Is prior course of illness relevant to acute or longer-term outcomes in depressed out-patients? A STAR*D report

Abstract

Major depressive disorder (MDD) is commonly chronic and/or recurrent. We aimed to determine whether a chronic and/or recurrent course of MDD is associated with acute and longer-term MDD treatment outcomes.
This cohort study recruited out-patients aged 18-75 years with non-psychotic MDD from 18 primary and 23 psychiatric care clinics across the USA. Participants were grouped as: chronic (index episode >2 years) and recurrent (n = 398); chronic non-recurrent (n=257); non-chronic recurrent (n=1614); and non-chronic non-recurrent (n = 387). Acute treatment was up to 14 weeks of citalopram (≤ 60 mg/day) with up to 12 months of follow-up treatment. The primary outcomes for this report were remission [16-item Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR(16)) ≤ 5] or response (≥ 50% reduction from baseline in QIDS-SR(16)) and time to first relapse [first QIDS-SR16 by Interactive Voice Response (IVR) ≥ 11].
Most participants (85%) had a chronic and/or recurrent course; 15% had both. Chronic index episode was associated with greater sociodemographic disadvantage. Recurrent course was associated with earlier age of onset and greater family histories of depression and substance abuse. Remission rates were lowest and slowest for those with chronic index episodes. For participants in remission entering follow-up, relapse was most likely for the chronic and recurrent group, and least likely for the non-chronic, non-recurrent group. For participants not in remission when entering follow-up, prior course was unrelated to relapse.
Recurrent MDD is the norm for out-patients, of whom 15% also have a chronic index episode. Chronic and recurrent course of MDD may be useful in predicting acute and long-term MDD treatment outcomes.

Full text

Is prior course of illness relevant to acute or
longer-term outcomes in depressed out-patients?
A STAR*D report
A. J. Rush
1
, S. R. Wisniewski
2
, S. Zisook
3
, M. Fava
4
, S. C. Sung
1
, C. L. Haley
1
, H. N. Chan
5
,
W. S. Gilmer
6
, D. Warden
7
, A. A. Nierenberg
4
, G. K. Balasubramani
2
, B. N. Gaynes
8
, M. H. Trivedi
6
*
and S. D. Hollon
9
1
Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore
2
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
3
Department of Psychiatry, University of California, San Diego, San Diego VA Medical Center, San Diego, CA, USA
4
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA, USA
5
Department of Psychiatry, Singapore General Hospital, Singapore
6
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
7
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
8
Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA
9
Department of Psychology, Vanderbilt University, Nashville, TN, USA
Background. Major depressive disorder (MDD) is commonly chronic and/or recurrent. We aimed to determine
whether a chronic and/or recurrent course of MDD is associated with acute and longer-term MDD treatment
outcomes.
Method. This cohort study recruited out-patients aged 18–75 years with non-psychotic MDD from 18 primary and 23
psychiatric care clinics across the USA. Participants were grouped as : chronic (index episode >2 years) and recurrent
(n=398); chronic non-recurrent (n=257); non-chronic recurrent (n=1614); and non-chronic non-recurrent (n=387).
Acute treatment was up to 14 weeks of citalopram (f60 mg/day) with up to 12 months of follow-up treatment.
The primary outcomes for this report were remission [16-item Quick Inventory of Depressive Symptomatology – Self-
Rated (QIDS-SR
16
)f5] or response (o50 % reduction from baseline in QIDS-SR
16
) and time to first relapse [first
QIDS-SR
16
by Interactive Voice Response (IVR) o11].
Results. Most participants (85 %) had a chronic and/or recurrent course; 15 % had both. Chronic index episode was
associated with greater sociodemographic disadvantage. Recurrent course was associated with earlier age of onset
and greater family histories of depression and substance abuse. Remission rates were lowest and slowest for those
with chronic index episodes. For participants in remission entering follow-up, relapse was most likely for the chronic
and recurrent group, and least likely for the non-chronic, non-recurrent group. For participants not in remission
when entering follow-up, prior course was unrelated to relapse.
Conclusions. Recurrent MDD is the norm for out-patients, of whom 15 % also have a chronic index episode. Chronic
and recurrent course of MDD may be useful in predicting acute and long-term MDD treatment outcomes.
Received 23 February 2011 ; Revised 2 September 2011; Accepted 13 September 2011 ; First published online 19 October 2011
Key words : Chronic, course of illness, depression, outcomes, recurrent.
Introduction
The symptomatic course of major depressive disorder
(MDD) is variable. Some patients have only a single
brief major depressive episode (MDE) but most
patients will suffer several lifetime episodes (Solomon
et al. 1997). Between MDEs, symptom levels vary from
full recovery (i.e. absence of symptoms) to a continu-
ing clinically important level of symptoms that rarely,
if ever, remit. MDE lengths can vary from weeks to
years (Kanai et al. 2003; Gilmer et al. 2005). Chronic
and recurrent courses of illness are associated with
earlier onset, greater symptom severity, suicidality,
psychiatric and medical co-morbidity, familial loading
and service utilization (Gilmer et al. 2005; Hollon et al.
2006; Mondimore et al. 2006; Angst et al. 2009 ;
Satyanarayana et al. 2009; Blanco et al. 2010). Longer
* Address for correspondence : M. H. Trivedi, M.D., University of
Texas Southwestern Medical Center at Dallas, Bass Center, 6363 Forest
Park Road, 13.354, Dallas, TX 75235, USA.
(Email : madhukar.trivedi@utsouthwestern.edu)
Psychological Medicine (2012), 42, 1131–1149. fCambridge University Press 2011
doi:10.1017/S0033291711002170
ORIGINAL ARTICLE

episodes, more episodes and incomplete inter-episode
recovery each suggest the need for longer-term main-
tenance treatment in this population (Depression
Guideline Panel, 1993; APA, 2000a; Anderson et al.
2008; Nutt, 2010).
Recent studies have examined the prevalence and
correlates of chronic and/or recurrent MDD in com-
munity and primary care settings to better understand
the impact of prior course on subsequent depressive
illness. Prospective longitudinal community studies
have found that individuals with a chronic course
of adolescent-onset MDD report less favorable adult
outcomes than those with an episodic course, as evi-
denced by greater psychiatric co-morbidity, suicide
attempts, more frequent and longer duration of treat-
ment, and a greater number of recurrent episodes
(Jonsson et al. 2011). A more chronic/recurrent course
during adolescence (defined using a composite score
based on age of onset, recurrence and duration of
illness) has also been associated with poorer adult
psychosocial functioning in several domains (Pettit
et al. 2009). Prospective data from adult primary care
settings indicate that greater severity of MDD at
baseline is associated with a more chronic course
when assessed at 18-month (Vuorilehto et al. 2009) and
39-month follow-up (Stegenga et al. 2010). A recent
comparison of primary care patients with single-
episode versus recurrent MDD also found that symp-
tom severity was greater among those with recurrent
episodes (Roca et al. 2011).
These studies suggest that prior course of illness is
an important contributor to longer-term outcomes in
MDD, but the literature in this area has been marked
by numerous methodological limitations. The lack of
consistent definitions of chronic and recurrent MDD
makes it difficult to compare and interpret results
across studies. Furthermore, many patients with
chronic MDD will also experience recurrent episodes,
but few studies have attempted to tease out the com-
bined and independent contribution of these two
aspects of prior course. Those studies that have
examined chronic and recurrent MDD in isolation
have neglected the considerable overlap between
these two constructs (Klein, 2008 ; Pettit et al. 2009),
whereas those that lump them together artificially
conflate two related but distinct aspects of MDD.
Despite growing research interest in understanding
the impact of prior course on longer-term outcomes
(e.g. Kaymaz et al. 2008; Pettit et al. 2009; Klein, 2010),
few studies have attempted to fully examine the extent
to which recurrence and/or chronicity affect treatment
outcomes in representative samples of out-patients
with MDD. Data from acute treatment efficacy and
longer-term maintenance trials do not adequately
describe outcomes based on patients’ prior course of
illness. For example, many acute trials exclude chronic
patients (i.e. with a current MDE of >2 years) and do
not provide long-term follow-up. Longer-term main-
tenance trials may selectively enroll patients with re-
current depression (either with or without a chronic
index episode), thereby excluding those with non-
chronic non-recurrent depressions. Consequently,
these studies do not provide a full picture of baseline
sociodemographic or clinical features, or acute and
longer-term outcomes, in representative patients over
a full range of prior illness courses (i.e. single brief
episode, single chronic episode, non-chronic recurrent
episodes, and both chronic and recurrent episodes).
To address this information gap, we analyzed data
from the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) sample (Fava et al. 2003; Rush
et al. 2004; Trivedi et al. 2006) (www.star-d.org) with
participants defined by their prior illness course. Both
acute and longer-term outcomes were obtained. Based
on participant self-report and DSM-IV (APA, 2000b)
definitions, we created four participant groups : those
who had both a chronic (>2-year) index episode
and a recurrent course (BOTH) ; those who had only a
chronic index episode (CHRONIC-ONLY) ; those who
had only a recurrent course (RECURRENT-ONLY) ;
and those who had neither a chronic index episode nor
a recurrent course (NEITHER). This report addresses
the following questions:
(1) Do these patient groups have different baseline
sociodemographic and clinical features?
(2) Do these patient groups differ in terms of acute
treatment symptomatic outcomes with citalo-
pram?
(3) Do these patient groups differ regarding longer-
term treatment symptomatic outcomes with cita-
lopram?
Method
Study overview and organization
The STAR*D trial aimed to define the next best treat-
ment steps for out-patients with non-psychotic MDD
if the initial treatment with the selective serotonin re-
uptake inhibitor (SSRI) citalopram did not produce an
acceptable outcome (e.g. remission with acceptable
tolerance). The rationale, methods and design of the
STAR*D trial have been detailed elsewhere (Fava et al.
2003; Rush et al. 2004).
The study was conducted at 18 primary and 23
psychiatric care settings serving public and private
sector patients. Clinical Research Coordinators (CRCs)
at each Clinical Site assisted participants and clinicians
in protocol implementation. Neither participants nor
clinicians were masked to treatment.
1132 A. J. Rush et al.

Participants
From July 2001 to April 2004, STAR*D enrolled out-
patients aged 18–75 years with non-psychotic MDD.
All risks, benefits and adverse events associated with
STAR*D participation were explained to the partici-
pants, who provided written informed consent prior
to study entry. The protocol was approved and moni-
tored by the National Coordinating Center (University
of Texas Southwestern Medical Center, Dallas, TX,
USA), the Data Coordinating Center (University of
Pittsburgh, Pittsburgh, PA, USA), the Institutional Re-
view Boards at each Clinical Site and Regional Center,
and the Data Safety and Monitoring Board of the
National Institute of Mental Health (NIMH ; Bethesda,
MD, USA).
Only self-declared out-patients seeking medical
care were eligible; recruiting by advertisements was
proscribed. Broad inclusion and minimal exclusion
criteria ensured a widely representative sample of
participants. Out-patients with a baseline score o14
on the 17-item Hamilton Rating Scale for Depression
(HAMD
17
; Hamilton, 1960, 1967) (by CRC evaluation)
were eligible if their clinicians determined that out-
patient treatment with an antidepressant medication
was both safe and indicated. Patients were excluded
if they had bipolar or psychotic disorders ; a primary
diagnosis of obsessive–compulsive or eating disorder;
substance dependence requiring in-patient detoxifica-
tion; a clear history of non-response or intolerance
(in the current MDE) to, or general medical conditions
(GMCs) contraindicating, any protocol medication
in the first two treatment steps; or were pregnant,
planning to become pregnant, or breastfeeding (Rush
et al. 2004).
Diagnostic and outcome measures
Clinicians’ diagnoses of non-psychotic MDD were
confirmed by a checklist using DSM-IV (APA, 2000b)
criteria. Prior personal and family histories, and
sociodemographic and clinical information, were
gathered using self-reports. The Psychiatric Diagnostic
Screening Questionnaire (PDSQ; Zimmerman &
Mattia, 2001a,b; Rush et al. 2005 b) (completed at
baseline) determined the presence/absence of 11
potential concurrent Axis I (psychiatric) disorders
(using a 90% specificity threshold). The CRCs ob-
tained the initial HAMD
17
and the 16-item Quick
Inventory of Depressive Symptomatology – Clinician-
rated (QIDS-C
16
) and Self-report (QIDS-SR
16
) (Rush
et al. 2003, 2006 a; Trivedi et al. 2004) to assess de-
pressive symptom severity at each clinic visit. The
QIDS-C
16
was used to inform dose adjustments. The
CRCs also completed the 14-item Cumulative Illness
Rating Scale (CIRS; Linn et al. 1968; Miller et al. 1992)
to gauge the severity/morbidity of GMCs relevant to
different organ systems. Each of the 14 illness cat-
egories was scored 0 (no problem) to 4 (extremely se-
vere/immediate treatment required/end organ
failure/severe impairment in function). CIRS scores
included Categories Endorsed (0–14) (the number of
co-morbid GMCs), Severity Index (0–4) (the average
severity of the categories endorsed), and Total Severity
(the number of categories endorsed multiplied by the
average severity).
Courses of illness were defined by participant
self-report elicited by the CRC. If the index episode
was >2 years, a chronic index episode was ascribed,
consistent with DSM-IV. If participants had more than
one episode (inclusive of the index episode), a recur-
rent course was ascribed. Thus, four groups were
created: chronic recurrent (BOTH); chronic non-
recurrent (CHRONIC-ONLY); non-chronic recurrent
(RECURRENT-ONLY); and non-chronic non-
recurrent (NEITHER).
Research Outcome Assessors (ROAs) not located at
any clinical site collected the HAMD
17
and the 30-item
Inventory of Depressive Symptomatology – Clinician-
rated (IDS-C
30
; Rush et al. 1996, 2000; Trivedi et al.
2004) using telephone-based structured interviews in
English or Spanish. Responses to items on the baseline
IDS-C
30
or the HAMD
17
were used to estimate the
presence of atypical (Novick et al. 2005), anxious (Fava
et al. 2004a) and melancholic (Khan et al. 2006) symp-
tom features.
For this report, the outcomes in acute treatment
were computed based on the QIDS-SR
16
(primary
outcome) and the HAMD
17
, which was obtained at
baseline and at the end of acute treatment. Response
was defined as either a o50 % reduction from base-
line in the QIDS-SR
16
or in the HAMD
17
. Remission
was defined as an exit QIDS-SR
16
of f5 or an exit
HAMD
17
f7. Of the two, we chose the QIDS-SR
16
as the primary outcome for this report because it
had fewer missing data than the HAMD
17
and because
it compares well with the QIDS-SR obtained by
Interactive Voice Response (IVR) drug follow-up
(Rush et al. 2006b). Participants who had missing
HAMD
17
ratings were assigned to the not-remitted
group.
In follow-up, all of the outcomes relied on the QIDS-
SR
16
, which was obtained by the telephone-based IVR
system (Rush et al. 2006 a). Relapse was defined a priori
when the QIDS-SR
16
by the IVR was o11, which is
equivalent to an HAMD
17
score of o14 (Rush et al.
2003). The QIDS-SR
16
was chosen as the primary (in
fact sole) longer-term outcome because previous work
(Rush et al. 2005a, 2006a,b; Carmody et al. 2006 ;
Bernstein et al. 2007) has found the QIDS-SR
16
by paper
Prior course of illness and depression treatment outcomes 1133

and pencil, and the QIDS-SR by IVR each relate
highly to the QIDS-C
16
(clinician rating) and the
HAMD
17
.
Intervention and measurement-based care
The aim of treatment was to achieve symptom re-
mission (defined by a QIDS-C
16
score f5 collected at
each treatment visit). The protocol (Fava et al. 2003 ;
Rush et al. 2004) required a fully adequate dose of
citalopram for a sufficient time to ensure that par-
ticipants who did not reach remission were truly re-
sistant to the medication. Citalopram was selected as
a representative SSRI because of the relative absence
of discontinuation symptoms, demonstrated safety in
elderly and medically fragile patients, once-a-day
dosing, the small number of dose adjustment steps
and a favorable drug–drug interaction profile (Fava
et al. 2003; Rush et al. 2004).
High-quality measurement-based care was pro-
vided by use of a clinician manual (www.star-d.org),
initial didactic instruction, ongoing support and
guidance by the CRC, the systematic evaluation of
symptoms (QIDS-C
16
completed by the CRC) and side-
effects [Frequency, Intensity and Burden of Side
Effects Ratings (FIBSER); Wisniewski et al. 2006] at
each visit to guide treatment, and a centralized treat-
ment monitoring and feedback system (Trivedi et al.
2006, 2007).
Treatment aimed to optimally dose citalopram
following dosing recommendations in the treatment
manual, which also allowed individualized starting
doses and dose adjustments to minimize side-
effects, maximize safety and optimize the chances of
therapeutic benefit for each participant. Appropriate
flexibility was allowed so that participants with con-
comitant GMCs, substance abuse/dependence or
other psychiatric disorders could be included safely in
the sample.
The protocol recommended treatment visits at
weeks 2, 4, 6, 9 and 12 (with an optional week-14 visit
if needed). After an optimal trial (based on dose and
duration), responders (defined as those with o50 %
improvement over their baseline QIDS-C
16
score)
could enter the 12-month naturalistic follow-up,
although all participants without remission (QIDS-C
16
>5) were encouraged to enter the subsequent
randomized trial. Participants could discontinue
citalopram before 12 weeks if (a) intolerable side-
effects required a medication change, (b) an optimal
dose increase was not possible due to side-effects or
participant choice, or (c) significant symptoms (QIDS-
C
16
o9) were present after 9 weeks at maximally
tolerated doses. Participants could opt to move to the
next treatment level if they experienced intolerable
side-effects or if the QIDS-C
16
score was >5 after an
adequate trial in terms of dose and duration. In follow-
up, the protocol recommended that participants be
seen for clinic visits every 2–3 months with measures
gathered by IVR every month.
Safety assessments
In addition to the FIBSER completed by participants
at each treatment visit to measure the frequency,
intensity and global burden of side-effects, serious
adverse events (SAEs) were monitored using a multi-
tier approach involving the CRCs, study clinicians,
the IVR system, the clinical manager, the safety offi-
cers, the Regional Center Directors (Nierenberg et al.
2004) and the NIMH Data Safety and Monitoring
Board.
Concomitant medications
Concomitant treatments were permitted for current
GMCs (as part of ongoing clinical care), for associated
symptoms of depression (e.g. sleep, anxiety, agitation)
and for citalopram side-effects (e.g. insomnia, sexual
dysfunction) based on clinical judgment. Stimulants,
anticonvulsants, antipsychotics, alprazolam, non-
protocol antidepressants (except trazodone f200 mg
at bedtime for insomnia) and depression-targeted
psychotherapies were proscribed.
Statistical analysis
All analyses were based on the analyzable sample
(n=2656) (Trivedi et al. 2006). Summary statistics
(mean percentages) of the sociodemographic, clinical
and treatment characteristics (e.g. maximum dose
achieved, number of treatment visits), in addition to
SAEs and side-effects, are presented by prior course of
illness (PCI) status. x
2
and one-way ANOVAs com-
pared the discrete and continuous baseline character-
istics, respectively, by PCI status. Logistic regression
models assessed the association of PCI with depress-
ive symptom outcomes (e.g. remission, response),
independent of the effect of Regional Center and in-
dependent of baseline differences between those with
various PCIs. Kaplan–Meier curves estimated the
cumulative proportion of remission and response
and also the cumulative proportion of relapse by
PCI. Log-rank tests were used to test for differences
in the cumulative proportions among the groups.
If significant differences were detected, post-hoc
pairwise comparisons were made with a Bonferroni
correction (pvalue <0.05/6 indicting statistical sig-
nificance).
1134 A. J. Rush et al.

Results
Division of sample
Supplementary Fig. 1 shows how the study sample
was generated. Of the 2876 participants who were
eligible for analysis, 220 had insufficient data to define
prior course of illness. Of the remaining 2656 partici-
pants, 15% (398/2656) were chronic and recurrent
(BOTH), 9.7% (257/2656) were chronic but not re-
current (CHRONIC-ONLY), 60.8% (1614/2656) were
not chronic but were recurrent (RECURRENT-ONLY),
and 14.6% (387/2656) were neither chronic nor re-
current (NEITHER). Overall, 24.7 % (655/2656) of
participants had a chronic index episode regardless
of recurrence, and 75.8% (2012/2656) had a recurrent
course regardless of whether the index episode was
chronic. Supplementary Fig. 2 shows the unique
and overlapping proportions of participants in each
group.
Baseline sociodemographic and clinical features
Table 1 shows the baseline sociodemographic and
clinical features of the sample. In general, participants
with a chronic index episode were more likely to be
socially disadvantaged, whereas participants with a
recurrent course were more likely to have an early age
of onset and a family history of depression and sub-
stance use disorders. Participants who were BOTH
chronic and recurrent tended to show the character-
istics associated with each course of illness. Partici-
pants who were either chronic or recurrent were more
likely to have made suicide attempts than those who
were NEITHER. Participants with a recurrent course
(whether or not chronic) were more likely to be found
in psychiatric clinics.
There were few differences between participants
with BOTH features and those who were CHRONIC-
ONLY. The former were more likely to be treated in
psychiatric settings and to have more prior episodes
(by definition), shorter episodes, a longer length of
illness, a positive family history of depression, and to
experience their first MDE before age 18 years.
Among those with a recurrent course, those with
BOTH a chronic and recurrent course (as opposed to
RECURRENT-ONLY) were more likely to be non-
white, older, unemployed, and have less income and
less education. They were less likely to be married or
have private insurance. Participants with BOTH were
also at a relative social disadvantage, and they had
greater illness burden with more GMCs, more gen-
eralized anxiety and post-traumatic stress disorders,
more depressive episodes, a longer index episode
(as expected), fewer total depressive episodes, and a
longer length of illness.
Participants with BOTH a chronic and recurrent
course were most distinct from those who were
NEITHER chronic nor recurrent. Participants with
BOTH were older, had less income and were more
likely to be divorced or uninsured, to have more
suicide attempts, an earlier age of first onset, more
severe depression, more depressive episodes, a longer
length of current episode (as expected) and illness, a
higher proportion with family histories of depression,
more concurrent GMCs, alcohol or drug abuse, and
more concurrent Axis I disorders (including general-
ized anxiety disorder, social phobia, post-traumatic
stress disorder and bulimia).
When we compared the CHRONIC-ONLY and
the RECURRENT-ONLY participants, the CHRONIC-
ONLY were older, had less income and education,
were more likely to be unemployed or treated in pri-
mary care, and were more likely to have never married
or have private insurance. The CHRONIC-ONLY
participants also had more GMCs and higher rates
of generalized anxiety and hypochondriasis. The
CHRONIC-ONLY participants reported fewer epi-
sodes and longer index episodes (by definition), and
they had a considerably later age of onset and shorter
duration of overall illness than the RECURRENT-
ONLY group.
Acute treatment outcomes
Table 2ashows the unadjusted acute treatment
outcomes by the HAMD
17
and the QIDS-SR
16
. The
groups did not differ on remission based on the
HAMD
17
, but did on the QIDS-SR
16
, though no pair-
wise differences were identified after a Bonferroni
correction for multiple comparisons. The CHRONIC-
ONLY participants had significantly lower response
rates and significantly less percentage change in
the QIDS-SR
16
than the RECURRENT-ONLY par-
ticipants after Bonferroni correction. Controlling for
site and baseline covariates that differentiated the
course of illness groups eliminated these differences
(Table 2b).
The chronic and recurrent (BOTH) group received
higher doses and longer treatment than the non-
chronic non-recurrent (NEITHER) group (Table 3a).
Side-effect frequency, intensity, burden and the types
and frequencies of SAEs were not different among the
groups (Table 3b).
Figure 1ashows the times to first QIDS-SR
16
re-
mission by prior course of illness. The chronic and re-
current (BOTH) participants had significantly worse
acute treatment outcomes than those without a chronic
index episode regardless of recurrence (NEITHER
or RECURRENT-ONLY), whereas the CHRONIC-
ONLY participants were intermediate. Figure 1b
Prior course of illness and depression treatment outcomes 1135

Log-rank statistic=14.7, p= 0.0021
Groups
Both 394 373 325 275 193 127 44
Chronic-only 256 242 206 165 115 72 27
Recurrent-only 1611 1515 1270 994 677 397 144
Neither 385 351 289 229 154 80 35
Total 2646 2481 2090 1663 1139 676 250
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.006 = 83).
BOTH v. RECURRENT-ONLY, BOTH v. NEITHER.
1.00 BOTH
CHRONIC–ONLY
RECURRENT–ONLY
NEITHER
0.75
0.50
0.25
0.00
0246 9 1214
Cumulative probability of remission
Weeks in treatment with citalopram
(a)
Log-rank statistic=7.1, p= 0.0689
Groups
Both 389 359 290 221 139 76 23
Chronic-only 250 236 180 138 92 40 11
Recurrent-only 1569 1478 1119 783 480 236 88
Neither 372 348 259 172 108 50 21
Total 2580 2421 1848 1314 819 402 143
1.00 BOTH
CHRONIC–ONLY
RECURRENT–ONLY
NEITHER
0.75
0.50
0.25
0.00
0246 9 1214
Cumulative probability of response
Weeks in treatment with citalopram
(b)
Fig. 1. Time to (a) remission, (b) response and (c) relapse by course of illness. BOTH refers to participants with a chronic
index episode and recurrent course ; CHRONIC-ONLY refers to participants with a chronic index episode without a recurrent
course ; RECURRENT-ONLY refers to participants with a recurrent course without a chronic index episode ; NEITHER refers
to participants with neither a recurrent course nor a chronic index episode.
1136 A. J. Rush et al.

shows analogous results for times to first response.
Although group differences were not significant with
respect to response, the general pattern was preserved.
Chronic participants took longer to remit (but not
significantly longer to respond) than non-chronic par-
ticipants.
Among those who reached response or remission,
the times to reach these goals was not different for the
four groups. Average times to QIDS-SR
16
remission
were 6.8¡4.1 weeks (BOTH), 7.4¡4.1 weeks
(CHRONIC-ONLY), 6.7¡3.7 weeks (RECURRENT-
ONLY), and 6.9¡3.7 weeks (NEITHER). For the QIDS-
SR
16
responders, times to response were 6.0¡3.8
weeks (BOTH), 5.8¡3.6 weeks (CHRONIC-ONLY),
5.7¡3.6 weeks (RECURRENT-ONLY), and 5.6¡3.3
weeks (NEITHER).
Longer-term treatment outcomes
About half of the sample treated acutely (1337/2656)
entered follow-up with a QIDS-SR
16
<11. Compared
to those who did not enter follow-up, those entering
follow-up were more likely to be white, married,
employed, privately insured, better schooled and have
higher incomes. They also had less general medical
co-morbidity, were less severely depressed at the
beginning of acute treatment and were less likely to
have family histories of depression, suicide, or alcohol
or drug abuse. Rates of anxious, atypical and melan-
cholic features were all lower, as were rates of con-
current Axis I disorders. In brief, participants who
entered follow-up were more socially advantaged and
exhibited less psychopathology than those who did
not.
Fig. 1cshows the probability of relapse for all par-
ticipants who entered follow-up, grouped by course of
illness. Participants with BOTH a chronic and recur-
rent course were more likely to relapse than those who
were NEITHER chronic nor recurrent. Participants
who were CHRONIC-ONLY or RECURRENT-ONLY
had intermediate relapse rates.
Fig. 2(a,b) show the probability of relapse for
participants who entered the follow-up without full
remission and those who entered in full remission
respectively. For participants who were not in full re-
mission at entry into follow-up, the course of illness
was not related to likelihood of relapse, whereas it was
related to likelihood of relapse for participants in full
remission at follow-up entry. These differences were
no longer apparent after controlling for other baseline
Months in follow-up
Log-rank statistic=11.7, p= 0.0084
Groups
Both 181 109 67 47 19
Chronic-only 126 64 48 31 11
Recurrent-only 820 462 299 204 66
Neither 210 122 82 52 20
Total 1337 757 496 334 116
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.006 = 83).
BOTH v. NEITHER.
1.00 BOTH
CHRONIC–ONLY
RECURRENT–ONLY
NEITHER
0.75
0.50
0.25
Survival distribution function
0.00
036912
(c)
Fig. 1 (cont.)
Prior course of illness and depression treatment outcomes 1137

(a)
Months in follow-up
Log-rank statistic=0.46, p= 0.9280
Groups
Both 58 32 18 11 2
Chronic-only 29 11 75 2
Recurrent-only 194 94 54 33 8
Neither 47 18 11 6 1
Total 328 155 90 55 13
Log-rank statistic=9.6, p= 0.0220
Groups
Both 123 77 49 36 17
Chronic-only 97 53 41 26 9
Recurrent-only 626 368 245 171 58
Neither 163 104 71 46 19
Total 1009 602 406 279 103
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.006 = 83).
BOTH v. NEITHER.
1.00 BOTH
CHRONIC–ONLY
RECURRENT–ONLY
NEITHER
0.75
0.50
0.25
0.00
036912
Survival distribution functionSurvival distribution function
1.00 BOTH
CHRONIC–ONLY
RECURRENT–ONLY
NEITHER
0.75
0.50
0.25
0.00
036912
Months in follow-up
(b)
Fig. 2. Time to relapse by course of illness : (a) non-remitted participants ; (b) remitted participants. BOTH refers to participants
with a chronic index episode and recurrent course ; CHRONIC-ONLY refers to participants with a chronic index episode
without a recurrent course ; RECURRENT-ONLY refers to participants with a recurrent course without a chronic index episode ;
NEITHER refers to participants with neither a recurrent course nor a chronic index episode.
1138 A. J. Rush et al.

Table 1. Baseline sociodemographic and clinical features of the sample
BOTH
n=398 (15%)
CHRONIC-
ONLY
n=257 (9.7%)
RECURRENT-
ONLY
n=1614 (60.8 %)
NEITHER
n=387
(14.5 %)
Total
n=2656 pvalue
(a)Baseline demographic characteristics associated with chronic and recurrent MDD
Setting
b,d,f
<0.0001
Primary care 40.7 49.4 33.1 46.0 37.7
Psychiatric care 59.3 50.6 66.9 54.0 62.3
Race
b
0.0228
White 70.4 72.4 78.5 76.0 76.3
African American 22.1 20.2 15.5 17.3 17.2
Others 7.5 7.4 6.0 6.7 6.5
Ethnicity – Hispanic
d,f
<0.0001
No 86.2 79.8 89.5 82.4 87.1
Yes 13.8 20.2 10.5 17.6 12.9
Sex 0.9178
Male 35.9 38.1 36.2 37.2 36.5
Female 64.1 61.9 63.8 62.8 63.5
Marital status
b,c,d,f
<0.0001
Never married 21.6 26.9 30.5 25.6 28.1
Married 43.0 41.6 40.4 50.9 42.4
Divorced 30.7 25.3 26.8 21.2 26.4
Widowed 4.7 6.2 2.3 2.3 3.1
Employment status
b,d
<0.0001
Unemployed 44.5 46.3 34.6 38.0 37.7
Employed 47.7 48.2 60.6 56.3 56.8
Retired 7.8 5.5 4.8 5.7 5.5
Insurance status
b,c,d,e,f
<0.0001
Private insurance 43.9 38.3 55.3 57.7 52.3
Public insurance 16.9 22.6 10.4 17.5 13.6
No insurance 39.2 39.1 34.3 24.8 34.1
Age (years)
b,c,d
44.2 (13.1) 42.6 (13.0) 39.7 (12.8) 40.4 (13.5) 40.7 (13.1) <0.0001
Years of schooling
b,d
13.0 (3.2) 12.5 (3.4) 13.7 (3.2) 13.3 (3.2) 13.4 (3.2) <0.0001
Income (US$/month)
b,c,d,e
2031 (3404) 1863 (2313) 2469 (2887) 2789 (3610) 2392 (3043) <0.0001
(b)Baseline clinical features associated with chronic and recurrent MDD
CIRS
Categories endorsed
b,c,e,f
3.9 (2.6) 3.5 (2.2) 3.0 (2.2) 2.5 (2.2) 3.1 (2.3) <0.0001
Total score
b,c,d,e
5.6 (4.3) 5.2 (3.7) 4.2 (3.6) 3.6 (3.6) 4.4 (3.7) <0.0001
Severity Index
c,d,e
1.3 (0.5) 1.4 (0.6) 1.2 (0.6) 1.1 (0.7) 1.2 (0.6) <0.0001
Symptom severity
HAMD
17
22.3 (5.3) 21.9 (5.6) 21.8 (5.1) 21.5 (5.0) 21.8 (5.2) 0.1651
IDS-C
30
c
39.7 (9.6) 38.8 (10.8) 38.6 (9.3) 37.4 (9.4) 38.6 (9.6) 0.0096
QIDS-SR
16
16.6 (3.9) 16.2 (4.0) 16.2 (4.0) 15.7 (4.0) 16.2 (4.0) 0.0318
Age at onset of first
MDE (years)
a,c,d,e,f
18 (27–13) 36 (47–21) 18 (29–13) 39 (50–29) 22 (35–15) <0.0001
Number of episodes
a,b,c,d,f
3 (6–2) 1 (1–1) 4 (6–2) 1 (1–1) 3 (5–1) <0.0001
Length of current
episode (months)
a,b,c,d,e,f
40 (66–30) 60 (129–35) 5 (9–2) 6 (12–3) 8 (24–3) <0.0001
Length of illness (years)
a,b,c,d,e,f
22 (32–11) 5 (10–3) 15 (26–8) 0.5 (1–0.5) 12 (23–4) <0.0001
(c)Baseline clinical features associated with chronic and recurrent major depressive disorder
Family history of depression
a,c,f
60.4 49.8 58.4 42.0 55.5 <0.0001
Family history of alcohol abuse
c,f
45.0 38.0 43.3 30.6 41.2 <0.0001
Family history of drug abuse
c,f
28.8 19.9 25.7 15.1 24.1 <0.0001
Family history of mood disorder
a,c,f
62.6 52.2 60.3 44.1 57.5 <0.0001
Family history of suicide 4.6 3.1 3.8 2.1 3.6 0.2723
Attempted suicide
c,e,f
19.4 13.6 20.5 5.2 17.5 <0.0001
Onset <18 years
a,c,d,e,f
45.3 16.0 45.5 0.5 36.1 <0.0001
[continues overleaf
Prior course of illness and depression treatment outcomes 1139

factors that differentiated the course of illness groups
(including site).
Discussion
These analyses revealed clinically important baseline
differences between patient groups defined by the
prior course of illness. Consistent with data from
community and primary care samples (Satyanarayana
et al. 2009; Stegenga et al. 2010), participants with
chronic index episodes were generally at greater social
disadvantage and suffered greater general medical
and psychiatric burden than non-chronic participants,
regardless of whether they had a recurrent course.
Table 1 (cont.)
BOTH
n=398 (15%)
CHRONIC-
ONLY
n=257 (9.7%)
RECURRENT-
ONLY
n=1614 (60.8 %)
NEITHER
n=387
(14.5 %)
Total
n=2656 pvalue
Anxious features 55.5 55.3 52.7 53.2 53.5 0.7118
Atypical features
c,e
21.1 23.0 18.6 13.4 18.6 0.0086
Melancholic features 24.9 24.1 23.6 24.0 23.9 0.9559
No. of general medical
conditions
b,c,e,f
<0.0001
0 7.0 6.2 9.9 17.1 10.1
1 10.1 10.9 16.7 17.3 15.2
2 16.3 18.3 17.5 20.4 17.9
3 11.6 16.7 14.6 16.0 14.6
o4 55.0 47.9 41.3 29.2 42.2
(d)Concurrent Axis I co-morbidities associated with chronic and recurrent MDD
Axis I disorder
g
Generalized anxiety disorder
b,c,d,e
28.8 31.2 22.3 17.1 23.3 <0.0001
OCD 16.1 18.7 13.6 13.4 14.4 0.1266
Panic 15.4 15.1 12.7 10.5 13.0 0.1599
Social phobia
c,f
34.7 31.5 31.2 22.8 30.5 0.0023
PTSD
b,c
26.6 19.8 19.8 17.6 20.5 0.0096
Agoraphobia 13.3 14.3 11.3 8.7 11.5 0.0958
Alcohol abuse 10.2 12.3 13.0 9.7 12.0 0.2041
Drug abuse 6.7 6.8 8.6 4.7 7.5 0.0629
Somatoform 2.3 2.4 2.8 0.8 2.4 0.1620
Hypochondriasis
d
5.1 7.6 3.6 3.9 4.3 0.0255
Bulimia 12.8 13.9 13.6 8.4 12.8 0.0481
No. of Axis I disorders
c,e,f
0.0005
0 29.7 30.7 35.1 43.7 35.1
1 25.3 25.4 26.8 27.8 26.6
2 20.9 17.3 16.3 13.2 16.7
3 8.3 11.7 9.7 5.8 9.1
o4 15.8 14.9 12.1 9.5 12.5
MDE, Major depressive disorder ; CIRS, Cumulative Illness Rating Scale ; HAMD
17
, 17-item Hamilton Rating Scale for
Depression ; IDS-C
30
: 30-item Inventory of Depressive Symptomatology – Clinician-rated ; QIDS-SR
16
: 16-item Quick Inventory
of Depressive Symptomatology – Self-report; MDE, major depressive episode ; OCD, obsessive–compulsive disorder ; PTSD,
post-traumatic stress disorder.
Bold indicates statistically significant values.
Values given as percentage, mean (standard deviation) or median (interquartile range).
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.0083).
a
BOTH versus CHRONIC-ONLY.
b
BOTH versus RECURRENT-ONLY.
c
BOTH versus NEITHER.
d
CHRONIC-ONLY versus RECURRENT-ONLY.
e
CHRONIC-ONLY versus NEITHER.
f
RECURRENT-ONLY versus NEITHER.
g
Estimated by the Psychiatric Diagnostic Screening Questionnaire (PDSQ) using 90 % specificity.
1140 A. J. Rush et al.

Table 2. (a)Unadjusted remission and response status by chronic and/or recurrent major depressive disorder (MDD)
Outcome
BOTH
n=398 (15%)
CHRONIC-
ONLY
n=257 (9.7%)
RECURRENT-
ONLY
n=1614 (60.8 %)
NEITHER
n=387 (14.5%)
Total
n=2656 pvalue
HAMD
17
remission 0.0631
No 72.1 79.0 71.6 69.8 72.1
Yes 27.9 21.0 28.4 30.2 27.9
QIDS-SR
16
remission 0.0342
No 70.7 71.9 66.3 62.8 67.0
Yes 29.3 28.1 33.7 37.2 33.0
QIDS-SR
16
response
a
0.0165
No 54.3 62.1 51.5 52.5 53.1
Yes 45.7 37.9 48.5 47.5 46.9
Exit QIDS-SR
16
a,b
9.3 (5.8) 10.1 (6.1) 9 (6.0) 8.5 (5.7) 9.1 (5.9) 0.0060
QIDS-SR
16
change x7.2 (5.7) x6.1 (5.9) x7.1 (6.0) x7.2 (5.8) x7.1 (5.9) 0.0415
QIDS-SR
16
change (%)
a,b
x43.3 (32.8) x36.9 (35.6) x43.3 (36.1) x44.7 (34) x42.9 (35.3) 0.0237
HAMD
17
, 17-Item Hamilton Rating Scale for Depression; QIDS-SR
16
, 16-item Quick Inventory of Depressive
Symptomatology – Self-Report.
Bold indicates statistically significant values.
Values given as percentage or mean (standard deviation).
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.0083).
a
CHRONIC-ONLY versus RECURRENT-ONLY.
b
CHRONIC-ONLY versus NEITHER.
Table 2. (b)Adjusted remission and response status by chronic and/or recurrent MDD
Comparison
HAMD
17
remission
a
QIDS-SR
16
remission QIDS-SR
16
response
OR pvalue OR pvalue OR pvalue
Unadjusted
Ref. group=NEITHER 0.0631 0.0342 0.0165
RECURRENT-ONLY 0.91 0.86 1.04
CHRONIC-ONLY 0.61 0.66 0.67
Both chronic and recurrent 0.89 0.70 0.93
Adjusted
b
0.2152 0.1836 0.1587
RECURRENT-ONLY 0.87 0.82 1.01
CHRONIC-ONLY 0.68 0.74 0.73
Both chronic and recurrent 0.94 0.74 0.99
Adjusted
c
0.4474 0.8998 0.3444
RECURRENT-ONLY 0.87 0.93 1.10
CHRONIC-ONLY 0.78 0.89 0.85
Both chronic and recurrent 0.99 0.89 1.11
HAMD
17
, 17-Item Hamilton Rating Scale for Depression; QIDS-SR
16
, 16-item Quick Inventory of Depressive
Symptomatology – Self-Report ; OR, odds ratio.
Bold indicates statistically significant values.
a
The baseline severity of HAMD
17
is not included in the model because it does not show any differences between groups.
b
Adjusted for Regional center.
c
Adjusted for Regional center, clinical setting, race, ethnicity, marital status, employment status, insurance status, Cumulative
Illness Rating Scale (CIRS) total score, family history of alcohol abuse, family history of drug abuse, family history of mood
disorder, attempted suicide, age at onset, atypical depression, age, education, and baseline severity of QIDS-SR
16
.
Prior course of illness and depression treatment outcomes 1141

Table 3. (a)Treatment characteristics in relation to symptomatic outcome by chronic and recurrent major depressive disorder (MDD)
Treatment characteristic
BOTH
n=398 (15%)
CHRONIC-ONLY
n=257 (9.7%)
RECURRENT-ONLY
n=1614 (60.8 %)
NEITHER
n=387 (14.5 %) Total n=2656
pvaluen%n%n%n%n%
Maximum dose of citalopram (mg/day)
a
0.0356
<20 5 1.3 4 1.6 42 2.6 9 2.3 60 2.3
20–39 78 19.6 66 25.8 387 24.0 107 27.7 638 24.1
40–49 116 29.2 70 27.3 488 30.3 127 32.8 801 30.2
o50 198 49.9 116 45.3 694 43.1 144 37.2 1152 43.4
Dose of citalopram at study exit (mg/day)
a
0.0067
<20 11 2.8 8 3.1 67 4.2 13 3.4 99 3.7
20–39 88 22.2 78 30.5 435 27.0 115 29.7 716 27.0
40–49 112 28.2 62 24.2 494 30.7 129 33.3 797 30.1
o50 186 46.8 108 42.2 615 38.1 130 33.6 1039 39.2
Time in treatment (weeks)
a
0.0082
<4 27 6.8 28 10.9 179 11.1 59 15.3 293 11.0
o4 but <8 65 16.3 50 19.5 280 17.3 55 14.2 450 16.9
o8 306 76.9 179 69.6 1155 71.6 273 70.5 1913 72.0
Mean S.D. Mean S.D. Mean S.D. Mean S.D. Mean S.D.
Number of visits 5.0 1.4 4.7 1.5 4.8 1.5 4.7 1.6 4.8 1.5 0.0132
Time to first treatment visit (weeks) 2.3 0.9 2.4 1.3 2.3 1.2 2.3 1.0 2.3 1.1 0.2706
Time in treatment (weeks) 10.5 3.7 9.9 4.2 10.0 4.2 9.9 4.5 10.1 4.2 0.0771
Time from final dose to study exit (weeks) 5.2 3.6 5.0 3.8 5.1 4.1 5.3 4.2 5.1 4.0 0.7256
S.D., Standard deviation.
Bold indicates statistically significant values.
Post-hoc comparisons based on a Bonferroni correction for multiple comparisons (p<0.0083).
a
BOTH versus NEITHER.
1142 A. J. Rush et al.

Table 3. (b)Adverse events, side-effects by chronic and recurrent MDD
Treatment characteristic
BOTH
n=398 (15%)
CHRONIC-ONLY
n=257 (9.7 %)
RECURRENT-ONLY
n=1614 (60.8 %)
NEITHER
n=387 (14.5%) Total n=2656
pvaluen%n%n%n%n%
Maximum side-effect frequency 0.1064
None 69 17.3 41 16.1 238 14.9 65 16.8 413 15.6
10–25% of the time 122 30.7 67 26.3 441 27.5 111 28.8 741 28.1
50–75% of the time 102 25.6 85 33.3 528 32.9 135 35.0 850 32.2
90–100% of the time 105 26.4 62 24.3 396 24.7 75 19.4 638 24.1
Maximum side-effect intensity 0.4162
None 65 16.3 39 15.3 238 14.8 65 16.8 407 15.4
Trivial 115 28.9 68 26.7 432 27.0 118 30.6 733 27.7
Moderate 161 40.5 98 38.4 670 41.8 154 39.9 1083 41.0
Severe 57 14.3 50 19.6 263 16.4 49 12.7 419 15.9
Maximum side-effect burden 0.3703
No impairment 87 21.9 45 17.7 318 19.8 89 23.1 539 20.4
Minimal-mild impairment 159 40.0 110 43.1 647 40.4 166 43.0 1082 41.0
Moderate-marked impairment 116 29.1 74 29.0 500 31.2 109 28.2 799 30.2
Severe impairment – unable to function 36 9.0 26 10.2 138 8.6 22 5.7 222 8.4
Serious adverse events 12 3.0 9 3.5 69 4.3 12 3.1 102 3.8 0.5294
Death, non-suicide 1 0 2 0 3
Hospitalization for GMCs 9 5 27 8 49
Medical illness without hospitalization 0 0 3 1 4
Psychiatric hospitalization (substance abuse) 1 2 5 0 8
Psychiatric hospitalization (other) 0 0 2 0 2
Psychiatric hospitalization (suicidal ideation) 4 2 23 3 32
Psychiatric hospitalization (worsening depression) 0 0 4 2 6
Suicidal ideation (without hospitalization) 0 0 5 0 5
Any psychiatric serious adverse events 5 1.3 4 1.6 39 2.4 4 1.0 52 2.0 0.1930
Intolerance 54 13.6 48 18.7 277 17.2 67 17.3 446 16.8 0.2783
GMC, General medical co-morbidity.
Prior course of illness and depression treatment outcomes 1143

Participants with a recurrent course (with or without a
chronic index episode) typically had an earlier age of
onset and greater familial loading for depression and
substance abuse than non-recurrent participants.
These data are in line with research that has shown
positive associations between number of recurrent epi-
sodes, age of onset, and family history of depression
(Roca et al. 2011). Earlier onset and greater familial
loading may indicate an underlying genetic vulner-
ability. Participants with BOTH a chronic and recur-
rent course differed most from those who were
NEITHER chronic nor recurrent and showed the sep-
arate patterns of social disadvantage and familial load-
ing associated with each. Participants with NEITHER
a chronic nor a recurrent course had the least concur-
rent general medical and psychiatric burden, and were
least likely to have made prior suicide attempts.
The acute treatment outcomes (unadjusted) were
typically worse for those with a chronic (versus
non-chronic) index episode. Participants with BOTH
a chronic index episode and a recurrent course took
longer to remit than non-chronic participants (regard-
less of recurrence). Fewer CHRONIC-ONLY partici-
pants responded acutely (37.9%) than RECURRENT-
ONLY participants (48.5%). This same pattern held for
other outcome indices. Chronic participants (regard-
less of recurrence) had lower response or remission
rates than non-chronic participants. Overall, lower
acute treatment benefit can be expected among some
patients with chronic index episodes, but these out-
come differences are modest. These differences were
not due to differences in treatment. The differences in
acute outcome were generally eliminated after con-
trolling for site and other differentiating baseline
variables. Thus, the differences in acute outcomes
cannot be attributed solely to the course of illness. That
is, a chronic course may lead to additional psychiatric
and general medical burden, or vice versa. However,
when taken together, chronicity and these associated
burdens are associated with the worst acute treatment
outcome.
As for longer-term outcomes, those who were
NEITHER chronic nor recurrent had the lowest re-
lapse rate, whereas those who were BOTH chronic
and recurrent had the highest relapse rate. This
difference was significant. The remaining two groups
(the CHRONIC-ONLY and RECURRENT-ONLY) had
intermediate outcomes. These results suggest that
both chronicity and recurrence contribute to risk for
relapse in an independent (additive) fashion. This
finding suggests that chronicity and recurrence are
associated with different mechanisms, both of which
contribute to the propensity for relapse.
When we further divided the follow-up sample into
those with and those without remission upon entering
follow-up, these longer-term findings could be wholly
attributed to the participants who entered follow-up
in remission. There were no differences in relapse rates
as a function of course of illness among those not
in remission at follow-up entry. After controlling
for other baseline factors, the differences found for
those in remission were no longer apparent. Thus,
differences in relapse rates may not be wholly
attributable to chronic or recurrent course per se,
because other features associated with different
courses of illness may account for the different out-
comes.
In clinical practice, then, lack of remission is pre-
dictive of relapse. However, for those who have
remitted, either a chronic or recurrent course, and es-
pecially the presence of both, is predictive of relapse.
Thus, special vigilance is suggested for even fully
remitted patients who have had a chronic index
episode or a history of recurrence. The most appro-
priate strategies for managing these patients have
yet to be fully elucidated. For those with a recurrent
course of illness, the addition of psychotherapy after
successful antidepressant treatment has been shown
to reduce the risk of relapse and recurrence (Guidi
et al. 2011). Cognitive behavioral therapy, in particular,
is an effective therapeutic option in preventing
relapses for up to 6 years (Fava et al. 2004 b; Conradi
et al. 2008; Bockting et al. 2009). The optimal relapse
prevention treatment for chronic depression is less
clear. Continuation treatment using a combination of
medication and cognitive behavioral therapy seems to
be more effective in preventing relapse than either
monotherapy (Kocsis et al. 2003), but systematic re-
views to investigate the effectiveness of various treat-
ment options are still needed to shed light on this
important clinical issue (Kriston et al. 2010).
The strengths of our study include the analysis of a
large representative sample of treatment-seeking
patients with unipolar MDD and the inclusion of the
full range of prior course-of-illness variables. An
inherent study limitation is that some (but not all)
participants who have not yet developed a chronic
index episode or recurrent course at study entry will
subsequently develop such a course. On the one hand,
if clinically meaningful differences are found between
participants with various courses of illness, they might
be expected to be valid given this potential sample
bias. On the other hand, failure to find differences
could result from the fact that some non-chronic, non-
recurrent patients will develop chronic and/or recur-
rent course over time.
Other limitations include the use of a self-report
to diagnose concurrent Axis I and III conditions, the
use of self-report to assess chronicity and recurrence
(recall bias), reliance on the self-report by IVR to
1144 A. J. Rush et al.

identify relapse, and the fact that this is a secondary
analysis. Furthermore, the declaration of response,
remission and relapse were all based on a single
measurement occasion that covered only the past
7 days (Rush et al. 2006c). This limitation is likely
to inflate the relapse rates, and also the response
and remission rates. Because visit schedules were not
tightly controlled in the STAR*D study, we could not
easily require return visits and multiple measure-
ments to document that at least a 2-week duration was
achieved to declare relapse, response or remission.
Relapse was set at a robust QIDS-SR threshold of
o11, which in most cases corresponds to sufficient
symptoms to meet MDD criteria (equivalent to
HRDS
17
=14).
In conclusion, a chronic index episode was found in
one out of four out-patients with MDD and a recurrent
course was found in about three out of four.
Chronicity and recurrence are not mutually exclusive
because 15% of participants had both a chronic index
episode and a recurrent course. A chronic index epi-
sode was associated with social disadvantages
(e.g. less education, poorer function, lower quality
of life) and illness burden (e.g. co-morbidities). A re-
current course was associated with features compat-
ible with an underlying genetic vulnerability (early
onset and greater familial loading for depression and
substance abuse). One possible explanation for these
results is that recurrent course may be a consequence
of nature (genetics) and chronicity a function of nur-
ture (life events). Chronicity, but not recurrence, was
associated with a lower likelihood of, and a longer
time to, response and remission, in acute treatment.
Among remitted participants, both chronicity and re-
currence were associated with a higher risk for relapse
in an independent and additive fashion. Although
some of the differences between groups defined by
course of illness were modest, the differences between
those with neither versus both chronicity and recur-
rence argue for a different management approach
based on course.
These results suggest that central nervous system
mechanisms that delay the onset of remission or
contribute to relapse in treatment deserve further
study, particularly for patients with a chronic or
recurrent course of illness. Additional work is also
needed to determine the most effective approaches
for continuation treatment in these populations.
Although it is essential to target effective treatment for
chronicity and recurrence of depression, it is import-
ant to note that the best prognosis was found in par-
ticipants with neither a chronic index episode nor a
recurrent history. This underscores the notion that
treatment early in the course of illness may be most
effective.
Note
Supplementary material accompanies this paper on
the Journal’s website (http://journals.cambridge.org/
psm).
Acknowledgments
This project was funded by the NIMH under Contract
N01MH90003 to UT Southwestern Medical Center
at Dallas (PI: A. J. Rush). The content of this publi-
cation does not necessarily reflect the views or policies
of the Department of Health and Human Services,
nor does mention of trade names, commercial pro-
ducts, or organizations imply endorsement by the U.S.
Government. We appreciate the support of Bristol-
Myers Squibb, Forest Laboratories, GlaxoSmithKline,
King Pharmaceuticals, Organon, Pfizer, and Wyeth for
providing medications at no cost for this trial. We also
acknowledge the editorial support of J. Kilner. None
of these entities had a role in any part of the study
(e.g. design, execution, data collection, analysis, inter-
pretation of the data, writing any report, including this
one). Drs Rush and Wisniewski had full access to all
of the data in the study and take responsibility for
the integrity of the data and the accuracy of the data
analysis.
[Trial registry name: ClinicalTrials.gov. Regis-
tration identification number : NCT00021528. URL
for the registry (www.clinicaltrials.gov/ct/show/
NCT00021528?order=2).]
Declaration of Interest
A. J. Rush:Research support: Robert Wood Johnson
Foundation; the NIMH; the Stanley Medical Research
Institute. Advisory/consulting: Advanced Neuronetic
Systems, Inc.; AstraZeneca; Best Practice Project
Management, Inc.; Bristol-Myers Squibb Company;
Cyberonics, Inc.; Forest Pharmaceuticals, Inc.; Gerson
Lehman Group; GlaxoSmithKline; Healthcare Tech-
nology Systems, Inc.; Jazz Pharmaceuticals; Eli Lilly &
Company; Magellan Health Services; Merck & Co.,
Inc.; Neuronetics; Ono Pharmaceutical ; Organon USA
Inc.; Personality Disorder Research Corp.; Pfizer Inc. ;
The Urban Institute; and Wyeth-Ayerst Laboratories
Inc. Speaking: Cyberonics, Inc.; Forest Pharma-
ceuticals, Inc.; GlaxoSmithKline; Eli Lilly & Com-
pany; and Merck & Co., Inc. Equity holdings (exclude
mutual funds/blinded trusts): Pfizer Inc. Royalty/
patent, other income: Guilford Publications; Healthcare
Technology Systems, Inc. S. R. Wisniewski:Research
support: NIMH. Advisory/consulting: Cyberonics, Inc.
S. Zisook:Research support: NIMH; Aspect Medi-
cal; PamLab. Advisory/consulting: GlaxoSmithKline.
Prior course of illness and depression treatment outcomes 1145

Speaking: AstraZeneca Pharmaceuticals; Forest Phar-
maceuticals, Inc.; GlaxoSmithKline; Janssen Pharma-
ceutica Products, LP; Eli Lilly & Company; Pfizer
Inc.; Wyeth Pharmaceuticals. M. Fava:Research
support: Abbott Laboratories; Alkermes ; Aspect Medi-
cal Systems; Astra-Zeneca; Bristol-Myers Squibb
Company; Cephalon; Forest Pharmaceuticals Inc. ;
GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer
Pharma GmbH; Eli Lilly & Company; Lorex Pharma-
ceuticals; Novartis; Organon Inc. ; PamLab, LLC;
Pfizer Inc.; Pharmavite; Roche ; Sanofi/Synthelabo ;
Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Labora-
tories. Advisory/consulting: Aspect Medical Systems;
Astra-Zeneca; Bayer AG; Biovail Pharmaceuticals,
Inc.; BrainCells, Inc.; Bristol-Myers Squibb Company;
Cephalon; Compellis; Cypress Pharmaceuticals ;
Dov Pharmaceuticals; EPIX Pharmaceuticals; Fabre-
Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals
Inc.; GlaxoSmithKline; Grunenthal GmBH ; J & J
Pharmaceuticals; Janssen Pharmaceutica; Jazz Phar-
maceuticals; Knoll Pharmaceutical Company; Eli Lilly
& Company; Lundbeck; MedAvante, Inc.; Novartis ;
Nutrition 21; Organon Inc.; PamLab, LLC ; Pfizer
Inc.; PharmaStar; Pharmavite ; Roche ; Sanofi/Synthe-
labo; Sepracor; Solvay Pharmaceuticals, Inc. ; Somer-
set Pharmaceuticals; Wyeth-Ayerst Laboratories.
Speaking: Astra-Zeneca; Bristol-Myers Squibb Com-
pany; Cephalon; Forest Pharmaceuticals Inc. ;
GlaxoSmithKline; Eli Lilly & Company; Novartis ;
Organon Inc.; Pfizer Inc.; PharmaStar ; Wyeth-Ayerst
Laboratories. Equity holdings (exclude mutual funds/
blinded trusts): Compellis, MedAvante. W. S. Gilmer:
Research support: Abbott Laboratories, Aspect Medical;
Forest Pharmaceuticals Inc.; Janssen Pharmaceutica;
Neuronetics; Novartis; Pfizer Inc. ; NIMH. Advisory/
consulting: Astra-Zeneca; Bristol-Myers Squibb Com-
pany; Eli Lilly & Company; Forest Pharmaceuticals ;
GlaxoSmithKline; Pfizer, Inc.; Shire. Speaking : Bristol-
Myers Squibb Company; Forest Pharmaceuticals;
GlaxoSmithKline; Pfizer Inc.; Wyeth-Ayerst Labora-
tories. D. Warden:Research Support: NIMH, National
Institute of Drug Abuse, NARSAD; Equity holdings:
Pfizer, Bristol Myers Squib. A. A. Nierenberg :
Research support: Bristol-Myers Squibb Company;
Cederroth; Cyberonics, Inc.; Forest Pharmaceuticals
Inc.; GlaxoSmithKline; Janssen Pharmaceutica ;
Lichtwer Pharma; Eli Lilly & Company; Pfizer Inc. ;
NIMH; National Alliance for Research in Schizo-
phrenia and Depression, Stanley Foundation; Wyeth-
Ayerst Laboratories. Advisory/consulting : Bristol-
Myers Squibb Company; Eli Lilly & Company;
Genaissance; GlaxoSmithKline; Innapharma ; Neuro-
netics; Pfizer, Inc.; Sepracor ; Shire. Speaking : Eli Lilly
& Company; GlaxoSmithKline; Organon, Inc. ; Wyeth-
Ayerst Laboratories. B. N. Gaynes :Research support:
NIMH; Agency for Healthcare Research and Quality;
Robert Wood Johnson Foundation ; the M-3 Corpor-
ation; Bristol-Myers Squibb Company; Novartis ; Pfi-
zer, Inc.; and Ovation Pharmaceuticals. Advisory/
consulting: Pfizer, Inc.; Shire Pharmaceuticals ; Wyeth-
Ayerst. Speaking: GlaxoSmithKline. M. H. Trivedi:
Research support: Bristol-Myers Squibb Company;
Cephalon, Inc.; Corcept Therapeutics, Inc.; Eli Lilly &
Company; GlaxoSmithKline; Janssen Pharmaceutica ;
NIMH; National Alliance for Research in Schizo-
phrenia and Depression ; Pfizer Inc.; Predix Pharma-
ceuticals; Wyeth-Ayerst Laboratories. Advisory/
consulting: Abbott Laboratories, Inc.; Akzo (Organon
Pharmaceuticals Inc.); Bayer; Bristol-Myers Squibb
Company; Cyberonics, Inc.; Forest Pharmaceuticals;
GlaxoSmithKline; Janssen Pharmaceutica Products,
LP; Johnson & Johnson PRD; Eli Lilly & Company ;
Meade Johnson; Parke-Davis Pharmaceuticals, Inc.;
Pfizer, Inc.; Pharmacia & Upjohn; Sepracor; Solvay
Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories.
Speaking: Akzo (Organon Pharmaceuticals Inc.);
Bristol-Myers Squibb Company; Cyberonics, Inc.;
Forest Pharmaceuticals; Janssen Pharmaceutica Pro-
ducts, LP; Eli Lilly & Company; Pharmacia & Upjohn ;
Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Labora-
tories. S. D. Hollon :Research support: NIMH. Royalty/
patent, other income: Guilford Publications; Wiley.
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