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Greetings, I am David Rosenberg, representing the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will focus on the early and late emerging side effects of antidepressants in young people. We will discuss essential strategies for evaluating, monitoring, and managing these side effects. This is critical because antidepressants—especially selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)—are the primary pharmacotherapies for common neuropsychiatric disorders, such as depressive and anxiety disorders. Currently, our understanding of antidepressant-associated side effects and how to best identify, monitor, and manage them remains insufficient. Similarly, the discontinuation of antidepressants in children and adolescents lacks sufficient study, as most research has not reported whether these medications were immediately discontinued or tapered off. Unfortunately, the majority of clinical trials have not provided data on tapering or discontinuation side effects or rebound phenomena.
Strawn and colleagues have provided a comprehensive examination of the most common antidepressant-related side effects in children and adolescents. They also analyzed the largest SSRI trial in pediatric patients with anxiety disorder, the CAMS trial. This trial involved children and adolescents aged 7–17 who were randomized to receive sertraline plus cognitive–behavioral therapy (CBT), sertraline alone, CBT alone, or placebo. The authors provided guidance on how to manage side effects and strategies for discontinuing antidepressants.
The results showed that SSRIs and SNRIs are associated with early emerging—most often transient—and late emerging side effects in children and adolescents treated with these medications. Regrettably, clinical trials of antidepressants in young people typically do not report the timeline of side effects and adverse events. It is well-known that some side effects, such as activation, GI symptoms, and sedation, occur early and tend to resolve quickly. Therefore, discussing these potential transient side effects with patients and parents before initiating treatment is important. Other side effects that present later in treatment—particularly weight gain and sexual dysfunction—tend to persist. Thus, discussing these possible persistent and late emerging side effects is equally important.
A critical challenge lies in differentiating between the side effects of an antidepressant and the symptoms of depressive or anxiety disorders. Therefore, obtaining baseline functioning and symptomatology before starting medication is essential. For instance, sleep disturbances are a common side effect of antidepressants but also a hallmark symptom of depression and anxiety. By assessing these symptoms before initiating treatment, one can establish a baseline that can facilitate the delineation of side effects.
A promising area of research has found that many early emerging side effects, such as activation, and late emerging side effects, such as weight gain, are related to individual pharmacokinetic factors linked to cytochrome activity. This work is still ongoing but promises new insights that may guide clinicians in the future.
Early emerging side effects, such as GI symptoms, can be influenced by the underlying depression and/or anxiety and their severity. Fortunately, these symptoms typically improve with treatment—whether through antidepressant treatment, psychotherapy, or their combination.
Insomnia is another commonly reported side effect. Unfortunately, baseline rates of insomnia are not consistently reported in clinical trials. Like sleep disturbances, insomnia is associated with depression and anxiety, independent of antidepressant treatment. However, insomnia is often transient and can be managed with behavioral sleep hygiene and healthy sleep practices.
Low energy, fatigue, tiredness, and sedation can overlap with depressive and anxiety disorder symptoms. It seems that fluoxetine and fluvoxamine are associated with more side effects than placebo, which aligns with my experience with paroxetine.
Activation in SSRI-treated youth manifests as increased activity, irritability, disinhibition, and restlessness. Moreover, this can concern many people, mainly because we know that antidepressants can be associated with or trigger mania or hypomania. Activation typically occurs early in treatment or shortly after a dose increase of an antidepressant. Management includes educating the child and parents about its transient nature and potentially reducing the dose. Still, ensure the parents and adolescents know to call and let you know if this occurs. Typically, reducing the dose or using a more gradual upward dose escalation approach is best. Furthermore, in youth who experience activation at higher doses of SSRIs, decreasing the total daily dose or stopping the medication reduces activation.
Hyperhidrosis, or increased sweating, is a persistent or late emerging side effect of antidepressant use. This risk appears to be related to the affinity of the antidepressant for the dopamine receptor, so that it may be more common in second-generation antidepressants. This side effect is usually managed with low-dose glycopyrrolate, available in oral formulations and an orally dissolvable tablet. One advantage of glycopyrrolate is that, in contrast to other anticholinergic agents, glycopyrrolate is limited in its ability to cross the blood–brain barrier, so this can minimize CNS side effects. Topical agents, such as glycopyrronium tosylate, have also been used for children and adolescents with hyperhidrosis, and it is FDA approved for primary axillary hyperhidrosis in children older than 9 years.
Headaches are commonly reported in youth treated with antidepressants but are also prevalent in depressive and anxiety disorders. Interestingly, tricyclic antidepressants and 5-HT1B, 1D agonists have been used to treat headaches and for prophylaxis against getting a headache.
Antidepressant withdrawal syndrome in youth is not well-described. An area of interest is examining pharmacokinetic risk factors for discontinuation and withdrawal. Although more research is needed, it has been suggested that relapse risk may be highest in the first 3 months after discontinuing SSRIs, even those with long half-lives, such as fluoxetine.
Side effects and withdrawal effects in young people are also influenced by developmental pharmacology. Unfortunately, whereas side effects are listed in published clinical trials, their temporal stability, or lack thereof, has not been adequately addressed or reported. Therefore, future clinical trials should incorporate pharmacokinetic measures and proactively assess for early, late, and persistent medication side effects to properly delineate the stability of side effects, as well as the impact of discontinuation and tapering of the medication.
Abstract
Adverse Effects of Antidepressant Medications and their Management in Children and Adolescents
Jeffrey R Strawn, Jeffrey A Mills, Ethan A Poweleit, Laura B Ramsey, Paul E Croarkin
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.
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Reference
Strawn, J. R., Mills, J. A., Poweleit, E. A., Ramsey, L. B., & Croarkin, P. E. (2023).
Adverse Effects of Antidepressant Medications and their Management in Children and Adolescents
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Pharmacotherapy.
