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Cognitive models state that social anxiety (SA) involves biased cognitive processing that impacts what is learned and remembered within social situations, leading to the maintenance of SA. Neuroscience work links SA to enhanced error monitoring, reflected in error-related neural responses arising from mediofrontal cortex (MFC). Yet, the role of error monitoring in SA remains unclear, as it is unknown whether error monitoring can drive changes in memory, biasing what is learned or remembered about social situations. Motivated by the longer-term goal of identifying mechanisms implicated in SA, in the current study we developed and validated a novel paradigm for probing the role of error-related MFC theta oscillations (associated with error monitoring) and incidental memory biases in SA. Electroencephalography (EEG) data were collected while participants completed a novel Face-Flanker task, involving presentation of task-unrelated, trial-unique faces behind target/flanker arrows on each trial. A subsequent incidental memory assessment evaluated memory biases for error events. Severity of SA symptoms were associated with greater error-related theta synchrony over MFC, as well as between MFC and sensory cortex. Social anxiety also was positively associated with incidental memory biases for error events. Moreover, greater error-related MFC-sensory theta synchrony during the Face-Flanker predicted subsequent incidental memory biases for error events. Collectively, the results demonstrate the potential of a novel paradigm to elucidate mechanisms underlying relations between error monitoring and SA.
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We call for clinical trials researchers to carefully consider questions about use of intention-to-treat (ITT) analysis and per protocol analysis. We discuss how questions about efficacy and mechanisms of efficacy are appropriately answered through the application of per protocol analysis. ITT analysis is well-suited and appropriate for addressing questions related to treatment effectiveness, typically adherence to the treatment with respect to an outcome. While guided by admirable intentions, ITT analysis is often not guided by the right questions, leading to ITT misapplication. We address additional misconceptions that often lead to ITT misapplication, including issues relating to treatment noncompletion and violation of random assignment. We further highlight future directions and implications, particularly that future clinical child and adolescent research trial designs will be increasingly characterized by hybrid trials that combine elements of efficacy, effectiveness, and implementation research, where ITT and per protocol analysis will be appropriately applied to answer the right questions.
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Sleep-related problems often precede escalating anxiety in early adolescence. Pushing beyond broad sleep-mental health associations and toward mechanistic theories of their interplay can inform etiological models of psychopathology. Recent studies suggest that sleep depotentiates neural (e.g., amygdala) reactivity during reexposure to negative emotional stimuli in adults. Persistent amygdala reactivity to negative experiences and poor sleep characterize anxiety, particularly at the transition to adolescence. We propose that sleep depotentiates amygdala reactivity in youth but fails to do so among youth with anxiety. Participants (n = 34; 18 males; age, mean [M] = 11.35, standard deviation [SD] = 2.00) recruited from the community and specialty anxiety clinics viewed valenced images (positive, negative, and neutral) across two fMRI sessions (Study, Test), separated by a 10-12-hour retention period of sleep or wake (randomized). Mixed linear models regressed basolateral amygdala (BLA) activation and BLA-medial prefrontal cortex (mPFC) functional connectivity to negative images on Time, Condition, and Anxiety Severity. There were greater reductions in BLA activations to negative target images from Study to Test in the Sleep Condition, which was blunted with higher anxiety (b = -0.065, z = -2.355, p = 0.019). No such sleep- or anxiety-related effects were observed for BLA-mPFC functional connectivity (ps > 0.05). Sleep supports depotentiation of amygdala reactivity to negative stimuli in youth, but this effect is blunted at higher levels of anxiety. Disruptions in sleep-related affective habituation may be a critical, modifiable driver of anxiety.
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Tonsila do Cerebelo , Emoções , Masculino , Adulto , Adolescente , Humanos , Emoções/fisiologia , Tonsila do Cerebelo/fisiologia , Ansiedade , Córtex Pré-Frontal/fisiologia , Sono , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Social anxiety symptoms are most likely to emerge during adolescence, a developmental window marked by heightened concern over peer evaluation. However, the neurocognitive mechanism(s) underlying adolescent social anxiety remain unclear. Emerging work points to the error-related negativity (ERN) as a potential neural marker of exaggerated self/error-monitoring in social anxiety, particularly for errors committed in front of peers. However, social anxiety symptoms are marked by heterogeneity and it remains unclear exactly what domain(s) of social anxiety symptoms are associated with ERN variation in peer presence, particularly within the adolescent period. METHODS: To advance and deepen the mechanistic understanding of the ERN's putative role as a neural marker for social anxiety in adolescence, we leveraged a social manipulation procedure and assessed a developmentally salient domain of social anxiety during adolescence - fear of negative evaluation (FNE). Adolescents residing in Hanzhong, a small city in the southwestern region of mainland China, had EEG recorded while performing a flanker task, twice (peer presence/absence); FNE, as well as global social anxiety symptoms, was assessed. RESULTS: Overall ERN increases in peer presence. FNE specifically, but not global levels of social anxiety symptoms, predicted ERN in peer presence. CONCLUSIONS: These data are the first demonstration that the ERN relates to a specific domain of social anxiety in adolescents, as well as the first evidence of such relations within a non-WEIRD (Western, Educated, Industrialized, Rich and Democratic) sample. Results have important implications for theory and research into adolescent social anxiety.
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OBJECTIVE: Positive associations between therapeutic alliance and outcome (e.g. youth symptom severity) have been documented in the youth anxiety literature; however, little is known about the conditions under which early alliance contributes to positive outcomes in youth. The present study examined the relations between therapeutic alliance, session attendance, and outcomes in youths (N = 135; 55.6% female) who participated in a randomized clinical trial testing the efficacy of cognitive-behavioral therapy or client-centered therapy for anxiety. METHOD: We evaluated a conceptual model wherein: (1) early alliance indirectly contributes to positive outcomes by improving session attendance; (2) alliance-outcome associations differ by intervention type, with stronger associations in cognitive-behavioral therapy compared to client-centered therapy; and (3) alliance-outcome associations vary across outcome measurement timepoints, with the effect of early alliance on outcomes decaying over time. RESULTS: Contrary to hypotheses, provider ratings of early alliance predicted greater youth-rated anxiety symptom severity post-treatment (i.e. worse treatment outcomes). Session attendance predicted positive youth-rated outcomes, though there was no indirect effect of early alliance on outcomes through session attendance. CONCLUSIONS: Results show that increasing session attendance is important for enhancing outcomes and do not support early alliance as a predictor of outcomes.
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There has been increasing interest in applying integrative data analysis (IDA) to analyze data across multiple studies to increase sample size and statistical power. Measures of a construct are frequently not consistent across studies. This article provides a tutorial on the complex decisions that occur when conducting harmonization of measures for an IDA, including item selection, response coding, and modeling decisions. We analyzed caregivers' self-reported data from the ADHD Teen Integrative Data Analysis Longitudinal (ADHD TIDAL) dataset; data from 621 of 854 caregivers were available. We used moderated nonlinear factor analysis (MNLFA) to harmonize items reflecting depressive symptoms. Items were drawn from the Symptom Checklist 90-Revised, the Patient Health Questionnaire-9, and the World Health Organization Quality of Life questionnaire. Conducting IDA often requires more programming skills (e.g., Mplus), statistical knowledge (e.g., IRT framework), and complex decision-making processes than single-study analyses and meta-analyses. Through this paper, we described how we evaluated item characteristics, determined differences across studies, and created a single harmonized factor score that can be used to analyze data across all four studies. We also presented our questions, challenges, and decision-making processes; for example, we explained the thought process and course of actions when models did not converge. This tutorial provides a resource to support prevention scientists to generate harmonized variables accounting for sample and study differences.
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Depressão , Qualidade de Vida , Adolescente , Humanos , Inquéritos e Questionários , Autorrelato , Análise FatorialRESUMO
Youth with anxiety disorders report difficulty falling asleep and returning to sleep after sleep onset (i.e., poor sleep efficiency). Anxiety sensitivity, the excessive attention to physical symptoms of anxiety and their threatening interpretations, has been linked to poor sleep efficiency. We tested a conceptual model wherein attentional control, attentional focusing and attentional shifting would account for the relationship between anxiety sensitivity and poor sleep efficiency. 255 youths (6-17 years old, 78% Hispanic/Latino) who presented to a university-based research clinic completed measures on anxiety sensitivity, sleep, and attentional control. Poorer sleep efficiency was significantly correlated with higher anxiety sensitivity and lower attentional control, attentional focusing, and attentional shifting. Higher anxiety sensitivity was significantly correlated with lower attentional control and attentional focusing. Attentional control and attentional focusing, not attentional shifting, accounted for the relationship between anxiety sensitivity and poor sleep efficiency. These findings identify attentional control and attentional focusing as variables that may explain the association between anxiety sensitivity and sleep efficiency in youth.
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Psychological accommodation and control may help explain the finding that anxiety is more severe and common in Hispanic youth. Research with White samples conceptualizes psychological control as part of an authoritarian parenting style; however, research with Hispanic families suggests that psychological control is more likely to be indicative of a protective parenting style. Based on these findings, we hypothesized that in Hispanic families, psychological control would be related to protective parenting behaviors that ultimately maintain child anxiety. We tested a cross-sectional model hypothesizing that in Hispanic families the link between ethnicity and anxiety would be mediated through psychological control and parental accommodation of child anxiety, a parenting behavior which protects the child from the aversive experiences in the moment but ultimately serves to maintain child anxiety. A sample of mothers (n = 145; 48% Hispanic) and fathers (n = 59; 48% Hispanic) of youth from 8 to 18 years of age completed a survey assessing anxiety and parenting. With Hispanic mothers, the relation between ethnicity (Hispanic/non-Hispanic) and child anxiety was mediated through psychological control and accommodation. With fathers, although control was related to accommodation which, in turn, was related to child anxiety, ethnicity was not associated with control, accommodation, or child anxiety. Findings suggest that the context of parenting behavior should be considered in research, and adaptations of child anxiety treatments should consider ways to allow parents to express their desire to communicate warmth and protectiveness while avoiding negative reinforcement of child anxiety.
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OBJECTIVE: Treatment protocols for youth-internalizing disorders have been developed, however these protocols have yielded mixed findings in routine care settings. Despite increased recognition of the importance of flexibility when delivering evidence-based treatments (EBTs), little is known about the extent to which protocols offer guidance to providers in flexible EBT implementation. The current study examined the extent to which supported EBTs for youth internalizing disorders explicitly incorporate guidance for treatment modification. METHODS: Supported treatment protocols for youth internalizing disorders were identified (N = 44), from which 4,021 modification guidelines were extracted and coded using a structured coding system to classify modification strategies (i.e., the forms that recommended modifications take), and associated tailoring factors (i.e., the rationale for which modifications are recommended). RESULTS: Across all EBTs, modification guidelines were quite common, with the average protocol including almost 91 text passages providing guidance for modification. The majority of modification guidelines functionally increase session or treatment length by recommending the addition or repetition of material, whereas less than 5% of modification guidelines provided strategies for condensing or streamlining care. Strikingly, less than 2% of modification guidelines in EBT protocols address patient cultural factors, and rarely address provider or setting issues that can challenge standard implementation. CONCLUSIONS: Findings highlight critical gaps in the available guidance to modify EBTs for youth internalizing disorders, and suggest EBT protocols may not be optimally poised to flexibly address the broad diversity of children and adolescents across varied settings in need of mental health care.
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Transtornos Mentais , Guias de Prática Clínica como Assunto , Adolescente , Criança , Humanos , Transtornos Mentais/terapiaRESUMO
Early studies conceptualized the "anxious bully" as different from typical bullies due to their anxiety and home problems. Yet, empirical findings are mixed, and no study has reported associations between youth bullying perpetration, youth anxiety, and parent distress in a clinically anxious sample. We assessed 220 youths' anxiety symptom severity, frequency of the bullying perpetration in the past month, and parent levels of distress. Fifty percent of youths endorsed at least one perpetration act and 17% endorsed six or more. Youth anxiety, but not parent distress, was significantly associated with perpetration. We also found a significant interaction such that youth anxiety was positively associated with bullying perpetration when parent distress was high, but not low. Findings fill a glaring knowledge gap regarding this overlooked group of youth, anxious bullies, and provide novel insights into the interplay between youth distress and parent distress in predicting bullying perpetration.
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BACKGROUND: While taxonomy segregates anxiety symptoms into diagnoses, patients typically present with multiple diagnoses; this poses major challenges, particularly for youth, where mixed presentation is particularly common. Anxiety comorbidity could reflect multivariate, cross-domain interactions insufficiently emphasized in current taxonomy. We utilize network analytic approaches that model these interactions by characterizing pediatric anxiety as involving distinct, inter-connected, symptom domains. Quantifying this network structure could inform views of pediatric anxiety that shape clinical practice and research. METHODS: Participants were 4964 youths (ages 5-17 years) from seven international sites. Participants completed standard symptom inventory assessing severity along distinct domains that follow pediatric anxiety diagnostic categories. We first applied network analytic tools to quantify the anxiety domain network structure. We then examined whether variation in the network structure related to age (3-year longitudinal assessments) and sex, key moderators of pediatric anxiety expression. RESULTS: The anxiety network featured a highly inter-connected structure; all domains correlated positively but to varying degrees. Anxiety patients and healthy youth differed in severity but demonstrated a comparable network structure. We noted specific sex differences in the network structure; longitudinal data indicated additional structural changes during childhood. Generalized-anxiety and panic symptoms consistently emerged as central domains. CONCLUSIONS: Pediatric anxiety manifests along multiple, inter-connected symptom domains. By quantifying cross-domain associations and related moderation effects, the current study might shape views on the diagnosis, treatment, and study of pediatric anxiety.
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Ansiedade , Escalas de Graduação Psiquiátrica Breve , Internacionalidade , Pediatria , Ansiedade/epidemiologia , Ansiedade/fisiopatologia , Criança , Desenvolvimento Infantil , Comorbidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
BACKGROUND: We leveraged a recent efficacy trial to investigate directionality between parent anxiety and child anxiety at posttreatment and 12-month follow-up, and the potential role of parent psychological control as a mediator. We also explored child age and sex as moderators. METHOD: Two-hundred and fifty-four children were randomized to individual cognitive behavioral therapy (CBT) or to one of two CBT arms with parent involvement. Parent anxiety was not a treatment target in any of the three arms. RESULTS: Child anxiety at posttreatment was associated with parent anxiety and psychological control at 12-month follow-up, providing evidence of child-to-parent directionality. Parent anxiety at posttreatment was associated indirectly with child anxiety at 12-month follow-up through associations with parent psychological control, providing evidence of parent-to-child directionality. At posttreatment, parent psychological control contemporaneously mediated the relation between parent and child anxiety. Neither child age nor sex moderated any association. CONCLUSIONS: Findings highlight the directional effects between child anxiety, parent anxiety, and psychological control from posttreatment to 12-month follow-up, even when parent anxiety is not a treatment target. Research and clinical implications are discussed, with an emphasis on enhancing durability following treatment effects.
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Transtornos de Ansiedade , Relações Pais-Filho , Ansiedade/terapia , Transtornos de Ansiedade/psicologia , Transtornos de Ansiedade/terapia , Humanos , Pais/psicologia , Resultado do TratamentoRESUMO
To address the high demand for youth anxiety treatment, researchers have begun to evaluate stepped care approaches to use limited resources efficiently. Quantifying cost savings can inform policy decisions about optimal ways to use limited resources. This study presents a cost analysis of a stepped care treatment approach for anxiety disorders in youth. Youths (N = 112) completed an 8-session computer-administered attention bias modification treatment (Step 1), and families were given the option to "step up" to cognitive behavioral therapy (CBT; Step 2). Stepped care treatment cost estimates were based on (a) resources used in treatment (i.e., clinician/paraprofessional time, equipment/materials) and (b) Medicaid reimbursement rates for clinician and paraprofessional time. We compared these two cost estimates with a hypothetical standard treatment approach for youth anxiety disorders: CBT only. We also tested predictive models to determine whether they could guide decisions about which youths, based on baseline characteristics, should be assigned to stepped care or directly to CBT only to avoid the costs associated with Step 1. Compared to a hypothetical standard CBT approach, the stepped care treatment was associated with an overall cost savings of 44.4% for the Medicaid reimbursement model and 47.7% for the resource cost model. The predictive models indicated that assigning all youths to stepped care would be more cost-effective than assigning certain youths directly to CBT only. This study provides the first evidence that a stepped care treatment approach for youth anxiety is associated with substantial cost savings compared with a standard CBT.
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Transtornos de Ansiedade/psicologia , Terapia Cognitivo-Comportamental/métodos , Análise Custo-Benefício/métodos , Criança , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
This research draws upon the interpersonal-psychological theory of suicide in the development of the LEAP intervention, a web-based selective preventive suicide intervention targeting cognitions of perceived burdensomeness toward others. The pilot randomized controlled trial consisted of 80 adolescents (68.8% female, 65.8% Hispanic) 13-19 of age years who were randomly assigned to either the LEAP intervention or a psychoeducational control condition. Participants completed baseline, posttreatment, and 6-week follow-up assessments. All participants reported high levels of satisfaction with the program. Findings on outcome variables differed across intent-to-treat analyses and treatment completer analyses. Intent-to-treat analysis yielded no significant between-condition differences in perceived burdensomeness at posttreatment or follow-up. Treatment completer analyses revealed significant between-condition differences on outcome variables such that participants who completed the LEAP intervention showed significantly lower perceived burdensomeness scores at postintervention and significantly lower perceived burdensomeness, thwarted belongingness, and depressive symptom scores at follow-up as compared to participants in the control condition. No significant differences in suicidal ideation were found between conditions. These findings support the promise of the LEAP intervention as a brief, web-based selective preventive intervention for reducing perceived burdensomeness among adolescents who complete the intervention. This study provides evidence that perceived burdensomeness can be modified via a psychosocial intervention. Future research is needed to identify ways to enhance adolescent engagement with and completion of the intervention.
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Relações Interpessoais , Teoria Psicológica , Adolescente , Adulto , Feminino , Humanos , Masculino , Projetos Piloto , Fatores de Risco , Adulto JovemRESUMO
AIMS: This study examines the moderating role of parental neighborhood perceptions on the relationship between neighborhood structural disadvantage and adolescent depressive symptoms. METHODS: Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) consisting of 12,105 adolescents and their parents were used. RESULTS: Mixed effects multilevel modeling revealed that parental-perceived neighborhood disorder was associated with higher levels of adolescent depressive symptoms (ß = .27, p ≤ .001). The interaction between neighborhood concentrated poverty and parental-perceived neighborhood disorder was also significant (ß = -.14, p ≤ .01). Low and high levels of parental-perceived neighborhood disorder were associated with lower (ß = -.41, p < .05) and higher (ß = .46, p ≤ .01) levels of adolescent depressive symptoms, respectively, with increasing concentrated poverty. Parental-perceived collective efficacy was not associated with adolescent depressive symptoms nor was it a moderator. CONCLUSION: Findings suggest that the neighborhood's social environment may mitigate adolescent depressive symptoms. Implications for structural interventions are discussed.
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Depressão/psicologia , Pais/psicologia , Características de Residência , Meio Social , Adolescente , Adulto , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Análise Multinível , Pobreza/psicologia , Psicologia do Adolescente , Controles Informais da Sociedade , Adulto JovemRESUMO
BACKGROUND: Considerable research links threat-related attention biases to anxiety symptoms in adults, whereas extant findings on threat biases in youth are limited and mixed. Inconsistent findings may arise due to substantial methodological variability and limited sample sizes, emphasizing the need for systematic research on large samples. The aim of this report is to examine the association between threat bias and pediatric anxiety symptoms using standardized measures in a large, international, multi-site youth sample. METHODS: A total of 1,291 children and adolescents from seven research sites worldwide completed standardized attention bias assessment task (dot-probe task) and child anxiety symptoms measure (Screen for Child Anxiety Related Emotional Disorders). Using a dimensional approach to symptomatology, we conducted regression analyses predicting overall, and disorder-specific, anxiety symptoms severity, based on threat bias scores. RESULTS: Threat bias correlated positively with overall anxiety symptoms severity (ß = 0.078, P = .004). Furthermore, threat bias was positively associated specifically with social anxiety (ß = 0.072, P = .008) and school phobia (ß = 0.076, P = .006) symptoms severity, but not with panic, generalized anxiety, or separation anxiety symptoms. These associations were not moderated by age or gender. CONCLUSIONS: These findings indicate associations between threat bias and pediatric anxiety symptoms, and suggest that vigilance to external threats manifests more prominently in symptoms of social anxiety and school phobia, regardless of age and gender. These findings point to the role of attention bias to threat in anxiety, with implications for translational clinical research. The significance of applying standardized methods in multi-site collaborations for overcoming challenges inherent to clinical research is discussed.
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Ansiedade/fisiopatologia , Viés de Atenção/fisiologia , Medo/fisiologia , Transtornos Fóbicos/fisiopatologia , Adolescente , Criança , Feminino , Humanos , MasculinoRESUMO
Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at elevated risk for experiencing unipolar depressive symptoms and disorders. The current study describes the development of a behaviorally oriented depression preventive intervention tailored for adolescents with ADHD targeting variables empirically shown to mediate ADHD and depression (i.e., reward responsivity, emotion regulation, and family support). Eight adolescents with a history of ADHD and currently elevated depressive symptoms and their parents participated in an open trial of the Behaviorally Enhancing Adolescents' Mood (BEAM) program. Adolescents and their parents reported high satisfaction with BEAM. Staff reported BEAM was easy to implement with high adherence. Following BEAM, there were significant reductions in parent-report of adolescents' depressive symptoms and emotion regulation at posttreatment and the 6-week follow-up and adolescent-report of reward responsivity at posttreatment. Case vignettes are also provided to illustrate implementation of the BEAM program. In spite of the small sample, lack of a control group, and some discrepancies across informants, results overall support the feasibility and acceptability of the BEAM program, and suggest it has promise in reducing depressive symptoms in adolescents with ADHD.
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This article presents a pragmatic approach to assessing and managing suicide risk in children and adolescents. We first present general recommendations for conducting risk assessments with children and adolescents, followed by an algorithm for designating risk. Risk assessment and designation should be based on both distal (i.e., a prior history of self-harm behaviors) and proximal (i.e., suicide ideation, plans, intent, and preparations) predictors of suicide attempt. We then discuss safety planning as an easy-to-implement approach for intervening and managing suicide risk when working with children and adolescents. We end with a case example illustrating the implementation of risk assessment, risk designation, and safety planning with an adolescent client and her mother.
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OBJECTIVE: The present study examined the factor structure and concurrent validity of the Attentional Control Scale for Children (ACS-C; Muris, de Jong, & Engelen, 2004), a youth self-rating scale of attentional control. METHOD: A multisource assessment approach was used with 186 children and adolescents referred to an anxiety disorders specialty clinic. RESULTS: Exploratory factor analysis yielded a 2-factor structure with internally consistent and moderately correlated subscales of Attentional Focusing and Attentional Shifting. Total ACS-C and subscale scores demonstrated significant associations with youth and parent ratings of youth anxiety symptoms, youth self ratings of depressive symptoms, and youth diagnosis of attention deficit-hyperactivity disorder. CONCLUSIONS: These findings support use of the ACS-C as a self-rating scale of attentional control among referred youth. Future research is encouraged to examine retest reliability of the ACS-C and to evaluate whether its internal structure could be enhanced by removing or modifying items that performed poorly.
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Transtornos de Ansiedade/fisiopatologia , Atenção/fisiologia , Escalas de Graduação Psiquiátrica/normas , Autocontrole , Adolescente , Transtornos de Ansiedade/diagnóstico , Criança , Feminino , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
The current study presents an approach for empirically identifying tailoring variables at midtreatment of cognitive behavioral therapy (CBT) protocols for youth with anxiety disorders that can be used to guide moves to second-stage treatments. Using 2 independent data sets (Study 1 N = 240, M age = 9.86 years; Study 2 N = 341; M age = 9.53 years), we examined treatment response patterns after 8 sessions of CBT (i.e., CBT midtreatment). We identified and replicated 3 classes of response patterns at CBT midtreatment: Early Responders, Partial Responders, and Nonresponders. Class membership at CBT midtreatment was predictive of outcome at CBT posttreatment. Receiver operating characteristics curves were used to derive guidelines to optimize accuracy of assignment to classes at CBT midtreatment. These findings support the promise of treatment response at CBT midtreatment to identify tailoring variables for use in abbreviating first-stage treatments and facilitating moves to second-stage treatments.