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1.  Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia 
Objective: The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia.
Methods: In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12–17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE).
Results: A similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (−4.8 for 2.5 mg b.i.d., p=0.070; −5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean −0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by −16.1 points in the group previously treated with placebo (n=62) and by −11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26.
Conclusions: Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia.
Clinical Trials Registry: NCT01190254 and NCT1190267 at
PMCID: PMC4491161  PMID: 26091193
2.  A double-blind placebo controlled study of risperidone for the treatment of adolescents and young adults with anorexia nervosa: a pilot study 
The purpose of this double-blind, placebo controlled exploratory pilot study was to evaluate the safety and efficacy of risperidone for the treatment of anorexia nervosa (AN). Method: Forty females ages 12–21 (mean 16) years, with primary AN in an eating disorders program were randomized to receive risperidone (R, N=18) or placebo (PL, N=22). Subjects completed the Eating Disorder Inventory (EDI-2), Color-A-Person Test, Body Image Software and Multidimensional Anxiety Scale for Children at baseline and regular intervals. Weight, labs, and ECG were monitored. Study medication was started at 0.5 mg daily and titrated upward weekly in 0.5 mg increments to a maximum dose of 4 mg until the subject reached a study end point. Results: Mean dose for the risperidone group was 2.5 mg and in the Placebo group 3 mg, for a mean duration of 9 weeks. R subjects had a significant decrease on the EDI-2 "Drive for Thinness" subscale over the first 7 weeks (p=0.002, effect size 0.88), but this difference was not sustained to study end (p=0.13). The EDI-2 "Interpersonal Distrust" subscale decreased significantly more in R subjects (p=0.03, effect size 0.60). R subjects had increased prolactin levels (week 7, p=0.001). There were no significant differences between groups at baseline or study end for the other rating scales, change in weight or laboratory measures. Conclusions: This study does not demonstrate a benefit for the addition of risperidone in adolescents with AN during the weight restoration phase of care.
PMCID: PMC3171450  PMID: 21871373
Anorexia nervosa; adolescents; risperidone; neuroleptics; psychopharmacology
3.  Improving Psychiatric Hospital Care for Pediatric Patients with Autism Spectrum Disorders and Intellectual Disabilities 
Autism Research and Treatment  2012;2012:685053.
Pediatric patients with autism spectrum disorders (ASD) and/or intellectual disabilities (ID) are at greater risk for psychiatric hospitalization compared to children with other disorders. However, general psychiatric hospital environments are not adapted for the unique learning styles, needs, and abilities of this population, and there are few specialized hospital-based psychiatric care programs in the United States. This paper compares patient outcomes from a specialized psychiatric hospital program developed for pediatric patients with an ASD and/or ID to prior outcomes of this patient population in a general psychiatric program at a children's hospital. Record review data indicate improved outcomes for patients in the specialized program of reduced recidivism rates (12% versus 33%) and decreased average lengths of inpatient stay (as short as 26 days versus 45 days). Available data from a subset of patients (n = 43) in the specialized program showed a decrease in irritability and hyperactivity behaviors from admission to discharge and that 35 previously undetected ASD diagnoses were made. Results from this preliminary study support specialized psychiatric care practices with this population to positively impact their health care outcomes.
PMCID: PMC3420632  PMID: 22934179
4.  Asthma symptom perception and obesity in children☆ 
Biological Psychology  2009;84(1):135-141.
This study examined the relationship between obesity and asthma symptom perception in 200 youth with asthma. Repeated subjective and objective peak flow measurements were summarized using the Asthma Risk Grid (Klein et al., 2004), resulting in Accurate, Symptom Magnification and Danger Zone scores. Analyses were stratified by age and included ethnicity.
For younger children, obesity was not significantly related to perception scores. For older children, a significant obesity-by-ethnicity interaction for Accurate Symptom Perception scores indicated that obese white children had lower accuracy than white nonobese children, while there was no difference for obese versus nonobese minority children. Obesity was also related to higher Symptom Magnification scores regardless of ethnicity for older children.
These findings suggest that obesity may complicate asthma management by interfering with the ability to accurately perceive symptoms for some patients. More remains to be learned about the role of sociodemographic factors underlying this relationship.
PMCID: PMC3278964  PMID: 19941934
Asthma; Body mass index; Obesity; Symptom perception; Children
5.  Isochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder 
A small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder.
Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms.
We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features.
PMCID: PMC3274485  PMID: 22214315
Attention deficit hyperactivity disorder; Chromosome 13; Isochromosome; Schizophrenia; childhood
6.  The α7 Nicotinic Acetylcholine Receptor and The Acute Stress Response: Maternal Genotype Determines Offspring Phenotype 
Physiology & behavior  2010;104(2):321-326.
α7 nicotinic acetylcholine receptors (α7nAchRs) modulate immune activation by suppressing production of pro-inflammatory cytokines in peripheral immune cells. α7nAchRs also modulate inhibitory output in the hippocampus, which provides input to key circuits of the HPA axis. Therefore the α7 nicotinic acetylcholine receptor gene (CHRNA7) may be associated with cortisol stress response. Polymorphisms in the CHRNA7 promoter decrease its expression and may dampen the cholinergic response, leading to an increase in inflammation. Increased inflammation may change the intrauterine environment, altering neuroendocrine development in the offspring. Maternal CHRNA7 genotype could affect an offspring’s HPA regulation via reprogramming in utero. Patients with allergic disorders have a differential cortisol response to stress. This study utilized samples collected from a cohort of 198 adolescents in a previous study of atopic disorders, who demonstrated a disturbance in HPA response associated with atopy. Salivary cortisol samples collected from the adolescents after a series of laboratory procedures and DNA samples collected from the adolescents and their parents were used for further analysis. DNA samples were genotyped for allelic variation in the CHRNA7 promoter. Genetic association analyses with the cortisol levels were performed in the adolescents. Maternal genotype influences were investigated for the CHRNA7 gene. We also included maternal and child atopy diagnosis as covariates in determining cortisol levels and tested for association of CHRNA7 to atopy. Polymorphisms in the CHRNA7 promoter were associated with lower cortisol levels after a small laboratory stress. Our findings also show that although the child’s CHRNA7 genotype affects stress response, the maternal genotype has a stronger influence on cortisol release after stress in male offspring. These effects were independent of atopy status.
PMCID: PMC3094732  PMID: 21073885
Stress; Cortisol; Genetics; Association Study; Adolescents
7.  Do Family Mealtime Interactions Mediate the Association Between Asthma Symptoms and Separation Anxiety? 
Respiratory problems have been shown to be associated with the development of panic anxiety. Family members play an essential role for children to emotionally manage their symptoms. This study aimed to examine the relation between severity of respiratory symptoms in children with asthma and separation anxiety. Relying on direct observation of family interactions during a mealtime, a model is tested whereby family interactions mediate the relation between asthma severity and separation anxiety symptoms.
Sixty-three children (ages 9 – 12 years) with persistent asthma were interviewed via the Diagnostic Interview Schedule for Children IV; family interactions were assessed via direct observation of a mealtime; primary caregivers completed the Childhood Asthma Severity Scale; youth pulmonary function was ascertained with pre and post-bronchodilator spirometry; adherence to asthma medications was objectively tracked for six weeks.
Poorer pulmonary function and higher functional asthma severity were related to higher numbers of separation anxiety symptoms. Controlling for medication adherence, family interaction patterns mediated the relationship between poorer pulmonary function and child separation anxiety symptoms.
Family mealtime interactions may be a mechanism by which respiratory disorders are associated with separation anxiety symptoms in children, potentially through increasing the child's capacity to cognitively frame asthma symptoms as less threatening, or through increasing the child's sense of security within their family relationships.
PMCID: PMC2804777  PMID: 19754662
8.  Symptom Perception and Functional Morbidity Across a 1-Year Follow-up in Pediatric Asthma 
Pediatric pulmonology  2007;42(4):339-347.
The purpose of this study was to examine the association between asthma symptom perception measured during a 5–6 week baseline and functional morbidity measured prospectively across a 1-year follow-up. Symptom perception was measured by comparing subjective ratings with peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV1). We hypothesized that accurate symptom perception (ASP) would be associated with less functional morbidity. Participants consisted of 198 children with asthma ages 7–17 recruited from three sites. The children used a programmable electronic spirometer in the home setting to guess their PEFR prior to exhalation. Each “subjective” guess was classified as being in an ASP, dangerous symptom perception (DSP; underestimation of symptoms), or symptom magnification (SM; overestimation) zone based upon the corresponding measurement of PEFR or FEV1. An index of functional morbidity was collected by parent report at baseline and across 1-year follow-up. A greater proportion of ASP blows and a lower proportion of DSP blows based on PEFR predicted less functional morbidity reported at baseline, independent of asthma severity and race/ethnicity. A greater proportion of ASP blows (using PEFR and FEV1) and a lower proportion of SM blows (using FEV1) predicted less functional morbidity across 1-year follow-up. Symptom perception was not associated with emergency department visits for asthma at baseline or across follow-up. In comparison to PEFR, FEV1 more frequently detected a decline in pulmonary function that children did not report. Symptom perception measured in naturalistic settings was associated with functional morbidity at baseline and prospectively across 1-year follow-up. Support was found for including multiple measures of pulmonary function in the assessment of asthma symptom perception.
PMCID: PMC2966282  PMID: 17358038
asthma; forced expiratory volume; morbidity; peak expiratory flow rate; perception
9.  Frequency and Correlates of Overweight Status in Adolescent Asthma 
Debate exists within the literature concerning whether asthma and obesity are linked as comorbid conditions. Further study is required to understand the relationship between asthma and overweight status, and developmental considerations are an important priority area.
The present study addressed gaps in the existing literature by comparing rates of overweight status among a matched sample of adolescents with and without asthma and by examining correlates of overweight status among youth with asthma.
Rates and correlates of overweight status were compared among a matched cohort of 103 adolescents with asthma, 75 adolescents with asthma characterized by history of a severe acute event, and 92 normal controls.
Significantly higher rates of overweight status were found among the asthma groups compared to the control group and to population estimates. Significant correlates for overweight status included younger age and earlier age at asthma diagnosis, suggesting that receiving an asthma diagnoses in early childhood may increase the propensity for weight gain.
Asthma and obesity are problematic comorbid conditions, and specialized obesity prevention programs may be particularly necessary at the onset of a new asthma diagnosis.
Clinical Implications
Identifying and addressing the factors that may contribute to the potential for obesity among youth with asthma are key research and clinical practice priorities.
PMCID: PMC2694940  PMID: 18350405
asthma; adolescent; overweight; obesity
10.  Symptom Perception in Children with Asthma: Cognitive and Psychological Factors 
This study tested the differential effects of several cognitive and psychological variables on children's perception of asthma symptoms by use of an Asthma Risk Grid. Children's subjective and objective assessments of PEFR (peak expiratory flow rate) were characterized as representing perceptual accuracy, symptom magnification, and/or underestimation of asthma symptoms.
Two hundred and seventy children with asthma (ages 7-17) and their primary caregivers completed measures assessing cognitive and psychological factors and a 5-6 week symptom perception assessment.
Main Outcome Measures:
Children's symptom perception scores by use of the Asthma Risk Grid.
Children's attentional abilities had more of a bearing on their symptom monitoring abilities than their IQ estimates and psychological symptoms. The more time children took on Trails and Cancellation Tasks and the fewer errors they made on these tasks, the more likely they were to perceive their asthma symptoms accurately. More time on these tasks were associated with more symptom magnification scores, and fewer errors were related with fewer symptom magnification scores. More errors and higher total scores on the Continuous Performance Task were associated with a greater proportion of scores in the danger zone.
Statistical support was provided for the utility of attentional-based instruments for identifying children who may have problems with perceptual accuracy, and who are at risk for asthma morbidity.
PMCID: PMC2658619  PMID: 19290715
Asthma; symptom perception; cognitive and psychological factors
11.  Pediatric Asthma and Problems in Attention, Concentration, and Impulsivity 
This study assesses the relationships between ADHD symptoms, specific family asthma management domains, and pediatric asthma morbidity.
Participants were 110 children with asthma and a respective parent (ages 7-17, X = 11.6 years, 25% ethnic/racial minority). Parents completed measures of asthma morbidity and report of child ADHD symptoms. Children completed measures of attention, concentration, and impulsivity. Families participated in the Family Asthma Management System Scale (FAMSS) interview to assess the effectiveness of eight features of asthma management.
Parent report of ADHD symptoms and poor child performance on a computerized task of sustained visual attention were associated with asthma morbidity. Paper and pencil tasks of visual attention, and an index of auditory attention, were not related to asthma morbidity. Modest associations were found between parent report of ADHD symptoms, child performance-based indicators of attention and concentration, and features of family asthma management, although not across all measures. The family response to asthma partially mediated the relationship between ADHD symptoms and morbidity.
ADHD symptoms are modestly associated with difficulties in family asthma management.
PMCID: PMC2636964  PMID: 19198669

Results 1-11 (11)