The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis

Strawn, Jeffrey R.; Mills, Jeffrey A.; Sauley, Beau A.; Welge, Jeffrey A.

doi:10.1016/j.jaac.2018.01.015

Cited by 79 publications

(58 citation statements)

References 70 publications

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“…We performed the first meta‐analysis using longitudinal data from randomized placebo‐controlled trials (RCTs) of SSRIs/SNRIs for the treatment of anxiety in adults (Strawn, Mills, Sauley, & Welge, ). The goals of this meta‐analysis were to examine the efficacy of SSRIs and SNRIs for anxiety disorders examining (a) overall efficacy, (b) time course of treatment response, (c) individual pharmacological agent, (d) diagnostic indication, (e) dose, (f) tolerability, and (g) trial publication year.…”

Section: Introductionmentioning

confidence: 99%

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders

et al. 2018

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Background We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability. Methods We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo‐controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks. Results Meta‐analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects. Conclusions SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not.

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Section: Introductionmentioning

confidence: 99%

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders

et al. 2018

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“…The relationship between SSRI exposure and treatment response that have been observed in adolescents with treatment-resistant MDD ) and meta-analyses suggests that SSRI dose is related to the trajectory of response in pediatric patients with anxiety disorders (Strawn et al 2018). In addition, several lines of evidence suggest a relationship between SSRI dose (or plasma SSRI concentration) and side effects in pediatric patients.…”

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confidence: 99%

CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharmacokinetic Modeling Study

Poweleit

Ramsey

2019

Journal of Child and Adolescent Psychopharmacology

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Objective: Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs) that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth. Using pharmacokinetic (PK) models in adolescents, we sought to (1) model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under curve, AUC) and maximum concentration (C max ), (2) evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and C max , and (3) determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents. Methods: Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data for escitalopram and sertraline, we modeled exposure (AUC 0-24 ) and C max and determined CYP2C19-guided dosing strategies. Results: Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline, C max and AUC 0-24 were higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline. For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC 0-24 and C max similar to NMs receiving 150 mg/day, PMs require 100 mg/day, whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs. Conclusions: This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations could require dose adjustments in CYP2C19 poor metabolizers and UMs, although the magnitude of these differences were more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.

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“…The present findings suggest that while additional study is warranted, clinicians may consider SNRI treatment earlier in the treatment course of youth with treatment‐resistant MDD and predominant anxiety who have failed to respond to an initial SSRI trial. However, this finding contrasts with recent meta‐analyses and clinical trials of pediatric patients with primary anxiety disorders that suggest that SSRIs may be more beneficial compared to SNRIs (Dobson et al, 2019; Locher et al, 2017; Strawn et al, 2018). Whether this discrepancy is related to the sequence of treatment or to the differences in the pathophysiology of mixed anxiety and depression in adolescents (Wehry et al, 2014) compared to anxiety without co‐occurring depression remains to be determined.…”

Section: Discussionmentioning

confidence: 60%

“…Second, the standard random effects model requires asymptotic assumptions (i.e., assuming that the study sample is large enough to approximate the true population distribution) whereas contemporary approaches (e.g., Bayesian hierarchal modeling [BHM]) do not. Third, standard models of treatment effects over time that flexibly estimate the trajectory of improvement in clinical trials result in decreased precision relative to a model that specifies the functional form of improvement (Strawn, Mills, Sauley, & Welge, 2018; Varigonda et al, 2015). Leveraging a specific functional form (e.g., logarithmic trend) allows for greater degrees of freedom and more precise estimates treatment effects.…”

Section: Introductionmentioning

confidence: 99%

“…Third, we evaluated the robustness of heterogeneity assumptions employed in the original analyses of TORDIA on the detection of treatment response in adolescents with SSRI‐resistant MDD. We hypothesized—based on accumulating data that SSRIs are more efficacious than SNRIs—that switching to an SSRI would produce greater improvement (Dobson, Bloch, & Strawn, 2019; Locher et al, 2017; Strawn et al, 2018) in depressive symptoms compared to switching to venlafaxine.…”

Section: Introductionmentioning

confidence: 99%

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What next? A Bayesian hierarchical modeling re‐examination of treatments for adolescents with selective serotonin reuptake inhibitor‐resistant depression

Suresh

Mills

Croarkin

2020

Depression and Anxiety

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Background Psychiatrists frequently struggle with how to sequence treatment for depressed adolescents who do not respond to an adequate trial of a selective serotonin reuptake inhibitor (SSRI). This study leveraged recent statistical and computational advances to create Bayesian hierarchal models (BHMs) of response in the treatment of SSRI‐resistant depression in adolescents study to inform treatment planning. Methods BHMs of individual treatment trajectories were developed and estimated using Hamiltonian Monte Carlo no u‐turn sampling. From the Monte Carlo pseudorandom sample, 95% credible intervals, means, posterior tail probabilities, and so forth, were determined. Then, for the random effects model, posterior tail probabilities were used to create Bayesian two‐tailed p values to evaluate the null hypotheses: no difference in efficacy between SSRIs and venlafaxine. The robustness of the results was examined using the fixed effects model of treatment comparisons. Results In patients not receiving cognitive behavioral therapy (CBT; n = 168), SSRIs produced greater and faster improvement in depressive symptoms compared to venlafaxine (p = .015). No differences in response or trajectory of response for symptoms of anxiety were detected between SSRIs and venlafaxine (p = .168). For patients receiving CBT (n = 162), SSRIs and venlafaxine produced similar improvements in symptoms of anxiety and depression. Conclusions Findings from this novel computational approach suggest that a second trial of an SSRI is warranted for depressed adolescents who fail to respond to initial SSRI treatment.

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The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis

Abstract: In pediatric patients with generalized, separation, and/or social anxiety disorders, antidepressant-related improvement occurred early in the course of treatment, and SSRIs were associated with more rapid and greater improvement compared to SNRIs.

Cited by 79 publications

References 70 publications

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders

CYP2C19-Guided Escitalopram and Sertraline Dosing in Pediatric Patients: A Pharmacokinetic Modeling Study

What next? A Bayesian hierarchical modeling re‐examination of treatments for adolescents with selective serotonin reuptake inhibitor‐resistant depression

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