Graham J. Emslie, M.D. Beth D. Kennard, Psy.D. Fluoxetine Versus Taryn L. Mayes, M.S. Jeanne Nightingale-Teresi, R.N. Thomas Carmody, Ph.D. Carroll W. Hughes, Ph.D. Placebo in Preventing A. John Rush, M.D. Rongrong Tao, M.D., Ph.D. Jeanne W. Rintelmann, B.A. Relapse of Major Depression in Children and Adolescents Objective: The authors compared fluoxetine and placebo in continuation treatment to prevent relapse of major depres-
sive disorder in children and adolescents. Method: After a detailed evaluation, children and adolescents 7–18 years of
age with major depressive disorder were treated openly with fluoxetine. Those who had an adequate response after 12
weeks, as indicated by a Clinical Global Impression improvement score of 1 or 2 and a decrease of at least 50% in Chil-
dren’s Depression Rating Scale—Revised score, were randomly assigned to receive fluoxetine or placebo for an addi-
tional 6 months. The primary outcome measures were relapse and time to relapse. Relapse was defined as either a score
of 40 or higher on the Children’s Depression Rating Scale with a history of 2 weeks of clinical deterioration, or clinical
deterioration as judged by the clinician. Additional analyses were conducted with relapse defined only as a score of 40
or higher on the Children’s Depression Rating Scale. Results: Of 168 participants enrolled in acute fluoxetine treat-
ment, 102 were randomly assigned to continuation treatment with fluoxetine (N ϭ 50) or placebo (N ϭ 52). Of these,21 participants (42.0%) in the fluoxetine group relapsed, compared with 36 (69.2%) in the placebo group, a significant
difference. Similarly, under the stricter definition of relapse, fewer participants in the fluoxetine group relapsed (N ϭ 11; 22.0%) than in the placebo group (N ϭ 25; 48.1%). Time to relapse was significantly shorter in the placebo group. Conclusions: Continuation treatment with fluoxetine was superior to placebo in preventing relapse and in increasing
time to relapse in children and adolescents with major depression. (Reprinted with permission from the American Journal of Psychiatry 2008; 165:459 – 467)
Major depressive disorder is a serious disorder in
8). Thus, depression is a serious disorder requiring
the pediatric age group, with 2%– 8% of children
and adolescents afflicted (1, 2). Youths with depres-
Treatment for major depression may be divided
sion often have significant impairment in relation-
into three phases: acute, continuation, and mainte-
ships, school, and work and are at increased risk for
nance treatment. Acute treatment refers to initial
substance abuse, attempted and completed suicide,
treatment designed to achieve response (a signifi-
and depression in adulthood (1, 3, 4). Further-
cant reduction in depressive symptoms) and ulti-
more, it appears that early-onset major depression
mately remission (minimal or no symptoms). The
may be a more chronic and recurrent disorder than
goal of treatment is remission, although most ran-
depression that begins in adulthood (1, 5). As many
domized controlled trials include response as the
as 50%–75% of children with major depression
primary aim. Continuation treatment follows acute
have recurrent episodes (1, 3). Recurrence most of-
treatment with the goal of preventing relapse of
ten occurs within 6 –12 months after remission (6 –
symptoms from the treated episode and consolidat-
F O C U S THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY 348 EMSLIE ET AL.
ing symptom improvement for a longer duration
PARTICIPANTS
(recovery). Continuation treatment generally lasts4 –9 months after remission. Maintenance treat-
Participants were recruited from clinical referrals
ment, which lasts 1–3 years, is aimed at preventing
to a general child and adolescent psychiatry outpa-
new episodes or recurrences of depression in pa-
tient clinic as well as through advertisements. Gen-
tients who have recovered from their index episode
erally, inclusion and exclusion criteria were the
same as in our two previous acute double-blind,
Because the efficacy of antidepressants in acute
placebo-controlled trials of fluoxetine (18, 19). Par-
treatment has only recently been established in chil-
ticipants were outpatients 7–18 years of age who
dren and adolescents (12, 13), research on how
had a primary diagnosis of major depressive disor-
long to continue medication treatment after re-
der for at least 4 weeks, with a Children’s Depres-
sponse in this patient group is limited. Placebo-
sion Rating Scale-Revised (CDRS-R; 20) score
controlled continuation studies with adults have
Ն40 and a Clinical Global Impression (CGI; 21)
shown that continued treatment with an antide-
severity score Ն4. Major depressive disorder had to
pressant for 6 –9 months after acute treatment re-
be the primary cause for dysfunction in partici-
duces relapse rates compared with placebo (14 –
pants, although patients with concurrent disorders,
16). In a small pilot study conducted as part of a
such as anxiety, attention deficit hyperactivity dis-
large acute efficacy trial of fluoxetine in children
order (ADHD), and conduct disorder, were in-
and adolescents, continued fluoxetine reduced re-
cluded in the study. Participants were in good gen-
lapse rates compared with placebo (34% and 60%,
eral medical health and of normal intelligence.
respectively) and lengthened the time to relapse
Exclusion criteria included a lifetime history of any
(17). The study was limited by several factors: it was
psychotic disorder (including psychotic depres-
part of a double-blind acute study; it was a small
sion), bipolar disorder, anorexia nervosa, or bulim-
sample (N ϭ 40); randomization occurred at base-
ia; alcohol or substance abuse within the previous 6
line of acute treatment, so age groups were unbal-
months; a concurrent medical condition that
anced in the treatment groups during continuation
would interfere with the study or endanger the par-
treatment; and the length of treatment prior to ran-
ticipant; first-degree relatives with bipolar I disor-
domization included both acute treatment (9
der; severe suicidal ideation requiring inpatient
weeks) and some continuation treatment (10
treatment; previous failure of or intolerance to flu-
oxetine; or concurrent psychotropic medications
PUBLICATIONS INFLUENTIAL
Here we present the results of a randomized, pla-
other than stimulants in a stable regimen. In fe-
cebocontrolled discontinuation trial to evaluate the
males, pregnancy, lactation, and not using ade-
need for continuation treatment in depressed chil-
quate contraception were also exclusion criteria.
dren and adolescents who responded to 12 weeks of
Because the duration of the protocol (9 months)
precluded withholding appropriate treatment forADHD, participants were allowed to be on stimu-
lant treatment or to begin stimulant treatment dur-
ing the acute phase of the study. However, the ad-
This was a single-site, double-blind, randomized
dition of stimulant treatment was not allowed at
discontinuation trial funded by the National Insti-
the time of randomization or during continuation
tute of Mental Health (NIMH) from August 2000
to July 2006. After a 2-week, three-visit evaluationperiod, participants who met all inclusion criteria
EVALUATION
and no exclusion criteria were enrolled in a 12-weekopen-label acute treatment period with 10 – 40 mg
Patients referred to the study were screened by tele-
of fluoxetine. Those who responded at the end of
phone for possible inclusion. Appropriate subjects
12 weeks of acute treatment were randomly as-
were scheduled for an initial diagnostic interview. Af-
signed to receive fluoxetine or placebo for an addi-
ter the informed consent procedure was completed,
interviewers used the Schedule for Affective Disorders
The study was approved by the University of
and Schizophrenia for School-Age Children—
Texas Southwestern Medical Center Institutional
Present and Lifetime Version (K-SADS-PL) (22), in-
Review Board. All participants and their parents
terviewing parents and patients separately to deter-
provided written informed consent or assent after
mine whether patients met inclusion and exclusion
the purpose, procedures, risks, and benefits of the
diagnostic criteria. The interviewer also used the Fam-
study and the rights of study subjects were ex-
ily Global Assessment Scale (D. Mrazek, unpublished,
plained and all questions were answered.
1992) to obtain information about family functioning
Summer 2008, Vol. VI, No. 3 349 EMSLIE ET AL.
and the Family History Research Diagnostic Criteria
was not tapered given its long half-life. Randomiza-
(23) to obtain a family psychiatric history. A week
tion was accomplished by a computer implementa-
later, participants were evaluated by a psychiatrist or
tion of the minimization method in order to ac-
licensed psychologist. Information about course of ill-
commodate stratification by response category
ness and depression severity was obtained through the
(remission versus adequate clinical response), gen-
KSADS-PL, the CDRS-R, and the CGI severity of
der, and age (participants age 12 or under and those
illness item. Participants who met all inclusion criteria
age 13 and over). At the time the study was started,
and no exclusion criteria and continued to have a
these age groups were considered an appropriate
CDRS-R score Ն40 were scheduled to begin acute
division of children and adolescents. However, in
2003, the FDA recommended including 12-year-olds as adolescents, and many “adolescent” studies
included 12-year-olds (24). Therefore, for consis-
CUTE TREATMENT
tency with other trials, these suggested age groups
Beginning at the baseline visit (week 0), partici-
(age 11 and under for children and age 12 and over
pants received 10 mg/day of fluoxetine for 1 week,
for adolescents) were used in the analyses.
and then the dosage was increased to 20 mg/day.
During continuation treatment, participants
The dosage could be increased to 30 – 40 mg/day
were evaluated by the psychiatrist every other week
after 6 weeks of treatment if there was minimal or
for weeks 12–16 and monthly for weeks 16 –36,
no response (i.e., a CGI severity score Ն3). The
with two additional visits allowed if needed. The
dosage could be reduced to 10 mg/day if intolerable
rating instruments were administered at each visit.
A child psychiatrist conducted all treatment visits
OUTCOME MEASURES
and completed all rating scales. Visits were weeklyfor weeks 1– 4 and every other week until acute
The primary outcome measures for the study
treatment ended at week 12. Supportive clinical
were relapse and time to relapse. As noted by Rush
management (e.g., contact with schools and refer-
and colleagues (25), definitions of relapse must bal-
rals for treatment for family members) was pro-
ance refraining from declaring a minor worsening
vided during each visit, although no specific
as a full recurrence while also not requiring such a
psychotherapy was allowed. No concomitant psy-
high threshold for recurrence that study subjects
chotropic medications other than stimulants were
must endure undue pain and suffering. We defined
allowed during the treatment, including the con-
relapse as either a one-time CDRS-R score Ն40
tinuation phase. Participants were discontinued
with worsening of depressive symptoms for at least
from the study if they did not adhere to the medi-
2 weeks, or a clinician determination that there was
cation regimen; nonadherence was defined as hav-
significant clinical deterioration suggesting that full
ing taken Ͻ70% of pills, based on pill count, on
relapse would be likely without altering treatment,
two consecutive visits or a total of three visits dur-
even if the CDRS-R score was Ͻ40. When clinical
ing either phase of treatment. At week 12, partici-
deterioration occurred, the participant could be
pants who did not respond to treatment were
brought in for an interim visit reassessment or
discontinued from the study and given recommen-
could be withdrawn from study on the basis of the
second definition of relapse. We also conductedsecondary analyses on the more stringent relapse
ONTINUATION TREATMENT
Secondary outcome measures included depres-
Participants were eligible to enter the continua-
sion severity as measured by the CDRS-R; the
tion phase if they had remitted (defined as a CGI
CGI severity and improvement scales (an improve-
severity of illness score of 1 or 2 and a CDRS-R
ment score of 1 or 2 [very much or much improved] is
score Յ28) or had an adequate clinical response
considered an acceptable response to treatment); and
(defined as a CGI severity of illness score of 1 or 2
the Children’s Global Assessment Scale (26), which
and a decrease of 50% or more on the CDRS-R
measures overall functioning, with lower scores indi-
score) at week 12. Before randomization, the con-
cating greater impairment in functioning.
sent process was repeated with participants and par-ents for the double-blind continuation phase. Par-
ticipants were then randomly assigned to receivefluoxetine or placebo. Those in the fluoxetine
Adverse events were assessed at each visit through
group received the same dose they were receiving in
general inquiry about problems since the last visit.
acute treatment. In the placebo group, fluoxetine
Serious adverse events, as defined according to FDA
F O C U S THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY 350 EMSLIE ET AL.
criteria, include adverse events that lead to death; are
episode; the severity of depression as measured
life threatening; require hospitalization (initial or pro-
by the CGI severity scale was moderate for
longed); lead to disability, congenital anomaly, or
30.4%, marked for 56.5%, and severe for 13.1%.
birth defect; require intervention to prevent perma-
The mean CDRS-R score at baseline was 57.6
nent impairment or damage; and other important
(SD ϭ 7.3), which is consistent with previous
medical events that require medical or surgical inter-
vention (e.g., failed suicide attempt).
Of the 168 participants who entered acute treat-
ment, 49 did not undergo randomization because
of early withdrawal from the study or not meeting
TATISTICAL ANALYSES
efficacy criteria; another 17 participants were eligi-
Acute phase baseline characteristics were com-
ble but did not undergo randomization. Thus, 102
pared between participants who completed the 12-
participants underwent randomization for contin-
week acute phase and underwent randomization
uation treatment. The participant flow throughout
and those who dropped out of the acute phase.
Similarly, continuation phase baseline characteris-
The baseline demographic and clinical character-
tics were compared between participants in the flu-
istics of the participants who entered continuation
oxetine group and those in the placebo group. Un-
treatment were similar to those who did not (Table
adjusted relapse rates (using both the first and
1), although more participants in the younger age
second definition of relapse) were compared by chi-
group entered continuation treatment compared
square test. A logistic regression model was used to
with the older age group. In fact, of the adolescents
compare relapse rates after adjustment for the fol-
enrolled in acute treatment, just over half (51%)
lowing covariates, selected prior to conducting
entered continuation treatment, while about 71%
analyses: gender, age, race (Caucasian/non-Cauca-
of the children who entered acute treatment en-
sian), duration of illness episode, number of epi-
tered continuation treatment (2 ϭ 7.11, df ϭ 1,
sodes, duration of illness, age at illness onset, and
p ϭ 0.01). Similarly, 52% of the females who en-
continuation phase baseline scores on the
tered acute treatment entered continuation treatment,
CDRS-R, the CGI severity scale, the Children’s
while 67% of the males did so, although this differ-
Global Assessment Scale, and the Family Global
ence did not reach statistical significance and may be
Assessment Scale. Because the rate of anxiety disor-
confounded by age group (the adolescents were more
ders was found to be significantly different between
likely to be female). Overall, illness characteristics
PUBLICATIONS INFLUENTIAL
the fluoxetine and placebo groups in analyses of
were similar for those who entered continuation treat-
baseline characteristics, the regression was rerun to
ment compared with those who did not. Most of
include presence of anxiety disorders in the model.
those who entered continuation treatment were in
Presence of anxiety disorders was not a significant
their first episode of depression (72.6%).
predictor in the model, so it was removed and the
The mean dosage of fluoxetine for participants
originally selected covariates were maintained. Cox
who entered continuation treatment was 26.2 mg/
proportional hazards regression models both with
day (SD ϭ 9.4). The mean dosage was higher for
and without the covariates defined above were used
adolescents than for children (29.8 mg/day [SD ϭ
to compare time to relapse between groups.
10.1] compared with 23.3 mg/day [SD ϭ 7.9]; F ϭ13.1, df ϭ 1, 13.1, p Ͻ 0.001). Most of those who
entered continuation treatment (N ϭ 70; 68.6%)
had remained on 20 mg/day throughout acutetreatment. The dosage was increased to 30 – 40 mg/
day at week 6 or later in 32 participants (31.4%),
CUTE PHASE
most of whom were adolescents (N ϭ 22). In fact,
Of 331 children and adolescents evaluated,
almost half of the adolescents (48.9%) had in-
162 were screened out. Fluoxetine was given to
creased to a higher dose by the end of acute treat-
169 participants; one participant was lost to fol-
ment, while only 17.5% of the children were on a
low-up and did not return for a postbaseline
dosage Ͼ20 mg/ day by the end of acute treatment.
visit. Thus, a total of 168 youths entered acute
In one child, the dosage was reduced to 10 mg/day
treatment and had at least one postbaseline visit,
because of increased hyperactivity on 20 mg/day.
including 80 children (ages 7–11) and 88 adoles-cents (ages 12–18). The mean age for the overall
CONTINUATION PHASE
sample was 11.8 years (SD ϭ 2.8); 42.3% werefemale, and most participants (75%) were Cau-
Of 102 participants who underwent random-
casian. Most (69%) were in their first depressive
ization for the continuation phase, 50 were ran-
Summer 2008, Vol. VI, No. 3 351 EMSLIE ET AL.
score at randomization was 23.3 (SD ϭ 3.9) for the
Figure 1. Flow of Participants in a Study
fluoxetine group and 22.4 (SD ϭ 4.4) for the pla-
cebo group. Participants in the placebo group had
higher scores on the Children’s Global Assessment
Scale than those in the fluoxetine group (75.7[SD ϭ 9.3] and 71.9 [SD ϭ 8.9], respectively; F ϭ
No major depressive disorder diagnosis (N=88)Withdrew consent (N=52)Exclusion criteria met (N=17)
Excluded from acute treatment analyses (N=1):
Relapse occurred more frequently in participants
in the placebo group than in the fluoxetine group
(N ϭ 36 [69.2%] and N ϭ 21 [42.0%], respec-tively; 2 ϭ 7.67, df ϭ 1, p ϭ 0.009). Even using
the stricter definition (CDRS-R Ն40 only), relapse
was more frequent in the placebo group than in the
Withdrew consent (N=16)Lost to follow-up/moved (N=4)
fluoxetine group (N ϭ 25 [48.1%] and N ϭ 11
[22.0%], respectively; 2 ϭ 7.59, df ϭ 1, p ϭ
In our multivariate logistic regression model ex-
amining the effect of various demographic and clin-
ical variables on relapse rate, the treatment effectremained significant with all predictors in themodel (2 ϭ 5.9, df ϭ 1, p ϭ 0.0152). Given
patients with median values for all covariates, theodds of relapse for the placebo group were 3.2 timesthose for the fluoxetine group (95% confidence in-
terval [CI] ϭ 1.2– 8.2). Similar results were ob-tained with the stricter definition of relapse (resultsnot shown).
Cox proportional hazards regression showed that
participants in the placebo group had a significantly
greater risk of relapse than those in the fluoxetine
group without adjustment for covariates (risk ratio ϭ
2.1, 95% CI ϭ 1.3–3.6; 2 ϭ 3.1, df ϭ 1, p ϭ
0.0044). After adjustment for the same covariates as
for the logistic regression model, the risk ratio was 2.2
(95% CI ϭ 1.2–3.8) and remained significant (2 ϭ7.7, df ϭ 1, p ϭ 0.0055). Similar results were ob-tained with the stricter definition of relapse.
domized to fluoxetine and 52 to placebo. No
Figure 2 presents the survival curve for time to
statistical differences were noted between the
relapse, adjusted for covariates. For the placebo
two groups with regard to age, gender, race, du-
group, the median time to relapse was 8 weeks after
ration of episode, duration of illness, number of
discontinuation of fluoxetine. By 24 weeks after
episodes, or severity of depression at study base-
discontinuation, less than 50% of the fluoxetine
line. The fluoxetine group had higher rates of
group had relapsed; thus, the median time to re-
comorbid anxiety disorders than the placebo
lapse for the group could not be determined, al-
group (36% and 15.4%, respectively; 2 ϭ 5.7,
though it is greater than 24 weeks. Figure 3 presents
the survival curve for time to full relapse (CDRS
Participants entering the continuation phase had
score Ն40), adjusted for covariates. Median time to
either remitted (CDRS-R score Յ28) or responded
full relapse was 14 weeks for the placebo group and
(CGI severity score Յ2 and a decrease of Ն50% in
could not be determined for the fluoxetine group
CDRS-R score) by the end of the acute phase. Most
except that it is greater than 24 weeks.
participants were in remission at the time of ran-
Within 6 weeks of randomization, the estimated
domization (90.0% of the fluoxetine group and
probability of relapse was 38.7% for the placebo
86.5% of the placebo group). The mean CDRS-R
group, compared with 19.1% for the fluoxetine
F O C U S THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY 352 EMSLIE ET AL.
Table 1. Baseline Demographic and Clinical Characteristics of Participants WhoReceived Acute Phase Treatment With Fluoxetine, by Whether They Enteredthe Continuation Phase
Did Not Enter Entered Continuation Continuation Phase Phase (N ؍ 102) Characteristic
Baseline Children’s Depression Rating Scale—Revised score
Baseline Clinical Global Impression severity score
Baseline Children’s Global Assessment Scale score
PUBLICATIONS INFLUENTIAL
a Significant difference between groups (p ϭ 0.04).
b Significant difference between groups (p ϭ 0.01).
c Significant difference between groups (p ϭ 0.05).
group. By 12 weeks, the estimated probability of
RELAPSE RATES BY AGE, GENDER, AND
relapse was 65.7% for the placebo group, compared
PRESENCE OF RESIDUAL SYMPTOMS
with 35.7% for the fluoxetine group. Only a fewadditional participants relapsed between 12 weeks
Exploratory analyses were conducted to evaluate
and 24 weeks of continuation treatment in either
the effects of age, gender, and presence of residual
symptoms on relapse rates (Table 2). Overall, the
Summer 2008, Vol. VI, No. 3 353 EMSLIE ET AL.
difference between the fluoxetine and placebo
groups was greatest in males when the full relapse
definition was used and least in females when either
definition of relapse was used. Females overall con-
stituted a smaller group and tended to be in theolder age group, which may confound results.
At the end of acute treatment, 54 (52.9%) par-
ticipants reported at least one residual depressive
symptom. During continuation treatment, fullrelapse was significantly lower in participants
who had no residual symptoms at the end ofacute treatment (22.9%; 11/48) than those with
Percent 40
continued symptoms (46.3%; 25/54), regardlessof treatment assignment (2 ϭ 6.8, df ϭ 1, p ϭ
0.014). The greatest difference between the flu-oxetine and placebo groups was observed in par-ticipants who had no residual symptoms after
acute treatment (67% and 25%, respectively). Participants with no residual symptoms who
Time to Relapse (weeks)
were switched to placebo for continuation treat-
a Relapse was defined as either a one-time score Ն40 on the Children’s Depression
ment were six times as likely as those remaining
Rating Scale—Revised (CDRS-R) with worsening of depressive symptoms for atleast 2 weeks, or a clinician determination that significant clinical deterioration sug-
gested that full relapse would be likely without altering treatment, even if theCDRS-R score was Ͻ40. The survival model was adjusted for the following covari-ates: gender, age, race, duration of episode, number of episodes, duration of ill-ness, age at illness onset, and baseline continuation phase scores for the CDRS-R,
Clinical Global Impression severity scale, Children’s Global Assessment Scale, andFamily Global Assessment Scale.
Adverse events were similar between the two
groups, and there were no discontinuations due tophysical adverse events during continuation treat-ment. Three serious adverse events occurred duringthe continuation phase: two participants in the pla-cebo group were hospitalized for preexisting medi-cal conditions, and one participant in the fluoxetine
group was withdrawn after a suicide attempt (week
16); the patient had a history of self-injurious be-
havior and suicidal plans without intent prior to
Response in Acute Treatment WithFluoxetinea
DISCUSSION
This is the first randomized, placebo-controlled
study of the efficacy of continued antidepressant
(fluoxetine) treatment in pediatric patients withmajor depressive disorder who have had an ade-
quate response with 12 weeks of acute treatment. Fluoxetine was superior to placebo in preventing
Percent 40
relapse and in increasing time to relapse. Relapse
rates were high and occurred equally in children
and adolescents. In this sample, overall relapse rates
were similar in males and females, but the impact of
continued treatment with fluoxetine was greater in
males. Similarly, participants who had residual
Time to Relapse (weeks)
symptoms at the end of 12 weeks of acute treatment
were more likely to relapse during the subsequent 6
Full relapse was defined as a Children’s Depression Rating Scale— Revised(CDRS-R) score Ն40. The survival model was adjusted for the following covariates:
months of continuation treatment on both fluox-
gender, age, race, duration of episode, number of episodes, duration of illness, age
etine and placebo. Fluoxetine was most effective for
at illness onset, and baseline continuation phase scores for the CDRS-R, CGI sever-ity scale, Children’s Global Assessment Scale, and Family Global Assessment Scale.
preventing relapse (compared with placebo) in
F O C U S THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY 354 EMSLIE ET AL.
Table 2. Rates of Relapse in Participants Who Received Placebo or FluoxetineDuring Continuation Treatment, by Age Group, Gender, and Presence ofResidual Symptoms
Fluoxetine Subgroup and Relapse Measurea Difference (%) Odds Ratiob PUBLICATIONS INFLUENTIAL
a Relapse was defined as either a one-time score Ն40 on the Children’s Depression Rating Scale—Revised (CDRS-R) with worsening of depressive symptoms for
at least 2 weeks, or a clinician determination that significant clinical deterioration suggested that full relapse would be likely without altering treatment, even ifthe CDRS-R score was Ͻ40. Full relapse was defined as a CDRS-R score Ն40.
b Odds ratio for relapse in the placebo group relative to relapse in the fluoxetine group.
those who had no residual symptoms at the end of
Some participants did refuse randomization (N ϭ
17 of 119 eligible, or 14.3%), about half (N ϭ 8)
Overall, our continuation treatment sample was
because they were concerned about relapse or being
fairly young (mean age ϭ 11.5 years [SD ϭ 2.8]),
randomized to placebo. One concern in the plan-
attributable in part to the recruitment of partici-
ning stage was that if participants knew they were
pants in a children’s hospital. In addition, there was
being randomly assigned to treatment, they might
differential attrition for children and adolescents
relapse shortly thereafter in anticipation of possibly
prior to randomization to continuation treatment;
getting placebo. However, the pattern of relapse
adolescents were less likely than children to remain
was consistent with the half-life of the medication,
in the study until this point. For 70% of partici-
so it appears this concern was unfounded.
pants, this was their first episode of major depres-
There were substantial concerns about how to
sion, and comorbid disorders were common. While
define relapse to avoid allowing participants to be-
participants were outpatients and therefore could
come too ill before declaring a relapse as well as
not be in need of hospitalization for suicidal behav-
counting minor worsening (which might improve
ior, 43% had suicidal ideation during this episode.
spontaneously) as a sign of relapse. The majority of
Several methodological issues were raised prior to
difference between the fluoxetine and placebo
initiating the study, including concerns about the
groups in the study was driven by the stricter defi-
safety of discontinuation. Safeguards were recom-
nition of relapse, which required a CDRS-R score
mended by NIMH, among them the exclusion of
Ն40. Future studies might consider using a fairly
participants with a history of severe suicide at-
conservative definition of relapse, although this
tempts and the repetition of the consent protocol
would have to be balanced with what parents and
prior to randomization to continuation treatment.
Summer 2008, Vol. VI, No. 3 355 EMSLIE ET AL.
The study is significant for several reasons. It
Disclosure: Dr. Emslie receives research support from or served as
demonstrates that continuation treatment is re-
an adviser, consultant, or speaker for BioBehavioral Diagnostics,Eli Lilly, Forest Laboratories, GlaxoSmithKline, McNeil, NIMH,
quired beyond remission of symptoms to prevent
Somerset, Shire, and Wyeth-Ayerst. Dr. Hughes is a consultant for
relapse, which suggests that the adult guidelines
BioBehavioral Diagnostics. Dr. Rush has received research supportfrom or served as an adviser, consultant, or speaker for Advanced
recommending 6 –9 months of overall treatment
Neuromodulation Systems, AstraZeneca, Best Practice Project
for major depression would apply equally to chil-
Management, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest
dren and adolescents. It also reinforces the fact that
Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, JazzPharmaceuticals, Magellan Health Services, Merck, Neuronetics,
early-onset depression is associated with high rates
NIMH, Ono Pharmaceuticals, Organon, Pamlab, Personality
of relapse, even though the majority of participants
Disorder Research Corp., Pfizer, Robert Wood Johnson Founda-tion, Stanley Medical Research Institute, Urban Institute, and
in this sample were in their first episode of major
Wyeth-Ayerst; he has equity holdings in Pfizer and has royaltyincome affiliations with Guilford Publications and HealthcareTechnology Systems. All other authors report no competing interests.
In addition, the results support the efficacy of
fluoxetine over placebo, albeit through a design nottypically used to establish efficacy. The drug-pla-
R E F E R E N C E S
cebo difference in this study was 27%, which wassimilar to three prior acute efficacy trials that have
1. Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl R, Perel
J, Nelson B: Childhood and adolescent depression: a review of the past
been published (18, 19, 27), in which the differ-
10 years: part I. J Am Acad Child Adolesc Psychiatry 1996; 35:1427–
ences ranged from 15% to 26%. As noted by Dr.
2. Shaffer D, Fisher P, Dulcan MK, Davies M, Piacentini J, SchwabStone ME,
Robert Temple at a recent FDA workshop on med-
Lahey BB, Bourdon K, Jensen PS, Bird HR, Canino G, Regier DA: The
ication effectiveness (Jan. 9, 2007), it is possible
NIMH Diagnostic Interview Schedule for Children, version 2.3 (DISC-2.3):
that alternative designs, such as the discontinuation
description, acceptability, prevalence rates, and performance in theMECA study: Methods for the Epidemiology of Child and Adolescent
design used in this study, are potentially useful in
Mental Disorders study. J Am Acad Child Adolesc Psychiatry 1996;
3. American Academy of Child and Adolescent Psychiatry: Practice param-
Future research would benefit by examining
eter for the assessment and treatment of children and adolescents with
different treatment strategies to improve remis-
depressive disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:
sion rates and prevent relapse. As has been ob-
4. Bridge JA, Goldstein TR, Brent DA: Adolescent suicide and suicidal
served in adults, children and adolescents with
behavior. J Child Psychol Psychiatry 2006; 47:372–394
major depression who had residual symptoms af-
5. Kovacs M: Presentation and course of major depressive disorder during
childhood and later years of the life span. J Am Acad Child Adolesc
ter 3 months of medication and clinical manage-
ment were more likely than those without resid-
6. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Carmody T, Mayes TL:
Fluoxetine in child and adolescent depression: acute and maintenance
ual symptoms to relapse, regardless of whether
treatment. Depress Anxiety 1998; 7:32–39
they continued medication or switched to pla-
7. Vostanis P, Feehan C, Grattan EF, Bickerton WL: A randomised controlled
cebo. Participants with no residual symptoms
outpatient trial of cognitive-behavioural treatment for children and ado-lescents with depression: 9-month followup. J Affect Dis 1996; 40:105–
rarely relapsed on continued medication treat-
ment. Continuation treatment with fluoxetine
8. Wood A, Harrington R, Moore A: Controlled trial of a brief cognitive-
behavioural intervention in adolescent patients with depressive disorders.
alone after 12 weeks is unlikely to improve remis-
J Child Psychol Psychiatry 1996; 37:737–746
sion rates (29). However, fluoxetine combined
9. Depression Guideline Panel: Depression in Primary Care, vol 1: Detection
with cognitive-behavioral therapy (CBT) has demon-
and Diagnosis. Clinical Practice Guideline, No 5. AH-CPR Publication No. 93-0550. Rockville, Md, US Department of Health and Human Services,
strated improved remission rates overall (30). As dem-
Public Health Service, Agency for Health Care Policy and Research, 1993
onstrated in adults, it is possible that augmenting an-
10. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ,
Weissman MM: Conceptualization and rationale for consensus definitions
tidepressants with CBT after response in acute
of terms in major depressive disorder: remission, recovery, relapse, and
treatment could improve long-term outcome for chil-
recurrence. Arch Gen Psychiatry 1991; 48:851– 855
dren and adolescents, particularly for those who con-
11. Rush AJ, Kraemer HC, Sackeim HS, Fava M, Trivedi MH, Frank E, Ninan
PT, Thase ME, Gelenberg AJ, Kupfer DJ, Regier DA, Rosenbaum JF, Ray
tinue to have residual symptoms after an adequate trial
O, Schatzberg AF; ACNP Task Force: Report by the ACNP Task Force on
of medication (31–36). Another strategy to improve
response and remission in major depressive disorder. Neuropsychophar-macology 2006; 31:1841–1853
remission might include medication augmentation
12. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren
L, Brent DA: Clinical response and risk for reported suicidal ideation andsuicide attempts in pediatric antidepressant treatment: a meta-analysis
Treatment guidelines recommend maintenance
of randomized controlled trials. JAMA 2007; 297:1683–1696
treatment for 1–3 years for patients who have had
13. Cheung AH, Emslie GJ, Mayes TL: Review of the efficacy and safety of
multiple or severe depressive episodes (3, 39, 40).
antidepressants in youth depression. J Child Psychol and Psychiatry2005; 46:735–754
No maintenance trials have been conducted in pe-
14. Doogan DP, Caillard V: Sertraline in the prevention of depression. Br J
diatric depression; however, such trials are needed
15. Montgomery SA, Dunbar G: Paroxetine is better than placebo in relapse
to examine the utility of longterm medication as
prevention and the prophylaxis of recurrent depression. Int Clin Psycho-
well as to examine which patients are most likely to
need extended treatment beyond continuation
16. Reimherr FW, Amsterdam JD, Quitkin FM, Rosenbaum JF, Fava M,
Zajecka J, Beasley DM Jr, Michelson D, Roback P, Sundell K: Optimal
length of continuation therapy in depression: a prospective assessment
F O C U S THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY 356 EMSLIE ET AL.
during long-term fluoxetine treatment. Am J Psychiatry 1998; 155:1247–
30. Kennard B, Silva S, Vitiello B, Curry J, Kratochvil C, Simons A, Hughes J,
Feeny N, Weller E, Sweeney M, Reinecke M, Pathak S, Ginsburg G, Emslie
17. Emslie GJ, Heiligenstein JH, Hoog SL, Wagner KD, Findling RL, Mc-
G, March J; TADS Team: Remission and residual symptoms after acute
Cracken JT, Nilsson ME, Jacobson JG: Fluoxetine treatment for preven-
treatment of adolescents with major depressive disorder. J Am Acad
tion of relapse of depression in children and adolescents: a double-blind,
Child Adolesc Psychiatry 2006; 45:1404 –1411
placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004;
31. Bockting C, Schene A, Spinhoven P, Koeter M, Wouters L, Huyser J,
Kamphuis JH: Preventing relapse/recurrence in recurrent depression with
18. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T,
cognitive therapy: a randomized controlled trial. J Consult Clin Psychol
Rintelmann J: Double-blind, randomized placebo-controlled trial of flu-
oxetine in depressed children and adolescents. Arch Gen Psychiatry
32. Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA: Cognitive
behavioral treatment of residual symptoms in primary major depressive
19. Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E,
disorder. Am J Psychiatry 1994; 151:1295–1299
Neilsson M, Jacobson JG: Fluoxetine for acute treatment of depression in
33. Fava G, Fabbri S, Sonino N: Residual symptoms in depression: an
children and adolescents: a placebocontrolled, randomized clinical trial.
emerging therapeutic target. Prog Neuropsychopharmacol Biol Psychiatry
J Am Acad Child Adolesc Psychiatry 2002; 41:1205–1215
20. Poznanski E, Mokros H: Children’s Depression Rating Scale-Revised
34. Paykel ES, Scott J, Teasdale JD, Johnson AL, Garland A, Moore R,
(CDRS-R). Los Angeles, Western Psychological Services, 1996
Jenaway A, Cornwall PL, Hayhurst H, Abbott R, Pope M: Prevention of
21. Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Pub-
relapse in residual depression by cognitive therapy: a controlled trial.
lication ADM 76-338. Washington, DC, US Department of Health, Edu-
cation, and Welfare, 1976, pp 113–147, 534 –537
35. Perlis R, Nierenberg A, Alpert J, Pava J, Matthews J, Buchin J, Sickinger
22. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D,
AH, Fava M: The effects of adding cognitive therapy to fluoxetine dose
Ryan N: Schedule for Affective Disorders and Schizophrenia for School-
increase on risk of relapse and residual depressive symptoms in contin-
Age Children—Present and Lifetime Version (K-SADS-PL): initial reliability
uation treatment of major depressive disorder. J Clin Psychopharmacol
and validity data. J Am Acad Child Adolesc Psychiatry 1997; 36:980 –988
23. Andreasen NC, Rice J, Endicott J, Reich T, Coryell, W: The family history
36. Teasdale JD, Segal ZV, Williams JM, Ridgeway VA, Soulsby JM, Lau MA:
approach to diagnosis. Arch Gen Psychiatry 1986; 43:421– 429
Prevention of relapse/recurrence in major depression by mindfulness-
24. US Food and Drug Administration: Guidance for Industry and FDA Staff:
based cognitive therapy. J Consult Clin Psychol 2000; 68:615– 623
Pediatric Expertise for Advisory Panels. Rockville, Md, US Department of
37. Schatzberg AF, Rush AJ, Arnow BA, Banks PL, Blalock JA, Borian FE,
Health and Human Services, Food and Drug Administration, Center for
Howland R, Klein DN, Kocsis JH, Kornstein SG, Manber R, Markowitz
Devices and Radiological Health, Office of Device Evaluation, Office of In
JC, Miller I, Ninan PT, Rothbaum BO, Thase ME, Trivedi MH, Keller
Vitro Diagnostic Device Evaluation and Safety, June 3, 2003, http://
MB: Chronic depression: medication (nefezodone) or psychotherapy
(CBASP) is effective when the other is not. Arch Gen Psychiatry 2005;
25. Rush AJ, Koran LM, Keller MB, Markowitz JC, Harrison WM, Miceli RJ,
Fawcett JA, Gelenberg AJ, Hirschfeld RMA, Klein DN, Kocsis JH, McCul-
38. Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther
lough JP, Schatzberg AF, Thase ME: The treatment of chronic depression,
JF, Fava M, Nierenberg AA, McGrath PJ, Warden D, Niederehe G, Hollon
part 1: study design and rationale for evaluating the comparative efficacy
SD, Rush AJ: Cognitive therapy versus medication in augmentation and
of sertraline and imipramine as acute, crossover, continuation, and
switch strategies as second-step treatments: a STAR*D report. Am J
maintenance phase therapies. J Clin Psychiatry 1998; 59:589 –597
26. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Aluwahlia
39. Cheung A, Zuckerbrot RA, Jensen PS, Ghalib K, Laraque D, Stein REK;
S: A Children’s Global Assessment Scale (CGAS). Arch Gen Psychiatry
GLAD-PC Steering Group: Guidelines for Adolescent Depression in Pri-
mary Care (GLAD-PC), part II: treatment and ongoing management.
27. Treatment for Adolescents With Depression Study (TADS) Team: Fluox-
PUBLICATIONS INFLUENTIAL
etine, cognitive-behavioral therapy, and their combination for adolescents
40. Hughes CW, Emslie GJ, Crismon ML, Posner K, Birmaher B, Ryan N,
with depression: Treatment for Adolescents With Depression Study
Jensen P, Curry J, Vitiello B, Lopez M, Shon SP, Pliszka SR, Trivedi MH;
(TADS) randomized controlled trial. JAMA 2004; 292:807– 820
Texas Consensus Conference Panel on Medication Treatment of Child-
28. US Food and Drug Administration: NDA/Demonstrating Product Effectiveness,
hood Major Depressive Disorder: Texas Children’s Medication Algorithm
presented at the Marketed Unapproved Drugs Workshop, Jan 9, 2007.
Project: update from Texas Consensus Conference Panel on Medication
http://www.fda.gov/cder/drug/ unapproved_drugs/presentations.pdf
Treatment of Childhood Major Depressive Disorder. J Am Acad Child
29. Treatment for Adolescents With Depression Study (TADS) Team: The
Treatment for Adolescents With Depression Study (TADS): Long-termeffectiveness and safety outcomes. Arch Gen Psychiatry 2007; 64:1132–1143
Summer 2008, Vol. VI, No. 3 357
Arantza MENDIZABAL GOROSTIAGA TERRORISMO: Un desafío para la democracia ANTECEDENTES En España después de la muerte del dictador se inició un proceso de transición a la democracia ejemplar. Un proceso de recuperación de las libertades y de construcción de un país plural y tolerante. Los rescoldos del franquismo fueron desapareciendo, sólo quedaba ETA. El grupo terrorista
SEGREDOS QUADRADO MÁGICO QUADRADO COM 3 x 3 CASAS QUADRADOS MÁGICOS. Estes QUADRADOS costumavam ser gravados em placas deprata por serem considerados amuletos contra pragas. Suasorigens históricas são atribuídas à China e Índia. Perderamaquele valor dogmático mas preocupam a ciência matemática. QUADRADO COM 4 X 4 CASAS - O primeiro valor deverá ser inscrito