Myocardial ischemic disease is the major cause of death worldwide. After myocardial infarction, reperfusion of infracted heart has been an important objective of strategies to improve outcomes. ...However, cardiac ischemia/reperfusion (I/R) is characterized by inflammation, arrhythmias, cardiomyocyte damage, and, at the cellular level, disturbance in Ca²⺠and redox homeostasis. In this study, we sought to determine how acute inflammatory response contributes to reperfusion injury and Ca²⺠homeostasis disturbance after acute ischemia. Using a rat model of I/R, we show that circulating levels of TNF-α and cardiac caspase-8 activity were increased within 6 h of reperfusion, leading to myocardial nitric oxide and mitochondrial ROS production. At 1 and 15 d after reperfusion, caspase-8 activation resulted in S-nitrosylation of the RyR2 and depletion of calstabin2 from the RyR2 complex, resulting in diastolic sarcoplasmic reticulum (SR) Ca²⺠leak. Pharmacological inhibition of caspase-8 before reperfusion with Q-LETD-OPh or prevention of calstabin2 depletion from the RyR2 complex with the Ca²⺠channel stabilizer S107 ("rycal") inhibited the SR Ca²⺠leak, reduced ventricular arrhythmias, infarct size, and left ventricular remodeling after 15 d of reperfusion. TNF-α-induced caspase-8 activation leads to leaky RyR2 channels that contribute to myocardial remodeling after I/R. Thus, early prevention of SR Ca²⺠leak trough normalization of RyR2 function is cardioprotective.
We report active treatment group differences on response and remission rates and changes in anxiety severity at weeks 24 and 36 for the Child/Adolescent Anxiety Multimodal Study (CAMS).
CAMS youth (N ...= 488; 74% ≤ 12 years of age) with DSM-IV separation, generalized, or social anxiety disorder were randomized to 12 weeks of cognitive-behavioral therapy (CBT), sertraline (SRT), CBT+SRT (COMB), or medication management/pill placebo (PBO). Responders attended 6 monthly booster sessions in their assigned treatment arm; youth in COMB and SRT continued on their medication throughout this period. Efficacy of COMB, SRT, and CBT (n = 412) was assessed at 24 and 36 weeks postrandomization. Youth randomized to PBO (n = 76) were offered active CAMS treatment if nonresponsive at week 12 or over follow-up and were not included here. Independent evaluators blind to study condition assessed anxiety severity, functioning, and treatment response. Concomitant treatments were allowed but monitored over follow-up.
The majority (>80%) of acute responders maintained positive response at both weeks 24 and 36. Consistent with acute outcomes, COMB maintained advantage over CBT and SRT, which did not differ, on dimensional outcomes; the 3 treatments did not differ on most categorical outcomes over follow-up. Compared to COMB and CBT, youth in SRT obtained more concomitant psychosocial treatments, whereas those in SRT and CBT obtained more concomitant combined (medication plus psychosocial) treatment.
COMB maintained advantage over CBT and SRT on some measures over follow-up, whereas the 2 monotherapies remained indistinguishable. The observed convergence of COMB and monotherapy may be related to greater use of concomitant treatment during follow-up among youth receiving the monotherapies, although other explanations are possible. Although outcomes were variable, most CAMS-treated youth experienced sustained treatment benefit. Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); URL: http://clinicaltrials.gov. Unique identifier: NCT00052078.
To review the literature on the cognitive-behavioral treatment of children and adolescents with anxiety and depressive disorders within the conceptual framework of evidence-based medicine.
The ...psychiatric and psychological literature was systematically searched for controlled trials applying cognitive-behavioral treatment to pediatric anxiety and depressive disorders.
For both anxiety and depression, substantial evidence supports the efficacy of problem-specific cognitive-behavioral interventions. Comparisons with wait-list, inactive control, and active control conditions suggest medium to large effects for symptom reduction in primary outcome domains.
From an evidence-based perspective, cognitive-behavioral therapy is currently the treatment of choice for anxiety and depressive disorders in children and adolescents. Future research in this area will need to focus on comparing cognitive-behavioral psychotherapy with other treatments, component analyses, and the application of exportable protocol-driven treatments to divergent settings and patient populations.
Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in ...treating these disorders, little is known about their relative or combined efficacy.
In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12.
The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline.
Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.)
Objective: We sought to examine predictors and moderators of treatment outcomes among 488 youths ages 7-17 years (50% female; 74% ≤ 12 years) meeting Diagnostic and Statistical Manual of Mental ...Disorders (4th ed., text rev.; American Psychiatric Association, 2000) criteria for diagnoses of separation anxiety disorder, social phobia, or generalized anxiety disorder who were randomly assigned to receive either cognitive behavioral therapy (CBT), sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) in the Child/Adolescent Anxiety Multimodal Study (CAMS). Method: Six classes of predictor and moderator variables (22 variables) were identified from the literature and examined using continuous (Pediatric Anxiety Ratings Scale; PARS) and categorical (Clinical Global Impression Scale-Improvement; CGI-I) outcome measures. Results: Three baseline variables predicted better outcomes (independent of treatment condition) on the PARS, including low anxiety severity (as measured by parents and independent evaluators) and caregiver strain. No baseline variables were found to predict Week 12 responder status (CGI-I). Participants' principal diagnosis moderated treatment outcomes but only on the PARS. No baseline variables were found to moderate treatment outcomes on Week 12 responder status (CGI-I). Discussion: Overall, anxious children responded favorably to CAMS treatments. However, having more severe and impairing anxiety, greater caregiver strain, and a principal diagnosis of social phobia were associated with less favorable outcomes. Clinical implications of these findings are discussed.
Social phobia typically develops during the adolescent years, yet no nationally representative studies in the United States have examined the rates and features of this condition among youth in this ...age range. The objectives of this investigation were to: (1) present the lifetime prevalence, sociodemographic and clinical correlates, and comorbidity of social phobia in a large, nationally representative sample of U.S. adolescents; and (2) examine differences in the rates and features of social phobia across the proposed DSM-5 social phobia subtypes.
The National Comorbidity Survey Replication-Adolescent Supplement is a nationally representative face-to-face survey of 10,123 adolescents 13 to 18 years of age in the continental United States.
Approximately 9% of adolescents met criteria for any social phobia in their lifetime. Of these adolescents, 55.8% were affected with the generalized subtype and 44.2% exhibited nongeneralized social phobia. Only 0.7% met criteria for the proposed DSM-5 performance-only subtype. Generalized social phobia was more common among female adolescents and risk for this subtype increased with age. Adolescents with generalized social phobia also had a younger age of onset, higher levels of disability and clinical severity, and a greater degree of comorbidity relative to adolescents with nongeneralized forms of the disorder.
This study indicates that social phobia is a highly prevalent, persistent, and impairing psychiatric disorder among adolescent youth. Results of this study also provide evidence for the clinical utility of the generalized subtype and highlight the importance of considering the heterogeneity of social phobia in this age group.
Abstract Reports the characteristics of a large, representative sample of treatment-seeking anxious youth ( N = 488). Participants, aged 7–17 years (mean 10.7 years), had a principal DSM-IV diagnosis ...of separation anxiety disorder (SAD), generalized anxiety disorder (GAD), or social phobia (SP). Although youth with a co-primary diagnosis for which a different disorder-specific treatment would be indicated (e.g., major depressive disorder, substance abuse) were not included, there were few other exclusion criteria. Participants and their parent/guardian underwent an extensive baseline assessment using a broad array of measures capturing diagnostic status, anxiety symptoms and severity, and areas of functional impairment. Means and standard deviations of the measures of psychopathology and data on diagnostic status are provided. The sample had moderate to severe anxiety disorder and was highly comorbid, with 55.3% of participants meeting criteria for at least one non-targeted DSM-IV disorder. Anxiety disorders in youth often do not present as a single/focused disorder: such disorders in youth overlap in symptoms and are highly comorbid among themselves.