P. Jane Mutch

The Effect of Cognitive-Behavioral Therapy Versus Treatment as Usual for Anxiety in Children With Autism Spectrum Disorders: A Randomized, Controlled Trial

OBJECTIVE To examine the efficacy of a modular cognitive-behavioral therapy (CBT) protocol relative to treatment as usual (TAU) among children with high-functioning autism spectrum disorders (ASD) and clinically significant anxiety. METHOD A total of 45 children (7-11 years of age) with high-functioning ASD and clinically significant anxiety were randomized to receive 16 sessions of weekly CBT or TAU for an equivalent duration. After screening, assessments were conducted at baseline, post-treatment, and 3-month follow-up. Raters were blind to treatment condition. RESULTS Youth receiving CBT showed substantial improvement relative to TAU on primary anxiety outcomes. Of 24 children randomized to the CBT arm, 18 (75%) were treatment responders, versus only 3 of 21 children (14%) in the TAU arm. Gains were generally maintained at 3-month follow-up for CBT responders. CONCLUSIONS Relative to usual care, CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms. This study contributes to the growing literature supporting adapted CBT approaches for treating anxiety in youth with ASD.

Open label aripiprazole in the treatment of youth with tic disorders.

BACKGROUND Primarily safe and efficacious treatments for chronic tic disorders are needed. Also needed are such treatments that target co-morbid conditions. Aripiprazole, a dopaminergic/serotonergic agent with partial agonist properties at the D2 dopamine receptor and 5-hydrdoxytryptamine 1A (5-HT(1A)) receptor and antagonist properties at the 5-HT(2A) receptor, holds promise in both regards. OBJECTIVE This was an open-label, flexible-dose study to evaluate the safety of aripiprazole in children and adolescents with a primary diagnosis of a chronic tic disorder with/without co-morbid disorder(s). METHOD Sixteen children (15 males) aged 8-17 years participated in the 6-week trial. Ratings for tic, obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and side effects were administered weekly. Baseline and exit laboratory measures, electrocardiograms (ECGs), weight, and height were obtained. RESULTS The average daily aripiprazole dose was 3.3 mg (range 1.25-7.5 mg). Significant pre-and posttreatment differences were ascertained for the Yale Global Tic Severity Scale motor (p < or = 0.0001), phonic (p < or = 0.0001), and total tic (p < or = 0.0001) scores. Results of other rating scales suggested significant improvements in co-morbid disorders as well, including OCD, ADHD, and depressive disorders. Although aripiprazole was well tolerated, increases in weight were found. CONCLUSION In this preliminary open-label trial, aripiprazole was a well-tolerated treatment for tics and co-morbid OCD and ADHD symptoms. Improvements in co-morbid conditions may be secondary to tic reduction or to specific to aripiprazole therapy; however, further study is warranted.

Relationship of Movements and Behaviors to Group A Streptococcus Infections in Elementary School Children

BACKGROUND Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) research is based on the hypothesis that infections trigger changes in behavior and movement in children. METHODS We enrolled 693 children (ages 3 to 12 years) into a systematic, longitudinal study. Data were collected monthly for 8 months (October-May) to determine point prevalence of Group A Streptococcal (GAS) infections, tics, behavior, and choreiform movements. Simultaneous throat cultures were obtained, and relational analyses were made between GAS and movement/observation ratings. RESULTS Combined behavior/GAS associations (concurrent with or 3 subsequent months to GAS) revealed a strong relationship, relative risk (RR) of 1.71 (p < .0001). Detailed analysis revealed that balance/swaying and non-tic grimacing were responsible for a significant proportion of this association (RR = 2.92, p < .0001). A strong seasonal pattern was found, with fall being more significant for GAS infections and observation ratings (p < .0001) compared with winter/spring. Children with repeated streptococcus (n = 64) showed higher rates of behavior and distal choreiform observations (p = .005). CONCLUSIONS Motor/behavior changes were noted to occur in relationship to positive GAS culture with support that repeated GAS increases risk.

Defining Treatment Response in Pediatric Tic Disorders: A Signal Detection Analysis of the Yale Global Tic Severity Scale

OBJECTIVE To examine the optimal Yale Global Tic Severity Scale (YGTSS) percent reduction and raw cutoffs for predicting treatment response among children and adolescents with tic disorders. METHOD Youth with a tic disorder (N=108; range=5-17 years) participated in several clinical trials involving varied medications or psychosocial treatment, or received naturalistic care. Assessments were conducted before and after treatment and included the YGTSS and response status on the Clinical Global Impressions-Improvement Scale (CGI-I). RESULTS A 35% reduction on the YGTSS total tic severity score or a YGTSS raw total tic severity score change of 6 or 7 points were the best indicators of clinical treatment response in youth with tic disorders. CONCLUSIONS A YGTSS total tic severity score reduction of 35% or a raw total tic severity score change of 6 or 7 appears optimal for determining treatment response. A consistent definition of treatment response on the YGTSS may facilitate cross-study comparability. Practitioners can use these values for treatment planning decisions (e.g., change medications, etc.).

A RANDOMIZED CONTROLLED TRIAL OF COGNITIVE-BEHAVIORAL THERAPY VERSUS TREATMENT AS USUAL FOR ADOLESCENTS WITH AUTISM SPECTRUM DISORDERS AND COMORBID ANXIETY

Examine the efficacy of a personalized, modular cognitive‐behavioral therapy (CBT) protocol among early adolescents with high‐functioning autism spectrum disorders (ASDs) and co‐occurring anxiety relative to treatment as usual (TAU).

Clinical characteristics of high-functioning youth with autism spectrum disorder and anxiety.

AIM & METHODS Clinical characteristics were examined in 108 high-functioning youth (children with a full IQ scale of at least 70) with an autism spectrum disorder (ASD; aged 7-15 years) who were presenting for inclusion in one of four clinical trials examining the efficacy of cognitive behavioral therapy in youth with ASD and anxiety. RESULTS We present baseline characteristics of this cohort, including prevalence rates of anxiety and comorbid disorders, and correlates of anxiety (e.g., comorbid diagnoses, impairment, anxiety severity and mental health services received) as a function of age and ASD diagnosis in treatment-seeking youth. Primary anxiety disorders were: 41.7% (n = 45) social phobia, 25.9% (n = 28) generalized anxiety disorder, 15.7% (n = 17) separation anxiety disorder, 12.0% (n = 13) obsessive-compulsive disorder and 4.6% (n = 5) specific phobia. Overall, 91.6% of participants (n = 99) met criteria for two or more anxiety disorders. Parents reported considerable functional impairment as measured by the Columbia Impairment Scale and anxiety severity as measured by the Pediatric Anxiety Rating Scale; this did not statistically differ as a function of ASD diagnosis or age. Anxiety severity, the number of comorbid anxiety diagnoses and total comorbid diagnoses were directly associated with parent-reported child impairment. Youth with ASD and anxiety present as a heterogeneous cohort with significant impairments and complex diagnostic presentations. CONCLUSION These data provide information about the nature of anxiety in youth with ASD, which may foster the development of tailored treatment protocols.

Characterization of the Pediatric Acute-Onset Neuropsychiatric Syndrome Phenotype

OBJECTIVE Pediatric acute-onset neuropsychiatric syndrome (PANS) is a subtype of obsessive compulsive disorder (OCD) marked by an abrupt onset or exacerbation of neuropsychiatric symptoms. We aim to characterize the phenotypic presentation of youth with PANS. METHODS Forty-three youth (ages 4-14 years) meeting criteria for PANS were assessed using self-report and clinician-administered measures, medical record reviews, comprehensive clinical evaluation, and laboratory measures. RESULTS Youth with PANS presented with an early age of OCD onset (mean=7.84 years) and exhibited moderate to severe obsessive compulsive symptoms upon evaluation. All had comorbid anxiety and emotional lability, and scored well below normative means on all quality of life subscales. Youth with elevated streptococcal antibody titers trended toward having higher OCD severity, and presented more frequently with dilated pupils relative to youth without elevated titers. A cluster analysis of core PANS symptoms revealed three distinct symptom clusters that included core characteristic PANS symptoms, streptococcal-related symptoms, and cytokine-driven/physiological symptoms. Youth with PANS who had comorbid tics were more likely to exhibit a decline in school performance, visuomotor impairment, food restriction symptoms, and handwriting deterioration, and they reported lower quality of life relative to youth without tics. CONCLUSIONS The sudden, acute onset of neuropsychiatric symptoms, high frequency of comorbidities (i.e., anxiety, behavioral regression, depression, and suicidality), and poor quality of life capture the PANS subgroup as suddenly and severely impaired youth. Identifying clinical characteristics of youth with PANS will allow clinicians to diagnose and treat this subtype of OCD with a more strategized and effective approach.

Efficacy of Augmentation of Cognitive Behavior Therapy With Weight-Adjusted d-Cycloserine vs Placebo in Pediatric Obsessive-Compulsive Disorder: A Randomized Clinical Trial.

IMPORTANCE Cognitive behavior therapy (CBT) among youth with obsessive-compulsive disorder (OCD) is effective, but many patients remain symptomatic after intervention. d-cycloserine, a partial agonist at the N-methyl-d-aspartate receptor in the amygdala, has been associated with enhanced CBT outcome for OCD among adults but requires evaluation among youth. OBJECTIVES To examine the relative efficacy of weight-adjusted d-cycloserine (25 or 50 mg) vs placebo augmentation of CBT for youth with OCD and to assess if concomitant antidepressant medication moderated effects. DESIGN, SETTING, AND PARTICIPANTS In a placebo-controlled randomized clinical trial, 142 youths (age range, 7-17 years) enrolled between June 1, 2011, and January 30, 2015, at 2 academic health science centers (University of South Florida and Massachusetts General Hospital) with a primary diagnosis of OCD were randomized in a double-blind fashion to d-cycloserine plus CBT or placebo plus CBT. Intent-to-treat analysis was performed. INTERVENTIONS Patients were randomly assigned in a 1:1 ratio to either 10 sessions of d-cycloserine plus CBT or placebo plus CBT. d-cycloserine (25 or 50 mg) or placebo was taken 1 hour before sessions 4 through 10. MAIN OUTCOMES AND MEASURES Childrens Yale-Brown Obsessive Compulsive Scale at randomization, biweekly, midtreatment, and posttreatment. Secondary outcomes included the Clinical Global Impressions-Severity or Clinical Global Impressions-Improvement, remission status, Childrens Depression Rating Scale, Multidimensional Anxiety Scale for Children, and Childrens Obsessive-Compulsive Impact Scale-Parent Version. RESULTS The study cohort comprised 142 participants. Their mean (SD) age was 12.7 (2.9) years, and 53.5% (76 of 142) were female. A mixed-effects model using all available data indicated significant declines in the Childrens Yale-Brown Obsessive Compulsive Scale total score and Clinical Global Impressions-Severity. No significant interaction between treatment group and changes in the Childrens Yale-Brown Obsessive Compulsive Scale and Clinical Global Impressions-Severity indicated that the d-cycloserine plus CBT group and the placebo plus CBT group declined at similar rates per assessment point on the Childrens Yale-Brown Obsessive Compulsive Scale total score (estimate, -2.31, 95% CI, -2.79 to -1.83 and estimate, -2.03, 95% CI, -2.47 to -1.58, respectively) and Clinical Global Impressions-Severity (estimate, -0.29, 95% CI, -0.35 to -0.22 and estimate, -0.23, 95% CI, -0.29 to -0.17, respectively). No group differences in secondary outcomes were present. Antidepressant medication use at baseline did not moderate changes for either group. CONCLUSIONS AND RELEVANCE d-cycloserine augmentation of CBT did not confer additional benefit relative to placebo among youth with OCD. Other augmentation approaches should be examined to enhance outcome. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00864123.

Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders: A Pilot Randomized Trial

OBJECTIVE Previous studies suggest that the unexplained sudden and severe onset of obsessive-compulsive disorder (OCD) and/or tics may be infection or immune precipitated. Beta lactam antibiotics may be neuroprotective beyond their antimicrobial efficacy. We examine the preliminary safety and efficacy of cefdinir in reducing obsessive-compulsive and/or tic severity in children with new-onset symptoms. METHOD Twenty subjects were randomized to receive placebo or cefdinir for 30 days for the treatment of recent-onset OCD and/or tics. The placebo group received a comparable inactive treatment matched for taste, color, and consistency. The Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and Yale Global Tic Severity Scale (YGTSS) were the primary outcome measures utilized. RESULTS Subjects receiving cefdinir saw notable improvements in tic symptoms, with 44.4% showing at least a 25% reduction in YGTSS (mean decrease=9.5) scores compared with 9.1% of the placebo group (mean decrease=0.13). Despite improvements, significant group differences were not observed for YGTSS (F [1, 13]=4.03, p=0.066) although there were moderate differences between group treatment effects (d=0.72). For OCD symptoms, subjects receiving cefdinir saw improvements in OCD symptoms, with 33.3% showing at least a 25% reduction in CY-BOCS scores (mean decrease=7.8) compared with 27.3% of the placebo group (mean decrease=4.7), but there were also no significant differences for CY-BOCS (F [1, 13]=0.385, p=0.546; d=0.24). CONCLUSIONS Subjects assigned to cefdinir exhibited notable, albeit nonstatistically significant, improvements in tic symptoms, compared with the placebo group. There were also some improvements in OCD symptoms, although these were not significant. Overall, cefdinir was well tolerated. Given these preliminary results, a fully powered study is warranted to explore the efficacy of cefdinir as a therapeutic tool for new-onset pediatric neuropsychiatric symptoms, particularly those that appear to be precipitated by infection.

The Role of Co-Occurring Disruptive Behavior in the Clinical Presentation of Children and Adolescents with Anxiety in the Context of Autism Spectrum Disorders

This study explored the impact of disruptive behavior disorder (DBD) comorbidity on theoretically relevant correlates among 87 children and adolescents with autism spectrum disorders (ASD) and clinically significant anxiety. Relative to youth with ASD and anxiety alone, participants with ASD, anxiety, and DBD: (a) presented with significantly more severe anxiety symptoms per clinician-, parent-, and self-report; (b) were more likely to be prescribed antipsychotic medication but were no more likely to receive additional psychosocial and educational interventions; and (c) experienced significantly greater functional impairment and family interference. These results suggest that co-occurring DBD in the context of ASD and anxiety confers greater risk for heightened symptom severity and functional impairment, and may be linked with increased prescription of antipsychotic medication.