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Focus.psychiatryonline.org

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
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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
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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
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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
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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
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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
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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
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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.
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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 royalty income 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.
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Intervention mendizabal esp 2

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

Livro quadrado m gico

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

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