Treatment of Adolescents With Depression According to Symptom Clusters

young teen girl talking to therapist
young teen girl talking to therapist
When selecting the appropriate treatment modality for adolescents with depression, clinicians need to consider the clinical profile of each individual patient.

Distinct symptom clusters in adolescents with depression may be related to differential responses to treatment, namely pharmacotherapy or combined treatment with pharmacotherapy and cognitive behavioral therapy (CBT), according to results published in The Lancet Psychiatry. When selecting the appropriate treatment modality for adolescents with depression, clinicians need to consider the clinical profile of each individual patient.

As part of the randomized, placebo-controlled Treatment for Adolescents with Depression Study (TADS; identifier: NCT00006286), the investigators sought to evaluate whether specific clusters of symptoms in adolescent patients with depression responded differently to various types of treatment. A total of 439 adolescents ages 12 to 17 years from 13 academic and community clinics in the United States with a DSM-IV diagnosis of major depressive disorder and a minimum score of 45 on the Children’s Depression Rating Scale-Revised (CDRS-R) were randomly assigned in a 1:1:1:1 ratio to 1 of 4 treatments: (1) 10 to 40 mg/day fluoxetine; (2) CBT; (3) 10 to 40 mg/day fluoxetine plus CBT; or (4) placebo.

The secondary analysis focused on the acute phase of TADS, or the initial 12 weeks. In this analysis, groups of co-occurring symptoms were determined by clustering scores for each CDRS-R item at baseline. The symptoms were grouped into clusters according to similarity in baseline scores across the total sample. The primary outcome was CDRS-R score, which was measured at 6 weeks and at 12 weeks by a blinded evaluator. 

Overall, 54% (231 of 426 patients with complete data) of them were women, and the mean participant age was 14.6 years. Mean total corrected CDRS-R scores were similar across the 4 treatment groups at baseline.

There were 2 symptom clusters identified. Cluster 1 comprised depressed mood, difficulty having fun, irritability, social withdrawal, impaired schoolwork, excessive fatigue, sleep disturbance, and low self-esteem. In contrast, cluster 2 included increased appetite, physical complaints, excessive weeping, decreased appetite, excessive guilt, suicidal ideation, and morbid ideation. Additionally, there were significant interactions between symptom cluster and fluoxetine treatment, as well as the fluoxetine plus CBT treatment, in the mixed effects model (P <.0001 and P =.0008, respectively).

For cluster 1 symptoms, patients’ CDRS-R scores were decreased by 5.8 points (95% CI, 2.8 to 8.9) in those treated with fluoxetine plus CBT and by 4.1 points (95% CI, 1.1 to 7.1) in those treated with fluoxetine, as compared with placebo-treated adolescents. With respect to cluster 2 symptoms, there was no significant difference reported in improvements in CDRS-R scores between the active treatment and the placebo groups.

The investigators concluded that response to fluoxetine and CBT treatment among adolescents with depression is heterogeneous. They speculated that the contrast in response patterns between the 2 symptom clusters might offer opportunities for improving the efficacy of various treatments by focusing the development of new therapies on the resolution of specific symptoms.


Bondar J, Caye A, Chekroud AM, Kieling C. Symptom clusters in adolescent depression and differential response to treatment: a secondary analysis of the Treatment for Adolescents with Depression Study randomised trial. Lancet Psychiatry. 2020;7(4):337-343. doi: 10.1016/S2215-0366(20)30060-2.