Ada H. Zohar

An Epidemiological Study of Obsessive-Compulsive Disorder and Related Disorders in Israeli Adolescents

Five hundred and sixty-two, 16- to 17-year-old consecutive inductees into the Israeli Army, constituting a random sample of their cohort, were screened for obsessive-compulsive disorder (OCD), Tourettes syndrome, transient tics (TT), chronic multiple tics (CMT), and attention-deficit hyperactive disorder (ADHD). Two child psychiatrists interviewed the subjects, using screening items from structured interviews that implement DSM-III-R diagnostic criteria. For OCD, a point prevalence of 3.6% was found, 3.9% for ADHD, 1.8% for CMT, and 1.6% for TT. For ADHD, TT, and CMT, but not for OCD, there was a significantly higher prevalence for males than for females. Among the OCD individuals, there was an elevation of TT, CMT, and Tourettes syndrome relative to the population rates.

Haplotype relative risk study of catechol‐O‐methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): Association of the high‐enzyme activity val allele with adhd impulsive‐hyperactive phenotype

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness (chi(2) = 4.72, p = 0.03, df = 1). In particular, the impulsive-hyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria (chi(2) = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson chi(2) = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale (chi(2) = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinsons disease, might in due time be considered in the treatment of ADHD.

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive‐compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty‐three subjects with VCFS of mean age 18.3 ± 10.6 years were comprehensively assessed using semi‐structured psychiatric interview and the Yale–Brown obsessive compulsive scale (Y‐BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM‐IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive‐compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention‐deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early‐onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD.

Obsessive-Compulsive Characteristics: From Symptoms to Syndrome

OBJECTIVE To assess the distribution and severity of obsessions and compulsions in a nonclinical adolescent population. METHOD During preinduction military screening, 861 sixteen-year-old Israelis completed a questionnaire regarding the lifetime presence of eight obsessive-compulsive (OC) symptoms and three severity measures. The presence or absence of obsessive-compulsive disorder (OCD) or subclinical OCD was ascertained by an independent interview. RESULTS Although only 8.0% and 6.3% of respondents reported disturbing and intrusive thoughts, respectively, 27% to 72% of subjects endorsed the six remaining OCD symptoms. Twenty percent of subjects regarded the symptoms they endorsed as senseless and 3.5% found them disturbing; 8% reported spending more than an hour daily on symptoms. OCD and subclinical OCD cases differed significantly from non-OCD cases, but not from each other, in distress and mean number of symptoms. Although the distribution of nine of the items differed for noncases, compared with OCD and subclinical OCD cases, the distributions for all items overlapped markedly across the three groups. CONCLUSIONS OC phenomena appear to be on a continuum with few symptoms and minimal severity at one end and many symptoms and severe impairment on the other. Defining optimal cutoff points for distinguishing between psychiatric disorder and OC phenomena that are common in the general population remains an open question.

A haplotype relative risk study of the dopamine D4 receptor (DRD4) exon III repeat polymorphism and attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Several investigations have recently examined the role of the dopamine DRD4 exon III repeat polymorphism in ADHD. The long 7 repeat allele of this receptor was shown in three family-based studies, but not in one case control design, to be a risk factor for this disorder. We now report an additional family-based study of DRD4 exon III repeat region and ADHD. However, in the current study we fail to observe preferential transmission of the DRD4 exon III long 7 repeat allele, chi(2) = 0. 142, P < 0.1, df = 1. Nor was any preferential transmission observed when genotypes were compared, chi(2) = 0.180, P > 0.1, df = 1. Possible reasons are discussed, especially lack of sufficient power in analying more refined phenotypes, why the current results in contrast to previous findings fail to support a role for the long form of the DRD4 receptor as a putative risk factor for ADHD.

Ritualistic behavior in young children.

The aim of this study was to examine ritualistic behavior at its developmental peak. Children 20–59 months of age were sampled through a national system of daycare centers in Israel (N = 228). The order of onset of the ritual behaviors measured was virtually identical to that reported for an American sample (D. W. Evans et al., 1997). Gender and age effects were found for fearfulness but not for ritualistic behavior. Maternal reports of ritualistic behavior were highly correlated with reported fears, and with shy and emotional temperament. Mothers of the children who were in the top 10% in their use of rituals according to maternal report, worried about their childs ritualistic behavior, even though maternal worry was not correlated with ritualistic behavior for the whole distribution.

An examination of cognitive versus behavioral components of recovery from anorexia nervosa.

Definitions of “full recovery” from anorexia nervosa (AN) vary, and rarely include the cognitive criteria of lack of body image distortion and fear of weight gain. We investigated the implications of including or excluding cognitive criteria of AN in the definition of “full recovery”. Current symptomatology and personality characteristics associated with AN were assessed and compared in 42 behaviorally but not cognitively recovered women, 32 both behaviorally and cognitively recovered women, and 253 controls. On all measures included, the scores of the behaviorally recovered women were significantly more anorexic-like than those of the women recovered cognitively as well, who were indistinguishable from controls. Criteria for recovery from AN need to be refined and standardized, and cognitive criteria incorporated, to characterize a minority who recover to the extent that their eating attitudes and personality profiles are indistinguishable from those of women with no history of an eating disorder.

Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome.

Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-O-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMTL) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMTL is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158Val/Met polymorphism coding for COMT high/low-activity alleles. The COMTL allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, chi2=7.76, p=0.005) and obsessive-compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, chi2=7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMTL individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS.

Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4).

The dopamine D4 receptor (DRD4), a well‐characterized, polymorphic gene, is an attractive candidate for contributing risk to disordered eating and anorexia nervosa (AN). We tested association using UNPHASED for 5 DRD4 polymorphic loci, 3 promoter region SNPs (C‐521T, C‐616G, A‐809G), the 120 bp promoter region tandem duplication and the exon III repeat, in 202 AN trios and 418 control families. Since perfectionism characterizes AN, we tested these five loci for association with the Child and Adolescent Perfectionism Scale (CAPS) in the AN and control groups. Single locus analysis showed significant association between the ‘C’ C‐521T allele and AN. Haplotype analysis also showed significant association, particularly a 4‐locus haplotype (exon III&120 bp repeat&C‐521T&A‐809G). Association was also observed between DRD4 and CAPS scores both for AN and control subjects. The insulin‐like growth factor 2 (IGF2) and the arginine vasopressin 1a receptor (AVPR1a), previously shown to be associated with disordered eating, were also associated with CAPS scores. Three genes associated with AN were also associated with perfectionism. Personality traits are potential endophenotypes for understanding the etiology of eating disorders and one of the several pathways to eating pathology may be mediated by the impact of DNA sequences on perfectionism.

Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21

Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety‐related and novelty‐seeking traits. The first genome‐wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313–317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety‐related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21–24 and 22q12–13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21–23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues.