Evaluation of Outcomes With Citalopram For Depression Using Measurement-Based Care in STAR D: Implications For Clinical Practice
Evaluation of Outcomes With Citalopram For Depression Using Measurement-Based Care in STAR D: Implications For Clinical Practice
Evaluation of Outcomes With Citalopram For Depression Using Measurement-Based Care in STAR D: Implications For Clinical Practice
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1,262
14 AUTHORS, INCLUDING:
Madhukar H Trivedi
Diane Warden
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Kathy Shores-Wilson
Maurizio Fava
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Article
Results: Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic
or recurrent major depression; most also
had a number of comorbid general medical and psychiatric conditions. The mean
exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33%
(QIDS-SR). The response rate was 47%
(QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either
response or remission at study exit did so
at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education
or income had higher HAM-D remission
rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general
medical disorders, and lower baseline
function and quality of life were associated
with lower HAM-D remission rates.
Conclusions: The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in
8-week efficacy trials. The systematic use
of easily implemented measurementbased care procedures may have assisted
in achieving these results.
(Am J Psychiatry 2006; 163:2840)
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Method
Study Overview and Organization
The rationale, methods, and design of the STAR*D study have
been detailed elsewhere (7, 36). Investigators at each of 14 regional centers across the United States oversaw protocol implementation at two to four clinical sites providing primary (N=18)
or psychiatric (N=23) care to patients in both the public and private sectors. Clinical research coordinators at each clinical site assisted participants and clinicians in protocol implementation
and collection of clinical measures. A central pool of research outcome assessors conducted telephone interviews to obtain primary outcomes.
Participants
All risks, benefits, and adverse events associated with STAR*D
participation were explained to subjects, who provided written informed consent before entering the study. The University of Texas
Southwestern Medical Center at Dallas and the institutional review boards at each clinical site and regional center and the Data
Coordinating Center and the Data Safety and Monitoring Board of
the National Institute of Mental Health (NIMH) approved and
monitored the protocol.
To maximize generalizability of findings, only patients seeking
medical care in routine medical or psychiatric outpatient treatment (as opposed to those recruited through advertisements)
were eligible for the study. Minimal exclusion criteria and broad
inclusion criteria that allowed a majority of axis I and axis II disorders were used. Outpatients who were 1875 years of age and had
a nonpsychotic major depressive disorder determined by a baseline 17-item Hamilton Depression Rating Scale (HAM-D) (37, 38)
score 14 were eligible if their clinicians determined that outpatient treatment with an antidepressant medication was both safe
and indicated. The initial HAM-D at study entry was administered
and scored by the clinical research coordinators. Patients who
were pregnant or breast-feeding and those with a primary diagnosis of bipolar, psychotic, obsessive-compulsive, or eating disorders
were excluded from the study, as were those with general medical
conditions contraindicating the use of protocol medications in the
first two treatment steps, substance dependence (only if it required inpatient detoxification), or a clear history of nonresponse
or intolerance (in the current major depressive episode) to any
protocol antidepressant in the first two treatment steps (7).
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29
Screened
(N=4,790)
Consented
(N=4,177)
Ineligible
(N=136)
Eligible
(N=4,041)
HAM-D score 14
(N=3,110)
Failed to return
(N=234)
Study exit
(N=592)
Moved to follow-up
(N=1,083)
Moved to level 2
(N=1,201)
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Characteristic
Demographic domain
Race
Caucasian
African American
Other
Hispanic
No
Yes
Gender
Male
Female
Age group (years)
1830
3150
51
Age (years)
Education (years)
Social domain
Marital status
Never married
Married
Divorced
Widowed
Employment status
Employed
Unemployed
Retired
Education
< High school
High school but < college
College
Insurance status
Private
Public
None
Setting
Primary care
Psychiatric specialty care
Income ($/month)
Characteristic
Clinical domain
2,180
506
190
75.8
17.6
6.6
2,503
373
87.0
13.0
1,043
1,833
36.3
63.7
754
1,380
741
26.2
48.0
25.8
Mean
40.8
13.4
823
1,199
762
89
28.7
41.7
26.5
3.1
1,613
1,098
161
56.2
38.2
5.6
361
1,786
726
12.6
62.1
25.3
1,425
397
968
51.1
14.2
34.7
1,091
1,785
37.9
62.1
2,358
SD
13.0
3.2
3,030
(continued)
Safety Assessments
Side effects were evaluated with the ratings of frequency, intensity, and burden completed by patients at each treatment visit (7).
Three 7-point subscales measure the frequency, intensity, and
global burden of side effects.
Serious adverse events were monitored with a multitiered approach involving the clinical research coordinators, study clinicians, the interactive voice response system, the clinical manager,
safety officers, regional center directors (57), and the NIMH Data
Safety and Monitoring Board.
Concomitant Medications
Concomitant treatments for current general medical conditions (as part of ongoing clinical care), for associated symptoms
of depression (e.g., sleep, anxiety, and agitation), and for citalopram side effects (e.g., sexual dysfunction) were permitted on the
basis of clinical judgment. Stimulants, anticonvulsants, antipsychotics, alprazolam, nonprotocol antidepressants (except trazodone 200 mg at bedtime for insomnia), and depression-targeted psychotherapies were proscribed.
Am J Psychiatry 163:1, January 2006
1,077
1,585
515
37.8
55.6
17.9
720
2,019
1,530
25.3
75.7
53.2
671
407
372
891
586
335
343
209
68
126
370
23.6
14.3
13.1
31.3
20.6
11.8
12.0
7.4
2.4
4.4
13.0
980
749
466
258
364
34.8
26.6
16.5
9.2
12.9
Mean
SD
25.3
14.4
6.0
11.4
24.6
15.5
51.7
13.2
3.3
4.8
1.3
2.4
3.9
0.6
21.8
5.2
38.6
9.6
16.2
4.0
48.7
25.6
12.1
8.2
39.2
14.3
24.9
8.7
Statistical Analysis
Summary statistics of the demographic, social, and clinical
characteristics are presented for the analyzable sample of 2,876
patients. Summary statistics of treatment characteristics (e.g.,
maximum dose achieved, number of treatment visits), serious adhttp://ajp.psychiatryonline.org
31
No Remission (N=2,086)
N
%
Total (N=2,876)
N
%
56
466
574
983
2.7
22.4
27.6
47.3
7
228
288
267
0.9
28.9
36.4
33.8
63
694
862
1,250
2.2
24.2
30.0
43.6
95
552
562
870
4.6
26.5
27.0
41.9
10
232
294
254
1.3
29.4
37.2
32.1
105
784
856
1,124
3.7
27.3
29.8
39.2
308
444
1,333
14.8
21.3
63.9
14
41
735
1.8
5.2
93.0
322
485
2,068
11.2
16.9
71.9
SD
Mean
SD
Mean
Number of visits
Time to first treatment visit (weeks)
Time in treatment (weeks)
Time from final dose to study exit (weeks)
a
Remission (N=790)
N
%
4.5
2.4
9.3
4.4
1.6
1.2
4.4
3.7
5.5
2.3
12.0
6.6
1.1
0.8
2.6
3.7
Mean
4.8
2.3
10.0
5.0
SD
1.5
1.1
4.2
3.8
Remission was defined as an exit score of 7 on the 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.
verse events, and side effects are presented for the entire sample
and by remission status. Logistic regression models assessed the
association of the demographic, social, and clinical characteristics
with remission, independent of the effect of regional center and
baseline depression severity. As a subsequent analysis designed to
assess the unique and independent contribution of these variables to remission rates, a stepwise logistic regression model was
developed with both the HAM-D and the QIDS-SR. This model
identified baseline features associated with remission independent of baseline depression severity and regional center, both
within the three domains (demographic, social, and clinical) and
across all three domains.
Remission was defined as an exit HAM-D score 7 (or last observed QIDS-SR score 5). A reduction of 50% in baseline QIDSSR at the last assessment was defined as response. Intolerance
was defined a priori as either leaving treatment before 4 weeks or
leaving at or after 4 weeks with intolerance as the identified reason. As defined by the original proposal, patients were designated as not achieving remission when their exit HAM-D score
was missing. Sensitivity analyses were conducted to determine
whether this method of addressing missing data affected study
results. Two additional methods also addressed missing data in
the analysis of remission based on HAM-D scores: 1) a multiple
imputation method and 2) an imputed value generated from an
item response theory analysis of the relationship between the
HAM-D and the QIDS-C. Statistical significance was defined as a
two-sided p value less than 0.05. No adjustments were made for
multiple comparisons, so results must be interpreted accordingly.
Results
Figure 1 shows the disposition of patients during the
course of the study.
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Treatment Features
The study protocol recommended five postbaseline visits with an optional sixth visit (for those with meaningful
improvement short of remission). Overall, participants averaged 4.8 visits (SD=1.5) (Table 2). Those who met HAMD remission criteria had 5.5 visits (SD=1.1), and those who
did not averaged 4.5 visits (SD=1.6). The time from baseline to the next treatment visit (for both remitters and
nonremitters) was slightly over 2 weeks, which was within
the recommended visit schedule.
Citalopram treatment averaged 10 weeks (SD=4.2, median=11.6) or 70.2 days (SD=29.2, median=81). Patients
who achieved HAM-D remission remained in treatment
for a mean of 12 weeks (SD=2.6) (mean=83.8 days, SD=
18.1). Almost all (93%) of these patients completed at least
8 weeks, as opposed to only 64% of the patients who did
not achieve remission (Table 2).
The mean exit dose of citalopram (41.8 mg/day, SD=16.8)
was comparable for patients who did or did not achieve remission. Doses in primary care settings (40.6 mg/day, SD=
16.6) and psychiatric care settings (42.5 mg/day, SD=16.8)
were comparable.
Am J Psychiatry 163:1, January 2006
Mild symptoms
Moderate symptoms
Severe symptoms
8
7
Percent
6
5
4
3
2
1
0
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Last QIDS-SR Score
Symptomatic Outcomes
The overall remission rate was 27.5% (N=790) with the
HAM-D definition (primary outcome) and 32.9% (N=943)
with the QIDS-SR definition. Remission rates were comparable in primary and psychiatric care for the HAM-D
(26.6% versus 28.0%) and the QIDS-SR (32.5% versus
33.1%). The overall QIDS-SR response rate was 47% (N=
1,343) (46% primary care, 48% psychiatric care). Figure 2
shows the distribution of the exit QIDS-SR scores. A QIDSSR score of 10 approximates an HAM-D score of 13 (45).
Figure 3 shows the distribution of the time to first
remission and response for those who ultimately did
achieve remission and response in this study based on
QIDS-SR scores. For those who achieved QIDS-SR remission, the mean time to remission was 6.7 weeks (SD=
3.8) and was comparable in primary care (approximately 6
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
comparable in primary care (mean=5.7 weeks, SD=3.7)
and psychiatric specialty care (mean=5.6 weeks, SD=3.5).
For those who achieved remission according to QIDSSR scores, the mean time in treatment was approximately
12 weeks (SD=3).
Percent
15
10
0
2
10
12
13
Week of Treatment
a
Only 2% of the patients who achieved HAM-D remission were considered to have discontinued citalopram
because of intolerance, compared with 11% of those who
did not achieve HAM-D remission (Table 3). Those who
achieved HAM-D remission had lower rates of side effect
frequency, intensity, and burden at exit and lower rates of
serious adverse effects than those who did not achieve
HAM-D remission. Overall, 116 participants experienced
at least one serious adverse effect; most of these patients
(88.8% [N=103]) did not achieve HAM-D remission. There
were no suicides in the 2,876 participants in this acutephase citalopram study.
Table 5 presents pretreatment features that were nonoverlapping and independently associated with remission
after baseline depressive symptom severity and regional
center for each domain separately and across all domains
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33
Remission (N=790)
Total (N=2,876)
320
535
681
537
15.4
25.8
32.9
25.9
128
273
233
154
16.2
34.6
29.6
19.5
448
808
914
691
15.7
28.2
31.9
24.2
315
510
871
377
15.2
24.6
42.0
18.2
127
283
302
76
16.1
35.9
38.3
9.6
442
793
1,173
453
15.5
27.7
41.0
15.8
402
771
695
205
19.4
37.2
33.5
9.9
181
403
169
35
23.0
51.1
21.5
4.4
583
1,174
864
240
20.4
41.0
30.2
8.4
103
3
47
4
50
6
55
234
4.9
2.6
11.2
13
0
11
0
2
0
2
13
1.6
0.3
1.6
116
3
58
4
52
6
57
247
4.0
2.0
8.6
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.
a
Discussion
Results of this study should be generalizable to routine
clinical practice because this is the largest ecologically
valid real world study of outpatients with nonpsychotic
major depressive disorder treated in psychiatric and primary care settings with diligently followed guidelines.
Participants in the study were patients seeking treatment
in real world clinical practices who had high rates of
chronic or recurrent major depressive disorder and concurrent axis I and axis III (general medical conditions) disorders. Since there were very broad inclusion criteria and
few exclusion criteria, this study included patients who
would have been excluded from most efficacy trials (58
61).
The remission rates (28% for HAM-D; 33% for QIDS-SR)
were robust and similar to rates found in uncomplicated,
nonchronic symptomatic volunteers enrolled in placebocontrolled, 8-week, randomized, controlled trials with
SSRIs (4). These remission rates were better than those
found in efficacy studies among patients with chronic de-
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Patients With
Characteristic
N
Raced
Caucasian (N=2,180) (reference group)
African American (N=506)
Other (N=190)
Hispanic
No (N=2,503) (reference group)
Yes (N=373)
Gender
Male (N=1,043) (reference group)
Female (N=1,833)
Marital statuse
Never married (N=823)
Married (N=1,199) (reference group)
Divorced (N=762)
Widowed (N=89)
Employment statusf
Employed (N=1,613) (reference group)
Unemployed (N=1,098)
Retired (N=161)
Educationg
< High school (N=361)
High school but < college (N=1,786) (reference group)
College (N=726)
Insurance statush
Private (N=1,425) (reference group)
Public (N=397)
None (N=968)
Family history of depression
No (N=1,268) (reference group)
Yes (N=1,585)
History of attempted suicide
No (N=2,358) (reference group)
Yes (N=515)
Setting
Primary care (N=1,091) (reference group)
Psychiatric specialty care (N=1,785)
Age group (years)
1830 (N=754) (reference group)
3150 (N=1,380)
51 (N=741)
Age at onset (years)
<18 years (N=1,077) (reference group)
18 years (N=1,771)
Length of episode (months)
<24 (N=2,131) (reference group)
24 (N=720)
Analysisb
Odds
p
Ratio
Analysisc
Odds
p
Ratio
<0.02
637
94
59
29.2
18.6
31.1
696
94
27.8
25.2
251
539
24.1
29.4
203
374
192
21
24.7
31.2
25.2
23.6
519
234
37
32.2
21.3
23.0
62
472
256
17.2
26.4
35.3
0.70
1.14
1.00
1.35
<1.00
<0.002
<0.02
0.71
0.83
0.78
<0.01
766
111
66
35.1
22.2
34.7
826
117
33.1
31.4
1.09
325
618
31.3
33.7
1.16
257
427
238
21
31.3
35.7
31.3
23.6
612
280
51
38.0
25.6
31.7
91
544
308
25.4
30.5
42.4
551
88
284
38.7
22.2
29.5
392
546
31.0
34.5
804
139
34.2
27.0
0.81
354
589
32.5
33.1
0.92
273
448
221
36.2
32.5
30.0
0.88
0.80
354
581
32.9
32.9
1.07
729
202
34.2
28.2
0.87
0.65
1.08
0.56
0.97
0.63
0.001
0.71
0.86
0.0006
0.70
1.31
33.1
18.4
23.9
331
456
26.1
28.8
667
123
28.3
23.9
290
500
26.6
28.0
225
381
183
29.8
27.6
24.7
315
470
29.2
26.5
0.61
0.72
1.09
0.83
0.88
<0.36
<0.11
<0.24
<0.81
1.03
0.96
1.50
0.0005
0.58
0.81
0.15
1.13
0.07
0.39
606
176
28.4
24.4
0.91
<0.39
0.17
0.81
0.98
<0.0001
0.98
0.0004
472
73
231
<0.23
0.87
0.0007
0.70
0.74
<0.10
<0.47
<0.16
(continued)
35
Patients With
Characteristic
173
572
26.7
28.3
Analysisb
0.82
1.02
Analysisc
<0.44
219
662
33.8
32.8
0.92
523
420
38.9
27.5
0.77
764
171
35.3
25.5
847
89
34.8
21.9
863
74
35.0
19.9
685
250
35.2
28.1
0.87
814
122
36.1
20.8
0.60
871
66
34.8
19.8
0.64
843
94
33.7
27.4
0.80
882
52
33.6
24.9
0.75
926
9
33.5
13.4
911
24
33.6
19.2
0.66
825
112
33.4
30.3
1.01
402
257
148
53
70
41.2
34.4
31.8
20.5
19.3
0.83
0.83
0.47
0.52
0.67
450
340
33.4
22.2
641
142
29.5
21.2
706
76
29.0
18.7
719
64
29.1
17.2
0.96
<0.05
0.80
0.71
<0.02
<0.04
0.73
0.03
0.80
0.002
0.67
0.0007
0.62
0.11
567
215
29.1
24.1
0.86
0.12
0.0005
678
104
30.0
17.7
0.65
0.01
728
55
29.1
16.4
709
74
28.3
21.6
738
43
28.0
20.6
776
7
28.0
10.3
0.67
0.74
0.71
<0.04
<0.06
<0.03
0.41
28.1
16.7
0.72
27.8
25.7
0.90
33.7
29.2
27.0
17.4
15.9
0.87
0.82
0.50
0.55
<0.09
<0.10
0.08
0.0001
330
219
126
45
58
<0.02
0.40
0.40
688
95
<0.0001
0.01
0.19
762
21
<0.002
<0.95
<0.0001
(continued)
36
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Patients With
Characteristic
Analysisb
Odds
p
Ratio
Mean
SD
39.9
14.1
3,105
15.0
4.2
12.8
3.2
3,801
13.0
3.5
0.99
1.20
2.34
0.99
0.97
0.86
<0.0001
<0.0001
<0.56
0.01
15.4
20.4
4.0
4.7
0.83
0.002
52.7
25.6
10.6
8.4
1.16
0.98
43.4
22.8
13.5
8.6
1.10
0.88
Analysisc
Odds
p
Ratio
Mean
SD
40.1
13.9
2,902
14.7
4.2
12.9
3.3
3,529
12.8
3.6
0.96
1.14
1.79
0.97
0.96
0.26
<0.002
<0.0001
0.07
<0.005
15.1
20.4
4.1
4.8
0.78
<0.0001
<0.0001
0.53
51.9
26.0
11.0
8.4
1.14
1.00
<0.0001
<0.88
<0.0001
<0.0001
43.4
22.5
13.7
8.6
1.11
0.86
<0.0001
<0.0001
Remission was defined as an exit score of 7 on the HAM-D or an exit score of 5 on the QIDS-SR. Subjects with missing HAM-D exit scores
were classified as not in remission. Percents are based on the total number of subjects with each baseline characteristic. 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 Odds ratios for patients who did or did not achieve remission adjusted for regional center and baseline HAM-D score (completed by research
outcome assessor).
c Odds ratios for patients who did or did not achieve remission adjusted for regional center and baseline QIDS-SR score.
d Post hoc comparisons for remitted groups defined by either HAM-D or QIDS-SR: Caucasian significantly different from African American. No
other statistically significant differences based on a Bonferroni correction.
e Post hoc comparisons for remitted groups defined by either HAM-D or QIDS-SR: never married significantly different from married. No other
statistically significant differences based on a Bonferroni correction.
f Post hoc comparisons for remitted groups defined by either HAM-D or QIDS-SR: unemployed significantly different from employed. No other
statistically significant differences based on a Bonferroni correction.
g Post hoc comparisons for remitted groups defined by either HAM-D or QIDS-SR: < high school significantly different from college, and
< college significant different from college. No other statistically significant differences based on a Bonferroni correction.
h Post hoc comparisons for remitted group defined by HAM-D: private insurance significantly different from public insurance, and private insurance significantly different from no insurance. Post hoc comparisons for remitted group defined by QIDS-SR: private insurance significantly different from public insurance. No other statistically significant differences based on a Bonferroni correction.
i Post hoc comparisons for remitted group defined by HAM-D: no comorbid psychiatric conditions significantly different from three comorbid
psychiatric conditions, no comorbid psychiatric conditions significantly different from four or more comorbid psychiatric conditions, and one
comorbid psychiatric condition significantly different from four or more comorbid psychiatric conditions. Post hoc comparisons for remitted
group defined by QIDS-SR: no comorbid psychiatric conditions significantly different from three comorbid psychiatric conditions, no comorbid psychiatric conditions significantly different from four or more comorbid psychiatric conditions, one comorbid psychiatric condition significantly different from three comorbid psychiatric conditions, and two comorbid psychiatric conditions significantly different from three
comorbid psychiatric conditions. No other statistically significant differences based on a Bonferroni correction.
a
sion for other antidepressant medications or whether results would differ for psychotherapy or combination(s) of
antidepressant treatments.
In our sample, being married or living with someone
appeared to have a positive effect on the overall remission
rates; married or cohabiting patients met criteria for treatment response with greater frequency than single participants. Although Hagerty and Williams (68) found that
patients living alone were more likely to drop out of treatment, our findings indicate that participants who were
unmarried or living alone did not drop out early and yet
had lower remission rates. Not all studies have found social support to be a significant predictor of treatment outcome (69, 70), but most have suggested social support
and, even more specifically, marital status as positive predictors of response.
Am J Psychiatry 163:1, January 2006
37
All domains
Income ($) (units=10,000)
2.28
Female gender (reference group=male)
1.69
Comorbid axis I psychiatric disorders
Obsessive-compulsive disorder (reference group=no obsessive-compulsive disorder)
Remission Defined
by QIDS-SR
(N=943)
Odds Ratioc
<0.04
0.01
<0.0001
0.78
0.97
1.64
<0.02
0.0003
0.0005
0.001
0.004
0.66
1.04
1.22
<0.04
0.0002
0.97
1.47
0.70
0.67
0.02
<0.002
1.14
1.08
0.92
<0.0001
<0.04
<0.0001
<0.0001
1.67
1.35
0.002
0.005
<0.01
0.71
0.63
0.03
0.0009
<0.0001
<0.005
1.17
1.13
<0.0001
0.001
0.007
<0.0001
0.0007
0.02
Remission was defined as an exit score of 7 on the HAM-D or an exit score of 5 on the QIDS-SR. Subjects with missing HAM-D scores were
classified as not in remission. For HAM-D, area under the curve=0.70; for QIDS-SR, area under the curve=0.69.
b Odds ratios for patients who did or did not achieve remission adjusted for baseline HAM-D score (completed by research outcome assessor)
and regional center.
c Odds ratios for patients who did or did not achieve remission adjusted for baseline QIDS-SR and regional center.
a
38
http://ajp.psychiatryonline.org
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