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Summary Background Better understanding of the heterogeneity of treatment responses could help to improve care for adolescents with depression. We analysed data from a clinical trial to assess whether specific symptom clusters responded differently to various treatments. Methods For this secondary analysis, we used data from the Treatment for Adolescents with Depression Study (TADS), in which 439 US adolescents aged 12–17 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 (1:1:1:1) to treatment with fluoxetine, cognitive behavioural therapy (CBT), fluoxetine plus CBT, or pill placebo. Our analysis focuses on the acute phase of the trial (ie, the first 12 weeks). Groups of co-occurring symptoms were established by clustering scores for each CDRS-R item at baseline with Ward's method, with Euclidean distances for hierarchical agglomerative clustering. We then used a linear mixed-effects model to investigate the relationship between symptom clusters and treatment efficacy, with the sum of symptom scores within each cluster as the dependent measure. As fixed effects, we entered cluster, time, and treatment assignment, with all two-way and three-way interactions, into the model. The random effect providing better fit was established to be a by-subject random slope for cluster based on improvement in the Schwarz-Bayesian information criterion. Outcomes We identified two symptom clusters: cluster 1 comprised depressed mood, difficulty having fun, irritability, social withdrawal, sleep disturbance, impaired schoolwork, excessive fatigue, and low self-esteem, and cluster 2 comprised increased appetite, physical complaints, excessive weeping, decreased appetite, excessive guilt, morbid ideation, and suicidal ideation. For cluster 1 symptoms, CDRS-R scores were reduced by 5·8 points (95% CI 2·8–8·9) in adolescents treated with fluoxetine plus CBT, and by 4·1 points (1·1–7·1) in those treated with fluoxetine, compared with those given placebo. For cluster 2 symptoms, no significant differences in improvements in CDRS-R scores were detected between the active treatment and placebo groups. Interpretation Response to fluoxetine and CBT among adolescents with depression is heterogeneous. Clinicians should consider clinical profile when selecting therapeutic modality. The contrast in response patterns between symptom clusters could provide opportunities to improve treatment efficacy by gearing the development of new therapies towards the resolution of specific symptoms. Funding Conselho Nacional de Desenvolvimento Cientifico e Tecnologico.

Investment in workplace wellness programs is increasing despite concerns about lack of clinical benefit and return on investment (ROI). In contrast, outcomes from workplace mental health programs, which treat mental health difficulties more directly, remain mostly unknown.To determine whether participation in an employer-sponsored mental health benefit was associated with improvements in depression and anxiety, workplace productivity, and ROI as well as to examine factors associated with clinical improvement.This cohort study included participants in a US workplace mental health program implemented by 66 employers across 40 states from January 1, 2018, to January 1, 2021. Participants were employees who enrolled in the mental health benefit program and had at least moderate anxiety or depression, at least 1 appointment, and at least 2 outcome assessments.A digital platform that screened individuals for common mental health conditions and provided access to self-guided digital content, care navigation, and video and in-person psychotherapy and/or medication management.Primary outcomes were the Patient Health Questionnaire-9 for depression (range, 0-27) score and the Generalized Anxiety Disorder 7-item scale (range, 0-21) score. The ROI was calculated by comparing the cost of treatment to salary costs for time out of the workplace due to mental health symptoms, measured with the Sheehan Disability Scale. Data were collected through 6 months of follow-up and analyzed using mixed-effects regression.A total of 1132 participants (520 of 724 who reported gender [71.8%] were female; mean [SD] age, 32.9 [8.8] years) were included. Participants reported improvements from pretreatment to posttreatment in depression (b = -6.34; 95% CI, -6.76 to -5.91; Cohen d = -1.11; 95% CI, -1.18 to -1.03) and anxiety (b = -6.28; 95% CI, -6.77 to -5.91; Cohen d = -1.21; 95% CI, -1.30 to -1.13). Symptom change per log-day of treatment was similar post-COVID-19 vs pre-COVID-19 for depression (b = 0.14; 95% CI, -0.10 to 0.38) and anxiety (b = 0.08; 95% CI, -0.22 to 0.38). Workplace salary savings at 6 months at the federal median wage was US $3440 (95% CI, $2730-$4151) with positive ROI across all wage groups.Results of this cohort study suggest that an employer-sponsored workplace mental health program was associated with large clinical effect sizes for employees and positive financial ROI for employers.