Sequential Treatment With Fluoxetine and Relapse-Prevention CBT to Improve Outcomes in Pediatric Depression
Publication: American Journal of Psychiatry
Abstract
Objective
The authors evaluated a sequential treatment strategy of fluoxetine and relapse-prevention cognitive-behavioral therapy (CBT) to determine effects on remission and relapse in youths with major depressive disorder.
Method
Youths 8–17 years of age with major depression were treated openly with fluoxetine for 6 weeks. Those with an adequate response (defined as a reduction of 50% or more on the Children’s Depression Rating Scale–Revised [CDRS-R]) were randomly assigned to receive continued medication management alone or continued medication management plus CBT for an additional 6 months. The CBT was modified to address residual symptoms and was supplemented by well-being therapy. Primary outcome measures were time to remission (with remission defined as a CDRS-R score of 28 or less) and rate of relapse (with relapse defined as either a CDRS-R score of 40 or more with a history of 2 weeks of symptom worsening, or clinical deterioration).
Results
Of the 200 participants enrolled in acute-phase treatment, 144 were assigned to continuation treatment with medication management alone (N=69) or medication management plus CBT (N=75). During the 30-week continuation treatment period, time to remission did not differ significantly between treatment groups (hazard ratio=1.26, 95% CI=0.87, 1.82). However, the medication management plus CBT group had a significantly lower risk of relapse than the medication management only group (hazard ratio=0.31, 95% CI=0.13, 0.75). The estimated probability of relapse by week 30 was lower with medication management plus CBT than with medication management only (9% compared with 26.5%).
Conclusions
Continuation-phase relapse-prevention CBT was effective in reducing the risk of relapse but not in accelerating time to remission in children and adolescents with major depressive disorder.
Advances in the treatment of pediatric major depressive disorder have demonstrated effective acute-phase treatments, including antidepressant medication (1, 2), psychotherapy (3, 4), and their combination (5, 6). Despite these gains, 40%–70% of youths treated for depression will experience a relapse or recurrence (7–9). Most treatment studies focus on acute-phase outcomes, and studies that report long-term outcomes generally continue the acute-phase treatments into long-term care. Few studies have included specific sequential continuation treatment strategies developed to improve long-term outcomes.
Acute treatment strategies are designed to achieve symptom response (a significant reduction in depressive symptoms) and ultimately remission (minimal to no symptoms). Remission rates, however, have been low. Even with the combination of fluoxetine and cognitive-behavioral therapy (CBT) in the Treatment for Adolescent Depression Study (TADS), only 37% of patients remitted after 12 weeks of treatment (10). Residual symptoms after acute treatment are common and are associated with poorer longer-term outcomes in youths (10, 11).
Continuation treatment, on the other hand, follows acute treatment with the goals of targeting residual symptoms and preventing relapse. Over the past several years, sequential treatment models have been examined, typically beginning with pharmacotherapy for acute treatment, followed by another treatment modality to address residual symptoms once response has been achieved (12, 13). A meta-analysis of psychotherapy delivered after pharmacotherapy suggests that sequencing these two treatment modalities may be an optimal strategy for preventing relapse (13).
Research on continuation treatment in youths with major depressive disorder is limited. Continuing antidepressants for 6–9 months reduces relapse rates; however, some 34%–40% of these youths will relapse even while continuing on medication (7, 14). Only three continuation studies of CBT in youths have been reported to date, with mixed results (15–17). In a pilot study of 46 adolescents we reported in 2008 (17), a sequential treatment strategy using 12 weeks of fluoxetine to achieve response, followed by a specific relapse-prevention CBT delivered over 6 months, resulted in a lower risk of relapse in those who received continuation medication and relapse-prevention CBT compared with those who remained on medication alone. That study led to the larger randomized controlled trial we report here, designed to evaluate the efficacy of continuation-phase relapse-prevention CBT in reducing relapse rates. In this study, our aims were expanded to include not only relapse prevention but also shorter time to remission.
Method
This was a National Institute of Mental Health-funded single-site, randomized continuation trial in youths with major depressive disorder. The study was approved by the University of Texas Southwestern Medical Center Institutional Review Board. All participants and their parents provided written consent and assent after the purpose, procedures, and risks and benefits, as well as the rights of study subjects, were explained and all questions were answered.
Study Participants
To be included in the study, participants had to be outpatients 8–17 years of age in a general pediatric psychiatry outpatient clinic. They had to have a primary diagnosis of major depressive disorder for at least 4 weeks, with a score ≥40 on the Children’s Depression Rating Scale–Revised (CDRS-R) (18) and a severity score ≥4 on the Clinical Global Impressions Scale (CGI-S) (19). While major depressive disorder was the primary diagnosis, other concurrent disorders were allowed. Participants also had to be in good general medical health and of normal intelligence, and they and at least one parent had to be English speaking.
Exclusion criteria were lifetime psychotic disorder (including psychotic depression), bipolar I or II disorder, anorexia nervosa, or bulimia nervosa; alcohol or substance abuse or dependence within the past 6 months; a concurrent medical condition that would interfere with the conduct of the study or endanger the patient; concurrent use of medications with psychotropic effects; a first-degree relative with bipolar I disorder; severe suicidal ideation requiring more intensive treatment; and previous failure of an adequate trial of fluoxetine (≥4 weeks of at least 40 mg/day) or intolerance to fluoxetine. Female patients who were pregnant or lactating or were sexually active and not using adequate contraception were also excluded.
Diagnostic Evaluation
Trained master’s-level independent evaluators interviewed participants and parents, using the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime Version (K-SADS-PL) (20) to determine whether patients met the inclusion diagnostic criteria. Evaluators also obtained suicide and family history using the Columbia Suicide History Form and the Family History Screen. The CDRS-R, CGI-S, and Suicide Severity Rating Scale–Short were also administered.
Information regarding the course of illness and symptom severity were obtained by a child psychiatrist 1 week later through a review of the K-SADS-PL and interview of the participant and parents using the CDRS-R, the CGI-S, and the Suicide Severity Rating Scale–Short. Weekly meetings were held to review each participant for eligibility and appropriateness for the study.
Acute-Phase Treatment
After assessment, eligible participants began a 6-week course of fluoxetine. The decision to limit the acute-phase treatment to 6 weeks was based on previous trial experiences, which suggested that shortening time to remission leads to better long-term outcomes. Participants received an initial dosage of 10 mg/day of fluoxetine at the baseline visit, increasing to 20 mg/day at week 1 unless side effects were not adequately tolerated. The dosage could be increased (based on clinical judgment) to 30–40 mg/day after 4 weeks or reduced to 10 mg/day if necessary.
Medication management visits, which included assessment of symptoms and adverse events, were conducted weekly by a child psychiatrist during acute-phase treatment (weeks 0–6). Standard clinical management was provided, which followed the medication management manual from TADS (21) and included supportive care but no specific psychotherapy. Participants who were nonadherent to medication (defined as having taken <70% of prescribed pills on two consecutive visits, based on pill count) and those who required additional treatment were discontinued.
Randomization
After 6 weeks of treatment with fluoxetine, participants were assessed by independent evaluators reassessed for response, which was defined as a decrease of at least 50% in total score on the CDRS-R. Patients who did not respond were discontinued and given appropriate referrals. Those who responded were eligible for random assignment to continuation treatment. Patients were stratified by age group (≤11 years [children] and ≥12 years [adolescents]) and remission status (CDRS-R score ≤28 or >28), and randomly assigned in a 1:1 ratio either to continue on fluoxetine only (the medication management group) or to continue on fluoxetine while also receiving relapse-prevention CBT (the medication management plus CBT group).
Continuation Treatment
Medication management.
All patients who entered the continuation phase continued to receive fluoxetine for 6 months. Medication visit schedules for both the medication management and medication management plus CBT groups were every other week for 3 months and then monthly for the remainder of continuation treatment (at weeks 20, 24, and 30). Visits lasted 30–45 minutes and consisted of assessment of symptoms and safety. Dosage was flexible during this phase and based on clinical need. Patients who needed additional interventions were discontinued from study treatment but continued with assessments.
Relapse-prevention CBT.
Patients assigned to receive medication management plus CBT began CBT sessions at week 7. A total of eight to 11 CBT sessions were planned (Table 1). CBT visits were weekly for the first month, every other week for 2 months, and every 4–6 weeks for the last 3 months; however, the number and frequency of sessions were individualized based on patient need. Sessions typically lasted 1 hour, although the first two sessions, which included a family component, lasted 1.5 hours. Therapists were at the master’s level and above and had experience in manualized CBT. Therapy sessions were audiotaped, and a sample of sessions was reviewed by the CBT supervisors (B.D.K. and J.M.J.). Therapists also met weekly for supervision. Therapists and psychiatrists collaborated and communicated about the patient’s care.
| Treatment Stage | Stage Objectives | Session | Session Content |
|---|---|---|---|
| Stage 1 (4 weekly sessions) | Reduce residual symptoms through core skills | 1 | Psychoeducation (child and family) |
| Begin timeline (case conceptualization) | |||
| Mood monitoring | |||
| Assess and identify core beliefs | 2 | Psychoeducation | |
| Behavioral coping skills (behavioral activation) | |||
| Family module on negative emotion | |||
| Identify and increase areas of strength and wellness | 3 | Cognitive restructuring | |
| Core beliefs and positive self-schema | |||
| 4 | Problem solving | ||
| Begin wellness assessment | |||
| Family communication skills | |||
| Stage 2 (4 sessions over 8 weeks) | Consolidation and further practice of core skills and wellness skills to manage mood | 5–7 | Introduce concept of wellnessa |
| Relapse prevention | Practice and application of core and wellness skills for relapse prevention | ||
| Family wellness session | |||
| 8 | Relapse prevention and wellness plan | ||
| Stage 3 (3 monthly sessions) | Consolidation of treatment gains | 9–11 | Content varies depending on patient’s needs |
| Evaluate and revise the relapse-prevention and wellness plans as needed |
a
Six general areas of wellness: self-acceptance, social, success, self-goals, spiritual, and soothing. Using a wellness log designed for relapse-prevention cognitive-behavioral therapy, the therapist assessed for existing strengths and areas of improvement. The wellness aspect of the treatment resulted in the development of an individualized wellness plan for each patient.
The goals of relapse-prevention CBT include reducing residual symptoms, increasing periods of psychological well-being, and preventing relapse. Relapse-prevention CBT was developed as a brief individual treatment with a family component (an average of three sessions with the youth and one or both parents) (17). The treatment format is modular, designed to be tailored to the specific needs of the child. The treatment also addresses risk factors for relapse (negative attributional style, family conflict, and expressed emotion) and adds elements from well-being therapy, which was adapted from Ryff and Singer’s approach (22) and has been found to be effective in reducing relapse (23) and promoting wellness.
Outcome Measures
Outcomes were based on blind assessments by independent evaluators at the end of acute-phase treatment (at week 6) and every 6 weeks during continuation treatment (at weeks 6, 12, 18, 24, and 30). Assessments included measures of symptoms and functioning (CGI, CDRS-R, Suicide Severity Rating Scale–Short) and course of illness using the Adolescent Longitudinal Interval Follow-Up Evaluation (adapted from the Longitudinal Interval Follow-Up Evaluation [24]). Patients continued with assessments even if they discontinued study treatments.
The primary outcome measures for the study were time to remission and rate of relapse. Remission was defined as a CDRS-R score ≤28, with timing of remission determined through clinical interview and the Adolescent Longitudinal Interval Follow-Up Evaluation. Relapse was defined as a CDRS-R score ≥40 for at least 2 weeks, or a score <40 with significant clinical deterioration that would suggest full relapse if the patient’s treatment were not altered (7). Only youths who had achieved remission (at any point in the study) were assessed for relapse. Time to relapse was also measured.
“Time spent well in the study” was measured with the Adolescent Longitudinal Interval Follow-Up Evaluation. Although this instrument is generally used at 6-month intervals to show status change in psychiatric disorders, in this study the independent evaluators completed the ratings at each assessment. Time spent well was defined as each week that the youth received a rating of 1 or 2 (no or minimal disorder) on the Adolescent Longitudinal Interval Follow-Up Evaluation, and it was operationalized as number of weeks with a rating of 1 or 2 divided by total number of weeks in the study.
Safety
Adverse events were assessed by the psychiatrist at each visit. Adverse events were defined as any emergent or worsening untoward event requiring intervention. Serious adverse events were defined according to U.S. Food and Drug Administration criteria.
Statistical Analysis
Demographic and clinical characteristics were compared between the medication management and medication management plus CBT groups using an independent sample t test for continuous variables and chi-square or Fisher’s exact test for categorical variables.
A Cox proportional hazards regression with adjustment for CDRS-R score, age group (child versus adolescent), and gender was used to compare time to remission and, in a separate model, time to relapse between participants in the two treatment groups. Hazard ratios were estimated and interpreted as the effect size estimator for our Cox regression. As part of the survival analysis, right censoring was used and occurred when the information available about a given participant’s survival time was incomplete because the participant did not have an event during the study. Censoring (or a censored observation) occurred when a participant dropped out or completed the study without remitting or relapsing. We also estimated the probability of remitting or relapsing, as well as the rates of remission or relapse, at each week across the 30-week continuation treatment trial.
A Poisson regression with adjustment for CDRS-R score, age group (child versus adolescent), and gender was used to compare the log “time spent well” rates, or incidence of time spent well in the study, between the two groups. Maximum likelihood estimation and type 3 tests of fixed effects were used with the Wald chi-square statistic. The Poisson model also accounted for overdispersion by adjusting the standard errors and test statistics using the Pearson scaling parameter.
Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, N.C.) and MedCalc for Windows, version 12.7.5 (MedCalc Software, Ostend, Belgium). All analyses were intent-to-treat. For all tests, alpha was set at 0.05 (two-tailed); to address multiple testing (multiplicity), where applicable, p values were adjusted using the false-discovery-rate procedure.
Hedges’ g was calculated to estimate effect sizes for between-group comparisons. Effect size for Hedges’ g can be interpreted using Cohen’s convention (25), where 0.20, 0.50, and 0.80 are small, medium, and large effects, respectively.
Results
Participant Characteristics
A sample of 200 youths (54.5% female and 52% minorities) entered acute-phase treatment (the CONSORT flow diagram is available in the data supplement that accompanies the online edition of this article). The mean age was 13.8 years (SD=2.6), and 79% were adolescents (≥12 years). The baseline CDRS-R score was 58.3 (SD=7.7).
Of the 200 patients, 144 achieved response during acute-phase treatment and were randomly assigned to continuation treatment with medication management (N=69) or with medication management plus CBT (N=75) for 6 months (Table 2). The two treatment groups did not differ in baseline demographic and clinical characteristics, and there were no differences between those who entered continuation treatment and those who did not (N=56).
| Variable | All Participants (N=144) | Medication Management Plus CBT (N=75) | Medication Management Only (N=69) | |||
|---|---|---|---|---|---|---|
| N | % | N | % | N | % | |
| Age group | ||||||
| ≤11 years (children) | 31 | 21.5 | 19 | 25.3 | 12 | 17.4 |
| ≥12 years (adolescents) | 113 | 78.5 | 56 | 74.7 | 57 | 82.6 |
| Female | 77 | 53.5 | 38 | 50.7 | 39 | 56.5 |
| Race | ||||||
| Caucasian | 118 | 81.9 | 64 | 85.3 | 54 | 78.3 |
| African American | 15 | 10.4 | 8 | 10.7 | 7 | 10.1 |
| Asian or American Indian | 2 | 1.4 | 1 | 1.3 | 1 | 1.5 |
| Multiracial | 9 | 6.3 | 2 | 2.7 | 7 | 10.1 |
| Hispanic ethnicity | 43 | 29.9 | 23 | 30.7 | 20 | 29.0 |
| Number of Episodes | ||||||
| 1 | 127 | 88.2 | 68 | 90.7 | 59 | 85.5 |
| 2 | 25 | 10.4 | 7 | 9.3 | 8 | 11.5 |
| 3 or 4 | 2 | 1.4 | 0 | 0.0 | 2 | 2.8 |
| Attained remission by week 6 | 54 | 37.5 | 29 | 38.7 | 25 | 36.2 |
| CGI severity score at baseline | ||||||
| 4 | 25 | 17.4 | 16 | 21.3 | 9 | 13.0 |
| 5 | 69 | 47.9 | 38 | 50.7 | 31 | 45.0 |
| 6 | 50 | 34.7 | 21 | 28.0 | 29 | 42.0 |
| CGI severity score at week 6 | ||||||
| 1 | 3 | 2.1 | 1 | 1.3 | 2 | 3.0 |
| 2 | 48 | 33.3 | 27 | 36.0 | 21 | 30.4 |
| 3 | 76 | 52.8 | 39 | 52.0 | 37 | 53.6 |
| 4 | 16 | 11.1 | 7 | 9.4 | 9 | 13.0 |
| 5 | 1 | 0.7 | 1 | 1.3 | 0 | 0.0 |
| Comorbid anxiety disorder | 32 | 22.2 | 12 | 16.0 | 20 | 28.9 |
| Comorbid behavior disorder | 48 | 33.7 | 26 | 34.7 | 22 | 31.9 |
| Comorbid dysthymia | 24 | 16.7 | 10 | 13.3 | 14 | 20.3 |
| Baseline suicidal ideation | ||||||
| None | 42 | 29.2 | 26 | 34.7 | 16 | 23.2 |
| Morbid thoughts or death wishes | 23 | 16.0 | 10 | 13.3 | 13 | 18.8 |
| Suicidal thoughts | 53 | 36.8 | 28 | 37.3 | 25 | 36.2 |
| Suicidal plans | 5 | 3.5 | 2 | 2.7 | 3 | 4.4 |
| Suicide attempts | 21 | 14.6 | 9 | 12.0 | 12 | 17.4 |
| Number of suicide attempts | ||||||
| None | 123 | 85.4 | 66 | 88.0 | 57 | 82.6 |
| 1 | 12 | 8.33 | 5 | 6.7 | 7 | 10.1 |
| ≥2 | 9 | 6.33 | 4 | 5.3 | 5 | 7.3 |
| Mean | SD | Mean | SD | Mean | SD | |
| Age (years) | 13.8 | 2.6 | 13.5 | 2.7 | 14.2 | 2.4 |
| Duration of episode (weeks) | 43.7 | 38.6 | 41.3 | 36.9 | 46.4 | 40.4 |
| Number of episodes | 1.1 | 0.4 | 1.1 | 0.29 | 1.2 | 0.52 |
| CDRS-R score at baseline | 58.0 | 7.2 | 56.8 | 7.1 | 59.2 | 7.0 |
| CDRS-R score at week 6 | 30.9 | 5.7 | 30.5 | 5.6 | 31.4 | 5.9 |
| CGI severity score at baseline | 5.2 | 0.7 | 5.1 | 0.7 | 5.3 | 0.69 |
| CGI severity score at week 6 | 2.8 | 0.7 | 2.7 | 0.7 | 2.8 | 0.71 |
a
Participants received acute-phase treatment with fluoxetine for 6 weeks, after which they were randomly assigned to receive continuation treatment with medication management only or medication management plus CBT for 24 weeks. CGI=Clinical Global Impressions Scale; CDRS-R=Children’s Depression Rating Scale–Revised.
Attrition
Of the 144 youths who entered continuation treatment, 114 (79.2%) remained in the study assessments for all 30 weeks, with similar rates for the medication management plus CBT and medication management only groups (82.7% and 75.4%, respectively). The overall rate of treatment completion (defined as remaining in the assigned treatment condition up to week 30) was 66% (N=95), with a nonsignificantly higher treatment completion rate for the medication management plus CBT group than for the medication management only group (70.7% and 60.9%, respectively). The overall mean treatment exit week was similar between the two groups (26.3 [SD=6.7] and 25.2 [SD=7.1], respectively).
Fluoxetine Dosage
The number of medication management visits ranged from six to 16, with similar visit frequency between the medication management plus CBT and medication management only groups (mean=13.2 [SD=2.6] and mean=13.3 [SD=2.4], respectively). Patients in the medication management plus CBT group received an average of 9.8 CBT sessions (SD=4.0; range=0–20).
The daily dose of fluoxetine at the end of acute-phase treatment was similar for the medication management plus CBT and medication management only groups (mean=26.7 mg [SD=7.9] and mean=28.5 mg [SD=7.8], respectively). The dosage after the start of continuation treatment was based on the highest dosage received. The mean maximum daily dose received across all youths who entered continuation treatment was 32.5 mg (SD=8.5), with the medication management group receiving a significantly higher maximum daily dose than the medication management plus CBT group (mean=34.2 mg [SD=8.3] compared with mean=30.9 mg [SD=8.4]; p=0.02).
Hazard of Remission
After adjustment for baseline CDRS-R score, age group, and gender, the Cox regression revealed that participants in the medication management plus CBT group did not differ significantly in time to remission from those in the medication management only group during continuation treatment (hazard ratio=1.26, 95% CI=0.87, 1.82; n.s.).
The mean time to remission for the medication management plus CBT group was 11.33 weeks (SE=0.95), compared with 13.67 weeks (SE=1.17) for the medication management only group. A log-rank test showed that the mean time to remission between the two treatment groups was not significant. Figure 1 displays the survival curves, plotted at the mean of all covariates in the model. At weeks 12, 18, 24, and 30, the estimated probability of remitting for the medication management plus CBT group was about 68%, 79%, 86%, and 90%, respectively, compared with about 59%, 71%, 80%, and 84%, respectively, for the medication management only group. No significant treatment group effects on remission rates emerged at any individual week.
FIGURE 1. Remission Survival Curve After 30 Weeks for Youths With Depression Receiving Either Medication Management Only or Medication Management Plus Cognitive-Behavioral Therapy (CBT)a
a Participants received acute-phase treatment with fluoxetine for 6 weeks, after which they were randomly assigned to receive continuation treatment with medication management only or medication management plus CBT for 24 weeks.
Hazard of Relapse
Relapse was assessed in participants who achieved remission at any time during the study (N=115). After adjustment for CDRS-R score at the end of acute-phase treatment (at 6 weeks), age group, and gender, the Cox regression revealed that participants in the medication management plus CBT group had a significantly lower risk of relapse than those in the medication management only group during the 30-week continuation phase (hazard ratio=0.313, 95% CI=0.130, 0.753; χ2=6.64, p=0.010). Thus, the hazard of relapse for those who received medication management plus CBT was 0.313 times that of those who received medication management alone.
The survival curves in Figure 2, plotted at the mean of all covariates in the model, indicate that the survival probability of relapsing was greater at all times for medication management compared with medication management plus CBT. At weeks 12, 18, 24, and 30, the estimated probability of relapse for the medication management plus CBT group was about 1%, 3.5%, 7%, and 9%, respectively, compared with about 3%, 10%, 20.5%, and 26.5%, respectively, for the medication management only group. The two treatment groups differed significantly on relapse rates at week 24 (raw p=0.028; false-discovery-rate-adjusted p=0.049) and week 30 (raw p=0.011; false-discovery-rate-adjusted p=0.043), but not at week 12 and week 18.
FIGURE 2. Relapse Survival Curve After 30 Weeks for Youths With Depression Receiving Either Medication Management Only or Medication Management Plus Cognitive-Behavioral Therapy (CBT)
a Participants received acute-phase treatment with fluoxetine for 6 weeks, after which they were randomly assigned to receive continuation treatment with medication management only or medication management plus CBT for 24 weeks.
During continuation treatment, the mean time to relapse for medication management plus CBT was 28.77 weeks (SE=0.48), compared with 27.13 weeks (SE=0.68) for medication management only (log-rank test: p=0.009, g=0.439). While not all analyses were replicated to examine full relapse (CDRS-R score ≥40) versus clinical deterioration, it is important to note that nine of the 17 patients in the medication management plus CBT group who relapsed (52.9%) experienced full relapse, and 15 of the 28 patients in the medication management only group who relapsed (53.6%) experienced full relapse.
Time Spent Well
The incidence of time spent well was evaluated using a Poisson regression with adjustment for CDRS-R score at the end of the acute phase, age group, and gender. Participants in the medication management plus CBT group had a significantly higher estimated rate of time spent well than those in the medication management only group (55.9% compared with 46.2%; χ2=5.48, p=0.02, g=0.395). The medication management plus CBT group spent 16.0 weeks well (SD=9.1), compared with 12.8 weeks (SD=9.5) for the medication management only group (p=0.041, g=0.342).
Safety Outcomes
The rates of adverse events leading to treatment discontinuation did not differ significantly between the two treatment groups, with 2.7% (2/75) in the medication management plus CBT group and 4.3% (3/69) in the medication management only group. Adverse events related to hypomania occurred only during acute-phase treatment, with two patients discontinuing because of hypomania (N=1) or agitation (N=1). This rate (2%) is similar to that seen in the two randomized controlled trials of fluoxetine, in which 3.1% of fluoxetine patients had mania, hypomania, or agitation (1).
Sixteen participants experienced a total of 18 serious adverse events during continuation treatment. Seven events occurred in the medication management only group: one hospitalization for a suicide attempt, three for suicidal ideation, one for agitation, and two for medical conditions. Eleven events occurred in nine patients in the medication management plus CBT group: five hospitalizations for suicidal ideation, one case of suicidal behavior that did not result in hospitalization, and five hospitalizations for preexisting medical conditions. These events were reported to the institutional review board and the data safety monitoring board.
Discussion
To our knowledge, this is the first randomized controlled trial of a sequential treatment strategy to prevent relapse in youths with major depressive disorder. The results demonstrate that, as in adults (13), sequencing treatments can reduce risk of relapse and lengthen time to relapse in depressed youths. Adding CBT as part of a sequential treatment strategy after response to antidepressant medication, as opposed to continuation treatment with pharmacotherapy alone, significantly reduced the hazard of relapse and lengthened time to relapse in this trial.
While the treatment was developed to prevent relapse, we anticipated that it might also shorten time to remission and therefore included this as a primary outcome measure. Our results did not support this hypothesis, however. Nonetheless, it is worth noting that those who received medication management plus CBT reached remission about 2.5 weeks earlier on average than those who were on medication alone. While not statistically significant, in the life of a child, two and a half weeks has potential clinical relevance.
An unexpected but important finding was in differences in fluoxetine dosing. Youths who received CBT had lower medication dosages yet had better outcomes than those on higher dosages in the medication management only group. The difference in dosage, while statistically significant, may not be clinically significant, but it suggests that differences in outcomes were not attributable to higher dosing in one group over the other.
The optimal timing of adding CBT is still not well understood. The guidelines from the U.K. National Institute for Health and Care Excellence indicate that youths with depression should be treated with CBT as a first-line treatment; however, acute-phase CBT, at least in more severely depressed patients, does not compare as favorably to antidepressant medication or combination treatments (5, 26). In TADS, remission rates with CBT were not comparable to those with medication until 18–24 weeks into treatment (11). In the present study, we did not examine the effectiveness of antidepressant medication compared with CBT; rather, we assessed whether adding CBT after initial improvement with an antidepressant would lead to greater improvement and prevent relapse. Thus, this study demonstrates that CBT can be effective as a continuation strategy. While not tested in this study, it will be important in the future to determine the optimal timing of the onset of added CBT in continuation treatment. Also worthy of study is whether a different treatment modality could be used for the acute phase.
We acknowledge that this study has some limitations. The time period for the study’s primary outcomes was 30 weeks (follow-up data were collected at weeks 52 and 78 and will be included in a subsequent report). Truncating the study outcomes at 30 weeks may have limited our ability to find significance on remission outcomes. The TADS study demonstrated that remission rates increase over time across groups (11). In addition, while relapse rates were statistically and clinically significant (a relapse rate of 9% in the medication management plus CBT group compared with almost 27% in the medication management only group), mean time to relapse differed by only 1.6 weeks between the two groups.
Another limitation was that participants were not blind to treatment assignment, and there was a difference in clinical contact time between the two groups. We made every effort to limit additional clinic visits for the CBT condition, and in the treatment protocol we scheduled only two additional visits for these patients to reduce participant burden. Thus, all other CBT visits occurred in conjunction with medication management visits. As stated earlier, the number of medication visits was similar between the two groups. While we could have added a sham therapy to control for contact time, we wanted the study to be ecologically valid and to mirror real-world practice. We also note that results (not reported) from separate intercept-only frailty models (random-effects survival models), with therapist included as a random effect, suggest that the therapists did not introduce any significant concomitant variability in our basic findings.
Sequencing effective monotherapies improved outcomes in youths with depression in our study, and it may be a means of optimizing both medication and CBT treatment effects. This strategy is efficient, as it reduces the traditional number of CBT sessions required for positive outcomes (12–16 sessions) (3) and thus reduces the burdens of time and cost. Furthermore, we hypothesize—although this has yet to be empirically validated—that a child who has had a positive response to medication is more fully able to participate in CBT and may be more likely to assimilate the skills and complete the practice exercises between sessions. It might be asked whether the acute-phase treatment must be medication treatment. Would the results be similar if the acute-phase treatment were CBT followed by a continuation medication treatment? In adults with major depressive disorder, such sequencing (medication following acute cognitive therapy) has not been found to result in lower relapse rates compared with continuation CBT only (27). In addition, the CBT in this trial emphasized reducing residual symptoms, preventing relapse, and promoting wellness. Thus, as has been shown in adults (28), continuation strategies that focus on well-being may protect youths against relapse in depression.
Continuation-phase strategies designed to reduce the high rates of relapse in depressed youths have important public health implications, as recurrence of depression is more likely in youths with multiple episodes (9, 26). It is important that we move beyond the acute goal of getting children well to the enduring goal of promoting and maintaining wellness.
Acknowledgments
The authors are grateful to co-investigators Carroll Hughes and Rongrong Tao and to the clinicians, coordinators, and evaluators who were involved in the study, as well as to the children and families who participated in the study.
Supplementary Material
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References
1.
Cheung AH, Emslie GJ, Mayes TL: Review of the efficacy and safety of antidepressants in youth depression. J Child Psychol Psychiatry 2005; 46:735–754
2.
Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA: Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007; 297:1683–1696
3.
Compton SN, March JS, Brent DA, Albano AM, Weersing R, Curry JF: Cognitive-behavioral psychotherapy for anxiety and depressive disorders in children and adolescents: an evidence-based medicine review. J Am Acad Child Adolesc Psychiatry 2004; 43:930–959
4.
Weisz JR, McCarty CA, Valeri SM: Effects of psychotherapy for depression in children and adolescents: a meta-analysis. Psychol Bull 2006; 132:132–149
5.
Pediatric OCD Treatment Study (POTS) Team: Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004; 292:1969–1976
6.
Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M, Vitiello B, Ritz L, Iyengar S, Abebe K, Birmaher B, Ryan N, Kennard B, Hughes C, DeBar L, McCracken J, Strober M, Suddath R, Spirito A, Leonard H, Melhem N, Porta G, Onorato M, Zelazny J: Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA 2008; 299:901–913
7.
Emslie GJ, Kennard BD, Mayes TL, Nightingale-Teresi J, Carmody T, Hughes CW, Rush AJ, Tao R, Rintelmann JW: Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. Am J Psychiatry 2008; 165:459–467
8.
Kennard BD, Emslie GJ, Mayes TL, Hughes JL: Relapse and recurrence in pediatric depression. Child Adolesc Psychiatr Clin N Am 2006; 15:1057–1079
9.
Birmaher B, Brent DAACAP Work Group on Quality Issues, Bernet W, Bukstein O, Walter H, Benson RS, Chrisman A, Farchione T, Greenhill L, Hamilton J, Keable H, Kinlan J, Schoettle U, Stock S, Ptakowski KK, Medicus J: Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:1503–1526
10.
Kennard BD, Silva S, Vitiello B, Curry JF, Kratochvil C, Simons AD, Hughes JL, Feeny NC, Weller EB, Sweeney M, Reinecke MA, Pathak S, Ginsburg G, Emslie GJ, March JS; TADS Team: Remission and residual symptoms after short-term treatment in the Treatment of Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 2006; 45:1404–1411
11.
Kennard BD, Silva SG, Tonev S, Rohde P, Hughes JL, Vitiello B, Kratochvil CJ, Curry JF, Emslie GJ, Reinecke M, March J: Remission and recovery in the Treatment for Adolescents With Depression Study (TADS): acute and long-term outcomes. J Am Acad Child Adolesc Psychiatry 2009; 48:186–195
12.
Fava GA, Tomba E: New modalities of assessment and treatment planning in depression: the sequential approach. CNS Drugs 2010; 24:453–465
13.
Guidi J, Fava GA, Fava M, Papakostas GI: Efficacy of the sequential integration of psychotherapy and pharmacotherapy in major depressive disorder: a preliminary meta-analysis. Psychol Med 2011; 41:321–331
14.
Emslie GJ, Heiligenstein JH, Hoog SL, Wagner KD, Findling RL, McCracken JT, Nilsson ME, Jacobson JG: Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004; 43:1397–1405
15.
Clarke GN, Rohde P, Lewinsohn PM, Hops H, Seeley JR: Cognitive-behavioral treatment of adolescent depression: efficacy of acute group treatment and booster sessions. J Am Acad Child Adolesc Psychiatry 1999; 38:272–279
16.
Kroll L, Harrington R, Jayson D, Fraser J, Gowers S: Pilot study of continuation cognitive-behavioral therapy for major depression in adolescent psychiatric patients. J Am Acad Child Adolesc Psychiatry 1996; 35:1156–1161
17.
Kennard BD, Emslie GJ, Mayes TL, Nightingale-Teresi J, Nakonezny PA, Hughes JL, Jones JM, Tao R, Stewart SM, Jarrett RB: Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. J Am Acad Child Adolesc Psychiatry 2008; 47:1395–1404
18.
Poznanski EO, Mokros H: Children’s Depression Rating Scale–Revised (CDRS-R). Los Angeles, Western Psychological Services, 1996
19.
Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department of Health, Education, and Welfare, 1976, pp 218–222
20.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N: Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997; 36:980–988
21.
March JS: Treatment for Adolescents With Depression Study (TADS) Pharmacotherapy Treatment Manual. Durham, NC, Duke University Medical Center, the TADS Team, 2005
22.
Fava GA, Tomba E: Increasing psychological well-being and resilience by psychotherapeutic methods. J Pers 2009; 77:1903–1934
23.
Fava GA, Rafanelli C, Grandi S, Conti S, Belluardo P: Prevention of recurrent depression with cognitive behavioral therapy: preliminary findings. Arch Gen Psychiatry 1998; 55:816–820
24.
Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, McDonald-Scott P, Andreasen NC: The Longitudinal Interval Follow-Up Evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987; 44:540–548
25.
Cohen J: Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Hillsdale, NJ, Lawrence Erlbaum Associates, 1988
26.
Lewinsohn PM, Rohde P, Seeley JR: Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clin Psychol Rev 1998; 18:765–794
27.
Jarrett RB, Minhajuddin A, Gershenfeld H, Friedman ES, Thase ME: Preventing depressive relapse and recurrence in higher-risk cognitive therapy responders: a randomized trial of continuation phase cognitive therapy, fluoxetine, or matched pill placebo. JAMA Psychiatry 2013; 70:1152–1160
28.
Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA: Cognitive behavioral treatment of residual symptoms in primary major depressive disorder. Am J Psychiatry 1994; 151:1295–1299
Information & Authors
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History
Received: 5 November 2013
Revision received: 2 April 2014
Revision received: 21 April 2014
Accepted: 24 April 2014
Published online: 1 October 2014
Published in print: October 2014
Authors
Funding Information
National Institute of Mental Health10.13039/100000025: R01 MH39188
Dr. Emslie receives research support from Eli Lilly, BioMarin, Somerset, Duke University, Forest Laboratories, Valeant, GlaxoSmithKline, and Mylan; is a consultant for Allergan, Biobehavioral Diagnostics Company, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, INC Research, Lundbeck, Merck, Pfizer, Seaside Therapeutics, Shire, Texas Department of State Health Services, University of Miami, and Valeant; and is on the speakers bureau for Forest Laboratories. The other authors report no financial relationships with commercial interests.
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Supported by NIMH grant R01 MH39188 (principal investigators, Dr. Emslie and Dr. Kennard).Metrics & Citations
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