Meta-analysis of Major Depressive Disorder Relapse and Recurrence With Second-Generation Antidepressants

Article (PDF Available)inPsychiatric services (Washington, D.C.) 59(10):1121-30 · November 2008with49 Reads
DOI: 10.1176/appi.ps.59.10.1121 · Source: PubMed
Abstract
This meta-analysis reviewed data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phases of treatment, respectively. MEDLINE, EMBASE, and PsycINFO, the Cochrane Library, and International Pharmaceutical Abstracts were searched for the period of January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies on the topic. Two persons independently reviewed abstracts and full-text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction. Four comparative trials and 23 placebo-controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggested a relatively large effect size that persists over time. For preventing both relapse and recurrence, the number of patients needed to treat is five (95% confidence interval of 4 to 6). Differences in the length of open-label treatment before randomization, drug type, and trial duration did not affect pooled estimates of relapse rates. Across all trials, 7% of patients randomly assigned to receive active treatment and 5% of patients randomly assigned to receive a placebo discontinued treatment because of adverse events. This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants and emphasizes the need for additional studies of comparative differences among drugs.
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A
ntidepressants are used com-
monly as a first-line treatment
for major depressive disorder.
In particular, second-generation anti-
depressants such as selective sero-
tonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake
inhibitors, and other drugs that selec-
tively affect the activity of neurotrans-
mitters play a prominent role in treat-
ment. Although these drugs are be-
lieved to have similar efficacy to first-
generation agents (for example, tri-
cyclic antidepressants and mono-
amine oxidase inhibitors), they are
recommended over the first-genera-
tion agents because of their relatively
favorable side effect profile and re-
duced risk of harm in overdose or in
combination with certain medications
or food (1).
Current treatment guidelines for
major depression (2,3) suggest an
acute-phase treatment duration of six
to 12 weeks. For patients who
demonstrate an adequate response
(usually defined as remission) to
acute-phase treatment, continuation-
phase treatment of four to nine
months is recommended. The goal of
continuation-phase treatment is to
prolong the absence of depressive
symptoms such that the patient’s
episode can be considered complete-
ly resolved. Effective continuation-
phase treatment prevents relapse, de-
fined as the return of depressive
symptoms during the current depres-
Meta-analysis of Major Depressive
Disorder Relapse and Recurrence With
Second-Generation Antidepressants
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Dr. Hansen is affiliated with the Division of Pharmaceutical Outcomes and Policy, Dr.
Gaynes is with the Department of Psychiatry, Ms. Thieda is with Cecil G. Sheps Center for
Health Services Research, and Ms. Deveaugh-Geiss is with the Department of Epidemiolo-
gy, all at the University of North Carolina–Chapel Hill. Dr. Gartlehner is with the Depart-
ment for Evidence-Based Medicine and Clinical Epidemiology, Danube University, Krems,
Austria. Dr. Krebs is with the Department of Medicine, Indiana University, Indianapolis. Dr.
Lohr is with RTI International, Research Triangle Park, North Carolina. Send correspon-
dence to Dr. Hansen at the School of Pharmacy, University of North Carolina–Chapel Hill,
2205 Kerr Hall, Campus Box 7360, Chapel Hill, NC 27599 (e-mail: rahansen@unc.edu).
Objective: This meta-analysis reviewed data on the efficacy and effective-
ness of second-generation antidepressants for preventing major depression
relapse and recurrence during continuation and maintenance phases of
treatment, respectively. Methods: MEDLINE, EMBASE, and PsycINFO,
the Cochrane Library, and International Pharmaceutical Abstracts were
searched for the period of January 1980 through April 2007 for reviews,
randomized controlled trials, meta-analyses, and observational studies on
the topic. Two persons independently reviewed abstracts and full-text arti-
cles using a structured data abstraction form to ensure consistency in ap-
praisal and data extraction. Results: Four comparative trials and 23 placebo-
controlled trials that addressed relapse or recurrence prevention were in-
cluded. Results of comparative trials have not demonstrated statistically
significant differences between duloxetine and paroxetine, fluoxetine and
sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine.
Pooled data for the class of second-generation antidepressants compared
with placebo suggested a relatively large effect size that persists over time.
For preventing both relapse and recurrence, the number of patients need-
ed to treat is five (95% confidence interval of 4 to 6). Differences in the
length of open-label treatment before randomization, drug type, and trial
duration did not affect pooled estimates of relapse rates. Across all trials,
7% of patients randomly assigned to receive active treatment and 5% of pa-
tients randomly assigned to receive a placebo discontinued treatment be-
cause of adverse events. Conclusions: This review demonstrates the overall
benefits of continuation- and maintenance-phase treatment of major de-
pression with second-generation antidepressants and emphasizes the need
for additional studies of comparative differences among drugs. (Psychiatric
Services 59:1121–1130, 2008)
sive episode. After successful contin-
uation-phase treatment, a mainte-
nance phase of treatment to prevent
recurrence of a new, distinct episode
is considered. For patients with a his-
tory of recurrent depression, mainte-
nance-phase treatment can frequent-
ly last for years.
For acute treatment of depression,
approximately 60% of patients re-
spond to second-generation antide-
pressants (4). Evidence from the one-
year naturalistic follow-up phase of
the Sequenced Treatment Alterna-
tives to Relieve Depression (STAR
D)
trial indicates that at least 40% of
acute-phase responders relapse dur-
ing continuation treatment (5). Ran-
domized, double-blinded, controlled
trials have assessed how treatments
compare with placebo and with each
other for preventing relapse and re-
currence, but results for second-gen-
eration antidepressants have not been
systematically reviewed. Two reviews
have systematically assessed relapse
prevention during continuation-phase
treatment or recurrence prevention
during maintenance-phase treatment
(6,7), but these reviews included all
antidepressants rather than just sec-
ond-generation antidepressants. They
are limited by the dates of their litera-
ture searches—searches censored at
1987 (6) and 2000 (7)—and thus ex-
clude more recent studies. More re-
cently, Zimmerman and colleagues (8)
focused on second-generation antide-
pressants, although the intent of their
review was to illustrate how conclu-
sions differ between extension trials
and placebo substitution trials.
Because second-generation drugs
are now the most frequently pre-
scribed antidepressants, our goal was
to systematically evaluate data on the
efficacy of second-generation antide-
pressants for preventing relapse and
recurrence. We conducted a system-
atic review and meta-analysis of com-
parative and placebo-controlled evi-
dence for 12 second-generation anti-
depressants (bupropion, citalopram,
duloxetine, escitalopram, fluoxetine,
fluvoxamine, mirtazapine, nefazo-
done, paroxetine, sertraline, trazo-
done, and venlafaxine). We refer to
these agents collectively as antide-
pressants. We had two key questions
for this review. First, for adults with a
depressive syndrome, do antidepres-
sants differ in their efficacy or effec-
tiveness for maintaining remission
(specifically, preventing relapse dur-
ing the continuation phase and pre-
venting recurrence during the main-
tenance phase)? Second, for adults
with depressive syndrome, what is the
overall effect size for active treatment
compared with placebo, and is this ef-
fect size persistent over time?
Methods
Key questions
Key questions designed to address ef-
ficacy, effectiveness, and tolerability
of antidepressants for maintaining re-
mission guided our work. The key
questions were formulated through a
process involving the public, the Sci-
entific Resource Center for the Ef-
fective Health Care program of the
Agency for Healthcare Research and
Quality (AHRQ), and various stake-
holder groups. AHRQ provided fund-
ing for the initial review, although this
update and analysis were unfunded.
Literature search
To identify articles relevant to each
key question, we searched MED-
LINE, EMBASE, the Cochrane Li-
brary, PsycINFO, and International
Pharmaceutical Abstracts. Searches
covered studies published during the
period of January 1980 through April
2007. In addition, we manually
searched reference lists of relevant
review articles and letters to the edi-
tor. We also manually searched the
Center for Drug Evaluation and Re-
search (CDER) database to identify
unpublished research submitted to
the U.S. Food and Drug Administra-
tion (FDA).
Study selection
Two persons independently reviewed
article titles and abstracts. We in-
cluded head-to-head trials compar-
ing one antidepressant with another
and placebo-controlled trials. Studies
included adult inpatient and outpa-
tient populations with depressive ill-
ness in which individuals demon-
strated response to treatment or re-
mission. Head-to-head trials were in-
cluded if they reported relapse or re-
currence rates, regardless of whether
participants were randomly assigned
to treatment groups after successful
acute-phase or continuation-phase
treatment (that is, extension versus
randomized substitution trials). For
our meta-analysis, inclusion criteria
were more stringent for placebo-con-
trolled evidence; only studies that
randomly assigned participants after
demonstrating either an acute-phase
response or lack of relapse during the
continuation phase were included
(randomized placebo-substitution
trials).
Data abstraction
Trained reviewers abstracted data
from each study; a senior reviewer
read each abstracted article and eval-
uated completeness of data extrac-
tion. We recorded intention-to-treat
results if available. When intention-
to-treat results were not explicitly
presented, we derived intention-to-
treat results by using as the numera-
tor the number of patients who expe-
rienced the outcome (relapse for con-
tinuation phase or recurrence for
maintenance phase) and using as the
denominator the number randomly
assigned to that arm of the trial.
Quality and strength assessment
In terms of quality, we assessed the in-
ternal validity of trials on the basis of
predefined criteria—ratings of good,
fair, or poor—from the U.S. Preven-
tive Services Task Force (9) and the
National Health Service Centre for
Reviews and Dissemination (10). Ele-
ments of internal validity assessment
included randomization, allocation
concealment, similarity of compared
groups at baseline, use of intention-to-
treat analysis, and overall and differ-
ential loss to follow-up. Discrepancies
in quality assessment were resolved by
discussion and, when necessary, con-
sultation with a third party.
Data synthesis
We qualitatively summarized all stud-
ies. For placebo-controlled trials—a
majority of the included studies—we
also conducted quantitative analyses.
We calculated the relative risk of loss
of response for active treatment com-
pared with placebo. The primary out-
come measure was defined as loss of
response or remission (in other
words, continuation-phase relapse or
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maintenance-phase recurrence). In
most trials this was defined as an in-
crease in the Hamilton Rating Scale
for Depression (HAM-D) or Mont-
gomery-Asberg Depression Rating
Scale (MADRS) score above a prede-
fined cutoff point. We conducted rel-
ative risk meta-analysis of relapse
rates for trials stratified by duration of
follow-up: less than one year and one
year or more. Stratification of trials
lasting one year or more was intended
to represent a conservative delin-
eation of maintenance-phase treat-
ment (thus referring to recurrence),
whereas trials lasting less than one
year were assumed to represent re-
lapse prevention during the continua-
tion phase. Risk-difference meta-
analyses were used to calculate num-
bers of patients needed to treat to
prevent one relapse or recurrence
overall and for each time period.
Our analyses included trials with
multiple placebo comparisons. For
example, for trials that compared
multiple dosing arms with a single-
placebo group, we combined the dos-
ing arms for a single comparison as
long as doses were within the range of
FDA-approved doses. In trials that
compared more than one drug with
placebo, we included each drug-
placebo comparison as an observation
but reduced the sample size of the
placebo group proportionately so as
not to overrepresent the placebo
group (11). For example, if 300 pa-
tients were randomly assigned to re-
ceive drug A (N=100), drug B (N=
100), or placebo (N=100), our analy-
sis compared drug A (N=100) with
placebo (N=50) and drug B (N=100)
with placebo (N=50). Although the
proportion of placebo-treated partici-
pants having the outcome does not
change, this approach inflates the
variance of the log relative risk and ul-
timately results in a more conserva-
tive confidence interval. For each
meta-analysis, we tested for hetero-
geneity of treatment effects, using I
2
statistics. We report the results of the
more conservative random effects
models (12). To estimate possible pub-
lication bias, we used funnel plots, the
Beggs adjusted rank correlation test,
and the Egger regression approach
(13,14). However, because these tests
have low statistical power when the
number of trials is small (15), unde-
tected bias may still be present.
The most common trial design was
an open-label acute treatment phase
of six to 15 weeks, followed by a ran-
domized, double-blind, placebo-con-
trolled continuation phase, mainte-
nance phase, or both for acute-phase
responders or remitters. Because tri-
als differed in the length of open-la-
bel treatment before randomization
and in the duration of treatment after
randomization, we conducted a meta-
regression to explore how hetero-
geneity in design influenced esti-
mates of relative risk of relapse or re-
currence. Similarly, we used meta-re-
gression to explore whether pooling
antidepressants as a class was a rea-
sonable approach. For simplicity, this
analysis explored heterogeneity by
comparing SSRI trials (citalopram,
escitalopram, fluoxetine, fluvoxam-
ine, paroxetine, and sertraline) with
other second-generation antidepres-
sant trials (bupropion, duloxetine,
mirtazapine, nefazodone, trazodone,
and venlafaxine).
To balance our assessment of bene-
fits, we examined reported rates of
adverse events and rates of loss to fol-
low-up that were attributed to ad-
verse events. We qualitatively com-
pared the rates from studies on re-
lapse prevention and recurrence pre-
vention with rates reported in acute-
phase trials (4,16). We also conducted
a relative risk meta-analysis for active
treatment compared with placebo for
both overall loss to follow-up and loss
to follow-up attributed to adverse
events. However, because of variabil-
ity in study populations and in ad-
verse event assessment and reporting
among trials, caution should be taken
in interpreting this evidence.
All statistical analyses were con-
ducted with Stata 9.1 software.
Results
Our search identified 2,318 article ti-
tles and abstracts. [A flow diagram of
the study selection for the meta-analy-
sis is available as an online supplement
to this article at ps.psychiatryonline.
org.] Of these, we reviewed 902 full-
text articles and retained 29 articles
describing 27 unique trials that ad-
dressed relapse or recurrence preven-
tion (Tables 1 and 2). The most com-
mon reason for exclusion was “wrong
study design”; many excluded studies
assessed acute-phase treatment. In-
cluded studies differed in their design
(such as timing of randomization and
eligibility criteria), although most
studies randomly assigned acute-
phase responders or remitters to ongo-
ing treatment with active drug or
placebo. Most trials used a predefined
cutoff point on a standardized scale
(such as the HAM-D or MADRS) to
determine eligibility for randomiza-
tion, although the cutoff point varied
among trials. Likewise, operational
definitions of relapse and recurrence
varied among trials.
We gave most of the included tri-
als a quality rating of fair. They rep-
resent a broad range of methodolog-
ical quality.
The mean age of trial participants
was generally between 40 and 50
years. We excluded trials of children
and adolescents (under 18 years of
age). Two trials were conducted in
older populations (age range 65–87);
the age of participants was 75 in one
trial comparing citalopram with
placebo (17) and 77 in one trial com-
paring sertraline with placebo (18).
Comparative trials
Four head-to-head trials (five publi-
cations) directly compared the effica-
cy of one second-generation antide-
pressant with another for maintaining
remission (Table 1) (19–23). Compar-
isons included duloxetine with parox-
etine (23), fluoxetine with sertraline
(19), fluvoxamine with sertraline
(20,21), and trazodone with venlafax-
ine (22). Relapse and recurrence
rates did not differ significantly. Al-
though none of these studies were de-
signed to test an equivalence hypoth-
esis, absolute differences in relapse
and recurrence rates were consistent-
ly modest and likely not to be of clin-
ical significance. Further, these com-
parative trials did not use a substitu-
tion design to randomly assign partic-
ipants after successful acute-phase or
continuation-phase treatment.
Placebo-controlled trials
Twenty-three randomized controlled
trials provided placebo-controlled ev-
idence to support the general efficacy
of second-generation drugs for pre-
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venting relapse or recurrence among
patients with depressive disorders
(Table 2) (17,18,24–44). For 12 trials
(13 placebo comparisons) the ran-
domized follow-up was shorter than
one year, and the trials were deemed
to represent relapse prevention dur-
ing continuation-phase treatment
(24–34,44). These trials provide con-
sistent evidence in favor of active
drug over placebo. The unadjusted
frequency of relapse was 22% for ac-
tive treatment, compared with 42%
for placebo. An additional 11 ran-
domized controlled trials had follow-
ups of one year or longer and were
deemed to represent recurrence pre-
vention during maintenance-phase
treatment (17,18,35–43). These trials
also provide consistent evidence in fa-
vor of active treatment over placebo.
The unadjusted frequency of recur-
rence was 26% for active treatment,
compared with 48% for placebo.
Meta-analysis
Trials shorter than one year: relapse
prevention. Our relative risk meta-
analysis comprised 12 trials lasting
less than one year (Figure 1): one on
bupropion (24), three on citalopram
(25,33,44), one on escitalopram (26),
three on fluoxetine (27,28,34), and
one each on mirtazapine (29), nefa-
zodone (30), sertraline (31), and ven-
lafaxine (32). The pooled relative
risk of relapse was .54 (95% confi-
dence interval [CI]=.46–.62), and
the number of patients needed to
treat to prevent one additional re-
lapse over a mean time of eight
months was five (CI=4–6). Hetero-
geneity among these trials was mod-
erate (I
2
=47%). Tests for publication
bias were not statistically significant.
Trials one year or longer: recur-
rence prevention. Eleven trials pro-
vided data points for follow-up of one
year or more (Figure 2): one on
citalopram (17), one on escitalopram
(42), one on fluvoxamine (35), one on
nefazodone (36), two on paroxetine
(37,41), four on sertraline (18,38,39,
43), and one on venlafaxine (40). Tri-
als consistently favored active treat-
ment over placebo for preventing re-
currence, although differences were
not always statistically significant.
For example, during a 100-week
comparison of sertraline 50–100 mg
per day with placebo, 45% of sertra-
line-treated participants and 54% of
placebo-treated participants had a
recurrence, but differences were not
statistically significant (18). The
pooled relative risk of recurrence was
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TTaabbllee 11
Comparative studies reporting relapse or recurrence rates during continuation-phase or maintenance-phase treatment after
a major depressive episode
a
Eligibility criteria Recurrent Relapse or
for relapse or Dura- depression Dose recurrence
recurrence of Treatment tion (mg
Study
b
major depression
c
phase (weeks) N N % Medication per day) N % p
Perahia et al., 30% reduction in Acute 8 93 nr Duloxetine 80 na na
2006 (23) HAM-D total score Acute 8 102 nr Duloxetine 120 na na
Acute 8 96 nr Paroxetine 20 na na
Acute 8 99 nr Placebo na na
Continuation 24 71 nr Duloxetine 80 6 9 nr
Continuation 24 81 nr Duloxetine 120 12 15
Continuation 24 70 nr Paroxetine 20 2 3
Continuation 24 70 nr Placebo 11 16
Van Moffaert et 50% reduction in Acute 8 82 25 30 Fluoxetine 20–40 na na
al., 1995 (19) MADRS or HAM-D Acute 8 83 23 28 Sertraline 50–100 na na
score, or HAM-D Continuation 24 56 nr Fluoxetine 20–40 7 13 nr (ns)
score <10 and CGI-I Continuation 24 49 nr Sertraline 50–100 5 10
score 2
Franchini et al., Absence of DSM-IV Acute nr nr nr nr na na
1997 (20); depressive symptoms; Continuation 16 nr nr nr na na
2000 (21) absence of functional Maintenance, 2 year 104 32 32 100 Fluvoxamine 200 6 19 .88
impairment; HAM-D Maintenance, 2 year 104 32 32 100 Sertraline 100 7 22
score <8 Maintenance, 4 year 208 25 nr Fluvoxamine 200 5 20 .92
Maintenance, 4 year 208 22 nr Sertraline 100 3 14
Cunningham et CGI-I score 2 Acute 6 77 93
d
Trazodone 150–400 na na
al., 1994 (22) Acute 6 72 93
d
Venlafaxine 75–200 na na
Acute 6 76 93
d
Placebo na na
Maintenance 52 30 nr Trazodone 150–400 4 13 nr (ns)
Maintenance 52 37 nr Venlafaxine 75–200 3 8
Maintenance 52 29 nr Placebo 4 14
a
nr, not reported; na, not applicable; ns, not significant
b
Each study had a quality rating of fair.
c
HAM-D, Hamilton Rating Scale for Depression (possible scores on the first 17 items range from 0 to 52, with higher scores indicating greater severi-
ty of symptoms); MADRS, Montgomery-Asberg Depression Rating Scale (possible scores range from 0 to 60, with higher scores indicating greater
severity of symptoms); CGI-I, Clinical Global Impression of Improvement (possible scores range from 1 to 7, with lower scores indicating more im-
provement and higher scores indicating worsening; values of 4 represent no change)
d
Values reported overall rather than by treatment
.56 (CI=.48–.66) and the number of
patients needed to treat to prevent
one additional recurrence over a
mean time of 16 months was five
(CI=4–6). Heterogeneity among these
trials was moderate (I
2
=30%). Tests
for publication bias were not statisti-
cally significant.
Meta-regression
Our meta-regression explored het-
erogeneity among included trials with
regard to the duration of open-label
treatment before random assignment
of responders, the length of the post-
randomization phase, and drug type
(SSRI or other type of second-gener-
ation antidepressant). None of these
variables influenced our estimates of
effect size at a statistically significant
level.
Adverse events
The most common adverse event doc-
umented in continuation- and mainte-
nance-phase studies was headache,
followed by nausea (weighted mean
incidence=15.5% and 7.4%, respec-
tively). Compared with the incidence
of adverse events in acute-phase stud-
ies (4,45), the relative incidence of
these events during long-term treat-
ment was slightly lower. On the basis
of 22 trials that provided sufficient
data, loss to follow-up in general and
loss to follow-up because of adverse
events represented an average of 50%
and 7%, respectively, of patients ran-
domly assigned to receive active
treatment and 68% and 4%, respec-
tively, of patients randomly assigned
to receive placebo. Based on data
pooled from 17 placebo-controlled
trials, the relative risk of dropping out
for any reason was statistically signifi-
cantly lower for active treatment than
for placebo (relative risk=.75, CI=
.69–.83). Data pooled from 18 place-
bo-controlled trials demonstrated
that loss to follow-up because of ad-
verse events was not statistically sig-
nificantly different between active
treatment and placebo (relative risk=
1.42, CI=.92–2.20).
Discussion
We systematically assessed the effica-
cy and tolerability of second-genera-
tion antidepressants for the preven-
tion of relapse and recurrence during
treatment in the continuation and
maintenance phases of major depres-
sion, respectively. Only a small num-
ber of trials directly compared one
antidepressant with another. Results
of these trials did not demonstrate
statistically significant differences be-
tween duloxetine and paroxetine (23),
fluoxetine and sertraline (19), fluvox-
amine and sertraline (20,21), or tra-
zodone and venlafaxine (22) for pre-
venting relapse or recurrence.
Although results are relatively con-
sistent, we consider the strength of
comparative evidence to be moder-
ate because additional well-conduct-
ed studies could change our conclu-
sions. Pooled data for second-gener-
ation antidepressants as a class com-
pared with placebo suggest a rela-
tively large effect size that persists
over time, reflecting high-strength
evidence for continued treatment be-
yond the acute phase. The number
needed to treat to prevent one addi-
tional relapse during continuation-
phase treatment or recurrence during
maintenance-phase treatment is in
the range of four to six patients.
The tolerability profile of continua-
tion- and maintenance-phase treat-
ment is fair to good. In clinical trials,
7% of patients randomly assigned to
receive active treatment and 5% of
patients assigned to receive placebo
discontinued their continuation or
maintenance phase of treatment be-
cause of adverse events. Although
loss to follow-up was high (that is,
50% for active drug and 68% for
placebo), the relative risk of discon-
tinuing treatment because of adverse
events did not differ significantly be-
tween active treatment and placebo.
Overall loss to follow-up in acute-
phase studies has been estimated at
approximately 24% (16), which is
considerably lower than our estimates
from continuation- and maintenance-
phase studies. Our estimates likely
are high because of longer trial dura-
tion, the preventive aim of this treat-
ment, and misclassification of clinical
endpoints (relapse or recurrence) as
loss to follow-up.
Current practice guidelines for ma-
jor depression recommend continua-
tion-phase treatment for four to nine
months for patients who demonstrate
an adequate response to acute-phase
treatment (2,3). For patients with re-
current depression, maintenance
treatment is recommended. Our sys-
tematic review and meta-analysis pro-
vide relatively strong support for
these guidelines.
On the basis of consistency of effect
sizes over time, our review illustrates
stable benefits of active treatment
over placebo for up to two years of
treatment. Although we demonstrat-
ed continued benefits of drug treat-
ment over time, we were unable to
draw inferences as to the most appro-
priate duration of antidepressant
treatment. We identified only one
randomized controlled trial that com-
pared relapse rates for differing
lengths of antidepressant treatment
(27), but the sample size of the
longest treatment arm in this trial
may have been insufficiently pow-
ered. Still, fluoxetine was shown to be
more efficacious than placebo for up
to 38 weeks (or approximately nine
months) in this trial. More research is
needed to determine the most appro-
priate length of therapy.
In a well-conducted systematic re-
view of relapse prevention with first-
and second-generation antidepres-
sants in depressive disorders, Geddes
and colleagues (7) reported a 70%
reduction in the odds of relapse for
patients continuing antidepressant
treatment compared with patients
discontinuing treatment. The effect
sizes reported in their analysis were
“similar for all classes of antidepres-
sants,” but such unadjusted indirect
comparisons may not be valid. To ex-
plore this further, we used data re-
ported in the Geddes and colleagues
review and converted their odds ratio
to a relative risk ratio, specifically .45
for active drug compared with place-
bo (CI=.41–.49) and .41 for second-
generation antidepressants compared
with placebo (CI=.35–.48). The con-
fidence intervals for the relative risk
of relapse that we calculated for only
second-generation antidepressants
(less than one year, CI=.46–.62; one
year or longer, CI=.48–.66) over-
lapped this relative risk estimate from
the Geddes and colleagues study, and
our analysis included nearly twice as
many trials of newer antidepressants.
Even though a small number of
comparative studies found no statis-
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Placebo-controlled, randomized studies of prevention of relapse or recurrence of a major depressive episode
a
Recur-
rent de- Relapse or
Depression severity Dura- pression Dose recurrence
eligibility criteria for Treatment tion (mg
Study
b
random assignment
c
phase (weeks) N N % Medication per day) N % p
Weihs et al., CGI-I score 2 Acute 8 816 816 100 Bupropion SR
d
300 na na
2002 (24) Continuation 44 210 210 100 Bupropion SR 300 78 37 .004
Continuation 44 213 213 100 Placebo 111 52
Montgomery et MADRS score 12 Acute 6 nr nr Citalopram 20–40 na na
al., 1993 (44) Continuation 24 48 nr Citalopram 20 4 8 .02
e
Continuation 24 57 nr Citalopram 40 7 12
Continuation 24 42 nr Placebo 13 31
Robert & Mont- MADRS score 12 Acute 8 391 nr Citalopram 20–60 na na
gomery, 1995 Continuation 24 152 nr Citalopram 20–60 21 14 .04
(25) Continuation 24 74 nr Placebo 18 24
Hochstrasser et MADRS score 11 Acute 6–9 427 427 100 Citalopram 20–60 na na
al., 2001 (33) Continuation 16 327 327 100 Citalopram 20–60 na na
Continuation 48 132 132 100 Citalopram 20–60 24 18 .001
Continuation 48 137 137 100 Placebo 59 43
Klysner et al., MADRS score 11 Acute 8 230 35 15 Citalopram 20–40 na na
2002 (17) Continuation 16 172 nr Citalopram 20–40 na na
Continuation 48 60 nr Citalopram 20–40 19 32 nr
Continuation 48 61 nr Placebo 41 67
Kornstein et al., MADRS score 12 Acute 8 131 nr Citalopram 20–60 na na
2006 (42) Acute 8 129 nr Fluoxetine 20–80 na na
Acute 8 128 nr Paroxetine 20–50 na na
Acute 8 127 nr Sertraline 50–200 na na
Continuation 18 234 nr Escitalopram 10–20 na na
Maintenance 52 73 nr Escitalopram 10–20 20 27 nr
Maintenance 52 66 nr Placebo 43 65
Rapaport et al., MADRS score 12 Acute 8 502 331 66 Escitalopram 10–20 na na
2004 (26) Continuation 36 181 nr Escitalopram 10–20 47 26 .01
Continuation 36 93 nr Placebo 37 40
Reimherr et al., Absence of DSM-III Acute 12–14 839 nr Fluoxetine 20 na na
1998 (27) depressive symptoms; Continuation 14 299 nr Fluoxetine 20 77 26 .001
HAM-D score <7 Continuation 14 95 nr Placebo 47 49
Continuation
f
38 105 nr Fluoxetine 20 9 9 .04
Continuation
f
38 52 nr Placebo 12 23
Continuation
f
50 28 nr Fluoxetine 20 3 11 .54
Continuation
f
50 34 nr Placebo 5 6
Schmidt et al., Absence of DSM-IV Acute 13 932 nr Fluoxetine 20 na na
2000 (28) depressive symptoms, Continuation 25 189 143 76 Fluoxetine 20 49 26 .01
d
CGI-S score 2, and Continuation 25 190 137 72 Fluoxetine 90/week 70 37
HAM-D score 9 Continuation 25 122 80 66 Placebo 61 50
Gilaberte et al., Absence of DSM-III Acute 8 253 253 100 Fluoxetine 20–40 na na
2001 (34) depressive symptoms, Continuation 24 179 179 100 Fluoxetine 20–40 na na
CGI-S score 2, and Maintenance 52 70 70 100 Fluoxetine 20 14 20 .01
HAM-D score 8 Maintenance 52 70 70 100 Placebo 28 40
Terra & Mont- CGI-S score 2 and Acute 6 436 436 100 Fluvoxamine 100 na na
gomery, 1998 MADRS score <12 Continuation 18 283 283 100 Fluvoxamine 100 na na
(35) Maintenance 52 110 110 100 Fluvoxamine 100 14 13 .001
Maintenance 52 94 94 100 Placebo 33 35
Thase et al., CGI-S score 2 and Acute 8–12 410 211 52 Mirtazapine 15–45 na na
2001 (29) HAM-D score 7 Continuation 40 76 nr Mirtazapine 15–45 15 20 .001
Continuation 40 80 nr Placebo 35 44
Feiger et al., HAM-D score 10 Acute 16 467 nr Nefazodone 400–600 na na
1999 (30) Continuation 36 65 40 62 Nefazodone 400–600 1 2 .009
Continuation 36 66 41 62 Placebo 12 18
Gelenberg et al., 50% reduction in Acute 12 681 681 100 Nefazodone 300–600 na na
2003 (36) HAM-D score Continuation 16 269 269 100 Nefazodone 300–600 na na
Maintenance 52 76 76 100 Nefazodone 300–600 23 30 .043
Maintenance 52 84 84 100 Placebo 40 48
Montgomery & HAM-D score 8 Acute 8 172 172 100 Paroxetine 20–30 na na
Dunbar, 1993 Maintenance 52 68 68 100 Paroxetine 20–30 11 16 .01
(37) Maintenance 52 67 67 100 Placebo 29 43
Continues on next page
tically significant differences be-
tween second-generation antide-
pressants, we were unable to draw
firm conclusions as to whether one
drug may be better than another for
long-term treatment. These compar-
ative trials were extension trials and
did not reassign patients randomly to
continuation or maintenance treat-
ment but rather gave them the op-
tion to continue on with their blind-
ed acute-phase treatment. This trial
design has been shown to produce
overall lower relapse rates, but it also
yields larger differences between ac-
tive treatment and placebo than
placebo-substitution trials that ran-
domly assign participants at the time
of successful completion of acute-
phase or continuation-phase treat-
ment (8). For this reason, we limited
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Continued from previous page
Recur-
rent de- Relapse or
Depression severity Dura- pression Dose recurrence
eligibility criteria for Treatment tion (mg
Study
b
random assignment
c
phase (weeks) N N % Medication per day) N % p
Reynolds et al., HAM-D score 0–10 Acute nr 195 88 45 Paroxetine 10–40 na na
2006 (41) for 3 consecutive Continuation 16 151 nr Paroxetine 10–40 na na
weeks, plus 16 weeks Maintenance
g
110 35 15 43 Paroxetine 10–40 12 34 .06
of stable continuation Maintenance
g
110 18 7 39 Placebo 10 56
Doogan & Cail- Response satisfactory Acute 8 480 306 64 Sertraline 50–200 na na
lard, 1992 (31) to both patient and Continuation 44 185 nr Sertraline 50–200 24 13 .001
investigator Continuation 44 110 nr Placebo 48 46
Keller et al., CGI-I score 2 and Acute 12 309 145 47 Sertraline 50–200 na na
1998 (38) HAM-D score 7 or Continuation 16 209 nr Sertraline 50–200 na na
50% reduction in Maintenance 76 77 nr Sertraline 50–200 5 6 .002
HAM-D score, plus Maintenance 76 84 nr Placebo 19 23
HAM-D score 15,
CGI-I score 2, and
CGI-S score 3
Lepine et al., Absence of depressed Continuation 16 371 371 100 Not sertraline
h
na na na
2004 (39) mood and markedly Remission 8 371 371 100 Placebo na na
diminished interest or stability
according to DSM-IV, Maintenance 72 189 189 100 Sertraline 50–100 32 17 .002
and 2 of other 7 Maintenance 72 99 99 100 Placebo 33 33
DSM-IV criteria, and
2 for sum of first 2
MADRS items
Lustman et al., 4 consecutive twice- Acute 16 351 351 100 Sertraline 50–200 na na
2006 (43) monthly BDI scores Maintenance 52 79 79 100 Sertraline 50–200 27 34 nr
9 Maintenance 52 73 73 100 Placebo 38 52
Wilson et al., 50% reduction in Acute 8 318 nr Sertraline 50–200 na na
2003 (18) HAM-D score Continuation 16–20 254 nr Sertraline 50–200 na na
Maintenance 100 56 16 29 Sertraline 50–150 25 45 .21
Maintenance 100 57 15 26 Placebo 31 54
Simon et al., CGI-S score 3 and Acute 8 490 nr Venlafaxine XR
i
75–225 na na
2004 (32) HAM-D score 10 Continuation 26 161 nr Venlafaxine XR 75–225 45 28 .001
Continuation 26 157 nr Placebo 82 52
Montgomery et HAM-D score 12 Acute or 26 495 495 100 Venlafaxine 100–200 na na
al., 2004 (40) at day 56 with no continuation
HAM-D score 20 Maintenance 52 109 109 100 Venlafaxine 100–200 24 22 .001
and no 2consecutive Maintenance 52 116 116 100 Placebo 64 55
HAM-D scores >10
a
na, not applicable; nr, not reported
b
With the exception of the studies of Lepine and colleagues (39) and Lustman and colleagues (43), which each had a quality rating of good, each study
had a quality rating of fair.
c
CGI-I, Clinical Global Impression of Improvement (possible scores range from 1 to 7, with lower scores indicating more improvement and higher
scores indicating worsening; values of 4 represent no change); CGI-S, Clinical Global Impression of Severity (possible scores range from 1 to 7, with
lower scores indicating normalcy or mild illness and higher scores indicating more severe illness); MADRS, Montgomery-Asberg Depression Rating
Scale (possible scores range from 0 to 60, with higher scores indicating greater severity of symptoms); HAM-D, Hamilton Rating Scale for Depression
(possible scores range from 0 to 52, with higher scores indicating greater severity of symptoms); BDI, Beck Depression Inventory (possible scores range
from 0 to 63, with higher scores indicating greater severity of symptoms)
d
SR, sustained release
e
Active treatment versus placebo
f
Not included in meta-analysis; compared with placebo switchers in the specified time interval
g
Paroxetine plus clinical management and placebo plus clinical management groups only; psychotherapy groups were excluded.
h
Patients were eligible for the study if their depression was in remission with any antidepressant other than sertraline.
i
XR, extended release
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FFiigguurree 11
Meta-analysis of placebo-controlled trials with less than one year of double-blinded randomized follow-up for relapse
prevention
Bupropion SR 300
Citalopram 20–60 mg
Citalopram 20–40 mg
Citalopram 20–60 mg
Escitalopram 10–20 mg
Fluoxetine 20 mg
Fluoxetine 20 mg
Fluoxetine 20 mg
Fluoxetine 90 mg/week
Mirtazapine 15–45 mg
Nefazodone 400–600 mg
Sertraline 50–200 mg
Venlafaxine XR 75–225 mg
Weihs et al., 2002 (24)
Hochstrasser et al., 2001 (33)
Montgomery and Dunbar, 1993 (37)
Robert and Montgomery, 1995 (25)
Rapaport et al., 2004 (26)
Gilaberte et al., 2001, (34)
Reimherr et al., 1998 (27)
Schmidt et al., 2000 (28)
Schmidt et al., 2000 (28)
Thase et al., 2001 (29)
Feiger et al., 1999 (30)
Doogan and Caillard, 1992 (31)
Simon et al., 2004 (32)
Overall (95% CI) Pooled
.10
Favors active treatment
.25 .50 .75 1.00 1.30 2.00
Favors placebo
Relative risk
FFiigguurree 22
Meta-analysis of placebo-controlled trials with one year or more of double-blinded randomized follow-up for recurrence
prevention
Citalopram 20–40 mg
Escitalopram 10–20 mg
Fluvoxamine 100 mg
Nefazodone 300–600 mg
Paroxetine 20–30 mg
Paroxetine 10–40 mg
Sertraline 50–200 mg
Sertraline 50–100 mg
Sertraline 50–200 mg
Sertraline 50–150 mg
Venlafaxine 100–200 mg
Pooled
Klysner et al., 2002 (17)
Kornstein et al., 2006 (42)
Terra and Montgomery, 1998 (35)
Gelenberg et al., 2003 (36)
Montgomery and Dunbar, 1993 (37)
Reynolds et al., 2006 (41)
Keller et al., 1998 (38)
Lepine et al., 2004 (39)
Lustman et al., 2006 (43)
Wilson et al., 2003 (18)
Montgomery et al., 2004 (40)
Overall (95% CI)
.10
Favors active treatment
.25 .50 .75 1.00 1.30 2.00
Favors placebo
Relative risk
our meta-analyses to placebo-substi-
tution trials. Although this refine-
ment did not answer the question of
whether the extension or placebo-
substitution design provides a more
accurate assessment of the benefits
of drug treatment, we believe our re-
sults provide strong evidence for the
benefits of continuing versus discon-
tinuing antidepressant treatment af-
ter successful acute- or continuation-
phase treatment.
Although it is tempting to draw in-
ferences about one drug compared
with another by indirectly comparing
effect sizes among placebo-controlled
trials (Figures 1 and 2), we caution
against such inferences because in-
cluded trials differed in design and
because unadjusted comparisons may
be inaccurate. Adjusted indirect com-
parisons usually agree with results of
head-to-head comparisons, but only
when the trials being indirectly com-
pared are similar (46,47). Because of
differences in trial design and in op-
erational definitions (such as defini-
tion of relapse or recurrence) used by
investigators, we chose not to conduct
adjusted indirect comparisons. More
research is needed to verify whether
second-generation antidepressants
differ in relapse rates.
Our analysis is limited chiefly by
the sparse quantity and quality of
available evidence addressing our re-
search questions. Only a handful of
comparative studies have been pub-
lished, making it difficult to general-
ize about one drug compared with
any other. Selective publication of re-
lapse and recurrence prevention trials
could influence our conclusions, as
has been shown with acute-phase
treatment trials of antidepressants
(48). Although our statistical tests did
not detect significant bias toward the
publication of positive results, such
bias may nevertheless be present,
which would lead to an overestima-
tion of the treatment effect. This pos-
sibility is especially important given
that most of the included studies
were sponsored by pharmaceutical
companies. Evidence for some drugs
was limited to a single study. Al-
though we conducted a meta-regres-
sion to explore heterogeneity, data
were insufficient to assess all impor-
tant differences among trials. One
important distinction that we could
not address is whether presenting
with a history of a single depressive
episode versus recurrent episodes
made a difference in relapse or recur-
rence rates. Because this is a primary
decision point for psychiatrists in de-
ciding whether to continue with
maintenance-phase treatment, more
work is needed in this area.
Finally, we could not determine
whether demographic factors such as
patients’ age influenced relapse rates,
although results from trials with older
participants were generally consistent
with evidence from younger adult
populations. Evidence from children
was not considered.
Conclusions
This review confirms the benefits of
continuation- and maintenance-phase
treatment of major depression with
second-generation antidepressants.
Our review supports current clinical
practice guidelines. In addition, our
meta-regression provides some evi-
dence that the efficacy of different
types of second-generation antide-
pressants does not differ in clinically
significant ways, although more re-
search is needed to confirm this con-
clusion. Given that ongoing treatment
can prevent a relapse or recurrence of
depression for approximately one in
five patients, clinicians should contin-
ue to encourage treatment beyond the
acute phase and work with patients to
find the most suitable drug.
Acknowledgments and disclosures
No funding was provided for the literature
search and analysis. However, this review is
based in part on work funded through contract
290-02-0016 from the Agency for Healthcare
Research and Quality (AHRQ).
Dr. Gaynes has received financial support from
GlaxoSmithKline, Ovation Pharmaceuticals,
Pfizer, Shire Pharmaceuticals, and Wyeth Ay-
erst. Ms. Deveaugh-Geiss also has received
funding from GlaxoSmithKline. The other au-
thors report no competing interests.
References
1. Anderson IM, Ferrier NI, Baldwin CR, et
al: Evidence-based guidelines for treating
depressive disorders with antidepressants:
a revision of the 2000 British Association
for Psychopharmacology guidelines. Jour-
nal of Psychopharmacology 22:330–332,
2008
2. American Psychiatric Association: Practice
guideline for the treatment of patients with
major depressive disorder (revision). Amer-
ican Journal of Psychiatry 157:1–45, 2000
3. Depression Guideline Panel: Depression in
Primary Care: Vol 2—Treatment of Major
Depression. AHCPR pub no 93-0550.
Rockville, Md, US Department of Health
and Human Services, Public Health Ser-
vice, Agency for Health Care Policy and
Research, 1993
4. Hansen RA, Gartlehner G, Lohr KN, et al:
Efficacy and safety of second-generation
antidepressants in the treatment of major
depressive disorder. Annals of Internal
Medicine 143:415–426, 2005
5. Rush AJ, Trivedi MH, Wisniewski SR, et al:
Acute and longer-term outcomes in de-
pressed outpatients requiring one or sever-
al treatment steps: a STAR
D report.
American Journal of Psychiatry 163:1905–
1917, 2006
6. Loonen AJ, Peer PG, Zwanikken GJ: Con-
tinuation and maintenance therapy with an-
tidepressive agents: meta-analysis of re-
search. Pharmaceutisch Weekblad, Scien-
tific Edition 13:167–175, 1991
7. Geddes JR, Carney SM, Davies C, et al:
Relapse prevention with antidepressant
drug treatment in depressive disorders: a
systematic review. Lancet 361:653–661,
2003
8. Zimmerman M, Posternak MA, Ruggero
CJ: Impact of study design on the results of
continuation studies of antidepressants.
Journal of Clinical Psychopharmacology 27:
177–181, 2007
9. Harris RP, Helfand M, Woolf SH, et al:
Current methods of the US Preventive Ser-
vices Task Force: a review of the process.
American Journal of Preventive Medicine
20:21–35, 2001
10. Undertaking Systematic Reviews of Re-
search on Effectiveness: CRD’s Guidance
for Those Carrying Out or Commissioning
Reviews. CRD report no 4, 2nd ed. York,
United Kingdom, Centre for Reviews and
Dissemination, 2001
11. Higgins JPT, Green S (eds): Cochrane
Handbook for Systematic Reviews of Inter-
ventions, version 5.0.0. Oxford, United
Kingdom, Cochrane Collaboration, Feb
2008
12. Egger M, Smith GD, Altman DG: System-
atic Reviews in Health Care (2nd ed). Lon-
don, BMJ Publishing, 2001
13. Begg CB, Mazumdar M: Operating charac-
teristics of a rank correlation test for publi-
cation bias. Biometrics 50:1088–1101, 1994
14. Egger M, Davey Smith G, Schneider M, et
al: Bias in meta-analysis detected by a sim-
ple, graphical test. British Medical Journal
315:629–634, 1997
15. Sterne JA, Gavaghan D, Egger M: Publica-
tion and related bias in meta-analysis: pow-
er of statistical tests and prevalence in the
literature. Journal of Clinical Epidemiology
53:1119–1129, 2000
16. Gartlehner G, Hansen RA, Carey TS, et al:
Discontinuation rates for selective sero-
tonin reuptake inhibitors and other second-
generation antidepressants in outpatients
PSYCHIATRIC SERVICES ' ps.psychiatryonline.org ' October 2008 Vol. 59 No. 10
11112299
with major depressive disorder: a systemat-
ic review and meta-analysis. International
Clinical Psychopharmacology 20:59–69,
2005
17. Klysner R, Bent-Hansen J, Hansen HL, et
al: Efficacy of citalopram in the prevention
of recurrent depression in elderly patients:
placebo-controlled study of maintenance
therapy. British Journal of Psychiatry 181:
29–35, 2002
18. Wilson KC, Mottram PG, Ashworth L, et
al: Older community residents with depres-
sion: long-term treatment with sertraline—
randomised, double-blind, placebo-con-
trolled study. British Journal of Psychiatry
182:492–497, 2003
19. Van Moffaert M, Bartholome F, Cosyns P,
et al: A controlled comparison of sertraline
and fluoxetine in acute and continuation
treatment of major depression. Human
Psychopharmacology 10:393–405, 1995
20. Franchini L, Gasperini M, Perez J, et al: A
double-blind study of long-term treatment
with sertraline or fluvoxamine for preven-
tion of highly recurrent unipolar depres-
sion. Journal of Clinical Psychiatry 58:104–
107, 1997
21. Franchini L, Gasperini M, Zanardi R, et al:
Four-year follow-up study of sertraline and
fluvoxamine in long-term treatment of
unipolar subjects with high recurrence rate.
Journal of Affective Disorders 58:233–236,
2000
22. Cunningham LA, Borison RL, Carman JS,
et al: A comparison of venlafaxine, tra-
zodone, and placebo in major depression.
Journal of Clinical Psychopharmacology
14:99–106, 1994
23. Perahia DG, Wang F, Mallinckrodt CH, et
al: Duloxetine in the treatment of major de-
pressive disorder: a placebo- and paroxe-
tine-controlled trial. European Psychiatry
21:367–378, 2006
24. Weihs KL, Houser TL, Batey SR, et al:
Continuation phase treatment with bupro-
pion SR effectively decreases the risk for
relapse of depression. Biological Psychiatry
51:753–761, 2002
25. Robert P, Montgomery SA: Citalopram in
doses of 20–60 mg is effective in depression
relapse prevention: a placebo-controlled 6
month study. International Clinical Psy-
chopharmacology 10(suppl 1):29–35, 1995
26. Rapaport MH, Bose A, Zheng H: Escitalo-
pram continuation treatment prevents re-
lapse of depressive episodes. Journal of
Clinical Psychiatry 65:44–49, 2004
27. Reimherr FW, Amsterdam JD, Quitkin
FM, et al: Optimal length of continuation
therapy in depression: a prospective assess-
ment during long-term fluoxetine treat-
ment. American Journal of Psychiatry 155:
1247–1253, 1998
28. Schmidt ME, Fava M, Robinson JM, et al:
The efficacy and safety of a new enteric-
coated formulation of fluoxetine given once
weekly during the continuation treatment
of major depressive disorder. Journal of
Clinical Psychiatry 61:851–857, 2000
29. Thase ME, Nierenberg AA, Keller MB, et
al: Efficacy of mirtazapine for prevention of
depressive relapse: a placebo-controlled
double-blind trial of recently remitted
high-risk patients. Journal of Clinical Psy-
chiatry 62:782–788, 2001
30. Feiger AD, Bielski RJ, Bremner J, et al:
Double-blind, placebo-substitution study
of nefazodone in the prevention of relapse
during continuation treatment of outpa-
tients with major depression. International
Clinical Psychopharmacology 14:19–28,
1999
31. Doogan DP, Caillard V: Sertraline in the
prevention of depression. British Journal of
Psychiatry 160:217–222, 1992
32. Simon JS, Aguiar LM, Kunz NR, et al: Ex-
tended-release venlafaxine in relapse pre-
vention for patients with major depressive
disorder. Journal of Psychiatric Research
38:249–257, 2004
33. Hochstrasser B, Isaksen PM, Koponen H,
et al: Prophylactic effect of citalopram in
unipolar, recurrent depression: placebo-
controlled study of maintenance therapy.
British Journal of Psychiatry 178:304–310,
2001
34. Gilaberte I, Montejo AL, de la Gandara J,
et al: Fluoxetine in the prevention of de-
pressive recurrences: a double-blind study.
Journal of Clinical Psychopharmacology
21:417–424, 2001
35. Terra JL, Montgomery SA: Fluvoxamine
prevents recurrence of depression: results
of a long-term, double-blind, placebo-con-
trolled study. International Clinical Psy-
chopharmacology 13:55–62, 1998
36. Gelenberg AJ, Trivedi MH, Rush AJ, et al:
Randomized, placebo-controlled trial of
nefazodone maintenance treatment in pre-
venting recurrence in chronic depression.
Biological Psychiatry 54:806–817, 2003
37. Montgomery SA, Dunbar G: Paroxetine is
better than placebo in relapse prevention
and the prophylaxis of recurrent depres-
sion. International Clinical Psychopharma-
cology 8:189–195, 1993
38. Keller MB, Kocsis JH, Thase ME, et al:
Maintenance phase efficacy of sertraline
for chronic depression: a randomized con-
trolled trial. JAMA 280:1665–1672, 1998
39. Lepine JP, Caillard V, Bisserbe JC, et al: A
randomized, placebo-controlled trial of ser-
traline for prophylactic treatment of highly
recurrent major depressive disorder. Amer-
ican Journal of Psychiatry 161:836–842,
2004
40. Montgomery SA, Entsuah R, Hackett D, et
al: Venlafaxine versus placebo in the pre-
ventive treatment of recurrent major de-
pression. Journal of Clinical Psychiatry 65:
328–336, 2004
41. Reynolds CF III, Dew MA, Pollock BG, et
al: Maintenance treatment of major depres-
sion in old age. New England Journal of
Medicine 354:1130–1138, 2006
42. Kornstein SG, Bose A, Li D, et al: Escitalo-
pram maintenance treatment for preven-
tion of recurrent depression: a randomized,
placebo-controlled trial. Journal of Clinical
Psychiatry 67:1767–1775, 2006
43. Lustman PJ, Clouse RE, Nix BD, et al: Ser-
traline for prevention of depression recur-
rence in diabetes mellitus: a randomized,
double-blind, placebo-controlled trial.
Archives of General Psychiatry 63:521–529,
2006
44. Montgomery SA, Rasmussen JG, Tanghoj
P: A 24-week study of 20 mg citalopram, 40
mg citalopram, and placebo in the preven-
tion of relapse of major depression. Inter-
national Clinical Psychopharmacology 8:
181–188, 1993
45. Gartlehner G, Hansen RA, Thieda P, et al:
Comparative Effectiveness of Pharmaco-
logic Treatment of Depression. Rockville,
Md, Agency for Healthcare Research and
Quality, April 2006. Available at www.effec-
tivehealthcare.ahrq.gov/reports/final.cfm
46. Song F, Altman DG, Glenny AM, et al: Va-
lidity of indirect comparison for estimat-
ing efficacy of competing interventions:
empirical evidence from published meta-
analyses. British Medical Journal 326:472,
2003
47. Glenny AM, Altman DG, Song F, et al: In-
direct comparisons of competing interven-
tions. Health Technology Assessment
9(special issue):1–134, 2005
48. Turner EH, Matthews AM, Linardatos E,
et al: Selective publication of antidepres-
sant trials and its influence on apparent ef-
ficacy. New England Journal of Medicine
358:252–260, 2008
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    • "Adverse effects of use of antidepressants have been reported as well, especially based on observational (clinical) studies (Fava, 2014; Gøtzsche, 2014 ). Meta-analyses indicate that continuation ADM reduces the risk of relapses/recurrence compared to pill-placebo, although the odds ratios are modest, ranging from 0.12 to 0.35 (Geddes et al., 2003; Glue et al., 2010; Hansen et al., 2008; Kaymaz et al., 2008). However, it is not clear how long ADMs need to be continued. "
    [Show abstract] [Hide abstract] ABSTRACT: Prevention of recurrence is a challenge in the management of major depressive disorder (MDD). The long-term effects of Preventive Cognitive Therapy (PCT) in preventing recurrence in MDD are not known. A RCT comparing the addition of PCT to Treatment As Usual (TAU), versus TAU including patients with recurrent depression who were in remission at entry (N=172). PCT consisted of eight weekly group sessions. TAU involved standard treatment. Primary outcome is time to first recurrence of a depressive episode as assessed by blinded interviewers over 10 years based on DSM-IV-TR criteria. Also over 10 years, the protective effect of PCT was dependent on the number of previous episodes a patient experienced. The protective effect intensified with the number of previous depressive episodes (Cox regression; p=.004, Hazard ratio=.576, 95% CI=.396-.837) and is mainly established within the first half of the 10 year follow-up period. For patients with more than three previous episodes (52% of the sample), PCT significantly increased the median survival time (713.0 days) versus patients that received TAU (205.0 days). No enduring effects were found on secondary outcomes. Dropout rates were relatively high for secondary outcomes, but relatively low for the primary outcome. Results were comparable after multiple imputation. PCT in remitted patients with multiple prior episodes has long-term preventive effects on time to recurrence. To reduce recurrence rates, booster sessions might be necessary. A personalized medicine approach might be necessary to reduce recurrence rates even further. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015
    • "Adverse effects of use of antidepressants have been reported as well, especially based on observational (clinical) studies (Fava, 2014; Gøtzsche, 2014 ). Meta-analyses indicate that continuation ADM reduces the risk of relapses/recurrence compared to pill-placebo, although the odds ratios are modest, ranging from 0.12 to 0.35 (Geddes et al., 2003; Glue et al., 2010; Hansen et al., 2008; Kaymaz et al., 2008). However, it is not clear how long ADMs need to be continued. "
    [Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder (MDD) is highly disabling and typically runs a recurrent course. Knowledge about prevention of relapse and recurrence is crucial to the long-term welfare of people who suffer from this disorder. This article provides an overview of the current evidence for the prevention of relapse and recurrence using psychological interventions. We first describe a conceptual framework to preventive interventions based on: acute treatment; continuation treatment, or; prevention strategies for patients in remission. In brief, cognitive-behavioral interventions, delivered during the acute phase, appear to have an enduring effect that protects patients against relapse and perhaps others from recurrence following treatment termination. Similarly, continuation treatment with either cognitive therapy or perhaps interpersonal psychotherapy appears to reduce risk for relapse and maintenance treatment appears to reduce risk for recurrence. Preventive relapse strategies like preventive cognitive therapy or mindfulness based cognitive therapy (MBCT) applied to patients in remission protects against subsequent relapse and perhaps recurrence. There is some preliminary evidence of specific mediation via changing the content or the process of cognition. Continuation CT and preventive interventions started after remission (CBT, MBCT) seem to have the largest differential effects for individuals that need them the most. Those who have the greatest risk for relapse and recurrence including patients with unstable remission, more previous episodes, potentially childhood trauma, early age of onset. These prescriptive indications, if confirmed in future research, may point the way to personalizing prevention strategies. Doing so, may maximize the efficiency with which they are applied and have the potential to target the mechanisms that appear to underlie these effects. This may help make this prevention strategies more efficacious.
    Full-text · Article · Feb 2015
    • "Major depressive disorder (MDD) is a chronic disease with a relapsing and remitting course. Antidepressant medications (ADMs) form the front-line treatment for MDD and less than 50% of patients respond or remit to their first treatment (Gartlehner et al., 2012; Hansen et al., 2008). There are currently no objective measures to guide the treatment decisions in MDD, and the clinical standard is to use a " watch and wait " strategy relying on trial and error (Rush et al., 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: Less than 50% of patients with Major Depressive Disorder (MDD) reach symptomatic remission with their initial antidepressant medication (ADM). There are currently no objective measures with which to reliably predict which individuals will achieve remission to ADMs. 157 participants with MDD from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) underwent baseline MRIs and completed eight weeks of treatment with escitalopram, sertraline or venlafaxine-ER. A score at week 8 of 7 or less on the 17 item Hamilton Rating Scale for Depression defined remission. Receiver Operator Characteristics (ROC) analysis using the first 50% participants was performed to define decision trees of baseline MRI volumetric and connectivity (fractional anisotropy) measures that differentiated non-remitters from remitters with maximal sensitivity and specificity. These decision trees were tested for replication in the remaining participants. Overall, 35% of all participants achieved remission. ROC analyses identified two decision trees that predicted a high probability of non-remission and that were replicated: 1. Left middle frontal volume < 14 · 8 mL & right angular gyrus volume > 6 · 3 mL identified 55% of non-remitters with 85% accuracy; and 2. Fractional anisotropy values in the left cingulum bundle < 0 · 63, right superior fronto-occipital fasciculus < 0 · 54 and right superior longitudinal fasciculus < 0 · 50 identified 15% of the non-remitters with 84% accuracy. All participants who met criteria for both decision trees were correctly identified as non-remitters. Pretreatment MRI measures seem to reliably identify a subset of patients who do not remit with a first step medication that includes one of these commonly used medications. Findings are consistent with a neuroanatomical basis for non-remission in depressed patients. Brain Resource Ltd is the sponsor for the iSPOT-D study (NCT00693849).
    Full-text · Article · Jan 2015
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