Relationship between behaviour problems and perceived parenting practices in Korean youth.

BACKGROUND: Parenting practices have been accepted as powerful risk factors for behaviour problems, even though previous studies have suffered from significant methodological problems, such as small, non-representative samples, cross-sectional study designs, poor control for confounders, and minimal consideration of paternal parenting. This study examined whether three, specific maternal and paternal parenting practices are associated with internalizing and externalizing behavioural problems in youth. METHODS: A prospective, longitudinal, cohort study was conducted among 1641 seventh- and eighth-grade students from representative sample of middle school students. The measurements were the Korean Youth Self Report and the Childrearing Behavior Questionnaire (measuring three dimensions of parenting practice: warmth-acceptance, rejection-restriction and permissiveness-non-intervention). Descriptive and logistic regression analyses were performed. RESULTS: Maternal rejection-restriction increased risks for internalizing problems (OR = 1.112), whereas paternal control-rejection increased risks for externalizing behavioural problem (OR = 1.125). CONCLUSIONS: Specific parenting practices showed differential associations with youth behaviour problems. These results suggest that further studies are necessary to understand the importance of unique and shared parenting practices as well as their interactions with other factors in the aetiology of youth behaviour problems. In the meantime, these findings point to therapeutic opportunities for both parents and their children.

Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior.

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene x exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene x exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene x exposure interactions may shape behavior through associated changes in brain function.

Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

Maternal smoking during pregnancy and the risk of conduct disorder in boys.

BACKGROUND: Previous animal and human studies have indicated that prenatal exposure to nicotine is associated with adverse reproductive outcomes, including altered neural structure and functioning, cognitive deficits, and behavior problems in the offspring. Our study extends previous research on humans by controlling a broad range of correlates of maternal smoking during pregnancy to determine if smoking is associated with behavior problems in the offspring severe enough to qualify for DSM-III-R diagnosis. METHODS: Subjects were 177 clinic-referred boys, ages 7 to 12 years at the time of the first assessment, who underwent longitudinal assessment for 6 years using annual structured diagnostic interviews. Correlates of maternal smoking during pregnancy and previously identified demographic, parental, perinatal, and family risk factors for the disruptive behavior disorders were controlled in logistic regression analyses. RESULTS: Mothers who smoked more than half a pack of cigarettes daily during pregnancy were significantly more likely to have a child with conduct disorder (odds ratio, 4.4; P = .001) than mothers who did not smoke during pregnancy. This association was statistically significant when controlling for socioeconomic status, maternal age, parental antisocial personality, substance abuse during pregnancy, and maladaptive parenting. CONCLUSIONS: Maternal smoking during pregnancy appears to be a robust independent risk factor for conduct disorder in male offspring. Maternal smoking during pregnancy may have direct adverse effects on the developing fetus or be a marker for a heretofore unmeasured characteristic of mothers that is of etiologic significance conduct disorder.

Platelet 5-HT2 serotonin receptor binding sites in autistic children and their first-degree relatives.

We examined platelet serotonin2 [5-hydroxytryptamine2 (5-HT2)] receptor binding sites, whole blood serotonin (5-HT), and plasma norepinephrine (NE) in male autistic children and their first-degree relatives. Saturation studies utilizing 125I-spiroperidol labeled the 5-HT2 sites with an affinity of 224.6 +/- 84.4 pmol/L (Kd). No group differences, i.e., autistic (n = 12), siblings (n = 6), parents (n = 22), control (adult; n = 7: child; n = 10), were seen for either the Kd or the total number of sites (Bmax: 14.3 +/- 10.9 fmol/mg protein). No correlations were found in any group between binding parameters (Kd or Bmax) and whole blood 5-HT. For the parental group, inverse correlations were found between NE and Bmax (standing NE, rs = -0.67, n = 21, p = 0.001; supine NE, rs = -0.49, n = 22, p = 0.021). In the autistic group, no correlation was seen between plasma NE and Bmax. A correlation between the autistic boys' Bmax and their fathers' Bmax was observed (rs = 0.79, n = 11, p = 0.004). These findings suggest (1) circulating NE may be involved in heterologous regulation of 5-HT2 receptors in the platelet and (2) genetic (paternal-filial) factors may play a role in the expression of 5-HT2 binding sites in the platelet. These preliminary findings are discussed in relation to heterologous receptor regulation. The relationships between these findings and either the pathophysiology of autism or hyperserotonemia in autism are unknown.

Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with the l/l genotype. Further studies of the regulation of HTT gene expression are indicated.

Quantifying the phenotype in autism spectrum disorders.

Twin and family studies suggest that familial transmission in autism extends to a spectrum of social and behavioral deficits that characterize individuals who have significant impairments within the autism spectrum, but do not meet formal criteria for autistic disorder. Standardized diagnostic instruments, including the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS-WPS Edition), offer the opportunity to quantify deficits across the autism spectrum, controlling effects of language and cognitive delay, in individuals with significant impairments. It is suggested that quantitative measures of social reciprocity and repetitive behaviors and interests, with separate quantification of expressive language level and nonverbal intelligence, most accurately reflect the range of behavioral phenotypes in autism spectrum disorders.

Physical mapping of the serotonin 5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder.

The gene encoding the serotonin 5-HT(7) receptor (HTR7) has been considered as a candidate locus in several neuropsychiatric disorders, based on pharmacological evidence and ligand-binding studies. After determining over 3 kb of previously unpublished sequence from introns 1 and 2 of HTR7, a single base (C/T) polymorphism in the second intron of HTR7 was found. Allele-specific PCR was used to genotype the HTR7 marker in 53 trios consisting of subjects with autistic disorder and both parents. Using the transmission disequilibrium test (TDT), no evidence of preferential transmission of either allele was found (TDT chi(2) = 0.252, p = 0.602). Sequence data obtained from both intron 1 and intron 2 of HTR7, and from the 5-HT(7) pseudogene (HTR7P), was used to confirm localization of HTR7 to 10q23 and HTR7P to 12p13 using radiation hybrid analyses.

Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine.

BACKGROUND: Theophylline has been extensively studied as a treatment of asthma. However, some studies have suggested that theophylline may precipitate adverse behavioral and cognitive effects on children. Other reports have evaluated the effects of caffeine, another commonly used methylxanthine, as a treatment of attention-deficit hyperactivity disorder. OBJECTIVE: To present a meta-analysis of research on the behavioral and cognitive effects of methylxanthines in children. METHODS: The meta-analyses were conducted on 12 studies of theophylline and nine studies of caffeine that met inclusion criteria. RESULTS: In contrast to popular beliefs and earlier scientific reports, meta-analyses of controlled studies did not indicate that either theophylline or caffeine resulted in significant deleterious effects on cognition or behavior. In fact, there was a small, positive effect on parental report of externalizing behavior for both methylxanthines. CONCLUSIONS: There is little evidence to suggest that methylxanthines have adverse cognitive or behavioral effects on children. Questions remain with regard to the identification and determinants of either responsive or sensitive subgroups, dose-response relationships, and the effects of parent-teacher expectancies on behavioral ratings.

Fluoxetine effects on cerebral glucose metabolism.

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Fluoxetine treatment of children and adults with autistic disorder and mental retardation.

An open trial of pharmacological treatment with fluoxetine, ranging from 20 mg every other day to 80 mg per day, led to a significant improvement in Clinical Global Impressions ratings of Clinical Severity in 15 of 23 subjects with autistic disorder and 10 of 16 subjects with mental retardation. Six of 23 patients with autistic disorder and 3 of 16 patients with mental retardation had side effects which significantly interfered with function, consisting predominantly of restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Double-blind studies of the efficacy of pharmacological agents that potently inhibit 5-HT uptake in the treatment of mental retardation coexisting with Axis I psychiatric disorders (especially obsessive-compulsive disorder) and autistic disorder are warranted.

Autistic disorder and post-traumatic stress disorder.

The present case study examined an adolescent boy who initially was evaluated at our clinic and was found to meet DSM-III-R criteria for autistic disorder. After placement in a residential school using Daily Life Therapy for autistic disorder, the subject reported being physically abused by a staff member. Additional psychiatric evaluation revealed post-traumatic stress disorder (PTSD) including symbolic anxiety and repetition of the trauma. The diagnosis of PTSD should be considered in children with autistic disorder and other severe developmental disorders who have experienced physical and sexual abuse. Furthermore, parents, professionals, educators, and child care workers struggle with emotional reactions to children with severe developmental disorders and may have difficulty accepting the reality of the child rather than the fantasy of the "wished-for child." The disappointment of this fantasy and the equating of the child's weaknesses as one's own may lead to personal devaluation and increase the risk of abusive behavior.

Multisite, double-blind, placebo-controlled trial of porcine secretin in autism.

OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder.

Platelet serotonin (5-HT) studies were conducted with 12 hyperserotonemic and 12 normoserotonemic age-, sex-, and relationship-matched relatives of autistic probands. Each group consisted of 7 mothers, 4 fathers, and 1 sister of autistic children and adolescents. The density (Bmax) of platelet 5-HT2 receptor binding sites, labelled with [3H]-lysergic acid diethylamide (LSD), was significantly lower in 11 hyperserotonemic subjects compared to 12 normoserotonemic subjects (40.9 +/- 13.5 fmol/mg protein, 59.6 +/- 13.2; p < 0.004). The affinity (Kd) for [3H]-LSD binding did not differ. Although the density (Bmax) of [3H]-paroxetine binding did not differ between groups, there was a small difference in the affinity (Kd) for [3H]-paroxetine binding (hyperserotonemic 47.6 +/- 9.0 pM, normoserotonemic 54.8 +/- 12.1; p < 0.05). There were no significant differences in platelet 5-HT uptake, or in thrombin-stimulated 5-HT release. Basal, 5-HT-stimulated, and arginine-vasopressin (AVP)-stimulated inositol phosphate production, as well as basal, prostaglandin E1 (PGE1)-, and forskolin-stimulated cAMP production did not differ. There were significant correlations between whole blood 5-HT levels and LSD Bmax (rs = -0.63, N = 23, p < 0.002) and whole blood 5-HT levels and 5-HT uptake Vmax (rs = 0.56, N = 18, p < 0.02). However, [3H]-LSD labelled 5-HT2 binding and 5-HT uptake were not correlated with each other. Hyperserotonemia of autism may be heterogeneous with one subgroup of subjects with increased 5-HT uptake and another subgroup with decreased 5-HT2 binding.

Serotonin and measured intelligence.

Blood serotonin (5HT) has been shown to be elevated in 30% of autistic children and 50% of severely mentally retarded children. Ninety-eight normal adult subjects were studied to determine if there was an inverse relationship between whole blood 5HT in normal adults of average and above-average intelligence. There was a trend toward a negative correlation between whole blood 5HT and Vocabulary scores that would not account for hyperserotonemia in autistic or mentally retarded individuals. Female subjects had significantly greater whole blood 5HT than male subjects. There was no difference in whole blood 5HT collected before and after volume depletion of 450 ml, providing further evidence of the intraindividual stability of whole blood serotonin levels. There was no relationship between age and whole blood 5HT in a group of normal adult subjects.

Receptor inhibition by immunoglobulins: specific inhibition by autistic children, their relatives, and control subjects.

Forty-two parents of children with autistic disorder, 15 children with autistic disorder, 17 siblings of children with autistic disorder, and 12 unrelated normal adult controls were studied to determine if immunoglobulins isolated from their plasma would inhibit binding of the 5HT1A agonist, [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (DPAT) to 5HT1A receptors in human hippocampal membranes. There were no significant differences among the means of percentage inhibition of DPAT binding of parents, children with autistic disorder, siblings, or unrelated controls. In addition, there were no differences in the proportion of subjects with > 15% DPAT inhibition among autistic children, their parents, their siblings, or unrelated controls. Immunoglobulin inhibition was not specific for the 5HT1A receptor binding site, since immunoglobulins inhibited binding to 5HT2, D1, D2, and alpha 2-adrenergic binding sites. The immunoglobulins isolated from normal controls inhibited [3H]-rauwolscine binding at alpha 2-adrenergic sites less than immunoglobulins of children with autistic disorder and their parents and siblings. This study did not support the hypothesis that autoantibodies to 5HT1A or 5HT2 receptors are characteristic of autistic disorder.

Relationships of whole blood serotonin and plasma norepinephrine within families.

Whole blood serotonin (5HT) and plasma norepinephrine (NE) levels were determined in 47 families of autistic probands to study relationships within families of these measures. Whole blood 5HT, but not plasma NE, was significantly positively correlated between autistic children and their mothers, fathers, and siblings. Twenty-three of the 47 families studied had at least 1 hyperserotonemic member. Of these 23 families, 10 (43.5%) had 2 or more hyperserotonemic members; 5 families were identified in which each family member studied had hyperserotonemia (whole blood 5HT greater than 270 ng/ml). If the autistic child of a family was hyperserotonemic, the first-degree relatives were 2.4 times more likely to be hypersertonemic than if the autistic child was not hyperserotonemic. Mean whole blood 5HT levels were higher in autistic subjects than their parents or siblings. Siblings were found to have lower plasma NE than autistic probands. This study replicates a previous study showing familial relationships of hyperserotonemia within families with autistic children.

The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism.

The Autism Diagnostic Observation Schedule-Generic (ADOS-G) is a semistructured, standardized assessment of social interaction, communication, play, and imaginative use of materials for individuals suspected of having autism spectrum disorders. The observational schedule consists of four 30-minute modules, each designed to be administered to different individuals according to their level of expressive language. Psychometric data are presented for 223 children and adults with Autistic Disorder (autism), Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) or nonspectrum diagnoses. Within each module, diagnostic groups were equivalent on expressive language level. Results indicate substantial interrater and test-retest reliability for individual items, excellent interrater reliability within domains and excellent internal consistency. Comparisons of means indicated consistent differentiation of autism and PDDNOS from nonspectrum individuals, with some, but less consistent, differentiation of autism from PDDNOS. A priori operationalization of DSM-IV/ICD-10 criteria, factor analyses, and ROC curves were used to generate diagnostic algorithms with thresholds set for autism and broader autism spectrum/PDD. Algorithm sensitivities and specificities for autism and PDDNOS relative to nonspectrum disorders were excellent, with moderate differentiation of autism from PDDNOS.

Attention deficit hyperactivity disorder and whole-blood serotonin levels: effects of comorbidity.

Whole-blood serotonin (5-hydroxytryptamine, 5-HT) levels were measured in children with attention deficit hyperactivity disorder (ADHD) with and without comorbid conduct disorder (CD) or oppositional-defiant disorder (ODD). It was hypothesized that the whole-blood 5-HT levels of ADHD probands would be significantly correlated with the whole-blood 5-HT levels of their mothers. Fifty-two children who met DSM-III-R criteria for ADHD were selected consecutively from an ADHD clinic (47 males--35 Caucasians, 10 African-Americans, and 2 Hispanics; 10 females--all Caucasians). Whole-blood 5-HT was assayed by high performance liquid chromatography and compared between ADHD children with and without comorbid CD or ODD. The familiality of whole-blood 5-HT levels was studied by Spearman's rank-order correlation. There were no significant age, race, or sex effects. There was no significant difference in whole-blood 5-HT levels between children with ADHD only (n = 22; 190 +/- 45 ng/ml) and ADHD with CD or ODD (n = 30; 212 +/- 67). However, 7 out of 30 (23%) children with ADHD+CD/ODD had whole-blood 5-HT levels > 270 ng/ml, while none of the ADHD-only children had whole-blood 5-HT levels > 270 ng/ml, a statistically significant difference. Whole-blood 5-HT levels showed significant positive correlations between 36 children with disruptive behavior disorders and their biological mothers (rs = 0.47). There was no difference in mean levels of whole-blood 5-HT between subgroups of children with ADHD with or without comorbid CD or ODD.(ABSTRACT TRUNCATED AT 250 WORDS)