Biomedical subjects
Publications and source records attributed to Stephen V Faraone.
Schizotaxia is a stable syndrome of neuropsychological deficits and negative symptoms found in relatives of schizophrenic patients. These may represent special vulnerability to schizophrenia. Five areas of deficit are enumerated and suggestions as to the potential value of pre-illness interventions are discussed.
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Based on a strategy developed by Seidman et al. (Seidman, L.J., Faraone, S.V., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., 1993. Neuropsychological dysfunctions in the non-psychotic first-degree relatives of schizophrenic patients, Poster presented at the annual meeting of the Society for Research and Psychopathology. Chicago, IL) we examined neuropsychological heterogeneity in schizophrenia using clinical neuropsychological descriptions of individual cases as the starting point. We blindly rated neuropsychological profiles of 74 schizophrenia patients and 91 normal controls based primarily on prototypes from the clinical literature in neuropsychology. Patients were classified as having the following profile types: within normal limits (WNL) (23%, n=17), frontal/abstraction (46%, n=34), widespread/diffuse (14%, n=10), left temporal/verbal memory (8%, n=6) and other (9%, n=7). As expected based on our classification scheme, the groups had different profile shapes (group x function interactions). They were also significantly different from one another in terms of overall severity (main effects); however, severity differences were not inherent in the definition of all groups. Longer duration of illness and greater overall cognitive impairment were observed as one went from the left temporal to the frontal to the widespread groups. Longitudinal studies are needed to determine whether the different neuropsychological profiles reflect true subgroup differences or within-person change over time. Further research-probably including neuroimaging and genetic studies-will also be needed to determine the validity and the utility of this strategy for identifying neuropsychological profile types.
BACKGROUND: Previous findings in referred samples documented significant diagnostic specificity in patterns of transmission between parents with panic disorder (PD) and parents with major depression (MD) and their offspring. This study evaluated whether these patterns of transmission between parents and high-risk offspring are moderated by referral bias. METHODS: Parental PD/agoraphobia (AG) and parental MD were used to predict rates of offspring psychiatric disorders and functional outcomes using data from an opportunistic sample of parents (n = 991) and offspring (n = 734) ascertained from case-control family genetic studies of youth with and without attention-deficit hyperactivity disorder. Subjects were comprehensively assessed with structured diagnostic interview methodology to evaluate psychiatric disorders in parents and offspring. RESULTS: Parental PD/AG increased the risk for anxiety disorders in offspring, independently of parental MD while parental MD increased the risk for mood and disruptive behavior disorders in offspring, independently of parental PD/AG. Parental psychopathology was also associated with functional impairment in offspring. LIMITATIONS: The use of a sample ascertained by ADHD and control probands, and parent psychiatric diagnostic reports for children under 12. CONCLUSIONS: These results extend to non-referred samples previous findings from referred samples documenting diagnostic specificity in the familial transmission of PD/AG and MD from parents to offspring, suggesting that these patterns of transmission are not due to referral bias. These results could inform and enhance community programs aimed at screening for and treating pediatric psychopathology.
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The gene DRD2, which codes for dopamine receptor D2, has been considered a prime candidate for allelic association testing with schizophrenia based on the strong evidence for involvement of this protein in disease pathophysiology. Recent meta-analyses confirmed a small but reliable association between schizophrenia and the cysteine-coding allele of the Cys311Ser polymorphism of DRD2. In the present study, we sought to determine if another polymorphism (the -141C insertion/deletion) in the same gene, which has been reported to be associated with schizophrenia in several individual studies, would show a similar pattern of association with the disease in a pooled dataset. The pooled odds ratio for the insertion allele obtained from 10 case-control studies was 1.1, which was not significant (P = 0.580); however, there was marked heterogeneity among the findings of individual studies, suggesting that some underlying factor influenced the size of their observed effects. Yet, neither ethnicity, the age of the control group, nor the gender composition of the samples reliably influenced effect size. Because linkage disequilibrium patterns between various DRD2 polymorphisms are not yet known, it remains possible that divergent meta-analytic findings at both commonly examined mutation sites within DRD2 are accurate. Haplotype analysis within this gene would be useful for definitively specifying the role of this gene in the etiology of schizophrenia.
Molecular genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated the variable number of tandem repeat (VNTR) polymorphisms of two candidate genes, the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1). We sought to determine if these genes were relevant to the etiology of ADHD in China by using both family-based (N = 202 nuclear ADHD families) and case-control (N = 340 ADHD cases, and 226 controls) association study designs. Diagnoses and subtypes were ascertained according to Clinical Diagnostic Interview Scales (CDIS) using DSM-IV criteria. The repeat numbers at the DRD4 VNTR ranged from 2 to 6 repeats in the Han Chinese controls, with the most common being the 4-repeat (77%) and 2-repeat (19.4%) alleles. Neither the 7-repeat allele nor longer repeats were found. For the DAT1 VNTR, the repeat numbers ranged from 6 to 7 repeats and 9 to 11 repeats. The 10-repeat allele was the most frequent (90.7%). The long-repeat alleles of DRD4 (ranging from 4 to 6 repeats) and DAT1 (ranging from 11 to 12 repeats), were present more frequently in ADHD probands than controls (P < 0.05), although there was no significant allelic association when the alleles were analyzed separately from each other and there findings were not supported by within family tests of association. An exploratory stratification by gender suggests that long-repeat alleles of DRD4 and DAT1 may increase the risk for ADHD in Han Chinese children.
BACKGROUND: Recognition and treatment of attention-deficit/hyperactivity disorder (ADHD) in adults in psychiatry and primary care have faced many obstacles. METHODS: Review by 50 psychiatrists and 50 primary care practitioners (PCPs) of 537 and 317 medical records, respectively, of adults diagnosed as having ADHD. Information on other psychiatric disorders, time of onset of ADHD, source of referral, use of referrals for diagnosis, ADHD treatment, and use of drug holidays was recorded. RESULTS: Forty-five percent of the patient records reviewed by psychiatrists and 65% reviewed by PCPs indicated previous diagnoses of ADHD. Only 25% of the adults with ADHD had been first diagnosed as having the disorder in childhood or adolescence. A diagnosis of ADHD was the initial cause for referral in 80% of psychiatric patients and 60% of PCP patients. Most patients with previously diagnosed and undiagnosed ADHD were self-referred. Among patients who had not received a prior diagnosis, 56% complained about ADHD symptoms to other health professionals without being diagnosed; PCPs were the least aggressive in diagnosing ADHD. In psychiatric and PCP settings, there was a statistical difference in the use of pharmacotherapy (91% vs 78%, respectively) and the proportion of patients taking drug holidays (24% vs 17%, respectively); most drug holidays were initiated by the patient (57%). Stimulants were the treatment of choice for adult ADHD (84% treated with stimulants). CONCLUSION: Data contained within this medical record review suggest that adult ADHD is a substantial source of morbidity in both psychiatric and PCP settings.
Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.
Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.
Given the high rate of co-occurring major depression in patients with panic disorder, it is unclear whether patterns of comorbidity in individuals with panic disorder reported in the literature are associated with panic disorder or with the presence of major depression. Subjects were 231 adult subjects with panic disorder and major depression (n=102), panic disorder without comorbid major depression (n=29), major depression without comorbid panic disorder (n=39), and neither panic disorder nor major depression (n=61). Subjects were comprehensively assessed with structured diagnostic interviews that examined psychopathology across the life cycle. Panic disorder, independently of comorbidity with major depression, was significantly associated with comorbid separation anxiety disorder, simple phobia, obsessive-compulsive disorder, generalized anxiety disorder, and agoraphobia. Major depression, independently of comorbidity with panic disorder, was significantly associated with comorbidity with psychoactive substance use disorders and childhood disruptive behavior disorders. Overanxious disorder was associated with both panic disorder and major depression. Major depression has important moderating effects on patterns of comorbidity of panic disorder in referred adults.
BACKGROUND: This study reexamined gender differences in a large sample of adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: We assessed the effects of ADHD, gender, and their interaction on rates of psychiatric comorbidity and cognitive functioning in 219 adults with ADHD who were referred to an outpatient psychiatric clinic over the last 7 years compared with 215 control subjects group-matched to control subjects on age and gender, and ascertained from ongoing family genetic case control adults with ADHD. RESULTS: There was no evidence that gender moderated the association between ADHD and other psychiatric disorders. Attention-deficit/hyperactivity disorder was associated with cognitive deficits and higher rates of major depression, anxiety, substance use disorders, and antisocial personality disorder. CONCLUSIONS: Attention-deficit/hyperactivity disorder in adults is associated with psychiatric and cognitive impairment in both genders. These results bear striking similarities to findings reported in pediatric samples, supporting the validity of ADHD and stressing the importance of identifying and treating the disorder in adulthood.
BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness and show deficits on high-load information processing tasks. We used functional magnetic resonance imaging (fMRI) to test whether nonpsychotic relatives show altered functional activation in the prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a working memory task requiring interference resolution. METHODS: Twelve nonpsychotic relatives of persons with schizophrenia and 12 healthy control subjects were administered an auditory, verbal working memory version of the Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS: Compared with control subjects, relatives showed greater task-elicited activation in the PFC and the anterior and dorsomedial thalamus. When task performance was controlled, relatives showed significantly greater activation in the anterior cingulate. When effects of other potentially confounding variables were controlled, relatives generally showed significantly greater activation in the dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study suggests that relatives of persons with schizophrenia have subtle differences in brain function in the absence of psychosis. These differences add to the growing literature identifying neurobiological vulnerabilities to schizophrenia.
A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9-1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.
To determine whether perinatal complications predict childhood anxiety disorders independently of parental psychopathology, we systematically assessed pregnancy and delivery complications and psychopathology in a sample of children (mean age=6.8 years) at high risk for anxiety disorders whose parents had panic disorder with (n=138) or without (n=26) major depression, and in contrast groups of offspring of parents with major depression alone (n=47), or no mood or anxiety disorders (n=95; total N=306). Psychopathology in the children was assessed by structured diagnostic interviews (K-SADS), and pregnancy and delivery complications were assessed using the developmental history module of the DICA-P. Number of pregnancy complications predicted multiple childhood anxiety disorders independently of parental diagnosis (odds ratio=1.6 [1.4-2.0]). This effect was accounted for by heavy bleeding requiring bed-rest, hypertension, illness requiring medical attention, and serious family problems. Associations remained significant when lifetime child mood and disruptive behavior disorders were covaried. Results suggest that prenatal stressors may increase a child's risk for anxiety disorders beyond the risk conferred by parental psychopathology alone.
OBJECTIVE: To examine patterns of persistence and remission in pediatric bipolar disorder attending to syndromatic, symptomatic, functional and affective definitions of remission of bipolar symptomatology in a longitudinal sample of ADHD children with comorbid bipolar disorder. METHODS: ADHD boys (128) were followed over 1- and 4-year follow-up assessments with structured diagnostic interviews to assess the persistence of psychiatric comorbidity. The course and duration of bipolar disorder was estimated by calculating the time from age at onset and the age at remission reported at either the 1- or 4-year follow-up assessments. RESULTS: Twenty-two (17%, Prevalent Cases) subjects met criteria for bipolar disorder at the baseline assessment. The average age of these subjects was 10.5+/-3.0 (range: 6 to 17 years) at baseline and 14.4+/-3.1 years of age at follow-up. The rate of remission was heavily dependent on the definition used. The rate of functional remission was the lowest and the rate of syndromatic remission was the highest. Regardless of the definition used, however, the disorder was chronic and lasted many years. LIMITATIONS: These data should be considered preliminary due to the sample size and the absence of mood symptom rating scales. CONCLUSIONS: That less than 20% of subjects attained functional remission or euthymia over the entire time period evaluated provides further evidence that pediatric bipolar disorder is a chronic mood disorder with a poor prognosis.
Although twin and adoption show bipolar disorder (BP) has a strong genetic component, few chromosomal regions have been consistently implicated by molecular genetic studies. To address this issue, we sought to determine if quantitative dimensions of bipolar disorder symptoms would be useful for detecting genes that underlie the susceptibility to bipolar disorder. Subjects were 520 individuals diagnosed with bipolar I, bipolar II or schizoaffective disorder, bipolar type who had participated in the NIMH genetics initiative for bipolar disorder. We constructed symptom scores from 29 psychiatric symptoms recorded in the Diagnostic Interview for Genetic Studies (DIGS). Principal components factor analysis followed by a varimax rotation was used to extract symptom dimensions. Factor scores were calculated for all genotyped individuals in the sample, regardless of affection status. Heritable factors were used in a variance-components linkage analysis, which utilized the exact likelihoods of allele-sharing identical-by-descent for each pair of relatives within each pedigree. The principal components factor analysis resulted in five independent dimensions: depressed state, psychosis, sleep disturbances, psychomotor acceleration, and irritability. Two factors were significantly heritable: depression (h2=0.53, p<0.001) and irritable vs. euphoric mania (h2=0.35, p=0.03). These were subsequently used in a linkage analysis that resulted in LOD scores of <2.0, which are not statistically significant. The five constructs developed through factor analysis appear to be consistent with previous factor analyses. Notably, only the dimensions associated with the type of mood disturbance showed high heritability, which suggests that careful measurements of depression, euphoria and irritability may be particularly useful in clarifying the genetic etiology of bipolar disorder in future studies.