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Delays in autism spectrum disorder (ASD) diagnosis and treatment are significant clinical problems that can be addressed by timely, community-based assessment. This study examined tools for identifying ASD in community settings using machine learning (ML) models.

Native American children disproportionally face many risk factors for poor developmental outcomes, including poverty, environmental toxicant exposure, and limited medical and intervention services. To understand these risks, comprehensive documentation of developmental and behavioral phenotypes is needed. In this descriptive study, the neurodevelopment of young Diné (Navajo) children was assessed using standardized assessment instruments in combination with expert clinician judgment.

On a global scale, psychiatric disorders are among the most common of medical morbidity. Most psychiatric disorders have their onset in childhood and adolescence when prevention and early intervention can prevent a lifetime of suffering, disability, and stigma. Thus, we share in a global responsibility to transcend cultural and political boundaries to identify childhood-onset psychiatric illness as an international public health crisis that demands the attention and efforts of physicians and other clinicians, families, stakeholders, and policy makers around the world.

Numerous potential therapeutic targets are being investigated in autism spectrum disorder (ASD). Here, we discuss a platform trial approach for designing proof-of-concept (POC) clinical studies of ASD — via the Autism Spectrum POC Initiative (ASPI) — that can be conducted through a public–private partnership with the aim of finding effective treatments in the most expeditious manner.

Background: This pilot study examined the effectiveness of memantine hydrochloride in improving cognitive functioning and behavioral symptoms in children with pervasive developmental disorders (PDDs).Method: Subjects aged 3–12 years inclusive were enrolled in this 8-week, open-label study. Expressive and receptive language, nonverbal IQ, and nonverbal memory measures were administered at baseline and after 8 weeks of treatment with 0.4 mg/kg of memantine hydrochloride. Throughout the study, the Aberrant Behavior Checklist (ABC) was sent in weekly by parents as a measure of behavioral change.Results: Twelve of 14 subjects completed the study. Significant improvement from baseline was noted on the memory test (Children’s Memory Scale Dot Learning Subtest). There were no significant differences from baseline on measures of expressive or receptive language or nonverbal IQ. There were significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability. There were no overall significant statistical differences from baseline on the Clinical Global Improvement—Severity (CGI-S) scale. On the Clinical Global Improvement-Improvement (CGI-I), 4 of 14 subjects showed minimal improvement, and none was deemed “much-improved” or “very much improved.”Conclusions: This small, prospective, open-label study suggests that memantine may be useful in the treatment of memory functioning and some behavioral symptoms in PDDs. The investigators did not see the same degree of change as endorsed by caretakers. Controlled studies are needed to substantiate and clarify these preliminary findings.

The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5‐HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5‐HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5‐HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity‐impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5‐HTTLPR and ADHD (χ2 = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case‐control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population. © 2005 Wiley‐Liss, Inc.

The authors reviewed various statements describing the ethical use of placebo-controls in clinical trials involving minors. Attention was focused upon the Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, published by the American Academy of Pediatrics (AAP) (Kaufman et al. 1995). A brief review of certain key documents and a possible expansion of the guidelines are presented. Specifically, it is recommended that a review and update of guidelines for the use of placebo-controlled trials in children be undertaken by a working group comprised of stakeholders, including academic clinical and research professionals, bioethicists, consumers, members of key government agencies, and the pharmaceutical industry.

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER⁺. The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples. © 2002 Wiley-Liss, Inc.

Current pharmacological treatment of obsessive compulsive disorder involves the use of selective serotonin reuptake inhibitors (SSRIs). However, a large proportion of patients does not respond fully to these medications despite receiving optimal doses and concomitant cognitive-behavioral therapy. Finding efficacious augmentation strategies has become an important goal of researchers and clinicians working with this population. In this case series, we describe four patients with childhood-onset obsessive compulsive disorder, and with partial or no response to SSRI treatment, who subsequently had a reduction of their symptoms with Adderall augmentation.

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11-q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11-q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15-associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5' flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family-based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5' flanking region and intron 2 splicing region may be evaluated in further studies. © 2002 Wiley-Liss, Inc.

Many autistic children have associated problems of inattention, impulsivity, and hyperactivity that limit the effectiveness of educational and behavioral interventions. Few controlled psyehophar-macologic trials have been conducted in autistic children to determine which agents may be effective for these associated features. Eight male children (8.1 ± 2.8 years) with autistic disorder, diagnosed by DSM-III-R criteria, completed a placebo-controlled, double-blind crossover trial of clonidine. Subjects were included in the study if they had inattention, impulsivity, and hyperactivity that was excessive for their developmental level. Subjects had not tolerated or responded to other psychopharmacologic treatments (neuroleptics, methylphenidate, or desipramine). Teacher ratings on the Aberrant Behavior Checklist irritability, stereotypy, hyperactivity, and inappropriate speech factors were lower during treatment with clonidine than during treatment with placebo. Attention deficit disorder with hyperactivity: Comprehensive Teacher's Rating Scale ratings were not significantly improved during the study, except for oppositional behavior. Parent Conners Abbreviated Parent-Teacher Questionnaire ratings significantly improved during clonidine treatment. Clonidine led to increased ratings of the side effects of drowsiness and decreased activity. Clinician ratings (Children's Psychiatric Rating Scale Autism, Hyperactivity, Anger and Speech Deviance factors; Children's Global Assessment Scale; Clinical Global Impressions efficacy) of videotaped sessions were not significantly different between clonidine and placebo. Clonidine was modestly effective in the short-term treatment of irritability and hyperactivity in some children with autistic disorder.

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 5HT1Aagonist, [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (DPAT) to 5HT1Areceptors 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 5HT1Areceptor binding site, since immunoglobulins inhibited binding to 5HT2, D1, D2, and α2-adrenergic binding sites. The immunoglobulins isolated from normal controls inhibited [3H]-rauwolscine binding at α2-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 5HT1Aor 5HT2receptors are characteristic of autistic disorder.

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-deox-yglucose 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−1min−1) was compared to fluoxetine (8.22 ± 0.86 mg 100 g−1min−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.

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 thel/l genotype. Further studies of the regulation of HTT gene expression are indicated. © 1998 American College of Neuropsychopharmacology

The serotonin system has been implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin (5-hydroxytryptamine) levels in the blood of patients with autism. This has been clarified as elevation in the platelet content of serotonin. Subjects with elevated whole blood serotonin levels have been shown to have elevated platelet serotonin transport into platelets and decreased serotonin 5-HT2receptor binding. Most individuals with autism who are treated with potent serotonin transporter inhibitors have a reduction in ritualistic behavior and aggression. Reduction of central nervous system serotonin, induced by acute tryptophan depletion, causes a worsening of stereotyped behavior. Recent developments in the molecular biology of serotonin receptors are reviewed.

Treatment of autistic disorder and other pervasive developmental disorders (PDDs) requires identification of target symptoms, such as irritability, hyperactivity, self-injurious behavior, anxiety, or depression. If the target symptoms adhere to a comorbid syndrome such as obsessive compulsive disorder, treatment is specific to that comorbid syndrome with some exceptions. It is important to distinguish hyperactivity and inattention caused by difficulty with language and social impairment or rituals of autistic disorder and other PDDs from that caused by a comorbid syndrome similar to attention-deficit hyperactivity disorder. Psychopharmacologic classes discussed include potent serotonin transporter inhibitors (e.g., clomipramine and fluoxetine), other tricyclic antidepressants, stimulants, sympatholytics (clonidine and β-blockers), naltrexone, fenfluramine, typical (e.g., haloperi- dol) and atypical (e.g., clozapine and risperidone) neuroleptics, anticonvulsants (e.g., carbamazepine and sodium valproate), lithium, anxiolytics, pyredoxine, and newer agents.

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 > 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.

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 determined 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.

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 diagnoses. METHOD: 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 for conduct disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 105:36–38, 2001. © 2001 Wiley-Liss, Inc.

We previously established the contribution of de novodamaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novodamaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3(cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novocopy number variants in TD. Finally, we identify significant overlap of de novosequence variants between TD and obsessive-compulsive disorder and de novocopy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

In Reply.—We appreciate the opportunity to respond to Dr Kushner. Our initial response to Dr Gardner's question was focused on the issues he had raised concerning his patient. Dr Kushner is quite right, however, in noting the possibility of other interactions between diet and behavior.Besides migraine, there are a number of other disorders that may have either behavioral or emotional symptoms. The examples, just to mention a few, range from carbohydrate consumption in labile diabetes1,2 to phenylalanine consumption in phenylketonuria3 and dietary indiscretion in porphyria.4The symptoms cited by Drs Gardner and Kushner are specific neither to food allergy nor childhood migraine. Indeed, these common symptoms may suggest many other prevalent and potentially serious disorders. The chronic course of unrecognized lead poisoning, for instance, can be characterized by behavioral changes including hyperirritability, anorexia, hyperactivity, and decreased participation in play. These symptoms can be accompanied by