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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.
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Trastorno de Pánico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adolescente , Adulto , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Masculino , Proyectos Piloto , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: In pediatric patients with anxiety disorders, existing symptom inventories are either not freely available or require extensive time and effort to administer. We sought to evaluate a brief self-report scale-the Generalized Anxiety Disorder 7-item scale (GAD-7)-in adolescents with generalized anxiety disorder (GAD). METHODS: The Pediatric Anxiety Rating Scale (PARS) and the GAD-7 were administered to youth with GAD (confirmed by structured interview). Relationships between the measures were assessed, and sensitivity and specificity was determined with regard to a global symptom severity measure (Clinical Global Impression-Severity). RESULTS: In adolescents with GAD (N = 40; mean age, 14.8 ± 2.8), PARS and GAD-7 scores strongly correlated (R = 0.65, P ≤ .001) and a main effect for symptom severity was observed (P ≤ .001). GAD-7 scores ≥11 and ≥17 represented the optimum specificity and sensitivity for detecting moderate and severe anxiety, respectively. CONCLUSIONS: The PARS and GAD-7 similarly reflect symptom severity. The GAD-7 is associated with acceptable specificity and sensitivity for detecting clinically significant anxiety symptoms. GAD-7 scores may be used to assess anxiety symptoms and to differentiate between mild and moderate GAD in adolescents, and may be more efficient than the PARS.
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Trastornos de Ansiedad/diagnóstico , Escalas de Valoración Psiquiátrica , Autoinforme , Adolescente , Femenino , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The phenomenology and neurobiology of depressive symptoms in anxious youth is poorly understood. METHODS: Association networks of anxiety and depressive symptoms were developed in adolescents with generalized anxiety disorder (GAD; N=52, mean age: 15.4±1.6 years) who had not yet developed major depressive disorder. Community analyses were used to create consensus clusters of depressive and anxiety symptoms and to identify "bridge" symptoms between the clusters. In a subset of this sample (n=39), correlations between cortical thickness and depressive symptom severity was examined. RESULTS: Ten symptoms clustered into an anxious community, 5 clustered into a depressive community and 5 bridged the two communities: impaired schoolwork, excessive weeping, low self-esteem, disturbed appetite, and physical symptoms of depression. Patients with more depressive cluster burden had altered cortical thickness in prefrontal, inferior and medial parietal (e.g., precuneus, supramarginal) regions and had decreases in cortical thickness-age relationships in prefrontal, temporal and parietal cortices. LIMITATIONS: Data are cross-sectional and observational. Limited sample size precluded secondary analysis of comorbidities and demographics. CONCLUSIONS: In youth with GAD, a sub-set of symptoms not directly related to anxiety bridge anxiety and depression. Youth with greater depressive cluster burden had altered cortical thickness in cortical structures within the default mode and central executive networks. These alternations in cortical thickness may represent a distinct neurostructural fingerprint in anxious youth with early depressive symptoms. Finally, youth with GAD and high depressive symptoms had reduced age-cortical thickness correlations. The emergence of depressive symptoms in early GAD and cortical development may have bidirectional, neurobiological relationships.
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Trastorno Depresivo Mayor , Adolescente , Ansiedad , Trastornos de Ansiedad/epidemiología , Estudios Transversales , Depresión/epidemiología , HumanosRESUMEN
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.
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Trastornos de Ansiedad , Citalopram , Adolescente , Amígdala del Cerebelo , Ansiedad , Trastornos de Ansiedad/tratamiento farmacológico , Niño , Citalopram/farmacología , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
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.
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Amígdala del Cerebelo/fisiopatología , Trastornos de Ansiedad , Giro del Cíngulo/fisiopatología , Efecto Placebo , Corteza Prefrontal/fisiopatología , Adolescente , Trastornos de Ansiedad/diagnóstico por imagen , Trastornos de Ansiedad/fisiopatología , Encéfalo/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Lóbulo ParietalRESUMEN
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.
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Ansiolíticos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Citalopram/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Adolescente , Área Bajo la Curva , Niño , Citalopram/análogos & derivados , Citalopram/sangre , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Método Doble Ciego , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Resultado del TratamientoRESUMEN
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.
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Ansiolíticos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Buspirona/uso terapéutico , Adolescente , Ansiolíticos/efectos adversos , Teorema de Bayes , Buspirona/efectos adversos , Niño , Humanos , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricosRESUMEN
Among pediatricians, perceived knowledge of efficacy, tolerability, dosing, and side effects of antidepressants represent significant sources of variability in the use of these medications in youth with depressive and anxiety disorders. Importantly, the qualitative factors that relate to varying levels of comfort with antidepressants and willingness to prescribe are poorly understood. Using a mixed-methods approach, in-depth interviews were conducted with community-based and academic medical center-based pediatricians (N = 14). Interviews were audio recorded and iteratively coded; themes were then generated using inductive thematic analysis. The relationship between demographic factors, knowledge of antidepressants, dosing, and side effects, as well as prescribing likelihood scores for depressive disorders, anxiety disorders or co-morbid anxiety and depressive disorders, were evaluated using mixed models. Pediatricians reported antidepressants to be effective and well-tolerated. However, the likelihood of individual physicians initiating an antidepressant was significantly lower for anxiety disorders relative to depressive disorders with similar functional impairment. Pediatricians considered symptom severity/functional impairment, age and the availability of psychotherapy as they considered prescribing antidepressants to individual patients. Antidepressant choice was related to the physician׳s perceived knowledge and comfort with a particular antidepressant, financial factors, and the disorder-specific evidence base for that particular medication and consultation with mental health practitioners. Pediatricians noted similar efficacy and tolerability profiles for antidepressants in youth with depressive disorders and anxiety disorders, but tended to utilize "therapy first" approaches for anxiety disorders relative to depressive disorders. Parental and family factors that influenced prescribing of antidepressants by pediatricians included parental ambivalence, family-related dysfunction and impairment secondary to the child׳s psychopathology as well as the child׳s psychosocial milieu. Pediatricians consider patient- and family-specific challenges when choosing prescribing antidepressant medications and are, in general, less likely to prescribe antidepressants for youth with anxiety disorders compared to youth with depressive disorders. The lower likelihood of prescribing antidepressants for anxious youth is not related to perception of the efficacy or tolerability, but rather to a perception that anxiety disorders are less impairing and more appropriately managed with psychotherapy.