Antidepressant Tolerability in Pediatric Anxiety and Obsessive-Compulsive Disorders: A Bayesian Hierarchical Modeling Meta-analysis

Abstract

Objective: To compare adverse events (AEs), suicidality, and AE-related discontinuation in double-blind, placebo-controlled trials of pediatric patients with obsessive-compulsive disorder (OCD) and anxiety disorders treated with selective serotonin reuptake inhibitors (SSRIs) or serotoninnorepinephrine reuptake inhibitors (SNRIs). Method: MEDLINE, PubMed, Web of Science, PsycINFO, and Embase were searched for peer-reviewed, English-language articles from inception through March 1, 2019. We identified prospective, randomized SSRI and SNRI studies in patients <18 years of age with OCD or generalized, separation, or social anxiety disorders. AE rates were extracted and medication-placebo differences were examined using Bayesian hierarchical models, then posterior estimates of relative risk (RR) were determined for each AE by medication class and disorder. Results: Data were included from 18 trials (2,631 patients) and 7 medications (16 SSRI and 4 SNRI trials). Compared with placebo, SSRIs were associated with a greater likelihood of AE-related discontinuation (RR 3.59, credible interval [CrI] 0.019-0.067, p ¼ .0003), activation (RR 2.39, CrI 0.048-0.125, p ¼ .003), sedation (RR 1.94, CrI 0.035-0.157, p ¼ .002), insomnia (RR 1.93, CrI 0.040-0.149, p ¼ .001), abdominal pain (RR 1.53, CrI 0.032-0.164, p ¼ .005), and headache (RR 1.24, CrI 0.003-0.139, p ¼ .04). Activation was more common with SSRIs (versus SNRIs, RR 1.32, CrI 0.018-0.114, p ¼ .007). Neither SSRIs nor SNRIs were associated with treatment-emergent suicidality. Conclusion: In pediatric OCD and anxiety disorders, SSRIs (compared with placebo) are associated with distinct AEs and greater AE-related discontinuation, although their tolerability does not differ between anxiety disorders and OCD. Compared with SNRIs, SSRIs are more likely to produce activation. Class-related AEs are important for clinicians to consider, particularly in light of data suggesting differences in class-related efficacy. Whereas SSRIs are superior to SNRIs and the treatment of choice for anxiety, for youths who become activated on SSRIs, SNRIs might represent a good second choice given their reported efficacy and lower risk of activation.

Research Review: Pediatric anxiety disorders – what have we learnt in the last 10 years?

“…Based on recent meta‐analyses, selective serotonin reuptake inhibitors (SSRIs) are superior to other medication classes in pediatric anxiety disorders (Locher et al, 2017; Strawn, Mills, Sauley, & Welge, 2018), but patients are more likely to discontinue SSRIs because of adverse events compared with SNRIs (Mills and Strawn, 2020). Also, SSRIs are more likely to produce activation in children and adolescents with anxiety disorders compared with SNRIs (Mills and Strawn, 2020).…”

“…Based on recent meta‐analyses, selective serotonin reuptake inhibitors (SSRIs) are superior to other medication classes in pediatric anxiety disorders (Locher et al, 2017; Strawn, Mills, Sauley, & Welge, 2018), but patients are more likely to discontinue SSRIs because of adverse events compared with SNRIs (Mills and Strawn, 2020). Also, SSRIs are more likely to produce activation in children and adolescents with anxiety disorders compared with SNRIs (Mills and Strawn, 2020). Consistent with guidelines from the American Academy of Child & Adolescent Psychiatry that recommend SSRIs and SNRIs (Connolly & Bernstein, 2007), SSRIs are the most commonly prescribed initial medications for children and adolescents with anxiety disorders in the United States, and approximately half of these youth continue treatment for at least 6 months (Bushnell et al, 2018).…”

“…Activation was more common with SSRIs (vs. SNRIs, RR: 1.32, p = .007). Neither SSRIs nor SNRIs were associated with treatment‐emergent suicidality (Mills and Strawn, 2020). Among SSRIs, a meta‐analysis found differences in suicidality, with sertraline potentially having less treatment‐emergent suicidality, while six treatments including paroxetine had higher suicidality compared with placebo (Dobson, Bloch, & Strawn, 2019).…”

“…Activation was more common with SSRIs (vs. SNRIs, RR: 1.32, p = .007). Neither SSRIs nor SNRIs were associated with treatment-emergent suicidality (Mills and Strawn, 2020). Among SSRIs, a metaanalysis found differences in suicidality, with sertraline potentially having less treatment-emergent Beidel et al (2007) SoAD 122 SET-C > fluoxetine > placebo Walkup et al (2008) Mixed anxiety disorders 488 CBT = sertraline > placebo CBT + sertraline > sertraline/ CBT CBT + sertraline > placebo Birmaher et al (2003) Mixed anxiety disorders 74 Fluoxetine > placebo Abbreviations: ADHD, attention deficit hyperactive disorder; CBT, cognitive behavioral therapy; CGI-I, Clinical Global Impression-Improvement; CGI-S, Clinical Global Impression-Severity Scale; GAD, generalized anxiety disorder; PARS, pediatric anxiety rating scale; SET-C, Social Effectiveness Therapy for Children; SoAD, social anxiety disorder.…”

Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind, Placebo-Controlled Trial

“…53 Finally, it is possible that these early FC changes relate to tolerability, including "activation," a common side effect of SSRIs in youth with anxiety and affective disorders. 54,55 Importantly, activation-which consists of transient increases in anxiety, restlessness, and insomnia and emerges early in the course of treatment-is related to plasma SSRI concentrations and may relate to effects of SSRIs on amygdalaÀprefrontal circuits. 27,54 Although this is the first investigation of the acute effect of escitalopram on FC in adolescents, several limitations warrant discussion.…”