Gale Inoff-Germain

Support for association between ADHD and two candidate genes : NET1 and DRD1

Attention deficit hyperactivity disorder (ADHD) is a common, multifactorial disorder with significant genetic contribution. Multiple candidate genes have been studied in ADHD, including the norepinephrine transporter (NET1) and dopamine D1 receptor (DRD1). NET1 is implicated in ADHD because of the efficacy of atomoxetine, a selective noradrenergic reuptake inhibitor, in the treatment of ADHD. DRD1 is primarily implicated through mouse models of ADHD. DNA from 163 ADHD probands, 192 parents, and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes (5‐HT1B, 5‐HT2A, 5‐HT2C, ADRA2A, CHRNA4, COMT, DAT1, DRD1, DRD4, DRD5, NET1, and SNAP‐25). Analyses included case‐control and family‐based methods, and dimensional measures of behavior, cognition, and anatomic brain magnetic resonance imaging (MRI). Of the 12 genes examined, two showed a significant association with ADHD. Transmission disequilibrium test (TDT) analysis revealed significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD (P ≤ 0.009); case‐control analysis revealed significant association of two DRD1 SNPs with ADHD (P ≤ 0.008). No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01. This study provides support for an association between ADHD and polymorphisms in both NET1 and DRD1; polymorphisms in ten other candidate genes were not associated with ADHD. Because family‐based and case‐control methods gave divergent results, both should be used in genetic studies of ADHD.

Childhood Obsessive–Compulsive Disorder in the NIMH MECA Study: Parent Versus Child Identification of Cases

Because as many as 50% of obsessive–compulsive disorder (OCD) cases have had onset by age 15, interest in its detection in childhood is strong. Clinical experience indicates that children often try to keep their OCD secret and that parental report may give marked underestimates. The authors examined the prevalence of childhood OCD in the NIMH Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study, a four-site community survey which allowed comparison of both parent and child report of the childs OCD and related symptoms and disorders. OCD cases, based on structured interviews (DISC-2.3 with DSM-III-R criteria) with 1,285 caretaker-child pairs, were identified separately for parent and child (aged 9 through 17) informants from the MECA database. Cases were then examined for demographic characteristics, for obsessive–compulsive symptoms and other diagnoses reported in cases “missed” by one reporter, and for comorbid disorders. Of a total of 35 (2.7%) identified cases, four (0.3%) were identified by the parent and 32 (2.5%) were identified by the child, with only one overlapping case. In general, when OCD cases were “missed” by one reporter, that reporter did not substitute another disorder. These findings support clinical data that children with OCD often hide their illness and underscore the importance of child interviews for its detection.

Developmental processes in early adolescence: Relationships between adolescent adjustment problems and chronologic age, pubertal stage, and puberty-related serum hormone levels

Relations between adolescent psychosocial adjustment problems and markers of biologic development, including chronologic age, pubertal status, and serum hormone levels, were examined in 56 normal boys and 52 normal girls, ages 9 to 14 years. Adolescent psychosocial adjustment was assessed by adolescent self-ratings of various aspects of self-image (Offer Self-Image Questionnaire for Adolescents) and parent ratings of adolescent behavior problems (Child Behavior Checklist). The pubertal status measure used in the analyses was Tanner genital stage for boys and Tanner breast stage for girls. The hormone measures, determined by radioimmunoassay, were serum levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), sex steroids (testosterone and estradiol), and adrenal androgens (dehydroepiandrosterone and its sulfate, and androstenedione). The testosterone/estradiol ratio also was computed. Overall, findings were stronger, more consistent, and more generalized for boys than for girls. For boys, adjustment problems typically were associated with a multivariate profile that may be characteristic for later maturers: relatively low sex steroid levels, or lower pubertal stage, and relatively high adrenal androgen (androstenedione) levels, frequently in conjunction with higher chronologic age. Univariate relations predominated for girls; that is, associated with adjustment problems for girls were relatively high levels of gonadotropins, relatively low levels of dehydroepiandrosterone sulfate, and relatively high levels of androstenedione on their own or in conjunction with lower pubertal stage. Higher levels of androstenedione, a steroid particularly responsive to stress, were associated with adjustment problems in both boys and girls. This relation may reflect the stress of later maturation, which could result from environmental factors, such as adolescent self-comparisons with same-age peers, or endogenous effects of hormones.

Developmental processes in early adolescence: Relations among chronologic age, pubertal stage, height, weight, and serum levels of gonadotropins, sex steroids, and adrenal androgens

Cross-sectional data are presented on 108 young adolescents (56 boys, 52 girls), ages 9 to 14 years. The measures were: for all subjects, pubertal stage (Tanner criteria for genital/breast and pubic hair stage); height and weight; serum hormone concentrations for gonadotropins (luteinizing hormone and follicle-stimulating hormone), sex steroids (testosterone, estradiol, and the computed testosterone to estradiol ratio), adrenal androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione), and testosterone-estradiol binding globulin. In addition, testicular volume for boys and menarchial status for girls are reported. The study goal was to provide interrelations among these measures, based on the same sample, and examine their interchangeability. Results suggest that it would be reasonable to compare research across as well as within studies based on different markers. Multiple regression analysis showed that the strongest hormone correlates of pubertal development were androgen levels (primarily testosterone in boys and primarily dehydroepiandrosterone sulphate and androstenedione in girls). Estradiol level in girls was the strongest correlate only for menarchial status. Level of testosterone-estradiol binding globulin, which was lower at successive pubertal stages for boys and showed no consistent differences for girls, may be a useful measure for studying the developmental processes and gender differences during puberty.

The relation of relative hormonal levels and physical development and social-emotional behavior in young adolescents

The study examined the relation between timing of physical maturation and problems of adjustment and peer relations. The participants were 9-14-year-old boys (N=56) and girls (N=52). Assessments of physical maturation consisted of pubertal staging according to Tanner criteria and serum determinations of luteinizing hormone, follicle stimulating hormone, testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. There was approximately an equal number of boys and girls in each pubertal stage. The psychological measures were the Psychopathology and Emotional Tone subscales from the Offer Self-Image Questionnaire for Adolescents and interview questions to assess interactions with peers. Psychopathology and emotional tone (sad effect) scores were higher for boys with high-for-age adrenal androgens and lower for boys with high-for-age sex steroids. Behavioral manifestations of sexuality, interest in dating, was higher for boys with high-for-age adrenal androgens. Dating and spending time with friends were higher for boys with high-for-age gonadotropins. Psychopathology and emotional tone were higher for girls with high-for-age gonadotropins. The results indicate that high-for-age hormone level or early timing of puberty generally was related to adverse psychological consequences for boys and girls, with relations being stronger for boys than for girls.

Practitioner Review: Treatment of Obsessive‐Compulsive Disorder in Children and Adolescents

This paper reviews the treatment of obsessive-compulsive disorder (OCD) in children and adolescents. Focusing on clinical features of the disorder and its treatment particular to pediatric onset, diagnosis, assessment, and behavioral, pharmacological, as well as new investigative treatments are covered. Adaptation of cognitive-behavioral therapy for children and adolescents, use of augmenting agents in drug treatment, and subtyping of OCD cases are developments relevant for current practice.

Hormonal influences on aspects of psychological development during adolescence

Systematic study of the effects df hormones on psy ehological development of adolescents is in an embryonic state. At the folk-wisdom level, hormones have been implicated for the last few decades in the behavior changes that occur during adolescence. Research on the influence of hormones on behavior now is feasible and timely. Improvements in the sensitivity of biochemical assays have made it possible to measure minute amounts of circulating hormones in prepubertal and pubertal adolescents. Furthermore, research in the emerging field of psychoneuroendocrinology shows that hormones affect a wide array of behaviors of human bein the experiences of human beings affect hormone levels (1). Endocrine abnormalities also have been linked to many mental health disorders in adults (28). Endocrine processes involved in the develop ment of these disorders may be also linked to normal variations in mood and behavior. This paper will present a brief summary of how hormones have been conceptualized with regard to behavior and the approaches used in research to examine relations between hormones and behavior. Studies of hormones and behavior during adolescence are reviewed. In addition, questions that remain to be answered in the literature regarding

Evaluative communications between affectively ill and well mothers and their children.

Earlier research suggests that the natural verbal discourse of mothers with their children can be important in clarifying, verifying, and evaluating the behavior in which a child is engaged, in attributing qualities to the child, and in influencing the childs self-perceptions. We investigated the potential influences of parental affective illness (bipolar affective disorder and unipolar depression in contrast to no history of psychiatric illness) on such “labeling” behavior in a sample of 61 mothers and their older (school-age) and younger (preschool-age) children. It was hypothesized that the dispositions characterizing affective illness (specifically, negativity and disengagement) would be reflected in the labeling statements of mothers with a diagnosis as they interacted with their children. Based on videotaped interactions during a visit to a home-like laboratory apartment, labeling statements were identified in terms of speaker and person being labeled (“addressee”) and coded (positive, negative, mixed, or neutral) for judgmental and affective quality of the statement and reaction of the addressee. Data were analyzed (a) by family unit and (b) my mother to child statements. The general pattern of findings indicated, in relative terms, an excess of negativity on the part of family members in the bipolar group and a dearth of negative affect for mothers in the unipolar group. Negativity in the bipolar group appeared to be especially likely when the setting involved mothers and two male children. Additionally, findings are discussed in terms of sex differences in vulnerability to depression.

Variability in Hormone Concentrations and Self-Reported Menstrual Histories in Young Adolescents: Menarche as an Integral Part of a Developmental Process

Menarche has been considered a marker for examining interindividual differences in biobehavioral development and for separating pubertal development into 2 stages. The purpose of this study was (1) to compare hormone concentrations in pre- and postmenarcheal girls to determine whether they fit a continuous or dichotomous model of pubertal development surrounding menarche; and (2) to address methodological issues of variability in self-reports of menstrual histories and reliability in reporting age at menarche. Girls (N = 52) ages 9 to 14 years were enrolled in a longitudinal study. Blood was drawn for hormone concentrations. Menstrual-cycle information was collected by questionnaire and oral report. Discrepancies in reporting of age at menarche ranged from 0 to 18 months and variability was noted in length of cycle. There was great overlap in hormones between pre- and postmenarcheal categories. Future studies might consider menarche as the culmination of underlying developmental processes rather than as a discrete event. Limitations of each measure of puberty should be considered by investigators conducting biobehavioral studies of adolescents.

MEDICAL AND SURGICAL TREATMENT OF OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder (OCD) has been increasingly recognized as highly comorbid with Tourette syndrome (TS), 21,36 and some cases of OCD most probably are alternative expressions of genetically based TS. 32 Relations between OCD and TS also extend to models of pathophysiology, especially with regard to involvement of the basal ganglia in both disorders. 38 Thus, clarifying the complex interrelations of OCD and TS has important clinical implications for diagnosis and treatment of patients showing symptoms of either or both disorders. The last two decades have brought a wealth of new information on the medical treatment of OCD. Not only have a series of antidepressant drugs been shown to be effective, but this drug response has been used to explore a spectrum of related disorders. Drug treatment of OCD has been so well established in recent years that more recent reviews typically also address the management of drug treatmentrefractor y cases. Today, there are several alternative effective serotonergic agents, and there is some evidence for efficacy of intravenous clomipramine as well as for augmenting effects of other drugs. Additionally, OCD remains as one of the relatively few indications for neurosurgery, which is being implemented for OCD at several centers. The efficacy of neurosurgery has not yet been demonstrated in rigorous double-blind studies, but clinical data remain provocative. Given that neurosurgical intervention is used for only the most severely impaired OCD patients, the clinical reports indicating that about one half respond positively is impressive. 29 Neurosurgery also may benefit some cases of TS, although the evidence is far less clear than for OCD. 38 These drug and surgical treatments are reviewed here with respect to the treatment of children and adults with OCD. Where appropriate and in keeping with the theme of this issue, their relevance for the diagnosis of OCD comorbid with TS is also addressed.