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: Children's 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, Children's Depression Rating Scale, Multidimensional Anxiety Scale for Children, and Children's 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 Children's Yale-Brown Obsessive Compulsive Scale total score and Clinical Global Impressions-Severity. No significant interaction between treatment group and changes in the Children's 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 Children's 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.

Preliminary study of family accommodation in youth with autism spectrum disorders and anxiety: Incidence, clinical correlates, and behavioral treatment response.

Anxiety symptoms are common in youth with autism spectrum disorders (ASD) and directly associated with symptom severity and functional impairment. Family accommodation occurs frequently among individuals with obsessive-compulsive and anxiety disorders; to date, no data exist on the nature and correlates of family accommodation in youth with ASD and anxiety, as well as its relationship to cognitive-behavioral therapy outcome. Forty children with ASD and a comorbid anxiety disorder participated. Clinicians administered measures of ASD and anxiety disorder caseness, anxiety symptom severity, and family accommodation; parents completed questionnaires assessing social responsiveness, internalizing and externalizing behaviors, and functional impairment. A subsample of youth (n = 24) completed a course of cognitive-behavioral therapy. Family accommodation was common and positively correlated with anxiety symptom severity, but not functional impairment, general internalizing symptoms, externalizing behavior, or social responsiveness. Family accommodation decreased following cognitive-behavioral therapy with decreases in family accommodation being associated with decreases in anxiety levels. Treatment responders reported lower family accommodation frequency and lower parent impact relative to non-responders. Clinical implications of this study in assessing and psychotherapeutically treating youth with ASD and comorbid anxiety are discussed.

A randomized controlled trial of cognitive-behavioral therapy versus treatment as usual for adolescents with autism spectrum disorders and comorbid anxiety.

OBJECTIVE: 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). METHOD: Thirty-one children (11-16 years) with ASD and clinically significant anxiety were randomly assigned to receive 16 weekly CBT sessions or an equivalent duration of TAU. Participants were assessed by blinded raters at screening, posttreatment, and 1-month follow-up. RESULTS: Youth randomized to CBT demonstrated superior improvement across primary outcomes relative to those receiving TAU. Eleven of 16 adolescents randomized to CBT were treatment responders, versus 4 of 15 in the TAU condition. Gains were maintained at 1-month follow-up for CBT responders. CONCLUSIONS: These data extend findings of the promising effects of CBT in anxious youth with ASD to early adolescents.

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 Children's 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.

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.

Frequency and correlates of suicidal ideation in pediatric obsessive-compulsive disorder.

This study examined the frequency and sociodemographic and clinical correlates of suicidal ideation in a sample of children and adolescents with obsessive-compulsive disorder (OCD). Fifty-four youth with OCD and their parent(s) were administered the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime, Children's Yale-Brown Obsessive Compulsive Scale, and Children's Depression Rating Scale-Revised. Children completed the Suicidal Ideation Questionnaire-Junior (SIQ-JR), Child Obsessive Compulsive Impact Scale-Child, and Multidimensional Anxiety Scale for Children; parents completed the Child Obsessive Compulsive Impact Scale-Parent, Swanson, Nolan, and Pelham-IV Parent Scale, and Young Mania Rating Scale-Parent Version. Seven youth endorsed clinically significant levels of suicidal ideation on the SIQ-JR. Suicidal ideation was significantly related to clinician-rated depressive symptoms, age, child-rated impairment and anxiety symptoms, and symmetry, sexuality/religiosity and miscellaneous symptom dimensions. There was no significant association between suicidal ideation and obsessive-compulsive symptom severity, comorbidity patterns, or several parent-rated indices (e.g., impairment, impulsivity). These results provide initial information regarding the frequency and correlates of suicidal ideation in treatment-seeking youth with OCD. Clinical implications are discussed, as well as directions for future research.

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.

Double-blind, placebo-controlled, pilot trial of paliperidone augmentation in serotonin reuptake inhibitor-resistant obsessive-compulsive disorder.

OBJECTIVE: This pilot study explored the efficacy and tolerability of paliperidone augmentation of serotonin reuptake inhibitors (SRIs) in adults with treatment-resistant obsessive-compulsive disorder (OCD). METHOD: Thirty-four patients aged 24-67 years (mean = 43.7 years, SD = 11.4) who met DSM-IV criteria for OCD and remained symptomatic following 2 or more past adequate SRI trials (including their current medication) were enrolled from May 2008 to March 2012. Participants were treated for 8 weeks in a double-blind study with either paliperidone (up to 9 mg/d) or matching placebo in addition to their SRI. Blinded raters conducted outcome assessments. The primary outcome, obsessive-compulsive symptom severity, was assessed using the Yale-Brown Obsessive Compulsive Scale (YBOCS). Secondary outcomes included the Clinical Global Impressions-Severity of Illness and -Improvement scales. RESULTS: Paliperidone administration resulted in significant baseline-to-posttreatment reductions in obsessive-compulsive symptoms as measured by the YBOCS (P < .01, d = 0.66), although placebo administration also resulted in medium-sized, trend-level significant YBOCS changes (P = .05, d = 0.53). In exploratory analyses examining between-group differences, tests for paliperidone superiority relative to placebo were not significant (P = .14, d = 0.34); however, a numerical trend toward significant between-group differences was found, with a reduction of 7.98 points on the YBOCS for the paliperidone group compared to a reduction of 4.02 points for the placebo group. Paliperidone was generally well tolerated and not associated with significant weight gain (mean [SD] weight: paliperidone, pretreatment 84.70 [27.08] kg, posttreatment 84.84 [18.99] kg; vs placebo, pretreatment 77.50 [25.33] kg, posttreatment 77.43 [19.90] kg; P = .21). CONCLUSIONS: These results suggest that paliperidone augmentation is well tolerated and has potential efficacy in the short-term treatment of some patients with SRI-resistant OCD. Well-powered, randomized, controlled studies are necessary to more definitively address the efficacy of this treatment strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00632229.

The phenomenology and clinical correlates of suicidal thoughts and behaviors in youth with autism spectrum disorders.

This study investigated the phenomenology and clinical correlates of suicidal thoughts and behaviors in youth with ASD (N = 102; range 7-16 years). The presence of suicidal thoughts and behavior was assessed through the Anxiety Disorders Interview Schedule-Child and Parent Versions. Children and parents completed measures of anxiety severity, functional impairment, and behavioral and emotional problems. Approximately 11 % of youth displayed suicidal thoughts and behaviors. Children with autism were more likely to have suicidal thoughts and behaviors whereas children with Asperger's disorder were less likely. Suicidal thoughts and behaviors were associated with the presence of depression and post-traumatic stress disorder. Overall, results suggest that suicidal thoughts and behaviors are common in youth with ASD, and may be related to depression and trauma.

Tonsillectomies and adenoidectomies do not prevent the onset of pediatric autoimmune neuropsychiatric disorder associated with group A streptococcus.

BACKGROUND: In children presenting with obsessive compulsive disorder (OCD) and/or tics, especially those with a temporal association with streptococcal pharyngitis (eg, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), there is speculation about whether tonsillectomy/adenoidectomy might improve the child's neuropsychiatric course. Our objective was to examine whether removal of the tonsils and/or adenoids impacted streptococcal antibody titers, the timing of onset of OCD and/or tics and the clinical severity of these symptoms. METHODS: Study participants (N = 112; average age = 9.2 ± 2.4; 44 women) were recruited as part of a prospective investigation of neuropsychiatric phenomena with temporal association to streptococcal pharyngitis and examined by family history, diagnostic interview, physical examination, medical record review, psychological testing and streptococcal antibodies and divided into surgical or nonsurgical groups. The surgical group consisted of children having previously had a tonsillectomy and/or adenoidectomy (n = 32). The remaining children were categorized as nonsurgical group (n = 76). Measures of OCD and tic severity, streptococcal antibody titers and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus classification were compared between both groups. RESULTS: There were no significant differences as determined by streptococcal antibody titers, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus classification and OCD or tic severity between the surgical and nonsurgical groups. Most participants had surgery before the onset of neuropsychiatric symptoms and surgery did not affect symptomology. CONCLUSIONS: Streptococcal antibodies and neuropsychiatric symptom severity did not differ on the basis of surgical status. From these data, we cannot infer that tonsillectomy and adenoidectomy are likely to impact positively the course of OCD/tics or streptococcal antibody concentrations.

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.

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.).

Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus.

This study evaluated neurocognitive functioning in 26 youth with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and primarily obsessive-compulsive disorder (OCD) symptoms. Marked impairment in visuospatial recall memory (as assessed using the Rey-Osterrieth Complex Figure Test) was observed in spite of average to above-average performance on academic and other neurocognitive measures. Group A beta-hemolytic Streptococcus titer elevations were associated with worse performance on tasks of neurocognitive and executive ability (Stroop Color-Word Interference Test), visuospatial memory, and fine motor speed (finger tapping) as well as elevated obsessive-compulsive symptom severity.

Development and Psychometric Evaluation of the Treatment-Emergent Activation and Suicidality Assessment Profile.

Although effective in treating a range of childhood psychiatric conditions, selective serotonin reuptake inhibitors (SSRI) have been implicated in the induction of an "activation syndrome" (characterized by symptoms of irritability, restlessness, emotional labiality, etc.) that may represent an intermediary state change that fosters suicidality. SSRI-induced activation syndrome is well-accepted by many clinicians and thought to be relatively common, particularly in children and teens. However, gaps exist in empirical data on phenomenology and tools for early detection. With this in mind, we report on a recently funded National Institutes of Health grant to develop a measure of behavioral activation to be completed in a clinical setting. We discuss the development of this measure-the Treatment-Emergent Activation and Suicidality Assessment Profile (TE-ASAP)-as well as psychometric results from a sample of youth with internalizing disorders who were at varying stages of SSRI treatment. Overall, psychometric data were quite promising, with the TE-ASAP demonstrating excellent reliability (i.e., internal consistency, inter-rater, short-term test-retest stability) and strong validity properties. Through further evaluation of the TE-ASAP in the context of a controlled multimodal trial in youth with obsessive-compulsive disorder, we hope to augment understanding of activation syndrome and, in turn, mitigate risks through early detection of this potentially lifethreatening adverse effect.

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.