Background: A large and extensive body of research has examined comorbid anxiety and depression in adults. Children and adolescents also frequently present with comorbid anxiety and depression; however, research and treatment require unique environmental and neurodevelopmental considerations in children. As a result, our understanding of comorbid anxiety and depression in children and adolescents is limited. Objective: The goal of this systematic review was to examine the current literature focused on comorbid anxiety and depression in children and adolescents. The review included theoretical conceptualizations as well as diagnostic, neurobiological, prevention, and treatment considerations. In addition, a proposed algorithm for the treatment of comorbid anxiety and depression in children/adolescents is provided. Methods: This systematic literature review included 3 discrete searches in Ovid SP Medline, PsycInfo, and PubMed. Results: The review included and synthesized 115 articles published between 1987 and 2015. The available evidence suggests that anxiety and depression are common in clinical populations of children and adolescents, and that comorbidity is likely underestimated in children and adolescents. Children and adolescents with comorbid anxiety and depression have unique presentations, greater symptom severity, and treatment resistance compared with those who have either disease in isolation. A dimensional approach may be necessary for the future development of diagnostic strategies and treatments for this population. Nascent neuroimaging work suggests that anxiety and depression each represents a distinct neurobiological phenotype. Conclusions: The literature that is currently available suggests that comorbid anxiety and depression is a common presentation in children and adolescents. This diagnostic picture underscores the importance of comprehensive dimensional assessments and multimodal evidence-based approaches given the high disease severity. Future research on the neurobiology and the treatment of these common clinical conditions is warranted.

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.