Thomas W. Frazier

Meta-analysis of intellectual and neuropsychological test performance in attention-deficit/hyperactivity disorder.

Cognitive measures are used frequently in the assessment and diagnosis of attention-deficit/hyperactivity disorder (ADHD). In this meta-analytic review, the authors sought to examine the magnitude of differences between ADHD and healthy participants on several commonly used intellectual and neuropsychological measures. Effect sizes for overall intellectual ability (Full Scale IQ; FSIQ) were significantly different between ADHD and healthy participants (weighted d =.61). Effect sizes for FSIQ were significantly smaller than those for spelling and arithmetic achievement tests and marginally significantly smaller than those for continuous performance tests but were comparable to effect sizes for all other measures. These findings indicate that overall cognitive ability is significantly lower among persons with ADHD and that FSIQ may show as large a difference between ADHD and control participants as most other measures.

ADHD and Achievement Meta-Analysis of the Child, Adolescent, and Adult Literatures and a Concomitant Study With College Students

This article presents results from two interrelated studies. The first study conducted a meta-analysis of the published literature since 1990 to determine the magnitude of achievement problems associated with attention-deficit/hyperactivity disorder (ADHD). Effect sizes were significantly different between participants with and without ADHD (sample weighted r = .32, sample weighted d = . 71; p = .001). Effects were also examined according to the moderators of age, gender, achievement domain (reading, math, spelling), measurement method (standardized tests vs. grades, parent/teacher ratings, etc.), sample type (clinical vs. nonclinical), and system used to identify ADHD (DSM-III-R vs. DSM-IV). Significant differences emerged from the moderator comparisons. The second study, using averaged effect sizes from the first study as a baseline for comparison, investigated achievement levels for an understudied age group with ADHD, namely, college students. Unlike previous studies at the college level, the sample incorporated both student and parent ratings (N = 380 dyads). The results were comparable to outcomes from the meta-analysis for college students and adults. Analyses demonstrated modest (R = .21) but meaningful predictive validity across 1 year to end-of-first-year grades. However, unlike earlier studies with children and adolescents, student ratings were as predictive as parent ratings. Findings are discussed in terms of the impact of moderator variables on ADHD and achievement.

Sibling Recurrence and the Genetic Epidemiology of Autism

OBJECTIVE Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. METHOD The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. RESULTS A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families and a relative absence of quantitative autistic traits among siblings in single-incidence families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts. CONCLUSIONS These data suggest that, depending on how it is defined, sibling recurrence in autism spectrum disorder may exceed previously published estimates and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism and advance current understanding of the genetic epidemiology of autism spectrum conditions.

Validation of proposed DSM-5 criteria for autism spectrum disorder.

OBJECTIVE The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD). METHOD We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD. RESULTS A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97). CONCLUSIONS Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.

A Meta-Analysis of the Corpus Callosum in Autism

BACKGROUND Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism. METHOD PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements. RESULTS Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons. CONCLUSIONS Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

A randomized controlled pilot trial of oral N-acetylcysteine in children with autism.

BACKGROUND An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism. METHODS This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale. RESULTS Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96). CONCLUSIONS Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

Behavioral and Cognitive Characteristics of Females and Males With Autism in the Simons Simplex Collection

OBJECTIVE To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD). METHOD We analyzed data from 2,418 probands with autism (304 females and 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure that sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or were driven by cognitive ability. RESULTS Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability. CONCLUSIONS A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high-functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high-functioning cases are reduced if female-specific indicators of restricted interests are included.

Examining the Proposed Disruptive Mood Dysregulation Disorder Diagnosis in Children in the Longitudinal Assessment of Manic Symptoms Study

OBJECTIVE To examine the proposed disruptive mood dysregulation disorder (DMDD) diagnosis in a child psychiatric outpatient population. Evaluation of DMDD included 4 domains: clinical phenomenology, delimitation from other diagnoses, longitudinal stability, and association with parental psychiatric disorders. METHOD Data were obtained from 706 children aged 6-12 years who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) study (sample was accrued from November 2005 to November 2008). DSM-IV criteria were used, and assessments, which included diagnostic, symptomatic, and functional measures, were performed at intake and at 12 and 24 months of follow-up. For the current post hoc analyses, a retrospective diagnosis of DMDD was constructed using items from the K-SADS-PL-W, a version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children, which resulted in criteria closely matching the proposed DSM-5 criteria for DMDD. RESULTS At intake, 26% of participants met the operational DMDD criteria. DMDD+ vs DMDD- participants had higher rates of oppositional defiant disorder (relative risk [RR] = 3.9, P < .0001) and conduct disorder (RR = 4.5, P < .0001). On multivariate analysis, DMDD+ participants had higher rates of and more severe symptoms of oppositional defiant disorder (rate and symptom severity P values < .0001) and conduct disorder (rate, P < .0001; symptom severity, P = .01), but did not differ in the rates of mood, anxiety, or attention-deficit/hyperactivity disorders or in severity of inattentive, hyperactive, manic, depressive, or anxiety symptoms. Most of the participants with oppositional defiant disorder (58%) or conduct disorder (61%) met DMDD criteria, but those who were DMDD+ vs DMDD- did not differ in diagnostic comorbidity, symptom severity, or functional impairment. Over 2-year follow-up, 40% of the LAMS sample met DMDD criteria at least once, but 52% of these participants met criteria at only 1 assessment. DMDD was not associated with new onset of mood or anxiety disorders or with parental psychiatric history. CONCLUSIONS In this clinical sample, DMDD could not be delimited from oppositional defiant disorder and conduct disorder, had limited diagnostic stability, and was not associated with current, future-onset, or parental history of mood or anxiety disorders. These findings raise concerns about the diagnostic utility of DMDD in clinical populations.

A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder.

Bipolar disorder (BD) is an increasingly prevalent diagnosis in youth. As a result, there has been a corresponding increase in interest about neuropsychological and cognitive profiles in children and adolescents diagnosed with BD. Meta-analysis of the existing literature comparing individuals with BD to healthy controls indicated that the largest differences are observed for measures of verbal memory (d = 0.77). Moderate differences were found in the areas of attention (d = 0.62), executive functioning (d = 0.62), working memory (d = 0.60), visual memory (d = 0.51), visual perceptual skills (d = 0.48), and verbal fluency (d = 0.45). Small differences were found for measures of reading (d = 0.40), motor speed (d = 0.33), and full-scale intelligence quotient (IQ) (d = 0.32). Often, few studies have provided relevant information for a particular neurocognitive domain. Despite this, several domains displayed heterogeneity of effect sizes across studies. Methodological factors explained the variance in effect sizes to different extents depending upon the cognitive domain. The changing influence of method artifacts is likely due to variable coverage of cognitive domains across studies and the use of different measures across studies. Findings are consistent with previous meta-analyses of the adult BD neurocognitive literature, suggesting that many of the deficits observed in adults are present earlier in the course of the illness. Study reporting guidelines are offered that may help clarify the impact of illness definitions, mood state, medication status, and other methodological variables on neurocognition in pediatric BD.

Characteristics of children with elevated symptoms of mania: The Longitudinal Assessment of Manic Symptoms (LAMS) study

OBJECTIVE The aim of the Longitudinal Assessment of Manic Symptoms (LAMS) study is to examine differences in psychiatric symptomatology, diagnoses, demographics, functioning, and psychotropic medication exposure in children with elevated symptoms of mania (ESM) compared to youth without ESM. This article describes the initial demographic information, diagnostic and symptom prevalence, and medication exposure for the LAMS cohort that will be followed longitudinally. METHOD Guardians of consecutively ascertained new outpatients 6 to 12 years of age presenting for treatment at one of 10 university-affiliated mental health centers were asked to complete the Parent General Behavior Inventory-10-Item Mania Scale (PGBI-10M). Patients with scores ≥ 12 on the PGBI-10M (ESM+) and a matched sample of patients who screened negative (ESM-) were invited to participate. Patients were enrolled from December 13, 2005, to December 18, 2008. RESULTS 707 children (621 ESM+, 86 ESM-; mean [SD] age = 9.4 [2.0] years) were evaluated. The ESM+ group, compared to the ESM- group, more frequently met DSM-IV criteria for a mood disorder (P < .001), bipolar spectrum disorders (BPSD; P < .001), and disruptive behavior disorders (P < .01). Furthermore, they showed poorer overall functioning and more severe manic, depressive, attention-deficit/hyperactivity, disruptive behavioral, and anxiety symptoms. Nevertheless, rates of BPSD were relatively low in the ESM+ group (25%), with almost half of these BPSD patients (12.1% of ESM+ patients) meeting DSM-IV criteria for bipolar disorder not otherwise specified. ESM+ children with BPSD had significantly more of the following: current prescriptions for antipsychotics, mood stabilizers, and anticonvulsants (P < .001 for each); psychiatric hospitalizations (P < .001); and biological parents with elevated mood (P = .001 for mothers, P < .013 for fathers). ESM+ children with BPSD were also lower functioning compared to ESM+ children without BPSD. CONCLUSIONS Although ESM+ was associated with higher rates of BPSD than ESM-, 75% of ESM+ children did not meet criteria for BPSD. Results suggest that longitudinal assessment is needed to examine which factors are associated with diagnostic evolution to BPSD in children with elevated symptoms of mania.