Mills, Jeffrey A.

Abstract Introduction Selective serotonin reuptake inhibitors (SSRIs) and, to a lesser extent, serotonin‐norepinephrine reuptake inhibitors (SNRIs) are the cornerstone of pharmacotherapy for children and adolescents with anxiety and depressive disorders. These medications alleviate symptoms and restore function for many youths; however, they are associated with a distinct adverse effect profile, and their tolerability may complicate treatment or lead to discontinuation. Yet, SSRI/SNRI tolerability has received limited attention in the pediatric literature. Methods This review examines the early‐ (e.g., activation, gastrointestinal symptoms, sedation) and late‐emerging (e.g., weight gain) adverse effects of SSRIs and some SNRIs in pediatric patients. Results We provide a framework for discussing SSRI/SNRI tolerability with patients and their families and describe the pharmacologic basis, course, and predictors of adverse events in youth. Strategies to address specific tolerability concerns are presented. For selected adverse events, using posterior simulation of mean differences over time, we describe their course based on Physical Symptom Checklist measures in a prospective, randomized trial of anxious youth aged 7–17 years who were treated with sertraline ( n = 139) or placebo ( n = 76) for 12 weeks in the Child/Adolescent Anxiety Multimodal Study (CAMS). Main Results In CAMS, the relative severity/burden of total physical symptoms ( p < 0.001), insomnia ( p = 0.001), restlessness ( p < 0.001), nausea ( p = 0.002), abdominal pain ( p < 0.001), and dry mouth ( p = 0.024) decreased from baseline over 12 weeks of sertraline treatment, raising the possibility that these symptoms are transient. No significant changes were observed for sweating ( p = 0.103), constipation ( p = 0.241), or diarrhea ( p = 0.489). Finally, we review the antidepressant withdrawal syndrome in children and adolescents and provide guidance for SSRI discontinuation, using pediatric pharmacokinetic models of escitalopram and sertraline—two of the most used SSRIs in youth. Conclusion SSRI/SNRIs are associated with both early‐emerging (often transient) and late‐emerging adverse effects in youth. Pharmacokinetically‐informed appraoches may address some adverse effects and inform SSRI/SNRI discontinuation strategies.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%–95% change in CDRS-R scores at 4–6 weeks across three datasets. CGI-I scores of 2 mapped to 56%–94% change in CDRS-R scores at 4–6 weeks across three studies. CGI-I scores of 3 mapped to 30%–68% changes in CDRS-R scores at 4–6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%–44% at 4–6 weeks across three studies. There was no significant difference ( p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference ( p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Objective: To guide clinicians in selecting the “next line” selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine ( p = 0.247) or for fluoxetine compared with paroxetine ( p = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p = 0.055). For efficacy–tolerability models, citalopram and fluoxetine were superior to paroxetine ( p = 0.029 and p = 0.022, respectively) but did not differ between each other ( p = 0.146). Conclusions: Joint efficacy–tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.