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Artigo em Inglês | MEDLINE | ID: mdl-33548492


OBJECTIVE: Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs), impact this circuitry is unknown. We examined the impact of SSRI on functional connectivity (FC) within this circuit, and whether early FC changes predict treatment response in adolescents with generalized anxiety disorder (GAD). METHOD: Resting-state functional MR images were acquired before and after 2-weeks of treatment in 41 adolescents with GAD (age: 12-17) who received double-blind escitalopram or placebo over 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=0.002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p<0.001) but not placebo (p=0.169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p=0.013). Further, this FC change predicted improvement better than baseline FC or demographics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA)-VLPFC (F=19.64, p<0.001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F=22.92, p=0.001 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 increases amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicts 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.

J Affect Disord ; 280(Pt A): 305-314, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33221716


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.

Hum Brain Mapp ; 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32596977


The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Brain Behav Immun ; 67: 36-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28736033


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.

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
Ann Clin Psychiatry ; 29(4): 227-234A, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29069107


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.

Transtornos de Ansiedade/diagnóstico , Escalas de Graduação Psiquiátrica , Autorrelato , Adolescente , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes
Artigo em Inglês | MEDLINE | ID: mdl-28057447


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.

Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Atitude do Pessoal de Saúde , Transtorno Depressivo/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Competência Clínica , Tomada de Decisão Clínica , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Feminino , Pesquisa sobre Serviços de Saúde/métodos , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pediatras/psicologia , Projetos Piloto , Estados Unidos