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2.
Artigo em Inglês | MEDLINE | ID: mdl-33548492

RESUMO

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.

3.
J Clin Psychiatry ; 81(5)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32857933

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Citalopram/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Área Sob a Curva , Criança , Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacocinética , Resultado do Tratamento
4.
J Child Adolesc Psychopharmacol ; 30(10): 606-616, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32721213

RESUMO

Objectives: Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12-17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results: Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion: Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by "variable" dynamic but "weak" static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.

5.
Depress Anxiety ; 37(9): 926-934, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579280

RESUMO

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.

6.
J Am Acad Child Adolesc Psychiatry ; 59(11): 1240-1251, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31682918

RESUMO

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.

7.
J Child Adolesc Psychopharmacol ; 29(4): 250-255, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30810350

RESUMO

Objective: To guide clinicians in selecting the "next line" selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine (p = 0.247) or for fluoxetine compared with paroxetine (p = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p = 0.055). For efficacy-tolerability models, citalopram and fluoxetine were superior to paroxetine (p = 0.029 and p = 0.022, respectively) but did not differ between each other (p = 0.146). Conclusions: Joint efficacy-tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Fluoxetina/efeitos adversos , Fluoxetina/uso terapêutico , Humanos , Método de Monte Carlo , Paroxetina/efeitos adversos , Paroxetina/uso terapêutico , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento
8.
J Am Acad Child Adolesc Psychiatry ; 57(4): 235-244.e2, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29588049

RESUMO

OBJECTIVE: To determine the trajectory and magnitude of antidepressant response as well as the effect of antidepressant class and dose on symptomatic improvement in pediatric anxiety disorders. METHOD: Weekly symptom severity data were extracted from randomized, parallel group, placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) in pediatric anxiety disorders. Treatment response was modeled for the standardized change in continuous measures of anxiety using Bayesian updating. Posterior distributions for each study served as informative conjugate prior to distributions update subsequent study posteriors. Change in symptom severity was evaluated as a function of time, class and, for SSRIs, standardized dose. RESULTS: Data from 9 trials (SSRIs: n = 5; SNRIs, n = 4) evaluating 7 medications in 1,673 youth were included. In the logarithmic model of treatment response, statistically, but not clinically, significant treatment effects emerged within 2 weeks of beginning treatment (standardized medication-placebo difference = -0.054, credible interval [CI] = -0.076 to -0.032, p = .005, approximate Cohen's d ≤ 0.2) and by week 6, clinically significant differences emerged (standardized medication-placebo difference = -0.120, CI = -0.142 to -0.097, p = .001, approximate Cohen's d = 0.44). Compared to SNRIs, SSRIs resulted in significantly greater improvement by the second week of treatment (p = .0268), and this advantage remained statistically significant through week 12 (all p values <.03). Improvement occurred earlier with high-dose SSRI treatment (week 2, p = .002) compared to low-dose treatment (week 10, p = .025), but SSRI dose did not have an impact on overall response trajectory (p > .18 for weeks 1-12). CONCLUSIONS: 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.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Adolescente , Humanos , Inibidores de Captação de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia
9.
Brain Behav Immun ; 67: 36-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28736033

RESUMO

BACKGROUND: While disruption of acid-base homeostasis has been pathoetiologically implicated in panic disorder (PD), the mechanism by which pH imbalance is translated to panic pathophysiology is poorly understood. Recently, in a translational rodent model of PD, we reported a role of microglial acid sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) in panic-associated behavior and physiology. However, the clinical validity of the TDAG8 receptor has not been investigated. OBJECTIVE: To assess TDAG8 in PD, we evaluated TDAG8 receptor expression in adolescents and young adults with PD and healthy comparison subjects. METHODS: Relative expression of TDAG8 mRNA was determined in peripheral blood mononuclear cells from patients with PD, and compared to expression in healthy subjects. Linear models were utilized to evaluate the relationship between TDAG8 expression and panic disorder symptom severity scale (PDSS) score as well as other potential explanatory variables (e.g., CRP, body mass index, sex, age). Models were refined based on the estimated parameter significance, evidence of omitted variable bias and Bayesian/Akaike information criteria. RESULTS: Relative to healthy comparison subjects (n=17), expression of TDAG8 mRNA was significantly increased in patients with PD (n=15) (1.60±0.65 vs. 1.01±0.50, p=0.008). TDAG8 mRNA expression predicted PD symptom severity in a fixed effect model incorporating age and sex (p=0.003). CONCLUSIONS: Collectively, our results suggest greater TDAG8 expression in patients with PD compared to healthy subjects, and directly link TDAG8 expression and the severity of the PD symptoms. Further investigation of the TDAG8 receptor in panic pathophysiology is warranted.


Assuntos
Transtorno de Pânico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Projetos Piloto , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
10.
J Child Adolesc Psychopharmacol ; 28(1): 2-9, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28846022

RESUMO

OBJECTIVES: An increasing number of abandoned clinical trials have forestalled efforts to advance the evidence base for the treatment of mood and anxiety disorders in children and adolescents. With this in mind, we sought to present and validate a Bayesian approach for the reanalysis of summary data in abandoned clinical trials and to review and re-evaluate available pharmacokinetic, tolerability, and efficacy data from two large, randomized controlled trials of buspirone in pediatric patients with generalized anxiety disorder (GAD). METHODS: Prospective, randomized, parallel-group controlled trials of buspirone in pediatric patients with GAD as well as associated pharmacokinetic studies were identified and data were extracted. In addition to descriptive statistics, marginal posterior densities for each variable of interest were determined and a Monte Carlo pseudosample was generated with random draws obtained from the Student's t-distribution to assess, with inferential statistics, differences in variables of interest. RESULTS: Buspirone was evaluated in one flexibly dosed (N = 227) and one fixed-dose (N = 341) trial in children and adolescents aged 6-17 years with a primary diagnosis of GAD. With regard to improvement in the sum of the Columbia Schedule for Affective Disorders and Schizophrenia GAD items, buspirone did not separate from placebo in the fixed-dose trial at low (95% CI: -0.78 to 2.39, p = 0.32) or high dose (95% CI: -0.87 to 1.87, p = 0.47) nor did it separate from placebo in the flexibly dosed study (95% CI: -0.3 to 1.9, p = 0.15). Drop out as a result of a treatment-emergent adverse event was significantly greater in buspirone-treated patients compared to placebo (p = 0.011). Side effects were consistent with the known profile of buspirone with lightheadedness occurring more frequently in buspirone-treated patients (p < 0.001). CONCLUSIONS: Buspirone is well tolerated in pediatric patients with GAD, although two randomized controlled trials were underpowered to detect small effect sizes (Cohen's d < 0.15). Finally, Bayesian approaches may facilitate re-examination of data from abandoned clinical trials.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Buspirona/uso terapêutico , Adolescente , Ansiolíticos/efeitos adversos , Teorema de Bayes , Buspirona/efeitos adversos , Criança , Humanos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
11.
J Child Adolesc Psychopharmacol ; 27(6): 501-508, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28384010

RESUMO

OBJECTIVES: The aim of this study is to identify predictors of pill placebo response and to characterize the temporal course of pill placebo response in anxious youth. METHODS: Data from placebo-treated patients (N = 76) in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multisite, randomized controlled trial that examined the efficacy of cognitive-behavioral therapy, sertraline, their combination, and placebo for the treatment of separation, generalized, and social anxiety disorders, were evaluated. Multiple linear regression models identified features associated with placebo response and models were confirmed with leave-one-out cross-validation. The likelihood of improvement in patients receiving pill placebo-over time-relative to improvement associated with active treatment was determined using probabilistic Bayesian analyses. RESULTS: Based on a categorical definition of response (Clinical Global Impressions-Improvement Scale score ≤2), nonresponders (n = 48), and pill placebo responders (n = 18) did not differ in age (p = 0.217), sex (p = 0.980), race (p = 0.743), or primary diagnosis (all ps > 0.659). In terms of change in anxiety symptoms, separation anxiety disorder and treatment expectation were associated with the degree of pill placebo response. Greater probability of placebo-related anxiety symptom improvement was observed early in the course of treatment (baseline to week 4, p < 0.0001). No significant change in the probability of placebo-related improvement was observed after week 4 (weeks 4-8, p = 0.07; weeks 8-12, p = 0.85), whereas the probability of improvement, in general, significantly increased week over week with active treatment. CONCLUSIONS: Pill placebo-related improvement occurs early in the course of treatment and both clinical factors and expectation predict this improvement. Additionally, probabilistic approaches may refine our understanding and prediction of pill placebo response.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Efeito Placebo , Adolescente , Teorema de Bayes , Criança , Terapia Cognitivo-Comportamental , Terapia Combinada , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/uso terapêutico
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