Biomedical subjects

Stephen V Faraone

Publications and source records attributed to Stephen V Faraone.

At least 91 records · Page 5Linked to original sources

PubMed2005

Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review.

One of the most prominent neuropsychologic theories of attention-deficit/hyperactivity disorder (ADHD) suggests that its symptoms arise from a primary deficit in executive functions (EF), defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal. To examine the validity of the EF theory, we conducted a meta-analysis of 83 studies that administered EF measures to groups with ADHD (total N = 3734) and without ADHD (N = 2969). Groups with ADHD exhibited significant impairment on all EF tasks. Effect sizes for all measures fell in the medium range (.46-.69), but the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. Weaknesses in EF were significant in both clinic-referred and community samples and were not explained by group differences in intelligence, academic achievement, or symptoms of other disorders. ADHD is associated with significant weaknesses in several key EF domains. However, moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD. Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD.

Algorithms↗

PubMed2005

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.

Adoption↗

PubMed2005

In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter.

There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-naïve children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.

Age Factors↗

PubMed2005

Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication.

BACKGROUND: Despite growing interest in adult attention-deficit/hyperactivity disorder (ADHD), little is known about predictors of persistence of childhood cases into adulthood. METHODS: A retrospective assessment of childhood ADHD, childhood risk factors, and a screen for adult ADHD were included in a sample of 3197 18-44 year old respondents in the National Comorbidity Survey Replication (NCS-R). Blinded adult ADHD clinical reappraisal interviews were administered to a sub-sample of respondents. Multiple imputation (MI) was used to estimate adult persistence of childhood ADHD. Logistic regression was used to study retrospectively reported childhood predictors of persistence. Potential predictors included socio-demographics, childhood ADHD severity, childhood adversity, traumatic life experiences, and comorbid DSM-IV child-adolescent disorders (anxiety, mood, impulse-control, and substance disorders). RESULTS: Blinded clinical interviews classified 36.3% of respondents with retrospectively assessed childhood ADHD as meeting DSM-IV criteria for current ADHD. Childhood ADHD severity and childhood treatment significantly predicted persistence. Controlling for severity and excluding treatment, none of the other variables significantly predicted persistence even though they were significantly associated with childhood ADHD. CONCLUSIONS: No modifiable risk factors were found for adult persistence of ADHD. Further research, ideally based on prospective general population samples, is needed to search for modifiable determinants of adult persistence of ADHD.

Adolescent↗

PubMed2005

Taiwan schizophrenia linkage study: the field study.

One possible reason of the inconsistent results of linkage analyses of schizophrenia, a complex disorder, was mainly due to the small sample size of studies. This Taiwan Schizophrenia Linkage Study (TSLS) was designed to collect a large family sample with at least two affected siblings of a single ethnicity. The 17.6 millions of Taiwanese Chinese, age over 15, was the sample population, and 78 psychiatric hospitals or health centers participated in this TSLS program. Before data collection started, every study subject signed the informed consent. The ascertainment protocol for data collection included blood sample, structured Diagnostic Interview for Genetic Studies (DIGS), Structured Interview for Schizotypy (SIS), scales for assessment of positive and negative symptoms (SAPS, SANS), and continuous performance test (CPT), Wisconsin card sort test (WCST) of neuropsychological functions. We have contacted 831 families for this study and 607 families, comprised 2,490 subjects, were successfully recruited. The recruitment rate was 38.4% from the estimated total of 1,582 families with at least two affected siblings. These collected family samples were fairly evenly distributed all over Taiwan. Those 2,490 study subjects (1,283 male, 1,117 female) comprised 1,568 siblings (mean age 35.7 years old) and 922 parents (mean age 63.6 years old). Of these 1,568 siblings, 1,258 (80.2%) were affected (male 795, female 463), and the mean age of onset was 22.6 years old. Among 922 parents, 65 were affected (male 14, female 51) and the age of onset was 33.1 years old. This TSLS demonstrated a successful establishment of an efficient research infrastructure to collect a large nation-wise sample of schizophrenic family for genetic linkage study.

Adult↗

PubMed2005

Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report.

DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations.

Adult↗

PubMed2005

Functional neuroanatomy of working memory in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in adults is an increasingly recognized psychiatric disorder, linked with impairments in numerous life domains and with neurocognitive dysfunctions. However, the neural substrate of cognitive functioning in adults with this disorder has been relatively unexamined. The objective of this study was to examine neural functioning in ADHD adults during performance on a verbal working memory task. METHODS: A sample of unmedicated adults with ADHD (n = 20) and control subjects (n = 20) performed a 2-back task of working memory, and the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) response was used as a measure of neural activity during working memory performance. RESULTS: Though working memory performance did not differ significantly between ADHD adults and control subjects, ADHD adults showed significantly decreased activity in cerebellar and occipital regions and a trend toward decreased activation in an a priori predicted region of the prefrontal cortex. CONCLUSIONS: ADHD adults showed altered patterns of neural activity despite comparable performance on a verbal working memory task. These findings suggest that the cerebellum is involved in the pathophysiology of at least some cognitive deficits associated with ADHD and emphasize the need for additional research aimed at elucidating the role of the cerebellum in ADHD symptomatology.

Adolescent↗

PubMed2005

Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses.

NOTCH4 initially received consideration as a risk gene for schizophrenia based on its location within a region on chromosome 6p that had previously shown strong evidence for genetic linkage with the illness. The initial published test for allelic association found strong evidence for involvement of this gene in schizophrenia, but subsequent studies failed to confirm this finding. Presently, we have used meta-analysis to derive a best estimate of the nature and magnitude of the associations between schizophrenia and five polymorphisms in and around the NOTCH4 gene. No significant association was detected between schizophrenia and repeat length of alleles at the (TAA)n, (CTG)n, or (TTAT)n polymorphisms, or between the disease and specific risk alleles at these polymorphisms or at the SNP1 or SNP2 polymorphisms. Heterogeneity and stronger evidence of association with the putative risk alleles of the (TAA)n, (CTG)n, SNP1, and SNP2 polymorphisms was observed in family-based studies than in case-control studies, suggesting that these polymorphisms may reliably influence risk for schizophrenia under certain circumstances. Since more consistent and robust associations with schizophrenia risk have been observed for haplotypes of these polymorphisms [especially those containing SNP2 and (CTG)n], additional large family-based or genomic-controlled studies would be helpful for definitively specifying the role of NOTCH4 haplotypes in risk for schizophrenia.

Alleles↗

PubMed2005

Genome-wide scan of homogeneous subtypes of NIMH genetics initiative schizophrenia families.

In the light of the potential etiological heterogeneity of schizophrenia, we reanalyzed the NIMH genetics initiative data for schizophrenia. We performed linkage analyses on schizophrenia families divided into more homogeneous subgroups. The African-American and European-American families were divided into groups that were successively more homogeneous. The first group included schizophrenia families that were highly familial, meaning that they contained a minimum specified number of affected individuals. We also excluded patients with environmental influences that may affect disease status. These influences included obstetric complications (OC) and viral infections during the neurodevelopmental stage (VIN). In the African-American sample, a linkage analysis of highly familial schizophrenia families without any environmental influences resulted in a single-point LOD (SLOD) score of 2.90, a multipoint LOD (MLOD) of 2.11, a single-point heterogeneity LOD (SHLOD) score of 3.04, and a multipoint heterogeneity LOD (MHLOD) score of 2.11 at marker D8S1819 (8p23.1) under a dominant parametric model. The highly familial European-American schizophrenia families resulted in an SLOD of 0.91 and an MLOD of 1.85, an SHLOD of 1.64 and an MHLOD of 1.97 at marker D22S1169 (22q13.32) using a recessive parametric model. Although this work should be interpreted cautiously and requires replication, these results suggest that schizophrenia may be linked to chromosomal regions 8p23.1 and 22q12.3-q13.32.

Black or African American↗

PubMed2005

Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders.

Family, twin, and adoption studies show that psychiatric diseases including bipolar disorder (BP) and unipolar disorder (UP) have a substantial genetic component. For these illnesses, both positive and negative associations have been reported for two polymorphisms located in the serotonin transporter gene (5-HTT) on chromosome 17: a 17-base-pair (bp) variable-number tandem-repeat (VNTR) in intron 2 and a 44-bp insertion/deletion in the promoter region. Thus, associations between these 5-HTT polymorphisms and affective disorders remain unclear. The present work investigates these potential associations in meta-analyzes that maximize the power to find associations between each disease and the two 5-HTT polymorphisms. We applied meta-analysis techniques to case-control studies of two 5-HTT polymorphisms and two affective disorders (BP and UP), resulting in four meta-analyzes. For each polymorphism, we assessed the evidence for allelic associations, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short allele(s) of the 44-bp insertion/deletion polymorphism showed a significant association for BP (odds ratio (OR) = 1.13, P = 0.001) but not UP. For the 17-bp VNTR, an increase in the number of tandem repeats had no significant association with any of the disorders. The small but significant effects of the 44-bp insertion/deletion polymorphism for BP is consistent with being one of many genes that contributes to the multi-factorial nature of these psychiatric disorders.

Alleles↗

PubMed2005

Meta-analysis shows schizophrenia is not associated with the 40-base-pair repeat polymorphism of the dopamine transporter gene.

OBJECTIVE: Several case-control studies examined an association between schizophrenia and the 40-bp variable number tandem repeat (VTNR) polymorphism in the 3'-UTR of the dopamine transporter gene (SLC6A3). The results of these studies have been equivocal due to small sample size and low power. This meta-analysis has the aim to evaluate the collective evidence for an association between the VTNR polymorphism and schizophrenia. METHOD: Different meta-analyses were performed, sequentially considering the 9- and 10-repeat alleles and different genotypes (genotypes 9/9, 9/10, 10/10) as risk factors for schizophrenia. Analyses of the alleles included 659 cases and 563 controls from six case-control studies. RESULTS: The pooled OR from each analysis approximated 1.0, and none were significant. Lack of significance attributable to the negative effects of single large studies or to heterogeneity between the studies was excluded. CONCLUSION: Despite over 90% power to detect a significant odds ratio as small as 1.3, no association was observed. Considering the cumulative evidence from six case-control studies and results from additional family-based studies, it seems unlikely that the 40-base-pair VTNR polymorphism of the SLC6A3 gene influences risk for schizophrenia.

Alleles↗

PubMed2005

Molecular genetics of attention-deficit/hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.

Adoption↗

PubMed2005

Serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects.

Serotonin is an endogenous neurotransmitter that regulates aggressive and impulsive behavior and may be involved in the development of attention deficit hyperactivity disorder (ADHD). 5-HT1B knockout mice display hyperactivity, increased exploratory activity and aggression, reduced anxiety, increased vulnerability to cocaine self-administration, and elevated alcohol consumption. Many of these same behaviors are seen in patients with ADHD. Prior studies reported excess transmission of the 861G allele of 5-HT1B to ADHD offspring. We used the transmission disequilibrium test (TDT) and haplotype analysis to investigate the A-161T and G861C polymorphisms in the 5-HT1B receptor gene in ADHD trios from the Chinese Han population. We found no association with ADHD but did find a tendency for excess transmission of the 861G allele (chi(2) = 3.766, P = 0.052) and the G/A haplotype (chi(2) = 2.925, df = 1, P = 0.087), and under-transmission of C/A haplotype (chi(2) = 3.707, df = 1, P = 0.054) to offspring with inattentive ADHD.

Alleles↗

PubMed2005

Patterns of comorbidity in panic disorder and major depression: findings from a nonreferred sample.

Previous findings in referred adult samples document major depression as having important moderating effects on the patterns of comorbidity for panic disorder and major depression. This study evaluated whether these patterns of comorbidity are moderated by referral bias. Panic disorder (PD) and major depression (MD) were used to predict the risk for comorbid psychiatric disorders and functional outcomes using data from a large sample of adults who had not been ascertained on the basis of clinical referral (N=1,031). Participants were comprehensively assessed with structured diagnostic interview methodology to evaluate childhood and adult comorbid psychiatric disorders. PD increased the risk for anxiety disorders, independently of MD. MD increased the risk for mania, antisocial personality disorder, psychoactive substance use disorder, disruptive behavior disorders, overanxious disorder, social phobia, and generalized anxiety disorder, independently of PD. These results extend to nonreferred samples' previously reported findings documenting that MD has important moderating effects on patterns of comorbidity for PD and indicate that patterns of comorbidity for PD are not due to referral bias.

Adult↗

PubMed2005

Parental predictors of pediatric panic disorder/agoraphobia: a controlled study in high-risk offspring.

Our objective was to evaluate parental risk factors for pediatric-onset panic disorder/agoraphobia (PD/AG) in offspring at high risk for PD/AG. Comparisons were made between parents with PD who had a child with PD or AG (N = 27) and parents with PD without children with PD or AG (N = 79). Comparisons were also made between the spouses of these parents with PD. Separation anxiety disorder, social phobia, obsessive-compulsive disorder, and bipolar disorder in the parents with PD and their spouses accounted for the risk for childhood onset PD/AG in the offspring. This risk was particularly high if both parents were affected with social phobia. These findings suggest that psychiatric comorbidity with other anxiety disorders and with bipolar disorder in parents with PD and their spouses confer a particularly high risk in their offspring to develop PD/AG in childhood.

Adolescent↗

PubMed2005

Correspondence of parent and teacher reports in medication trials.

Although much has been written about the agreement of parents and teachers regarding the diagnosis of attention-deficit/hyperactivity disorder (ADHD), some uncertainty remains about their agreement when assessing change during drug treatment. To address this issue, we analyzed data from a placebo-controlled short-term study and an open-label long-term study of ADHD children treated with OROS methylphenidate (MPH). Both reporters agreed that OROS MPH was efficacious for symptoms of inattention/overactivity and oppositionality/defiance and that the effect was greater for inattention/overactivity than oppositionality/defiance. Thus, in clinical trials, having two reports may not be absolutely essential for assessing the efficacy of ADHD medications. We also computed diagnostic efficiency statistics and found a high probability that parents would confirm teacher reports of therapeutic improvement and a somewhat lower probability that teachers would confirm parent reports of therapeutic improvement. In contrast, neither reporter was likely to confirm the other reporter's report of no improvement or worsening. Thus, when given a report of no improvement from one setting, clinicians cannot be certain about clinical status in the other setting. For symptoms of oppositionality and defiance, we also saw that parent- teacher agreement about improvement was better than agreement about lack of improvement. However, for these symptoms, teacher reports were somewhat better predictors of parent reports than vice-versa.

Adolescent↗

PubMed2005

The scientific foundation for understanding attention-deficit/hyperactivity disorder as a valid psychiatric disorder.

Continued questioning of the validity of a diagnosis of attention-deficit/hyperactivity disorder (ADHD) has created uncertainties about its management in the minds of many clinicians and the public. Inaccurate beliefs about the validity of ADHD hinder the clinical care of many ADHD patients and lead to confusion about the need to seek out or accept treatment. Critics describe ADHD as a diagnosis used to label difficult children who are not ill but whose behavior is at the extreme end of normal. They further contend that, far from having a biological basis, ADHD results from poor parenting and ineffective teaching practices. Such attitudes do much to further stigmatize patients and their families and increase the burden of this debilitating condition. This review attempts to address these challenges by presenting evidence to show that ADHD meets the criteria for a valid psychiatric diagnosis. Not only does it cause specific disabling symptoms that frequently persist into adulthood, but many studies show it has a biological basis and a characteristic response to treatment. Such data support the idea that ADHD is a valid diagnostic category.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study.

Using proton magnetic resonance spectroscopy ((1)H-MRS) to investigate possible neurometabolic differences between the predominantly inattentive subtype (ADHD-I), the combined subtype (ADHD-C) and normal controls. Proton spectra were acquired bilaterally on the lenticular nucleus in 20 schoolboys having ADHD and 10 matched controls. The boys with ADHD were divided into ADHD-C subtype (n=10) and ADHD-I subtype (n=10) according to DSM-IV criteria. The peaks of N-acetylaspartate (NAA), Choline moieties (Cho), myo-inositol (mI), creatine (Cr) and alpha-Glx were measured and their ratios to Cr were calculated. One-way ANOVA and post-hoc Bonferroni tests were used to detect the difference of the peak-area ratios of NAA, Cho, mI, and alpha-Glx to Cr among the three groups. There was a significant overall group difference in the NAA/Cr ratio both in the right and left lenticular nucleus (right: P=0.002; left: P=0.003). Only the ADHD-C subtype group showed a significant difference with controls (right: P=0.001; left: P=0.003) the right lenticular nucleus, the NAA/Cr ratio in the ADHD-C group was significantly lower than that in the ADHD-I group (P=0.012). In the left lenticular nucleus, the NAA/Cr ratio in the ADHD-C group showed a significant trend compared to the ADHD-I group (P=0.06). This study demonstrated the existence of measurable difference between children with ADHD-C and ADHD-I using (1)H-MRS.

Adolescent↗