Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice
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Article
Evaluation of Outcomes With Citalopram for Depression
Using Measurement-Based Care in STAR*D:
Implications for Clinical Practice
Madhukar H. Trivedi, M.D. Objective: Selective serotonin reuptake Results: Nearly 80% of the 2,876 outpa-
inhibitors (SSRIs) are widely used to treat tients in the analyzed sample had chronic
depression, but the rates, timing, and base- or recurrent major depression; most also
A. John Rush, M.D. line predictors of remission in “real world” had a number of comorbid general medi-
patients are not established. The authors’ cal and psychiatric conditions. The mean
Stephen R. Wisniewski, Ph.D. primary objectives in this study were to exit citalopram dose was 41.8 mg/day. Re-
evaluate the effectiveness of citalopram, mission rates were 28% (HAM-D) and 33%
Andrew A. Nierenberg, M.D. an SSRI, using measurement-based care in
(QIDS-SR). The response rate was 47%
actual practice, and to identify predictors
(QIDS-SR). Patients in primary and psychi-
of symptom remission in outpatients with
Diane Warden, Ph.D., M.B.A. atric care settings did not differ in remis-
major depressive disorder.
sion or response rates. A substantial por-
Louise Ritz, M.B.A. Method: This clinical study included out- tion of participants who achieved either
patients with major depressive disorder
response or remission at study exit did so
who were treated in 23 psychiatric and 18
Grayson Norquist, M.D. primary care “real world” settings. The pa-
at or after 8 weeks of treatment. Partici-
pants who were Caucasian, female, em-
tients received flexible doses of citalopram
Robert H. Howland, M.D. ployed, or had higher levels of education
prescribed by clinicians for up to 14 weeks.
or income had higher HAM-D remission
The clinicians were assisted by a clinical re-
rates; longer index episodes, more concur-
Barry Lebowitz, Ph.D. search coordinator in the application of
measurement-based care, which included rent psychiatric disorders (especially anxi-
the routine measurement of symptoms ety disorders or drug abuse), more general
Patrick J. McGrath, M.D. medical disorders, and lower baseline
and side effects at each treatment visit and
the use of a treatment manual that de- function and quality of life were associated
Kathy Shores-Wilson, Ph.D. scribed when and how to modify medica- with lower HAM-D remission rates.
tion doses based on these measures. Re-
Conclusions: The response and remis-
Melanie M. Biggs, Ph.D. mission was defined as an exit score of ≤7
on the 17-item Hamilton Depression Rat- sion rates in this highly generalizable sam-
ing Scale (HAM-D) (primary outcome) or a ple with substantial axis I and axis III co-
G.K. Balasubramani, Ph.D. morbidity closely resemble those seen in
score of ≤5 on the 16-item Quick Inventory
of Depressive Symptomatology, Self-Re- 8-week efficacy trials. The systematic use
Maurizio Fava, M.D. port (QIDS-SR) (secondary outcome). Re- of easily implemented measurement-
sponse was defined as a reduction of ≥50% based care procedures may have assisted
STAR*D Study Team in baseline QIDS-SR score. in achieving these results.
(Am J Psychiatry 2006; 163:28–40)
R emission, the virtual absence of symptoms, is the
aim of depression treatment because it is associated with
remission, lower rates of relapse, lower risk of suicide and
alcohol/drug abuse, and lack of disabling symptoms (1–3).
better function and a better prognosis than is response Few efficacy studies, even in research settings, have em-
without remission. Response is typically defined as a clin- ployed remission as an outcome (4–7). Remission rates
ically meaningful reduction in symptoms (e.g., a reduction from research-based, 8-week, randomized, placebo-con-
of at least 50% in baseline symptom levels). However, re- trolled efficacy trials with depressed, symptomatic volun-
sponse that falls short of remission is suboptimal because teers range from 25% to 40% (4), and 12-week efficacy tri-
it is associated with continued disabling symptoms, nega- als with subjects suffering from chronic depression reveal
tive effects on other axis I and axis III disorders, higher even more modest remission rates of 22%–30% (8, 9).
rates of relapse and recurrence, poorer work productivity, Results from these efficacy trials lack ecological validity
more impaired psychosocial functioning, higher levels of and generalizability to clinical practice (10, 11). Typically,
health care use, and potentially higher risk for suicide. Re- they enroll symptomatic volunteers (often recruited through
mission, on the other hand, is associated with return of advertising) with uncomplicated (minimal comorbid gen-
normal psychosocial function, higher rates of sustained eral medical or psychiatric conditions), nonchronic, non-
28 http://ajp.psychiatryonline.org Am J Psychiatry 163:1, January 2006TRIVEDI, RUSH, WISNIEWSKI, ET AL.
substance-abusing, nonsuicidal depression and treat in disorder, length of the current major depressive episode,
research clinics as opposed to enrolling patients already number of major depressive episodes, length of illness,
seeking health care in typical clinical treatment settings. course of illness [single or recurrent], major depressive
Unfortunately, no large-scale antidepressant medication disorder subtype [anxious, melancholic, and atypical fea-
trials have evaluated safety, efficacy, and tolerability in tures], family history of depression, concurrent general
“real world” primary or psychiatric care settings with re- medical and axis I psychiatric disorders, symptom sever-
mission as the predefined primary endpoint. ity, and functional status at baseline).
Evidence from practice settings (12) also demonstrates This report addresses the following questions about
that antidepressant medication treatment is often inade- treatment with citalopram, a representative of the SSRI
quate in dose and/or duration and that there are unac- class of medications:
ceptably high dropout rates—all of which likely contribute
1. What are the remission and response rates in represen-
to lower remission rates. In the available effectiveness tri-
tative outpatients with nonpsychotic major depressive
als conducted in real clinical practice settings, even the
disorder in primary and psychiatric care settings?
addition of depression care specialists leads to modest re-
2. Which citalopram doses, treatment durations, and
mission rates (15% to 35%) (10, 13, 14).
adverse events characterize patients who do or do
The Sequenced Treatment Alternatives to Relieve De-
not achieve remission?
pression (STAR*D) study was designed to assess effective-
3. What pretreatment features in demographic, social,
ness of treatments in generalizable samples and ensure
and clinical domains are associated with remission?
the delivery of adequate treatments. The study aimed to
define the symptomatic outcomes for outpatients with
nonpsychotic major depressive disorder treated initially Method
with citalopram, a prototype of selective serotonin re- Study Overview and Organization
uptake inhibitors (SSRIs). The primary outcome was re-
The rationale, methods, and design of the STAR*D study have
mission. Adequate doses of citalopram had to be given for been detailed elsewhere (7, 36). Investigators at each of 14 re-
a sufficient time period to ensure that an adequate treat- gional centers across the United States oversaw protocol imple-
ment trial was conducted to assess efficacy in representa- mentation at two to four clinical sites providing primary (N=18)
tive practice settings and to ensure that those patients or psychiatric (N=23) care to patients in both the public and pri-
who progressed to the next treatment step in STAR*D were vate sectors. Clinical research coordinators at each clinical site as-
sisted participants and clinicians in protocol implementation
truly treatment resistant. To that end, a systematic but and collection of clinical measures. A central pool of research out-
easily implemented approach to treatment, measure- come assessors conducted telephone interviews to obtain pri-
ment-based care, was developed. Measurement-based mary outcomes.
care includes the routine measurement of symptoms and
Participants
side effects at each treatment visit and the use of a treat-
All risks, benefits, and adverse events associated with STAR*D
ment manual describing when and how to modify medi-
participation were explained to subjects, who provided written in-
cation doses based on these measures. The manual allows formed consent before entering the study. The University of Texas
for flexible dosing and was designed to maximize ade- Southwestern Medical Center at Dallas and the institutional re-
quate dosing and duration of treatment. view boards at each clinical site and regional center and the Data
Finally, since most depressed patients do not achieve re- Coordinating Center and the Data Safety and Monitoring Board of
the National Institute of Mental Health (NIMH) approved and
mission with any initial treatment, baseline features (mod-
monitored the protocol.
erators) that identify who will achieve remission (15, 16) To maximize generalizability of findings, only patients seeking
are clinically important. With a rare exception (17), no ade- medical care in routine medical or psychiatric outpatient treat-
quately powered previous studies have searched for base- ment (as opposed to those recruited through advertisements)
line features predicting which patients will achieve remis- were eligible for the study. Minimal exclusion criteria and broad
inclusion criteria that allowed a majority of axis I and axis II disor-
sion as opposed to those who will respond to treatment.
ders were used. Outpatients who were 18–75 years of age and had
Response moderator studies with small samples have a nonpsychotic major depressive disorder determined by a base-
yielded inconsistent correlates of response (18), except for line 17-item Hamilton Depression Rating Scale (HAM-D) (37, 38)
pretreatment depressive symptom severity, which has score ≥14 were eligible if their clinicians determined that outpa-
been associated consistently with lower response rates tient treatment with an antidepressant medication was both safe
and indicated. The initial HAM-D at study entry was administered
(19–35). Therefore, STAR*D also aimed to evaluate moder-
and scored by the clinical research coordinators. Patients who
ators of symptom remission. were pregnant or breast-feeding and those with a primary diagno-
This study defined remission as the a priori primary sis of bipolar, psychotic, obsessive-compulsive, or eating disorders
endpoint and divided baseline moderators into three do- were excluded from the study, as were those with general medical
mains: 1) demographic features (e.g., age, race, ethnicity, conditions contraindicating the use of protocol medications in the
first two treatment steps, substance dependence (only if it re-
and gender), 2) social features (e.g., education, employ- quired inpatient detoxification), or a clear history of nonresponse
ment status, income, insurance, and marital status), and or intolerance (in the current major depressive episode) to any
3) clinical features (e.g., age at onset of major depressive protocol antidepressant in the first two treatment steps (7).
Am J Psychiatry 163:1, January 2006 http://ajp.psychiatryonline.org 29MEASUREMENT-BASED CARE IN STAR*D
FIGURE 1. Participant Flow (CONSORT Chart) for the comes were based on the QIDS-SR collected at baseline and at
Sequenced Treatment Alternatives to Relieve Depression each treatment visit.
(STAR*D) Study An automated, telephonic, interactive voice response system
(7, 50–52) was used to collect ratings on the 12-item Short-Form
Health Survey (53) (perceived physical functioning and mental
Screened Not offered consent health functioning), the 16-item Quality of Life Enjoyment and
or refused to consent Satisfaction Questionnaire (54), the Work and Social Adjustment
(N=4,790)
(N=613) Scale (55), and the 5-item Work Productivity and Activity Im-
pairment (56).
Consented Ineligible Intervention and Measurement-Based Care
(N=4,177) (N=136) Citalopram was selected as a representative SSRI given the ab-
sence of discontinuation symptoms, demonstrated safety in el-
derly and medically fragile patients, once-a-day dosing, few dose
Eligible HAM-D scoreTRIVEDI, RUSH, WISNIEWSKI, ET AL.
TABLE 1. Baseline Characteristics of 2,876 Outpatients With TABLE 1. Baseline Characteristics of 2,876 Outpatients With
Nonpsychotic Major Depressive Disordera Nonpsychotic Major Depressive Disordera (continued)
Characteristic N % Mean SD Characteristic N % Mean SD
Demographic domain Clinical domain
Race
Caucasian 2,180 75.8 Age at onsetMEASUREMENT-BASED CARE IN STAR*D
TABLE 2. Treatment Characteristics and End-of-Study Remission Status of 2,876 Outpatients With Nonpsychotic Major
Depressive Disordera
Characteristic No Remission (N=2,086) Remission (N=790) Total (N=2,876)
N % N % N %
Maximum dose of citalopram (mg/day)TRIVEDI, RUSH, WISNIEWSKI, ET AL.
FIGURE 2. Total Exit Scores on the 16-Item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), of 2,876
Outpatients With Nonpsychotic Major Depressive Disorder
No depression Mild symptoms Moderate symptoms Severe symptoms Very severe symptoms
8
7
6
Percent
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Last QIDS-SR Score
Symptomatic Outcomes FIGURE 3. Percent of 2,876 Outpatients With Nonpsychotic
Major Depressive Disorder Who Achieved Response or Re-
The overall remission rate was 27.5% (N=790) with the mission Defined by 16-Item Quick Inventory of Depressive
HAM-D definition (primary outcome) and 32.9% (N=943) Symptomatology, Self-Report (QIDS-SR), Scores by Week of
Treatmenta
with the QIDS-SR definition. Remission rates were com-
parable in primary and psychiatric care for the HAM-D 25
(26.6% versus 28.0%) and the QIDS-SR (32.5% versus Remission (N=943)
33.1%). The overall QIDS-SR response rate was 47% (N= Response (N=1,343)
1,343) (46% primary care, 48% psychiatric care). Figure 2 20
shows the distribution of the exit QIDS-SR scores. A QIDS-
SR score of 10 approximates an HAM-D score of 13 (45).
15
Figure 3 shows the distribution of the time to first
Percent
remission and response for those who ultimately did
achieve remission and response in this study based on 10
QIDS-SR scores. For those who achieved QIDS-SR re-
mission, the mean time to remission was 6.7 weeks (SD=
3.8) and was comparable in primary care (approximately 6 5
weeks) and psychiatric care (approximately 7 weeks). For
those who achieved a QIDS-SR response, the mean time to
response was approximately 5.7 weeks (SD=3.5) and was 0
2 4 6 8 10 12 ≥13
comparable in primary care (mean=5.7 weeks, SD=3.7)
Week of Treatment
and psychiatric specialty care (mean=5.6 weeks, SD=3.5).
a Response was defined as improvement of ≥50% in QIDS-SR score
For those who achieved remission according to QIDS- from baseline. Remission was defined as a QIDS-SR score of ≤5 at
SR scores, the mean time in treatment was approximately endpoint.
12 weeks (SD=3).
Intolerance and Adverse Events Pretreatment Correlates of Remission
Only 2% of the patients who achieved HAM-D remis- Several pretreatment demographic, social, and clinical
sion were considered to have discontinued citalopram features were associated with remission based on either
because of intolerance, compared with 11% of those who the HAM-D or QIDS-SR following adjustments for base-
did not achieve HAM-D remission (Table 3). Those who line symptom severity and regional center (Table 4). Find-
achieved HAM-D remission had lower rates of side effect ings were almost identical for the HAM-D and the QIDS-
frequency, intensity, and burden at exit and lower rates of SR except that anxious depression and concurrent gener-
serious adverse effects than those who did not achieve alized anxiety disorder were also associated with lower
HAM-D remission. Overall, 116 participants experienced QIDS-SR remission rates.
at least one serious adverse effect; most of these patients Table 5 presents pretreatment features that were non-
(88.8% [N=103]) did not achieve HAM-D remission. There overlapping and independently associated with remission
were no suicides in the 2,876 participants in this acute- after baseline depressive symptom severity and regional
phase citalopram study. center for each domain separately and across all domains
Am J Psychiatry 163:1, January 2006 http://ajp.psychiatryonline.org 33MEASUREMENT-BASED CARE IN STAR*D
TABLE 3. Adverse Events, Side Effects, Attrition, and End-of-Study Remission Status of 2,876 Outpatients With Non-
psychotic Major Depressive Disordera
No Remission (N=2,086) Remission (N=790) Total (N=2,876)
Adverse Events, Side Effects, and Attrition N % N % N %
Maximum side effect frequencyb
None 320 15.4 128 16.2 448 15.7
10%–25% of the time 535 25.8 273 34.6 808 28.2
50%–75% of the time 681 32.9 233 29.6 914 31.9
90%–100% of the time 537 25.9 154 19.5 691 24.2
Maximum side effect intensityb
None 315 15.2 127 16.1 442 15.5
Trivial–mild 510 24.6 283 35.9 793 27.7
Moderate–marked 871 42.0 302 38.3 1,173 41.0
Severe–intolerable 377 18.2 76 9.6 453 15.8
Maximum side effect burdenb
No impairment 402 19.4 181 23.0 583 20.4
Minimal–mild impairment 771 37.2 403 51.1 1,174 41.0
Moderate–marked impairment 695 33.5 169 21.5 864 30.2
Severe impairment, unable to function 205 9.9 35 4.4 240 8.4
Serious adverse events
Total 103 4.9 13 1.6 116 4.0
Death, nonsuicide 3 — 0 — 3 —
Hospitalization for general medical conditions 47 — 11 — 58 —
General medical conditions without hospitalization 4 — 0 — 4 —
Psychiatric hospitalization 50 — 2 — 52 —
Suicidal ideation (without hospitalization)c 6 — 0 — 6 —
Any psychiatric serious adverse eventd 55 2.6 2 0.3 57 2.0
Intolerance 234 11.2 13 1.6 247 8.6
a Remission was defined as an exit score of ≤7 on the 17-item Hamilton Depression Rating Scale (HAM-D). Subjects with missing exit HAM-D
scores were considered not in remission. Numbers do not always add up to total N because of missing data; percents are based on number
of subjects for whom data were available.
b Maximum ratings of intensity, frequency, and burden of side effects are the highest ratings during citalopram treatment.
c Includes psychiatric hospitalization and suicidal ideation without hospitalization.
d Includes hospitalizations for worsening depression, substance abuse, suicidal ideation, and other.
were controlled for. Lower remission rates were associated pression (22%) (9), possibly because of a number of factors
with being unemployed; having a lower income; being discussed below, including the use of measurement-based
non-Caucasian, male, and less educated; and having care and the clinical research coordinators.
poorer function and lower quality of life at baseline. Re- Higher remission rates were found with the QIDS-SR
markably consistent findings were obtained with the HAM- than with the HAM-D because our primary analyses classi-
D and the QIDS-SR. fied patients with missing exit HAM-D as nonremitters a
priori. Of the 690 patients with missing exit HAM-D scores,
Discussion 152 (22.1%) achieved QIDS-SR remission at the last treat-
ment visit.
Results of this study should be generalizable to routine As described earlier, a sensitivity analysis was con-
clinical practice because this is the largest ecologically ducted to evaluate the methods used to address the miss-
valid “real world” study of outpatients with nonpsychotic ing HAM-D data. Both the multiple imputation approach
major depressive disorder treated in psychiatric and pri- and the use of values imputed from the observed exit QIDS-
mary care settings with diligently followed guidelines. C score based on item response theory revealed remark-
Participants in the study were patients seeking treatment ably similar findings, indicating that the analyses were not
in “real world” clinical practices who had high rates of affected by the missing data methodology.
chronic or recurrent major depressive disorder and con- Of participants who responded, 56.0% did so only at or
current axis I and axis III (general medical conditions) dis- after 8 weeks of treatment. Not surprisingly, remission fol-
orders. Since there were very broad inclusion criteria and lowed response in most cases. Of those who achieved
few exclusion criteria, this study included patients who QIDS-SR remission, 40.3% did so only at or after 8 weeks of
would have been excluded from most efficacy trials (58– citalopram.
61). Results also highlight the feasibility, safety, tolerability,
The remission rates (28% for HAM-D; 33% for QIDS-SR) and effectiveness of delivering high-quality care with
were robust and similar to rates found in uncomplicated, easy-to-use clinical methods employed at each treatment
nonchronic symptomatic volunteers enrolled in placebo- visit to ensure adequate treatment delivery (measure-
controlled, 8-week, randomized, controlled trials with ment-based care approach). The approach may have con-
SSRIs (4). These remission rates were better than those tributed to the better-than-expected remission rates in
found in efficacy studies among patients with chronic de- this group of patients as well, although a firm conclusion
34 http://ajp.psychiatryonline.org Am J Psychiatry 163:1, January 2006TRIVEDI, RUSH, WISNIEWSKI, ET AL.
TABLE 4. Factors Associated With Remission Defined According to the 17-Item Hamilton Depression Rating Scale (HAM-D)
or the 16-Item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), in Outpatients With Nonpsychotic
Major Depressive Disordera
Remission Defined by HAM-D (N=790) Remission Defined by QIDS-SR (N=943)
Patients With Patients With
Baseline Characteristic Characteristic Analysisb Characteristic Analysisc
Odds Odds
N % Ratio p N % Ratio p
RacedMEASUREMENT-BASED CARE IN STAR*D
TABLE 4. Factors Associated With Remission Defined According to the 17-Item Hamilton Depression Rating Scale (HAM-D)
or the 16-Item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), in Outpatients With Nonpsychotic
Major Depressive Disordera (continued)
Remission Defined by HAM-D (N=790) Remission Defined by QIDS-SR (N=943)
Patients With Patients With
Baseline Characteristic Characteristic Analysisb Characteristic Analysisc
Recurrent depression 0.82TRIVEDI, RUSH, WISNIEWSKI, ET AL.
TABLE 4. Factors Associated With Remission Defined According to the 17-Item Hamilton Depression Rating Scale (HAM-D)
or the 16-Item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), in Outpatients With Nonpsychotic
Major Depressive Disordera (continued)
Remission Defined by HAM-D (N=790) Remission Defined by QIDS-SR (N=943)
Patients With Patients With
Baseline Characteristic Characteristic Analysisb Characteristic Analysisc
Odds Odds
Mean SD Ratio p Mean SD Ratio p
Age (years) (units=10) 39.9 12.8 0.99 0.86 40.1 12.9 0.96 0.26
Education (years) (units=3) 14.1 3.2 1.20MEASUREMENT-BASED CARE IN STAR*D
TABLE 5. Factors Independently Associated With Remission Defined According to the 17-Item Hamilton Depression Rating
Scale (HAM-D) or the 16-Item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR), in Outpatients With
Nonpsychotic Major Depressive Disordera
Remission Defined Remission Defined
by HAM-D by QIDS-SR
(N=790) (N=943)
Factor Odds Ratiob p Odds Ratioc p
Social domain
Employment status (reference group=employed) 0.01TRIVEDI, RUSH, WISNIEWSKI, ET AL.
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