provided in the outpatient primary care setting
as well as outpatient psychiatric centers, the findings are particularly perti-
nent to primary care physicians. The extensive use of measurement-based
treatment protocols promotes objectivity in a realm of often subjective clin-
ical decision-making. Although STAR*D was unable to provide specific
treatment comparisons for patients at all levels of the study, it succeeded
on a grand scale in defining the prevalence of treatment-resistant depression,
and serves as a model for further practical clinical outcomes studies.

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