Biomedical subjects

Stephen V Faraone

Publications and source records attributed to Stephen V Faraone.

At least 37 records · Page 2Linked to original sources

PubMed2006

Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with structural alterations in brain networks influencing cognitive and motor behaviors. Volumetric studies in children identify abnormalities in cortical, striatal, callosal, and cerebellar regions. In a prior volumetric study, we found that ADHD adults had significantly smaller overall cortical gray matter, prefrontal, and anterior cingulate volumes than matched controls. Thickness and surface area are additional indicators of integrity of cytoarchitecture in the cortex. To expand upon our earlier results and further refine the regions of structural abnormality, we carried out a structural magnetic resonance imaging study of cortical thickness in the same sample of adults with ADHD (n = 24) and controls (n = 18), hypothesizing that the cortical networks underlying attention and executive function (EF) would be most affected. Compared with healthy adults, adults with ADHD showed selective thinning of cerebral cortex in the networks that subserve attention and EF. In the present study, we found significant cortical thinning in ADHD in a distinct cortical network supporting attention especially in the right hemisphere involving the inferior parietal lobule, the dorsolateral prefrontal, and the anterior cingulate cortices. This is the first documentation that ADHD in adults is associated with thinner cortex in the cortical networks that modulate attention and EF.

Adolescent↗

PubMed2006

The IMAGE project: methodological issues for the molecular genetic analysis of ADHD.

The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions. With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality--the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD. The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.

Journal Article↗

PubMed2006

Neuropsychological studies of late onset and subthreshold diagnoses of adult attention-deficit/hyperactivity disorder.

BACKGROUND: Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. METHODS: We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. RESULTS: Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. CONCLUSIONS: Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder.

Adolescent↗

PubMed2006

Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging.

OBJECTIVES: Gray and white matter volume deficits have been reported in a number of studies of children with attention-deficit/hyperactivity disorder (ADHD); however, there is a paucity of structural magnetic resonance imaging (MRI) studies of adults with ADHD. This structural MRI study used an a priori region of interest approach. METHODS: Twenty-four adults with DSM-IV ADHD and 18 healthy controls comparable on age, socioeconomic status, sex, handedness, education, IQ, and achievement test performance had an MRI on a 1.5T Siemens scanner. Cortical and sub-cortical gray and white matter were segmented. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere. Based on a priori hypotheses we focused on prefrontal, anterior cingulate cortex (ACC) and overall gray matter volumes. General linear analyses of the volumes of brain regions, adjusting for age, sex, and total cerebral volumes, were used to compare groups. RESULTS: Relative to controls, ADHD adults had significantly smaller overall cortical gray matter, prefrontal and ACC volumes. CONCLUSIONS: Adults with ADHD have volume differences in brain regions in areas involved in attention and executive control. These data, largely consistent with studies of children, support the idea that adults with ADHD have a valid disorder with persistent biological features.

Adult↗

PubMed2006

No association of G72 and D-amino acid oxidase genes with schizophrenia.

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.

Carrier Proteins↗

PubMed2006

Contribution of 5-HT2A receptor gene -1438A>G polymorphism to outcome of attention-deficit/hyperactivity disorder in adolescents.

Attention-deficit/hyperactivity disorder (ADHD) typically emerges before 7 years of age and may persist into adolescence or adulthood. The adolescent outcome can be classified into four types, including non-remission, syndromatic remission, symptomatic remission, and functional remission. Genetic factors are believed to contribute to symptom stability and change across development, so adolescent outcome may be a sub-phenotype for molecular genetic studies of ADHD. Serotonin system genes are prime candidates for this sub-phenotype, since the development of this neurotransmitter system parallels the course of ADHD. The current study examined the association between adolescent outcome in ADHD and serotonin system genes, including the -1438A>G polymorphism of the serotonin 2A receptor gene (HTR2A) and the -759C>T polymorphism of the serotonin 2C receptor gene (HTR2C). The -1438A>G polymorphism was found to be related to remission in ADHD, especially functional remission (P = 0.029). Due to potential phenotypic and etiologic heterogeneity in ADHD, the results of this study must be replicated in additional samples before they can be generalized to other populations.

Adolescent↗

PubMed2006

Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type.

BACKGROUND: Previous investigations have demonstrated that an MspI polymorphism at the adrenergic alpha2A receptor gene (ADRA2A) is associated with severity of attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms in clinical samples composed mainly of subjects with ADHD, combined type. This study aimed to investigate the association between this ADRA2A polymorphism and attention-deficit/hyperactivity disorder-inattentive type (ADHD-I) in a nonreferred sample. METHODS: In a case-control study, we assessed a sample of 100 children and adolescents with ADHD-I and 100 non-ADHD controls. Cases and controls were matched by gender and age and were screened by using teacher reports in a revised version of the Swanson, Nolan, and Pelham rating scale at 12 schools. Psychiatric diagnoses were derived through structured diagnostic interviews. RESULTS: Homozygous subjects for the G allele at the ADRA2A had significantly higher odds ratio (OR) for ADHD-I than did those with other genotypes (CC + CG genotypes), even after adjusting for potential confounders (p = .02; OR = 3.78; 95% confidence interval = 1.23-11.62). In family-based analyses, no significant associations were detected. CONCLUSIONS: Our results suggest that the ADRA2A may be associated with ADHD-I, replicating previous findings from clinical samples that have suggested the importance of this gene for the dimension of inattention. In addition, these results support the role of the noradrenergic system in ADHD.

Adolescent↗

PubMed2006

Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.

BACKGROUND: To examine the association between anxiety disorders in parents and offspring in a sample of children at risk for panic disorder. We hypothesized that individual anxiety disorders will breed true in offspring. METHODS: Comparisons were made between offspring of parents with PD+MD (N=136), PD (N=27), MD (N=27), and Controls (N=103). All subjects were assessed with structured diagnostic interviews. Individual anxiety disorders in the offspring were used as dependent variables in logistic regression models where parental PD status, parental MD, and the same parental anxiety diagnosis were used as independent binary variables. RESULTS: Social phobia and separation anxiety disorder in the offspring were accounted for by the same disorders in the parent, whereas agoraphobia and OCD in the offspring were accounted for by parental panic disorder. CONCLUSIONS: These findings suggest that differing risk factors underlie the expression of individual anxiety disorders in children at risk for panic disorder.

Adolescent↗

PubMed2006

Evaluation of RGS4 as a candidate gene for schizophrenia.

Several studies have suggested that the regulator of G-protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM-IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers.

Alleles↗

PubMed2006

When is a "positive" association truly a "positive" in psychiatric genetics? A commentary based on issues debated at the World Congress of Psychiatric Genetics, Boston, October 12-18, 2005.

The accumulated literature on candidate gene findings in psychiatric genetics is extensive. There is concern that many of the published findings to data are false positives. At the October 2005 World Congress of Psychiatric Genetics this issue was discussed by a panel of experts. This manuscript describes the panel discussion, its implications for the reporting of association studies of psychiatric disorders and suggestions for when to decide that a positive finding is truly positive.

Genetic Linkage↗

PubMed2006

Psychopathology in females with attention-deficit/hyperactivity disorder: a controlled, five-year prospective study.

BACKGROUND: Despite the importance of understanding the long-term outcome of children with attention-deficit/hyperactivity disorder (ADHD), the available literature is predominantly based on male samples. This study estimated the lifetime burden of comorbid psychopathology in a large sample of girls with and without ADHD followed up over five years. METHODS: We conducted a blind, five-year prospective longitudinal study of girls with (n=140) and without (n=122) ADHD, aged 6-18 years at baseline, consecutively ascertained from either community pediatricians or psychiatrists at an academic medical center. At the five-year follow-up, 123 (88%) and 112 (92%) of the ADHD and control children, respectively, were re-assessed at a mean age of 16.7 years. Psychiatric disorders were assessed using blinded structured diagnostic interviews. RESULTS: At follow-up, females with ADHD were at significantly higher risk than controls to manifest disruptive behavior, mood and anxiety disorders, and substance dependence. The magnitude of increased risk was greatest for major depression and oppositional-defiant disorder, followed by substance dependence and anxiety disorders. CONCLUSIONS: These prospective follow-up findings documenting high morbidity associated with ADHD extend to females previously reported findings in male samples and underscore the importance of early recognition and intervention efforts for youth with ADHD of both genders.

Adolescent↗

PubMed2006

Neuropsychological functioning in adolescents and young adults at genetic risk for schizophrenia and affective psychoses: results from the Harvard and Hillside Adolescent High Risk Studies.

Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12-25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community controls (CCs) recruited in metropolitan Boston and New York. Groups were compared on overall neurocognitive functioning, 6 domains, and 13 test scores, controlling for age, parental education, and correlated data within families. The HR-SCZ group was significantly impaired overall, while the HR-AFF group demonstrated a trend toward overall impairment. HR-SCZ subjects showed significantly lower Verbal Ability (d = .73) and Executive Functioning/Working Memory (d = .47) than CCs. HR-AFF subjects showed reduced Verbal Ability (d = .64) compared to CCs. Excluding 12 CCs with a parental history of depression (without psychosis) led to larger differences between HR and CC groups across domains. Moreover, HR-SCZ and CC group differences in Verbal Memory (d = .39) and Visual-Spatial (d = .34) became statistically significant. There were no significant differences between HR-SCZ and HR-AFF groups. Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ. Future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples. Ascertainment criteria for controls may markedly influence results and interpretation of group differences.

Adolescent↗

PubMed2006

No association of attention-deficit/hyperactivity disorder with genes of the serotonergic pathway in Han Chinese subjects.

Attention-deficit/hyperactivity disorder (ADHD) is a complex psychiatric syndrome with cardinal symptoms of inattention, hyperactivity and impulsivity, and is a significant risk factor for poor health outcomes in both adolescence and adulthood. Etiology is clearly multifactoral, with probable contributions from both genetic and environmental factors. The genetic contribution is prominent, with estimated heritability at about 0.80. Although effects in dopamine metabolism have long been implicated in the etiology of ADHD, the role for serotonin has gained more attention in recent years. The current study examined five variants in three serotonin genes [those that code for serotonin receptors 2A (HTR2A), 5A (HTR5A) and 6 (HTR6)] in a relatively large sample of ADHD nuclear families. The transmission disequilibrium test (TDT) and the extended transmission disequilibrium test (ETDT) were performed to test for evidence of distorted transmission of alleles or haplotypes. No significant biased transmission was observed. These results do not support a substantial role of these serotonin gene in ADHD, however, additional work may be warranted before this association is definitively discounted.

Asian People↗

PubMed2006

A controlled longitudinal 5-year follow-up study of children at high and low risk for panic disorder and major depression.

BACKGROUND: To evaluate the longitudinal course of psychiatric disorders in children of parents with panic disorder (PD) and major depression (MD) as they transition through the period of risk from childhood into adolescence. METHOD: Over a 5-year follow-up, we compared psychiatric disorders in four groups of children: (1) offspring of parents with PD plus MD (n=136); (2) offspring of parents with PD without MD (n=27); (3) offspring of parents with MD but without PD (n=53); and (4) offspring of non-PD non-MD parents (n=103). RESULTS: Parental PD was significantly associated with increased risk for anxiety disorders, irrespective of parental MD. Parental MD was associated with increased risk for MD, disruptive behavior disorders, and deficits in psychosocial functioning, irrespective of parental PD. CONCLUSIONS: These longitudinal findings confirm and extend previous cross-sectional results documenting significant associations between PD and MD in parents and patterns of psychopathology and dysfunction in their offspring.

Adolescent↗

PubMed2006

Is there heterogeneity among syndromes of substance use disorder for illicit drugs?

The use of DSM criteria to evaluate liability to substance use disorders (SUDs) and to identify SUD phenotypes may not provide the sensitivity required to identify genes associated with vulnerability to SUDs. The purpose of this study is to evaluate a number of basic aspects of substance use that may be more proximal than full SUDs to risk genes, some of which may thus have greater potential utility as phenotypes in subsequent molecular genetic analyses. In this paper we present results from the first stage of our planned analyses, focusing on how individual symptoms of abuse and dependence may be used to create alternate phenotypes for SUDs. Specifically, we used factor analysis and biometrical modeling on each symptom of illicit substance abuse and dependence within different types of substances, and compared and contrasted factor patterns and heritabilities across the different substances. These analyses were carried out using a population-based sample of 3372 male-male twin pairs from the Vietnam Era Twin Registry who participated in the Harvard Twin Study of Substance Abuse. We obtained extensive data from these participants on substance use and SUDs via telephone interview in 1992, including data on the illicit substances: opiates, cocaine, cannabis, sedatives, stimulants, and psychedelics. The results indicate that: A) although a one-factor model assuming a single underlying liability for abuse and dependence symptoms and behaviors can be rejected for most substances, there is no uniform support for a two-factor model differentiating between abuse versus dependence; B) patterns of symptoms or behaviors reported by substance users vary across substances; C) not all symptoms or behaviors contribute equally to the presentation of an SUD; and D) the heritability of symptoms or behaviors of substance users varies both within and between substances. These results represent important first steps in facilitating the search for SUD-risk genes in subsequent high-throughput molecular genetic analyses by providing alternate phenotypes that may have both optimal validity and increased heritability.

Adult↗

PubMed2006

Is ADHD a valid disorder in children with intellectual delays?

To assess the validity of ADHD in children with mental retardation, we applied Robins and Guze's [Robins, E., and Guze, S.B. (1970). Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. American Journal of Psychiatry, 126, 983-987.] criteria for determining the validity of a psychiatric disorder. We review the literature describing clinical correlates, family history, treatment response, laboratory studies, course, and outcome of children with ADHD and mental retardation. Although clearly an area in need of further research, there is preliminary evidence to suggest that ADHD is a valid psychiatric condition in children with mental retardation. Nevertheless, without knowing the base rates of ADHD symptoms in the mental retardation population, the positive predictive power and negative predictive power of ADHD symptoms in this population remain an open question. In addition to assessment of base rate symptoms, future research should consider what diagnostic algorithm may best be applied to the diagnosis of ADHD in mental retardation.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline.

A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice, and conclusions are reported: (1) Long-acting preparations should be available and used; (2) They should not replace short-acting drugs (which will be the initial treatment for many children for reasons of cost and flexibility of dosing). Individual clinical choice is needed. (3) Both ATX and extended-release preparations of stimulants should be available. The choice will depend upon the circumstances, and detailed recommendations are made.

Atomoxetine Hydrochloride↗

PubMed2006

Latent class analysis shows strong heritability of the child behavior checklist-juvenile bipolar phenotype.

BACKGROUND: The Child Behavior Checklist (CBCL) has been used to provide a quantitative description of childhood bipolar disorder (BPAD). Many have reported that children in the clinical range on the Attention Problems (AP), Aggressive Behavior (AGG), and Anxious-Depressed (A/D) syndromes simultaneously are more likely to meet the criteria for childhood BPAD. The purpose of this study was to determine if Latent Class Analysis (LCA) could identify heritable phenotypes representing the CBCL-Juvenile Bipolar (CBCL-JBD) profile and whether this phenotype demonstrates increased frequency of suicidal endorsement. METHODS: The CBCL data were received by survey of mothers of twins in two large twin samples, the Netherlands Twin Registry. The setting for the study was the general community twin sample. Participants included 6246 10-year-old Dutch twins from the Netherlands Twin Registry. The main outcome measure consisted of the LCA on the items comprising the AP, AGG, and A/D subscales and means from the suicidal items #18 and #91 within classes. RESULTS: A 7 class model fit best for girls and an 8 class fit best for boys. The most common class for boys or girls was one with no symptoms. The CBCL-JBD phenotype was the least common--about 4%-5% of the boys and girls. This class was the only one that had significant elevations on the suicidal items of the CBCL. Gender differences were present across latent classes with girls showing no aggression without the CBCL-JBD phenotype and rarely showing attention problems in isolation. Evidence of high heritability of these latent classes was found with odds ratios. CONCLUSIONS: In a general population sample, LCA identifies a CBCL-JBD phenotype latent class that is associated with high rates of suicidality, is highly heritable, and speaks to the comorbidity between attention problems, aggressive behavior, and anxious/depression in children.

Aggression↗