Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

BACKGROUND: How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. RESULTS: Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p < 0.001). By week 8, the response for benzodiazepines and SSRIs (p = 0.103) and SNRIs (p = 0.911) did not differ nor did SSRIs and SNRIs differ (p = 0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference - 12.42, CrI: -25.05 to -0.78, p = 0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4 weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. CONCLUSIONS: Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Gastrointestinal Symptoms in Pediatric Patients with Anxiety Disorders and Their Relationship to Selective Serotonin Reuptake Inhibitor Treatment or Placebo.

Gastrointestinal symptoms are commonly reported as adverse effects of selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacologic treatment for pediatric anxiety disorders; however, the temporal course of these symptoms during treatment, although believed to be transient, has never been prospectively evaluated. Additionally, rates of gastrointestinal symptoms and functional gastrointestinal syndromes in anxious youth are poorly understood. We examined gastrointestinal symptoms in youth with anxiety disorders during a double-blind, placebo-controlled trial of escitalopram (n = 51). Then, in a separate sample of prospectively treated children and adolescents with generalized, social and/or separation anxiety disorders (n = 56), we examined the frequency of gastrointestinal symptoms based on the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS) and ROME III criteria and the association of these symptoms with clinical and demographic characteristics using logistic regression. The frequency/severity of abdominal pain, diarrhea, bloating constipation or total gastrointestinal symptoms did not differ between patients receiving placebo (n = 25) or escitalopram (n = 26). However, escitalopram-treated youth had transient changes in nausea/vomiting and total upper gastrointestinal symptoms during the first two weeks of treatment. ROME III criteria for functional gastrointestinal syndromes were present in 12/56 patients (21.4%). QPGS-related functional gastrointestinal syndromes and symptoms were unrelated to treatment, treatment type, or clinical or demographic variables. Gastrointestinal symptoms are common in youth with anxiety and SSRIs produce transient-rather than sustained-gastrointestinal symptoms. Assessing gastrointestinal symptoms prior to pharmacotherapy and discussing factors that increase (or decrease) the likelihood of transient SSRI-related symptoms in youth may decrease patient uncertainty related to side effects and decrease medication-related anxiety.

What Is the Added Benefit of Combining Cognitive Behavioral Therapy and Selective Serotonin Reuptake Inhibitors in Youth with Obsessive Compulsive Disorder? A Bayesian Hierarchical Modeling Meta-Analysis.

Background: Treatment of obsessive-compulsive disorder (OCD) in children and adolescents frequently involves cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or their combination. However, how adding CBT to SSRIs affects the trajectory and magnitude of improvement has not been evaluated meta-analytically. Methods: We performed a meta-analysis using weekly data from prospective randomized parallel group trials of CBT and SSRIs in pediatric patients with OCD. Response was modeled for the change in the Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) using a Bayesian hierarchical model over 12 weeks. Results: Fourteen studies included pharmacotherapy arms, 4 studies included combined pharmacotherapy and psychotherapy, and 10 studies included a placebo or control arm. The studies included 1146 patients (mean age 12.7 ± 1.3 years, mean 42.1% female). In the logarithmic model of response, statistically significant differences in treatment effects for CBT+SSRI and SSRI monotherapy were observed compared with placebo (SSRI ß = -3.59, credible interval [95% CrI]: -4.13 to -3.02, p < 0.001; SSRI+CBT ß = -4.07, 95% CrI: -5.05 to -3.04, p < 0.001). Adding CBT to an SSRI produced numerically (but not statistically significantly) greater improvement over 12 weeks. Greater improvement was observed in studies with more boys (p < 0.001), younger patients (p < 0.001), and in studies with greater baseline symptom severity (p < 0.001). Conclusions: In children and adolescents with OCD, compared with placebo, both SSRIs and SSRI+CBT produced early and sustained improvement over 12 weeks, although the improvement was also related to sample characteristics. Longer term studies are needed to determine when the additive benefit of CBT emerges relative to SSRI monotherapy.

The impact of age on antidepressant response: A mega-analysis of individuals with major depressive disorder.

INTRODUCTION: Understanding how age affects antidepressant response in patients with major depressive disorder has been complicated by small and heterogeneous studies. Yet, understanding how age-across the lifespan-contributes to variation in response could inform treatment selection across the lifespan. This study sought to identify how age impacts antidepressant response using participant-level data from large, NIH-sponsored trials in individuals with MDD aged 12-74 years. MATERIALS AND METHODS: Participant-level data were abstracted from three NIH-sponsored trials of pharmacotherapy (Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study, Treatment of Adolescent Depression Study (TADS), and the Combining Medications to Enhance Depression Outcomes Study (COMED)) in patients with MDD. Bayesian Hierarchical Models (BHMs) of individual treatment trajectories were developed using Hamiltonian Monte Carlo No U-Turn Sampling. The individual trajectory of improvement in depressive symptoms (Clinical Global Impression-Severity [CGI-S] and CGI-S equivalent from COMED) was modeled across studies and across individuals with logarithmic trend "random effects" coefficients BHMs. Age and sex (and their interaction) were examined categorically across patients. RESULTS: Study participants (N = 907) were 29.7 ± 17 years of age, 66.3% women, and had a mean baseline CGI-S score of 4.6 ± 0.9. Patients ≤21 years and those >55 years had slower and less response to pharmacotherapy compared to those aged 21-35. Additionally, women improved more than men, and this effect did not differ across ages. DISCUSSION: The patient's age should be considered in predicting antidepressant response, particularly in older and younger individuals who may benefit from other interventions to enhance treatment response.

Applications of the Spectral Theory of Chemical Bonding to Simple Hydrocarbons.

The finite-basis, pair formulation of the Spectral Theory of chemical bonding is briefly surveyed. Solutions of the Born-Oppenheimer polyatomic Hamiltonian that are totally antisymmetric in electron exchange are obtained from diagonalization of an aggregate matrix built up from conventional diatomic solutions to atom-localized problems. A succession of transformations of the bases of the underlying matrices and the unique character of symmetric orthogonalization in producing the archived matrices calculated "once-of-all" in the pairwise-antisymmetrized basis are described. Application is made to molecules containing hydrogens and a single carbon atom. Results in conventional orbital bases are given and compared to experimental and high-level theoretical results. Chemical valence is shown to be respected and subtle angular effects in polyatomic contexts are reproduced. Means of reducing the size of the atomic-state basis and improving the fidelity of the diatomic descriptions for fixed basis size, so as to enable application to larger polyatomic molecules, are outlined along with future initiatives and prospects.

The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study.

While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms.

Adverse Effects of Antidepressant Medications and their Management in Children and Adolescents.

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.

Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis.

BACKGROUND: Despite frequent benzodiazepine use in anxiety disorders, the trajectory and magnitude of benzodiazepine response and the effects of benzodiazepine potency, lipophilicity, and dose on improvement are unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel group, placebo-controlled trials of benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in anxiety was evaluated as a function of medication, disorder, time, potency, lipophilicity, and standardized dose and compared among benzodiazepines. RESULTS: Data from 65 trials (73 arms, 7 medications, 7110 patients) were included. In the logarithmic model of response, treatment effects emerged within 1 week of beginning treatment (standardized benzodiazepine-placebo difference = -0.235 ± 0.024, CrI: -0.283 to -0.186, P < .001) and placebo response plateaued at week 4. Doses <6 mg per day (lorazepam equivalents) produced faster and larger improvement than higher doses (P = .039 for low vs medium dose and P = .005 for high vs medium dose) and less lipophilic benzodiazepines (beta = 0.028 ± 0.013, P = .030) produced a greater response over time. Relative to the reference benzodiazepine (lorazepam), clonazepam (beta = -0.217 ± 0.95, P = .021) had a greater trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam). CONCLUSIONS: In adults with anxiety disorders, benzodiazepine-related improvement emerges early, and the trajectory and magnitude of improvement is related to dose and lipophilicity. Lower doses and less lipophilic benzodiazepines produce greater improvement.

Initiation of Pharmacotherapy Following CBT in Anxious Youth: Results From the Child/Adolescent Anxiety Multimodal Study (CAMS).

Objective: To describe youth with anxiety disorders who initiate pharmacotherapy following cognitive-behavioral therapy (CBT) in a prospective, randomized trial and to identify predictors of the decision to use pharmacotherapy.Methods: Data from CBT-treated youth (aged 7-17 years, N = 139) in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multisite, randomized controlled trial that examined the efficacy of CBT, sertraline, their combination, and placebo for pediatric anxiety disorders (DSM-IV criteria), were evaluated. Initiation of pharmacotherapy following acute CBT treatment was examined over a 24-week period; the study was conducted from December 2002 through May 2007. Logistic regression models identified features associated with initiating pharmacotherapy, including symptom severity (scores on the Pediatric Anxiety Rating Scale [PARS] and the Screen for Child/Adolescent Anxiety Related Disorders [SCARED]), parent and child treatment expectations, Clinical Global Impressions-Improvement/Severity of Illness (CGI-I/S) scores, and clinical and demographic characteristics.Results: CBT non-remitters (CGI-S score > 2) who began pharmacotherapy (n = 10) and those who did not (n = 80) were similar in age (P = .445), sex (P = .324), race (P = .242), and symptom severity based on CGI-S (P = .753), PARS (P = .845), or SCARED (P = .678) scores. Mean ± SD improvement (CGI-I score) at week 12 did not differ between patients who initiated pharmacotherapy (3.00 ± 0.82) and those who did not (2.69 ± 0.89, P = .798). However, in the logistic regression, age (P = .003), race (P = .021), and parents' treatment expectation (P = .037) were significantly associated with the likelihood of initiating pharmacotherapy. Beginning pharmacotherapy in CBT non-remitters was associated with a significant improvement in CGI-S score (mean ± SD decline: -0.99 ± 0.46; 95% credible interval [CrI], -0.088 to -1.89; P = .035) from week 12 to week 36 compared to patients who did not begin pharmacotherapy.Discussion: Very few CBT non-remitters initiated pharmacotherapy, although beginning medication produced significant improvement. Younger and racial and ethnic minoritized patients as well as those with lower expectations for CBT were less likely to begin medication.Trial Registration: ClinicalTrials.gov identifier: NCT00052078.

A Characterization of the Clinical Global Impression Scale Thresholds in the Treatment of Adolescent Depression Across Multiple Rating Scales.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%-95% change in CDRS-R scores at 4-6 weeks across three datasets. CGI-I scores of 2 mapped to 56%-94% change in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 3 mapped to 30%-68% changes in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%-44% at 4-6 weeks across three studies. There was no significant difference (p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference (p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Executive Functioning in Pediatric Anxiety and Its Relationship to Selective Serotonin Reuptake Inhibitor Treatment Response: A Double-Blind, Placebo-Controlled Trial.

Objective: To characterize executive function in adolescents with generalized anxiety disorder (GAD) and its relationship to treatment. Methods: Using data from a double-blind, placebo-controlled trial of escitalopram in adolescents (N = 51) 12-17 years of age with GAD, we used the self-report version of the Behavior Rating Inventory of Executive Function (BRIEF-SR) to assess executive function, at baseline, and examined its relationship to treatment response as measured by the Pediatric Anxiety Rating Scale (PARS). Results: For all baseline subscores of the BRIEF-SR, T-scores were significantly elevated in adolescents with GAD compared to an age- and sex-matched normative healthy sample. In escitalopram-treated patients, baseline BRIEF-SR scores for Emotional Control (ß = 0.256, 95% credibility interval [CrI]: 0.367 to 0.146, p < 0.001), Working Memory (ß = 0.204, CrI: 0.2952 to 0.1134, p < 0.001), Planning/Organizing (ß = -0.223, CrI: -0.1021 to -0.3436, p = 0.004), and Task Completion (ß = -0.152, CrI: 0.075 to 0.228, p = 0.002) predicted the trajectory of improvement in PARS score over the 8-week trial. For youth who received placebo, only the Inhibit score was significantly, but weakly, associated with response trajectory (ß = -0.081, CrI: -0.0167 to -0.1461, p = 0.015). For adolescents who had clinically significant impairment in Emotional Control, Working Memory, Planning/Organizing, and Task Completion (i.e., T-score >65), the trajectory of improvement significantly differed from patients without scores in the clinically significant range. Conclusions: Taken together, these findings point to the potential value of assessing executive function in youth with anxiety disorders as one strategy for guiding treatment selection. These data suggest that executive function may predict treatment response to psychopharmacologic treatment and point to numerous avenues for further personalizing treatment.

Socioeconomic Predictors of Treatment Outcomes Among Adults With Major Depressive Disorder.

OBJECTIVE: In this study, the authors sought to examine the impact of socioeconomic variables on outcomes of pharmacotherapy treatments for major depressive disorder in analyses that controlled for treatment access and level of care. METHODS: The authors used data from the Combining Medications to Enhance Depression Outcomes study, a prospective clinical trial conducted from March 2008 to April 2014 with 665 adults who had major depressive disorder and were randomly assigned to three pharmacotherapeutic treatments, to develop Bayesian hierarchical models of treatment trajectories for change in Quick Inventory of Depressive Symptomatology-Self-Report ratings. Posterior tail probabilities were used to evaluate the effects of education, income, race-ethnicity, and employment on treatment outcomes. RESULTS: After sex, age, and treatment type were controlled for in the analyses, not having a college education (<16 years of schooling), being unemployed, or being non-White were each associated with slower and less improvement. At the end of treatment (week 12), not having a college degree reduced treatment responses by 9.6% (p=0.045), being unemployed by 6.6% (p=0.007), and being non-White by 11.3% (p<0.001). Treatment response was significantly related to income; having an income at the 25th percentile of the income distribution decreased improvement by 4.8% compared with having an income at the 75th percentile (p=0.018). CONCLUSIONS: Within a short-term, randomized controlled trial, socioeconomic factors had a critical role in the acute response of patients to pharmacotherapy for major depression.

Combining selective serotonin reuptake inhibitors and cognitive behavioral therapy in youth with depression and anxiety.

BACKGROUND: Treatment studies of children and adolescents with internalizing disorders suggest that the combination of a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy (CBT) consistently produces greater improvement than either treatment alone. We sought to determine how response to combined treatment varies across disorders (anxiety versus depression), and by specific patient characteristics. METHODS: Three large National Institutes of Health-funded trials of children and adolescents with major depression (n = 2) and anxiety disorders (n = 1) were evaluated, each comparing CBT + SSRI to SSRI only, Bayesian Hierarchical Models (BHMs) were used, for endpoint response, time course of response and predictors of response in participants who received SSRI or SSRI+CBT. RESULTS: SSRI+CBT significantly decreased symptoms by week 4 (p<0.001) across disorders. This improvement continued at week 8 and 12 (p<0.001); however, the additive benefit of CBT over SSRI monotherapy was not statistically significant until week 12 (p<0.001). The fastest response to SSRI+CBT was for patients who were younger, with milder baseline anxiety/depression symptoms and depressive disorders. The slowest response for SSRI+CBT was for boys, adolescents, minoritized children, those with severe symptoms and externalizing disorders. LIMITATIONS: Limitations included inconsistent moderators, variation in the number of observations over time and a lack of genetic or pharmacokinetic variables related to SSRI exposure across studies. CONCLUSIONS: The superiority of SSRI+CBT for youth with depression and anxiety is further supported. For purposes of rapid and greater relief, combination treatment is the superior approach across anxiety and depression and is robust to a range of participant characteristics. However, the added value of CBT (with an SSRI) occurs late in treatment. These findings represent a step towards understanding heterogeneity of treatment response and raise the possibility that interventions could be better tailored or adapted based on patient characteristics.

Acute neurofunctional effects of escitalopram during emotional processing in pediatric anxiety: a double-blind, placebo-controlled trial.

Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments-selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

Pharmacogenetically Guided Escitalopram Treatment for Pediatric Anxiety Disorders: Protocol for a Double-Blind Randomized Trial.

Current pharmacologic treatments for pediatric anxiety disorders (e.g., selective serotonin reuptake inhibitors (SSRIs)) frequently use "one size fits all" dosing strategies based on average responses in clinical trials. However, for some SSRIs, including escitalopram, variation in CYP2C19 activity produces substantial variation in medication exposure (i.e., blood medication concentrations). This raises an important question: would refining current SSRI dosing strategies based on CYP2C19 phenotypes increase response and reduce side effect burden? To answer this question, we designed a randomized, double-blind trial of adolescents 12-17 years of age with generalized, separation, and/or social anxiety disorders (N = 132). Patients are randomized (1:1) to standard escitalopram dosing or dosing based on validated CYP2C19 phenotypes for escitalopram metabolism. Using this approach, we will determine whether pharmacogenetically-guided treatment-compared to standard dosing-produces faster and greater reduction in anxiety symptoms (i.e., response) and improves tolerability (e.g., decreased risk of treatment-related activation and weight gain). Secondarily, we will examine pharmacodynamic variants associated with treatment outcomes, thus enhancing clinicians' ability to predict response and tolerability. Ultimately, developing a strategy to optimize dosing for individual patients could accelerate response while decreasing side effects-an immediate benefit to patients and their families. ClinicalTrials.gov Identifier: NCT04623099.

The Impact of Failed Antidepressant Trials on Outcomes in Children and Adolescents with Anxiety and Depression: A Systematic Review and Meta-Analysis.

Objective: To identify predictors of medication-placebo differences in double-blind placebo-controlled antidepressant trials in children and adolescents with anxiety and depression. Methods: Clinical trials in patients <18 years of age with major depressive disorder or generalized, separation or social anxiety disorders were obtained from PubMed, the Cochrane Database and clinicaltrials.gov searches from inception through 2019. Forty-nine trials (43 published and 6 unpublished) of anxiety (κ = 13) and depression (κ = 36) evaluated 19 antidepressants in 8642 child and adolescent patients; placebo and medication response rates, trial characteristics, disorder, medication class, and funding source were extracted. Antidepressant-placebo differences were examined using Bayesian hierarchical models and estimates of response were determined for trial design, disorder, and medication class variables. Using meta-regression, correlates of antidepressant-placebo difference and placebo response were examined. Results: Funding source differentiated medication-placebo differences regardless of disorder. Industry trials had larger placebo response rates (mean difference: 0.189 ± 0.066, credible interval [CrI]: 0.067 to 0.33, p = 0.0008) and smaller medication-placebo differences (-0.235 ± 0.078, CrI: -0.397 to -0.086, p = 0.005) compared with federally funded trials. However, medication response was similar for industry- and federally-funded studies (-0.046 ± 0.042, CrI: -0.130 to 0.038, p = 0.252). Conclusions: The impact of study sponsorship on trial outcome supports the assertion that industry-funded trials with high placebo response rates and small drug-placebo differences are "failed trials" and should not be described as "negative trials" or used to determine public health estimates of antidepressant efficacy in children and adolescents with anxiety and depression. Identifying the proper role and value of industry-funded trials is critical to establishing the evidence base for antidepressants in youth.

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

OBJECTIVE: Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD). METHOD: Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed. RESULTS: Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p < .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p < .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment. CONCLUSION: In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development. CLINICAL TRIAL REGISTRATION INFORMATION: Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.