More than 80% of the 168 participants completed the entire 12 weeks of acute phase of treatment. Reasons for discontinuation during the acute treatment were lack of efficacy (n = 6/168; 3.6%), moved or lost to follow-up (n = 5/168; 3.0%), withdrew consent (n = 11/168; 6.5%), noncompliance (n = 2/168; 1.2%), and adverse events (n = 8/168; 4.8%). Adverse events leading to discontinuation included rash (n = 2/168; 1.2%), multiple physical adverse events (n = 1; 0.6%), and suicide-related behaviors (n = 5/168; 3.0%), which included suicidal ideation (n = 3), suicide attempt (n = 1), and selfinjurious behavior (n = 1).
The mean age of participants was 11.8 ± 2.8 years, with children (ages 7–11 years) comprising 48% of the sample. Forty-two percent of the participants were girls; the sample was predominantly white (75%). The majority (70%) of the youths were in their first MDD episode. Concurrent comorbid disorders were common; 74% had at least one comorbid psychiatric diagnosis, with ADHD being the most common comorbid illness. Approximately 71% of the sample had a positive first-degree family history of depression. The mean baseline CDRS-R total score was 57.6 (SD 7.3), with no significant differences between boys (mean 56.8, SD 6.0) and girls (mean 58.7, SD 8.8; t = −1.7, p = .94) or between children (mean 56.4, SD 6.6) and adolescents (mean 58.6, SD 7.8; t = −2.0, p = .52). Baseline characteristics for participants who entered the acute phase of treatment are shown in . Patient features were similar between remitters (n = 110) and nonremitters (n = 58; ).
Demographic and Baseline Clinical Features
Predicting Remission Status From Baseline Characteristics
Based on previous studies,7,8
age, sex, ethnicity, MDD episodes, number of concurrent psychiatric comorbidities, length of illness, length of current episode, baseline depression severity, global functioning of the child and family, suicidal behaviors, and first-degree family history of depression were assessed in the regression model to test their predictability of remission status at the end of acute treatment. Of these variables, only positive family history of depression was a significant predictor of remission status at the end of acute treatment (p
values adjusted using the false discovery rate). The logistic regression revealed that, among the 168 participants, those with a positive first-degree family history of depression were 3.21 (95% CI 1.60–6.51) times more likely to remit than those without a family history of depression (χ2
= 10.92, p
Patterns of Response: Remitters Versus Nonremitters
The mixed linear model analysis of repeated measures revealed that the patterns of symptom improvement (percent reduction in CDRS-R total score) were significantly different for remitters and nonremitters (F = 116.34, p = .0001) over the 12 weeks of acute treatment (). In addition, a significant remission group × time interaction effect was found (F = 9.36, p = .0001).
Percent reduction in CDRS-R scores at each week for remitters versus nonremitters. CDRS-R = Children’s Depression Rating Scale-Revised.
Remitters had an overall higher percent symptom reduction (adjusted least squares mean 65.3%) than nonremitters (42.3%; p = .0001). In addition, percent symptom reduction scores were significantly different at each of the assessment weeks (p < .01) for remitters and nonremitters. As early as 1 week, remitters experienced greater symptom reduction (least squares mean 22.7%) than nonremitters (least squares mean 15.6%), p = .01, after adjustments for age group and family history of depression.
The mixed model analysis also revealed a significant omnibus main effect of age group (F = 13.17, p = .0004) while controlling for (or independent of) family history of depression and remission status. Adjusted least squares means for percent symptom reduction were higher for children than adolescents (56.85 versus 50.78). In other words, children had a higher mean percent reduction over the 12 weeks of treatment than adolescents regardless of family history of depression or remission status.
How Early Can We Identify Patients Who Will Achieve Remission?
The ROC analysis was used to assess how well the rate of symptom reduction during the early weeks of treatment identified remission status at the end of acute treatment. A subsample of 145 participants who had completed at least 8 weeks of acute treatment were included in the ROC analysis. presents the AUC and CIs for weeks 1, 2, 3, 4, 6, and 8. All AUCs were significant (z’s > 3.08, p’s < .0021), indicating that the rate of symptom reduction at each early week identified remission status (or discriminated remitters from nonremitters) at the end of acute treatment (when compared with the nominal AUC of 0.50). The changes in the AUCs from weeks 4 to 8 were rather small, and there was overlap in the CIs of the AUCs among weeks 4, 6, and 8. Pairwise comparisons of the AUCs, with p values adjusted via the false discovery rate, indicated that week 4 percent reduction was as good at discriminating remission status when compared with weeks 6 (p = .12) and 8 (p = .32), respectively. In other words, an additional 4 weeks of continuing on the same treatment (from week 4 to week 8) did not significantly increase the ability to discriminate remitters from nonremitters. The area under the ROC curve at week 4 was 0.788, which would be considered “good” at discriminating remitters from nonremitters.
Receiver Operating Characteristic Analysis: Area Under the Curve for Percent Reduction in CDRS-R Score at Each Week Relative to Remission Status at the End of Acute Treatment
What Percent of Symptom Improvement at Week 4 Provides the Best Combined Sensitivity and Specificity in Identifying Eventual Remission Status?
presents the combined sensitivity and specificity of CDRS-R percent reduction score at week 4 relative to remission status at week 12 or exit. The ROC analysis determined that, at week 4, a cutoff greater than 57.9% of reduction in the CDRS-R total score represented the best combined sensitivity (71.6%) and specificity (72.2%), and hence area under the ROC curve (0.72), with a PPV of 88.6% and NPV of 45.6% in identifying or discriminating patients who experienced remission status at week 12 or exit. That is, 71.6% of remitters had a greater than 57.9% of reduction in their CDRS-R score at week 4, whereas 72.2% of nonremitters had a 57.9% or lower of reduction. At week 4, the odds of achieving remission at the end of acute treatment was 6.54 (95% CI 2.90–15.76) times higher in patients with a CDRS-R percent reduction threshold of greater than 57.9% than those with a CDRS-R percent reduction threshold of 57.9% or lower (χ2 = 21.63, p < .0001). Using a lower percent reduction cutoff point (e.g., 30%), sensitivity is increased (95% for a 30% reduction); however, this leads to increased false positives.
Sensitivity and specificity associated with percent reduction in CDRS-R score at week 4 relative to remission status at week 12. CDRS-R = Children’s Depression Rating Scale-Revised.
To examine whether there were age-related differences on sensitivity and specificity, the ROC analysis was conducted separately for children (11 years or younger) and adolescents (older than 11 years). Although the cutoff scores for the best combined sensitivity and specificity were different for children and adolescents, week 4 percent reduction score was as good at discriminating remitters from nonremitters when compared with weeks 6 (p = .38) and 8 (p = .47) for children and with weeks 6 (p = .36) and 8 (p = .55) for adolescents. A slightly higher percent reduction score (>63.9%) for children than for adolescents (>55.2%) yielded the best combined sensitivity and specificity. For children (with a cutoff score higher than 63.9%), the sensitivity, specificity, PPV, and NPV were 70.2%, 72.7%, 93.0%, and 32.0%, respectively. For adolescents (with a cutoff score higher than 55.2%), the sensitivity, specificity, PPV, and NPV were 71.2%, 72.0%, 84.1%, and 54.5%, respectively. The odds of remitting at the end of acute treatment were 6.27 (95% CI 1.60–31.38) times higher in children with a CDRS-R percent reduction of greater than 63.9% at week 4 than in children with a CDRS-R percent reduction of 63.9% or lower (χ2 = 7.08, p = .007). For adolescents, the odds of achieving remission at the end of acute treatment was 5.24 (95% CI 1.92–15.40) times higher if their CDRS-R percent reduction score was higher than 55.2% at week 4 than if their CDRS-R percent reduction score was 55.2% or lower (χ2 = 10.71, p = .001).