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 serotonin-norepinephrine 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 = .0003), activation (RR 2.39, CrI 0.048-0.125, p = .003), sedation (RR 1.94, CrI 0.035-0.157, p = .002), insomnia (RR 1.93, CrI 0.040-0.149, p = .001), abdominal pain (RR 1.53, CrI 0.032-0.164, p = .005), and headache (RR 1.24, CrI 0.003-0.139, p = .04). Activation was more common with SSRIs (versus SNRIs, RR 1.32, CrI 0.018-0.114, p = .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.

Keywords: OCD; SNRI; SSRI; antidepressant; anxiety.

Figure 1.

Hierarchical dependencies for the data from trials of SSRIs and SNRIs in pediatric patients with OCD and anxiety disorders.

Figure 2.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.

Figure 3.. Relative Risk of Antidepressant-Related Adverse Events (AEs), Suicidality and Discontinuation Secondary to Adverse Events.

The relative risk of each AE is show in addition to the 95% credible interval. The large interval estimates for AE-related discontinuation and suicidality relate to the small number of occurrences relative to number of patients leading to a skewed distribution when converting the estimated relative probabilities to the log odds scale, rather than an indication of large potential chances of these outcomes.