Showing papers by "Stephen V. Faraone published in 2001"

Normal Sexual Dimorphism of the Adult Human Brain Assessed by In Vivo Magnetic Resonance Imaging

Abstract: The etiology and consistency of findings on normal sexual dimorphisms of the adult human brain are unresolved. In this study, we present a comprehensive evaluation of normal sexual dimorphisms of cortical and subcortical brain regions, using in vivo magnetic resonance imaging, in a community sample of 48 normal adults. The men and women were similar in age, education, ethnicity, socioeconomic status, general intelligence and handedness. Forty-five brain regions were assessed based on T1-weighted three-dimensional images acquired from a 1.5 T magnet. Sexual dimorphisms of adult brain volumes were more evident in the cortex, with women having larger volumes, relative to cerebrum size, particularly in frontal and medial paralimbic cortices. Men had larger volumes, relative to cerebrum size, in frontomedial cortex, the amygdala and hypothalamus. A permutation test showed that, compared to other brain areas assessed in this study, there was greater sexual dimorphism among brain areas that are homologous with those identified in animal studies showing greater levels of sex steroid receptors during critical periods of brain development. These findings have implications for developmental studies that would directly test hypotheses about mechanisms relating sex steroid hormones to sexual dimorphisms in humans.

Meta-analysis of the association between the 7-repeat allele of the dopamine D (4) receptor gene and attention deficit hyperactivity disorder

Abstract: OBJECTIVE: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D4 receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. METHOD: Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. RESULTS: For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. CONCLUSIONS: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nea...

Further evidence of association between behavioral inhibition and social anxiety in children.

Abstract: OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibit...

Genes, environment and schizophrenia

Abstract: Background Data from family, twin and adoption studies show over whelming evidence of a substantial genetic component in schizophrenia and although molecular genetic studies have been more difficult to replicate, recent improvements in technology have resulted in the implication of genes at several chromosomal loci. Nevertheless, it remains clear that environmental factors both add to and interact with genetic factors to produce the disorder. Aims To incorporate genetic and environmental risk factors into a neurodevelopmental model in order to conceptualise the liability to schizophrenia. Method A representative selection of the literature related to this issue is reviewed, together with a reformulation of Meehl's term ‘ schizotaxia’ to describe the liability to the disorder. Results The literature supports a multi-factorial view of the liability to schizophrenia, which includes both genetic and environmental components. Conclusions Schizotaxia provides a useful way to conceptualise both the liability for schizophrenia, and also the development of treatment strategies aimed at the eventual prevention of the illness.

Developmental aspects of obsessive compulsive disorder: findings in children, adolescents, and adults.

Abstract: Although juvenile obsessive compulsive disorder (OCD) is increasingly recognized as a putative developmental subtype of the disorder, comparisons among children, adolescents, and adults with OCD have been lacking. We aimed to evaluate clinical correlates of OCD in three developmentally distinct groups. Subjects comprised children, adolescents, and adults meeting DSM-III-R and DSM-IV criteria for OCD referred to separate specialized OCD clinics. All subjects were systematically evaluated with structured diagnostic interviews and clinical assessments by OCD experts. Specific clinical correlates and symptom profiles were associated with the disorder in different age groups. These findings support a hypothesis of developmental discontinuity between juvenile and adult OCD and identify age specific correlates of the disorder across the life cycle. Further work is needed to validate whether juvenile-onset OCD represents a true developmental subtype of the disorder.

Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression.

Abstract: OBJECTIVE: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. METHOD: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). RESULTS: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and ...

Efficacy of a Mixed Amphetamine Salts Compound in Adults With Attention-Deficit/ Hyperactivity Disorder

Abstract: Background We report on a controlled trial of a mixed amphetamine salts compound (Adderall, dextroamphetamine sulfate, dextro-, levoamphetamine sulfate, dextroamphetamine aspartate, levoamphetamine aspartate, and dextroamphetamine saccharate) in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Methods This was a 7-week, randomized, double-blind, placebo-controlled, crossover study of Adderall in 27 well-characterized adults satisfying full DSM-IV criteria for ADHD of childhood onset and persistent symptoms into adulthood. Medication was titrated up to 30 mg twice a day. Outcome measures included the ADHD Rating Scale and the Clinical Global Impression Score. Comorbid psychiatric disorders were assessed to test for potential effects on treatment outcome. Results Treatment with Adderall at an average oral dose of 54 mg (administered in 2 daily doses) was effective and well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall (42% decrease on the ADHD Rating Scale, P P P = .001). Conclusions Adderall was effective and well tolerated in the short-term treatment of adults with ADHD. More work is needed to evaluate the long-term effects of Adderall, or other amphetamine compounds, in the treatment of adults with ADHD.

Social impairment in girls with ADHD: patterns, gender comparisons, and correlates.

Abstract: Objective To investigate social impairment in girls with attention-deficit/hyperactivity disorder (ADHD), compare the social functioning of boys and girls with ADHD, and explore the association between social dysfunction and conditions comorbid with ADHD. Method Four groups of index children were studied: 267 children (127 girls) with ADHD and 234 non-ADHD comparison children (114 girls). Groups were compared on social functioning, psychopathology, and demographic characteristics. Results Girls with ADHD manifested significant deficits in interpersonal functioning compared with girls without ADHD and evidenced a similar degree of social impairment compared with boys with ADHD. ADHD and associated comorbid disorders were significant correlates of specific domains of social dysfunction in boys and girls with ADHD. Conclusions Interpersonal deficits are a major correlate of ADHD, irrespective of gender, and appear to stem from the behaviors associated with ADHD as well as behaviors characteristic of conditions comorbid with ADHD.

Learning disabilities and executive dysfunction in boys with attention-deficit/hyperactivity disorder.

Abstract: The effect of comorbid reading or arithmetic learning disabilities (LDs) on neuropsychological function in attention-deficit/hyperactivity disorder (ADHD) was studied. Participants were young males diagnosed with ADHD, with and without LD, and non-ADHD, non-LD male controls of similar age. LD was defined by combined regression-based and low-achievement classifications. Analyses adjusted for the effect of psychiatric comorbidity, age, and socioeconomic status on neuropsychological function. Children who had both ADHD and LD were significantly more impaired on both executive and nonexecutive functions than ADHD children without LD. Neuropsychological performance was most impaired in ADHD with combined arithmetic and reading disability. These data indicate that comorbid LD, especially arithmetic disability, significantly increases the severity of executive function impairment in ADHD.

Should the diagnosis of Attention-Deficit/ Hyperactivity disorder be considered in children with Pervasive Developmental Disorder?

Abstract: Objective: To assess the overlap between Pervasive Developmental Disorder (PDD) and Attention-Deficit/Hyperactivity Disorder (ADHD) in a consecutive sample of referred youth. We hypothesized that children with PDD plus ADHD-like symptoms would have a symptom profile similar to ADHD children.Method: Subjects were consecutively referred children meeting DSM-III-R criteria for PDD with (PDD+ADHD, N = 50) and without (PDD, N= 10) ADHD-like symptoms and ADHD without PDD (ADHD, N= 105). All subjects were comprehensively assessed with structured diagnostic interviews.Results: Clinical characteristics of PDD were similar in those PDD children who did and who did not have ADHD, and ADHD features were very similar in ADHD children with and without PDD.Conclusion: These results suggest that children with PDD with concomitant symptoms of inattention, hyperactivity and impulsivity may have true comorbid ADHD. If confirmed, these findings challenge the exclusionary criteria for the diagnosis of ADHD in PDD youth.

An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder

Abstract: Objective: The goal of this study was to evaluate the tolerability and effectiveness of the experimental, noradrenergic specific reuptake inhibitor atomoxetine in the treatment of children with att...

Traumatic brain injury and Schizophrenia in Members of Schizophrenia and bipolar disorder pedigrees

Abstract: OBJECTIVE: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. METHOD: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. RESULTS: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those wit...

“Schizotaxia”: Clinical Implications and New Directions for Research

Abstract: We sought to show that (1) schizotaxia (Meehl's term for the predisposition to schizophrenia) is a clinically consequential condition, and (2) distinguishing it from schizotypal personality disorder may be useful from both clinical and scientific perspectives. We review the features of schizotaxia that may be relevant in clinical settings and discuss their implications for the diagnosis, psychosocial functioning, family intervention and treatment of people in schizophrenia families. Our review indicates that prior work finds some of the nonpsychotic and nonschizotypal relatives of schizophrenia patients to have a psychiatric syndrome characterized by negative symptoms, neuropsychological impairment, and psychosocial dysfunction. Following Meehl, we call this constellation of clinical and neurobiological features schizotaxia. The studies we review suggest it may be worthwhile to consider schizotaxia as a separate diagnostic class. Doing so would alert clinicians to a neurobehavioral syndrome not adequately covered by current diagnostic criteria and would motivate researchers to develop diagnostic and therapeutic approaches aimed at helping schizotaxic individuals and, perhaps, preventing the onset of schizophrenia.

Evidence for the multigenic inheritance of schizophrenia.

Abstract: Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the α7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci. © 2001 Wiley-Liss, Inc.

Impact of Tic Disorders on ADHD Outcome Across the Life Cycle: Findings From a Large Group of Adults With and Without ADHD

Abstract: OBJECTIVE: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. METHOD: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. RESULTS: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. CONCLUSIONS: These findings in adults with ADHD confirm and ex...

Patterns of remission and symptom decline in conduct disorder: a four-year prospective study of an ADHD sample.

Abstract: Objective To evaluate systematically the longitudinal course of conduct disorder (CD) in a sample of youths with attention-deficit hyperactivity disorder (ADHD) to determine the effects of a persistent course on outcome. Method One hundred forty children with ADHD and their nuclear families were assessed at baseline and again at 1 and 4 years. Subjects were examined by means of DSM-III-R–based structured interviews. They were also evaluated for cognitive and social functioning. Persistent (exhibiting symptoms of CD at either follow-up) and desistent (symptoms of CD at neither follow-up) cases were identified. Results Forty-two percent of CD cases followed a persistent course. Although both persistent and desistent subjects had high rates of antisocial disorders in relatives, increased family conflict and decreased family cohesion were selectively associated with a persistent course. In addition, subjects with persistent symptoms of CD exhibited more impaired ratings on the Aggression and Delinquency subscales of the Child Behavior Checklist, as well as higher rates of bipolar, oppositional defiant, and substance use disorders. Conclusions These findings suggest that the poor prognosis associated with CD is limited to an identifiable subgroup with a persistent course.

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.

Abstract: Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds.

A psychometric measure of learning disability predicts educational failure four years later in boys with Attention-Deficit/Hyperactivity Disorder

Abstract: Objective: Although most children with ADHD experience school problems, only a subset of these youth meet psychometric criteria for learning disabilities (LD) in reading or mathematics. Considering the well-documented adverse impact of both ADHD and LD on school performance, the presence of both conditions in a given child may herald a particularly poor educational outcome for affected youth. This issue has not been adequately addressed in previous follow-up studies of ADHD.Design: In a four-year follow-up study of ADHD children, the educational, psychiatric, and psychosocial outcomes in ADHD youth with and without LD were examined.Results: Among children with ADHD, LD at baseline selectively predicted poorer educational functioning at follow-up, as manifested by higher rates of grade retention, in-school tutoring, and placement in special classes. In contrast, psychiatric comorbidity and psychosocial outcomes were comparable in ADHD youth with and without LD.Conclusions: Results suggest that LD predicts ...

Adult attention deficit hyperactivity disorder.

Abstract: Monitor the cardiovascular health of those using the drugs, especially older adults with medical conditions. Health care practitioners should remain vigilant about the potential for misuse/abuse/diversion of stimulant medications. • Strategies and programs to prevent diversion could potentially reduce overall misuse of these medications. No age restriction should be applied to stimulants or atomoxetine. • There is insufficient evidence to suggest that age affects response to ADHD treatment in adult patients. • It is important to note that a review of the literature indicates that misuse/abuse/ diversion occurs, and is especially prevalent in college-age students. • However the number of potentially inappropriate prescriptions in Canada is low (<0.3% in 2013/14) and more research is needed. • Ontario had the highest rate, followed by Alberta, and British Columbia. • Overall, stimulant drugs are associated with an improvement in symptoms. • The non-stimulant drug, atomoxetine, has similar efficacy to the stimulants. • There are several common side effects with both types of drugs such insomnia, dry mouth and decreased appetite. ű Health Canada has issued several warnings including possible increased risk of sudden/cardiac death, and increased risk of suicidal thoughts and behaviours. • Long-term stimulant treatment is associated with increases in blood pressure and heart rate. However, there is little data on the long-term safety of stimulants in older adults (50+) with medical conditions. • In Canada, there are two types of treatment approved for the treatment of adult ADHD.

Disentangling chronological age from age of onset in children and adolescents with obsessive--compulsive disorder

Abstract: Although paediatric obsessive--compulsive disorder (OCD) is increasingly recognized as a putative developmental subtype of the disorder, it remains uncertain as to whether additional subtyping by age at onset in childhood or adolescence is warranted. Subjects included children and adolescents meeting DSM-III-R and DSM-IV criteria for OCD referred to a specialized OCD clinic. All youth were systematically evaluated with structured diagnostic interviews and clinical assessment by an OCD expert. Irrespective of current age, an earlier age at onset predicted increased risk for attention deficit hyperactivity disorder, simple phobia, agoraphobia and multiple anxiety disorders. In contrast, mood and psychotic disorders were associated with chronological age and were more prevalent in older subjects. Tourette's disorder showed associations with both chronological age and age at onset. Chronological age and age at onset predicted different patterns of comorbidity and dysfunction in children and adolescents with OCD. Considering the heterogeneity of OCD, age at onset may help identify meaningful developmental subtypes of the disorder beyond chronological age.

Long-term stability of the Child Behavior Checklist in a clinical sample of youth with attention deficit hyperactivity disorder.

Abstract: Evaluated the long-term stability of the Child Behavior Checklist (CBCL) in a longitudinal clinical sample of youth with attention deficit hyperactivity disorder (ADHD), testing the hypothesis that the CBCL scales will show stability over time. Participants were 105 Caucasian, non-Hispanic boys with ADHD between the ages of 6 and 17 assessed at baseline and at a 4-year follow-up. Stability of CBCL scales were computed for dimensional (intraclass correlation coefficients [ICCs], Pearson correlations) and dichotomized scale scores (kappa coefficients and odds ratios [ORs]). Evidence was found for stability of the categorical and dimensional types of scores, as demonstrated by statistically significant stability of the Pearson correlation coefficients, kappas, and ORs. The robust findings obtained from ICCs and kappa coefficients document substantial stability for CBCL scales over time within individuals with ADHD. These results support the informativeness of the CBCL as a useful measure of longitudinal course in clinical samples of youth with ADHD.

Report from the 4th international meeting of the attention deficit hyperactivity disorder molecular genetics network.

Abstract: Investigators from around the world have convened annually since 1999 to share their work on the molecular genetic basis of attention deficit hyperactivity disorder (ADHD). The 4th meeting of the ADHD Molecular Genetics Network was held in May 2002. This conference began with a discussion of ongoing and proposed collaborative projects. Ongoing collaborations include the International Multi-Center ADHD Genetics (IMAGE) project, a study of additive and interactive effects of DAT1 and DRD4 on ADHD and a meta-analysis of association studies of ADHD and the DRD5 gene. A new collaborative project regarding DNA pooling was also proposed. Over 20 investigators presented recent findings from their individual research sites. Participants also broke up into working groups to discuss additional projects and topics of mutual interest, including population genetic studies using dimensional phenotypic data and a QTL approach, endophenotypes for ADHD and the genetics of ADHD in adults. Finally, participant feedback was obtained about the utility of the ADHD Molecular Genetics Network conferences and the e-mail network. Although technological and statistical advances in the field of molecular genetics have allowed researchers to begin to identify specific genes that are associated with ADHD, continued collaborative efforts are needed to fully elucidate the genetic underpinnings of this complex phenotype. Data collected at the current conference indicate that the ADHD Molecular Genetics Network has facilitated new collaborative as well as single-site projects among ADHD researchers.

Genetic association analysis of behavioral inhibition using candidate loci from mouse models

Abstract: Genes influence the development of anxiety disorders, but the specific loci involved are not known. Genetic association studies of anxiety disorders are complicated by the complexity of the phenotypes and the difficulty in identifying appropriate candidate loci. We have begun to examine the genetics of behavioral inhibition to the unfamiliar (BI), a heritable temperamental predisposition that is a developmental and familial risk factor for panic and phobic disorders. Specific loci associated with homologous phenotypes in mouse models provide compelling candidate genes for human BI. We conducted family-based association analyses of BI using four genes derived from genetic studies of mouse models with features of behavioral inhibition. The sample included families of 72 children classified as inhibited by structured behavioral assessments. We observed modest evidence of association (P = 0.05) between BI and the glutamic acid decarboxylase gene (65 kDA isoform), which encodes an enzyme involved in GABA synthesis. No significant evidence of association was observed for the genes encoding the adenosine A(1A) receptor, the adenosine A(2A) receptor, or preproenkephalin. This study illustrates the potential utility of using candidate genes derived from mouse models to dissect the genetic basis of BI, a possible intermediate phenotype for panic and phobic disorders.