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Background The goal of this study was to identify chromosomal regions likely to contain susceptibility loci for obsessive-compulsive disorder (OCD). Methods We conducted a genome-wide linkage scan, with average marker spacing less than 10 centimorgans (cM), in 121 subjects from 26 families ascertained through probands with early-onset OCD. Best estimate lifetime psychiatric diagnoses were based on semistructured interviews and all other available sources of information. Parametric and nonparametric linkage analyses were conducted with GENEHUNTER+ and Allegro. Family-based association analyses were done using 35 single nucleotide polymorphisms (SNPs) in the 10p15 region. Results The maximum nonparametric log of odds (NLOD) score was 2.43 on chromosome 10p15 at position 4.37. When data from our first genome scan were added to data from this scan, the maximum NLOD score in the 10p15 region was 1.79. Association was detected on 10p15 with three adjacent SNPs, including the amino acid variant rs2271275 in the 3’ region of adenosine deaminase acting on RNA 3 (ADAR3) (p Conclusions The results provide suggestive evidence for linkage on chromosome 10p15. Evidence for association in the linkage region was found with three markers in the 3’ end of ADAR3. Limitations include the lack of significant linkage and association findings when corrected for multiple testing.

Background: The Social Communication Questionnaire (SCQ), formerly the Autism Screening Questionnaire (ASQ), is based on a well-validated parent interview, the Autism Diagnostic Interview (ADI). It has shown promise as a screening measure for autism spectrum disorders (ASDs) in a research-referred older sample, though recent studies with younger children reported lower sensitivities when using the suggested cutoff of ‡15 to differentiate ASDs from children with nonspectrum disorders (NS). Methods: Diagnostic discrimination of the SCQ was evaluated alone and in combination with the ADOS (Autism Diagnostic Observation Schedule) in a clinical and research-referred sample of 590 children and adolescents (2 to 16 years), with best estimate consensus diagnoses of autism, pervasive developmental disorder, not otherwise specified (PDD-NOS) and non-ASD disorders. The SCQ was completed before the evaluation in most cases. Performance of the SCQ was also compared with the Autism Diagnostic Interview ‐ Revised (ADI-R). Results: Absolute scores and sensitivity in the younger children and specificity for all groups were lower than reported in the original study. Using receiver operating curves (ROC) to examine the area under the curve (AUC), the SCQ was more similar to the ADI-R total score in differentiating ASD from NS disorders in the older (8‐10, >11) than younger age groups (

Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.

Background Family-based evidence for association at serotonin system genes SLC6A4, HTR1B , HTR2A , and brain-derived neurotrophic factor ( BDNF ) has been previously reported in obsessive-compulsive disorder (OCD). Early-onset OCD is a more familial form of the disorder. Methods We used the transmission-disequilibrium test of association at common polymorphisms in each of these genes in 54 parent–child trios ascertained through probands with early-onset OCD. Results No evidence for association was detected at any of the polymorphisms in the entire set of subjects. Nominally significant association was found at the HTR2A rs6311 polymorphism in subjects with tic disorder and OCD ( p = .05), replicating a previous finding in Tourette syndrome and OCD. Nominally significant association was also found for the SLC6A4 HT transporter gene–linked polymorphic region (5-HTTLPR) polymorphism for female subjects ( p = .03). Neither association would remain significant after statistical correction for multiple testing. Despite no individual study reporting replication, a pooled analysis of five replication studies of the SLC6A4 5-HTTLPR polymorphism supports association ( p = .02). Conclusions Low power across individual association studies in OCD may lead to a false acceptance of the null hypothesis. Accumulation of evidence from multiple studies will be necessary to evaluate the potential role for these genes in contributing to susceptibility to OCD.

Research on emotion and decision-making has suggested that arousal mediates risky decisions (e.g., Bechara et al., 1997), but several distinct and often confounded processes drive such choices. Here, we used econometric modeling to separate and quantify the unique contributions of loss aversion, risk sensitivity and choice consistency to risky decision-making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention’s pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision-making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e. as a function of initial loss aversion and body-mass index), and did not affect risk sensitivity or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of both emotion and risky decision-making.

Objective To assess the effect of escitalopram in the treatment of pervasive developmental disorders (PDDs). Method This 10-week study had a forced titration, open-label design. Twenty-eight subjects (mean age 125.1 ± 33.5 months) with a PDD received escitalopram at a dose that increased weekly to a maximum dose of 20 mg as tolerated. The Aberrant Behavior Checklist-Community Version (ABC-CV) and the Clinical Global Impression scale (CGI) were used to assess outcome. Results There was significant improvement in ABC-CV Irritability Subscale Scores (baseline mean 20.5 ± 5.9 to final mean 10.9 ± 7.2; p ≤ .001) and in the other ABC-CV Subscales. Improvement on Clinical Global Improvement Scale severity rating was also significant (baseline mean 5.2 ± 1.0 to final mean 4.6 ± 1.2; p ≤ .001). Twenty-five percent of the subjects responded at a dose less than 10 mg and did not tolerate the 10-mg dose, and an additional 36% responded at a dose greater than or equal to 10 mg. Final dose was unrelated to weight and only weakly correlated with age. Conclusions This open-label study found escitalopram to be useful in treating some difficulties common in PDDs. A wide variability in dose was found that could not be accounted for by weight and only partially by age. The study provides information useful for the design of double-blind, placebo-controlled studies of escitalopram in PDDs.

Objective. Being a victim or a perpetrator of school bullying, the most common type of school violence, has been frequently associated with a broad spectrum of behavioral, emotional, and social problems. In a Korean middle school community sample, this study specifically investigated the prevalence of suicidal ideations and behaviors in victims, perpetrators, and victim-perpetrators of school bullying and compared them with a group of students who were in the same schools and were not involved with bullying. Methods. In a cross-sectional study, 1718 seventh- and eighth-grade students in 2 middle schools participated in the study in October 2000. Students completed demographic information, Korean Peer Nomination Inventory, and Korean Youth Self-Report. Results. Compared with the students who were not involved with school bullying, victim-perpetrators reported more suicidal/self-injurious behaviors and suicidal ideation in the previous 6 months (odds ratio [OR]: 1.9 and 1.9, respectively). In female students, all 3 school bullying groups had increased suicidal ideation for the previous 2 weeks (OR: 2.8, 2.0, and 2.8, respectively) but not in male students (OR: 0.9, 1.1, and 1.3, respectively). Conclusions. Students who were involved in school bullying, especially victim-perpetrators and female students, had significantly higher risks for suicide ideation and suicidal behavior when compared with individuals who were not involved in school bullying. In addition to attempting to decrease bullying in a community, students who are involved in school bullying should be the targets for suicide monitoring and prevention programs.

There has been growing interest in the use of complementary and alternative medicine (CAM) for the treatment of a variety of medical conditions, especially psychiatric disorders. Why should ‘‘good, evidence-based practitioners’’ worry about such interventions? After all, they do not actually involve ‘‘our patients’’ who are working closely with us and are so attentive to our wisdom and reassurance. Well, that conclusion may be unwarranted, and failure to consider CAM in the course of patient care may place patients in jeopardy because ‘‘good, evidence-based practitioners’’ may actually miss two important bits of evidence. First, some CAM treatments may actually be helpful for some patients so these treatments may represent missed therapeutic opportunities for our patients. Second, whether we like it or not, there is plenty of evidence to suggest that many patients use CAM treatments that, if undetected, may impair treatment responses or, even worse, lead to serious adverse events. There is a long history of specialized, nontraditional treatments being used for a variety of medical conditions, especially for child and adolescent psychiatric disorders. But, why focus on child psychiatric disorders? There are a number of suggestions as to why this is the case but four seem to be the most salient. First, there is a general lack of consensus as to the specific pathophysiology that can be the target of treatment for most psychiatric disorders. Second, relative to the rest of clinical medicine, there is purportedly a dearth of safe, effective medications; never mind the evidence suggesting that the psychiatric medication responses are comparable to those in other areas of medicine (Leucht et al. 2012). Third, there is concern about possible, undetected, medication side effects that will have an adverse impact on the developing brains or bodies of our youth. And fourth, many are fearful that using even wellstudied medications is not good for children and adolescents and certainly not as good as using more ‘‘natural’’ approaches to treatment, even if those ‘‘natural’’ treatments have not been studied at all. However reasonable or unreasonable one finds these concerns, clinicians must face the reality that these concerns open the door for both the responsible and not so responsible use of CAM treatments. And this door is often open quite wide as many of these treatments are unregulated and unsupervised and sometimes, though certainly not always, offered by various ‘‘therapists’’ who weigh on the anxiety and guilt of deeply concerned parents. So, where do fact and fallacy separate, and what is a responsible clinician to do when faced with CAM treatments? In general, ‘‘complementary and alternative’’ refers to various types of more ‘‘traditional,’’ ‘‘natural,’’ and/or noninvasive forms of healing. In some instances, CAM seems to focus on treatments that some ‘‘clinicians’’ have determined to have face validity and then maintain use, with only anecdotal evidence. Many CAM treatments have been around for a long time—decades to millennia—while others are new creations; whether new or old, most lack a solid, empirical base. To counter this, many CAM proponents argue that this lack of an evidence base is due to the lack of funding for proper clinical trials—an argument that can also be made for many, more mainstream or even ‘‘off-label’’ treatments. Of course, there are also some more-radical CAM proponents who argue that scientists (and their corporate sponsors) are so biased that they will not allow fair trials to be performed. In the presence of a limited or absent evidence base for CAM treatments, there are still strong CAM advocates who insist that CAM treatments are natural and safe so why not use them alongside (complementary) traditional treatments or even to replace (alternative) traditional treatments. A recent study by Gabbay and her colleagues (Gabbay et al. 2012), demonstrates all too well that there need be nothing alternative about the use of a natural compound in the treatment of a known disorder. In a study on the use of omega-3 fatty acids (O3Fas) (a component of often-suggested fish oils) for children and adolescents with Tourette syndrome (TS), Dr. Gabbay and her colleagues were able to conduct a proper, randomized, doubleblind, placebo-controlled trial. The logic behind the use of O3FAs was clear and with face validity including connections to the previously studied ability of O3FAs to affect central monoamine and immunomodulatory mechanisms, both of which have been implicated in the etiology of TS. While this small, initial trial failed to support the primary hypothesis related to reducing tics, there are still important lessons to be learned from this study. First of all, with careful design and planning, a CAM study can be successfully executed. Second, even though there was not a statistically significant reduction in tics in the treated patients, some children did have favorable outcomes. Equally importantly, there are now favorable safety data on the use of O3FAs in children and adolescents. Is this the end of the story? Hardly. Replication and careful assessment of other possible outcomes will be essential, but this is surely a demonstration that a CAM treatment can survive the rigors of standard empirical investigation. It seems quite clear that there are a wide variety of other treatments that are considered to be in the realm of CAM. And, they appear to be in very wide use. Indeed, some have estimated that as many as 75% of American adults use CAM treatments at some point with about 60% using such treatments in the past 12 months

More than half of women who smoke in the USA continue to do so while pregnant. While socioeconomic and demographic factors that distinguish pregnancy quitters from persistent smokers have been identified, less is known about behavioral factors that are associated with persistent smoking. Because smoking during pregnancy is not only an individual, but also a maternal behavior, it may have different behavioral correlates than women's smoking has in general. We propose a conceptual framework in which smoking during pregnancy is viewed as a maternal problem behavior. We explore this conceptualization by examining whether persistent smoking during pregnancy is associated with a pattern of psychosocial risk- and health-compromising behaviors in multiple domains, with pilot data from a small clinic-based sample. Data are presented for 96 predominantly Caucasian, working-class pregnant women recruited from prenatal clinics in the USA. Smoking during pregnancy was measured repeatedly by self-report and biochemical assay. Participants were non-smokers (37%), pregnancy quitters (17%), and persistent smokers (46%). These groups were compared in terms of their history of problem behavior in three domains: interpersonal difficulties, problems in adaptive functioning and problematic health behaviors. With few exceptions, smokers were more likely to have problematic relationships, poorer adaptive functioning and to engage in problematic health behaviors, than both pregnancy quitters and non-smokers. This pattern of problem behavior may interfere with the effectiveness of standard public health prenatal cessation interventions for a sub-group of women. Examining pregnancy smoking as part of a broader matrix of problem behavior may help to identify pregnant women most at risk for persistent smoking and inform the development of targeted interventions.

Previous radioligand binding studies have demonstrated human platelet serotonin2A (5-HT2A) receptor binding sites. Pharmacological similarities between platelet and frontal cortex 5-HT2A receptor binding parameters have been demonstrated. However, it is not clear whether the platelet 5-HT2A receptor primary structure is identical to that of the brain receptor. Three overlapping cDNAs were obtained to span completely the coding region of the 5-HT2A receptor. These clones were sequenced with external and internal primers. The nucleotide sequence of human platelet 5-HT2A cDNA was identical to that reported for the human frontal cortex 5-HT2A receptor, except for nucleotide 102 (T C), which has been reported to represent a normal DNA polymorphism that does not alter the amino acid sequence. This finding may have implications in the study of neuropsychiatric disorders for which altered platelet 5-HT2A receptor binding has been demonstrated.

Objectives. Recent research suggests that in utero exposure to maternal smoking is a risk factor for conduct disorder and delinquency. We review evidence of causality, a controversial but important public health question. Methods. We analyzed studies of maternal prenatal smoking and offspring antisocial behavior within a causal framework. Results. The association is (1) independent of confounders, (2) present across diverse contexts, and (3) consistent with basic science. Methodological limitations of existing studies preclude causal conclusions. Conclusions. Existing evidence provides consistent support for, but not proof of, an etiologic role for prenatal smoking in the onset of antisocial behavior. The possibility of identifying a preventable prenatal risk factor for a serious mental disorder makes further research on this topic important for public health.

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.

Hyperserotonemia in autism is one of the longest-standing biochemical findings in a psychiatric disorder. This well-replicated finding and subsequent studies of platelet serotonin receptors in autism indicate that the serotonin 2A receptor gene (HTR2A) on chromosome 13q is a primary candidate gene in autism. Converging data from recent genome screens also implicates the genomic region containing HTR2A. Based on these lines of evidence, the transmission/disequilibrium test (TDT) was used to assess transmission disequilibrium between autism and haplotypes of three polymorphisms, including the promoter -1438 G/A single nucleotide polymorphism (SNP) in perfect linkage disequilibrium with the 102 T/C SNP in previous studies, a newly identified SNP in intron 1 near exon 2, and the SNP responsible for the His452Tyr amino acid change in exon 3. Because expression studies have shown HTR2A to be polymorphically imprinted in the brain, secondary analyses were split into maternal and paternal transmissions. No evidence was found for unequal transmission of haplotypes; however, power analysis reveals low power to detect a parent-of-origin effect in this sample size.

The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.

© 2015 Society of Biological Psychiatry. Understanding the pathogenesis of neurodevelopmental disorders has proven to be challenging. Using autism spectrum disorder (ASD) as a paradigmatic neurodevelopmental disorder, this article reviews the existing literature on the etiological substrates of ASD and explores how genetic epidemiology approaches including gene-environment interactions (G×E) can play a role in identifying factors associated with ASD etiology. New genetic and bioinformatics strategies have yielded important clues to ASD genetic substrates. The next steps for understanding ASD pathogenesis require significant effort to focus on how genes and environment interact with one another in typical development and its perturbations. Along with larger sample sizes, future study designs should include sample ascertainment that is epidemiologic and population-based to capture the entire ASD spectrum with both categorical and dimensional phenotypic characterization; environmental measurements with accuracy, validity, and biomarkers; statistical methods to address population stratification, multiple comparisons, and G×E of rare variants; animal models to test hypotheses; and new methods to broaden the capacity to search for G×E, including genome-wide and environment-wide association studies, precise estimation of heritability using dense genetic markers, and consideration of G×E both as the disease cause and a disease course modifier. Although examination of G×E appears to be a daunting task, tremendous recent progress in gene discovery has opened new horizons for advancing our understanding of the role of G×E in the pathogenesis of ASD and ultimately identifying the causes, treatments, and even preventive measures for ASD and other neurodevelopmental disorders.

The vast majority of mental illnesses can be conceptualized as developmental disorders of neural interactions within the connectome, or developmental miswiring. The recent maturation of pediatric in vivo brain imaging is bringing within reach the identification of clinically meaningful brain-based biomarkers of developmental disorders. Even more auspicious, is the ability to study the evolving connectome throughout life, beginning in utero, which promises to move the field from topological phenomenology to etiological nosology. Here, we scope advances in pediatric imaging of the brain connectome as the field faces the challenge of unraveling developmental miswiring. We highlight promises while also providing a pragmatic review of the many obstacles ahead that must be overcome to significantly impact public health.

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, singleblind 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. J. Am. Acad. Child Adolesc. Psychiatry, 2001, 40(6):658–665. Key Words: N-methyl-D-aspartate (NMDA), hyperactivity, irritability, placebo.

Young maternal age is a known risk factor for behavior problems in children, but links to specific clinical disorders have not been established. Although a history of conduct problems in girls increases the risk of early pregnancy, multigenerational links between maternal history of problem behavior, age at first birth, and child conduct disorder (CD) have not been previously studied. In this sample of 177 primarily White, clinic-referred boys, maternal age at first birth (MAFB) was associated with CD, even for boys who were not firstborn (53%). Maternal history of problem behavior was also associated with an early MAFB and the diagnosis of CD in their sons. Controlling for maternal pre- and postnatal history of problem behavior reduced the association of MAFB with CD in male offspring. To clarify the association of MAFB and CD in offspring, future research should prospectively examine an early age at first birth as part of a maternal problem behavior pathway.

The serotonin receptor 2B gene (HTR2B; MIM 601122) is a pharmacological and positional candidate gene in early-onset obsessive-compulsive disorder. Sequences of a putative promoter region and splice regions were first elucidated, then sequenced along with HTR2B coding regions. Probands from seven families included in a previous genome scan in which one of the strongest linkage findings was to a region including HTR2B, along with two genomic DNA pools of 10 unrelated control subjects and 10 unrelated autism probands were screened. One single nucleotide polymorphism was found in intron 1, that may be useful as a marker in genetic linkage and association studies. It does not appear likely to affect splicing. No evidence for functional mutation was found in the sequenced regions of HTR2B.

The gene encoding the serotonin 5-HT7 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 χ2 = 0.252, p = 0.602). Sequence data obtained from both intron 1 and intron 2 of HTR7, and from the 5-HT7 pseudogene (HTR7P), was used to confirm localization of HTR7 to 10q23 and HTR7P to 12p13 using radiation hybrid analyses.AM. J. Med. Genet. (Neuropsychiatr. Genet.) 88:472–475, 1999. © 1999 Wiley-Liss, Inc.

Large numbers of single nucleotide polymorphisms (SNPs) are being identified by several laboratories for the purpose of developing dense genetic maps. Single-strand conformation polymorphism (SSCP) analysis has been widely used as a method for detecting novel sequence variations in PCR products. Differences in migration of single-stranded DNA can be used not only to find mutations, but to genotype SNPs in large sample populations. Using PCR with fluorescent labeling and automated capillary electrophoresis SSCP (CE-SSCP), we have developed a panel of 15 functional candidate SNPs. With an automated single capillary instrument, relatively rapid and low cost CE-SSCP SNP genotyping using currently available technology is feasible for 135 000 genotypes per year. With parallel multiple array capillary electrophoresis, more genotypes per year may be attainable.

Paternal or maternal deletions in the 15q11.2-q13 region are known to result in Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Maternal duplications in 15q11.2-q13 have been found in patients with autism. A population of adults with moderate to profound mental retardation was studied to examine the usefulness of PCR based molecular methods in screening for proximal chromosome 15 abnormalities. Two hundred and eighty-five subjects were initially screened at five microsatellite markers with average heterozygosity values of 0.74 (range 0.54-0.82). Of these subjects, four had a single allele at all five loci, suggestive of a deletion or uniparental isodisomy. The four samples were further screened with additional markers located within 15q11.2-q13 as well as markers telomeric to this region. One subject had uniparental disomy (UPD) and three subjects had a deletion. To determine the parental origin of the 15q11-q13 region containing the single haplotype, samples were analysed with a newly developed methylation specific PCR technique at the SNRPN locus. Each of the four subjects showed presence of the paternal allele and absence of the maternal allele. All cases had a phenotype consistent with Angelman syndrome as expected for the level of mental retardation, but the subject with UPD was distinct from the other subjects with an absence of a history of seizures and presence of bilateral undescended testes and Parkinsonism. Although Angelman syndrome has an estimated population prevalence of 0.008%, at least 1.4% of the moderately to profoundly mentally retarded subjects screened were found to have Angelman syndrome.

PURPOSE To determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only. PATIENTS AND METHODS At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI. RESULTS Of 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality therapy (CMT). Nine of 80 patients randomized at the time of diagnosis to receive CMT did not receive radiation (RT) because of a protocol violation, but were monitored for EFS and OS and included in all analyses. The estimated EFS and OS rates at 5 years for the 179 eligible patients are 79% and 92%, respectively. The actuarial EFS at 5 years was 80% for patients who received CMT and 79% for patients who received MOPP-ABVD only. The OS for the former group is estimated to be 87% and for the latter patients 96%. Age < or = 13 years of age at diagnosis and the attainment of a clinical CR after three cycles of chemotherapy were associated with a statistically significant improved EFS. CONCLUSION Our results indicate that after the delivery of eight cycles of MOPP-ABVD, the addition of low-dose RT does not improve the estimated EFS or OS in pediatric patients with advanced-stage Hodgkin's disease.

The serotonin transporter gene (HTT) is a primary candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines. We initiated a candidate gene study of HTT in trios consisting of probands with autistic disorder and both parents. Preliminary transmission/disequilibrium test (TDT) analysis with 86 families revealed no evidence for linkage or linkage disequilibrium between autistic disorder and a polymorphism in the second intron of HTT. However, preferential transmission of a short variant of the HTT promoter was found in the same 86 trios (TDT chi 2 = 4.69, 1 d.f., P = 0.030). In further analyses, we considered haplotypes of the HTT promoter variant and second intron locus as alleles in a multiallelic TDT. Results confirmed the significance of the effect of this region (TDT chi 2 = 11.85, 4 d.f., P = 0.018). This provides preliminary evidence of linkage and association between HTT and autistic disorder.

Objective Changes in autism diagnostic criteria found in DSM-5 may affect autism spectrum disorder (ASD) prevalence, research findings, diagnostic processes, and eligibility for clinical and other services. Using our published, total-population Korean prevalence data, we compute DSM-5 ASD and social communication disorder (SCD) prevalence and compare them with DSM-IV pervasive developmental disorder (PDD) prevalence estimates. We also describe individuals previously diagnosed with DSM-IV PDD when diagnoses change with DSM-5 criteria. Method The target population was all children from 7 to 12 years of age in a South Korean community (N = 55,266), those in regular and special education schools, and a disability registry. We used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of screen-positive children were offered comprehensive assessments using standardized diagnostic procedures, including the Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule. Best-estimate clinical diagnoses were made using DSM-IV PDD and DSM-5 ASD and SCD criteria. Results DSM-5 ASD estimated prevalence was 2.20% (95% confidence interval = 1.77–3.64). Combined DSM-5 ASD and SCD prevalence was virtually the same as DSM-IV PDD prevalence (2.64%). Most children with autistic disorder (99%), Asperger disorder (92%), and PDD-NOS (63%) met DSM-5 ASD criteria, whereas 1%, 8%, and 32%, respectively, met SCD criteria. All remaining children (2%) had other psychopathology, principally attention-deficit/hyperactivity disorder and anxiety disorder. Conclusion Our findings suggest that most individuals with a prior DSM-IV PDD meet DSM-5 diagnostic criteria for ASD and SCD. PDD, ASD or SCD; extant diagnostic criteria identify a large, clinically meaningful group of individuals and families who require evidence-based services.

This is a copy of an article published in the Journal of Child and Adolescent Psychopharmacology © 2013 Copyright Mary Ann Liebert, Inc.; Journal of Child and Adolescent Psychopharmacology is available online at: http://www.liebertonline.com.

Foreword Richard Kohn.- 1. Introduction: Connecting Brain Development, Disruptive Behavior, and Children Patrick H. Tolan, Bennett L. Leventhal.- 2. Influences of Gene Environment Interaction Correlation on Disruptive Behavior in the Family Context Kristine Marceau, Jenae M. Neiderhiser.- 3. Neurobiology of Disruptive Behavior: A Developmental Perspective and Relevant Findings Elizabeth J. Susman, Seth Pollak.- 4. Callous-Unemotional Traits and Developmental Pathways to the Disruptive Behavior Disorders Paul J. Frick, R. James Blair, F. Xavier Castellanos.- 5. A Multidimensional Approach to Disruptive Behaviors: Informing Lifespan Research From An Early Childhood Perspective Alice S. Carter, Sarah A. O. Gray, Raymond H. Baillargeon, Lauren S. Wakschlag.- 6. Gender and the Development of Aggression, Disruptive Behavior, and Delinquency from Childhood to Early Adulthood Rolf Loeber, Deborah M. Capaldi, Elizabeth Costello.- 7. Tracking the Multiple Pathways of Parent and Family Influence on Disruptive Behavior Disorders Patrick H. Tolan, Kenneth Dodge, Michael Rutter.- 8. Advancing Our Understanding and Interventions for Disruptive Behavior Disorders Patrick H. Tolan, Bennett L. Leventhal.

This introduction explains the importance of disruptive behavior disorders (DBDs) as a mental illness, as representative of the value of developmental approaches to brain-based problems, and as a key public health problem. We provide a brief summary of current understanding of brain development relevant to DBDs as a framework for the symposium that was the basis for this volume. We identify important considerations and the many areas of work that are still just emerging and the many that are quite established but still rapidly developing. The roles of the included chapters in this overall understanding are described.

This volume has served as a focused review and discussion of key issues in advancing our understanding of Disruptive Behavior Disorders (DBDs), particularly Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD). The October 2008 symposium on which this book is based asked senior scientists to report on a single topic. That presentation and the ensuing discussions are reflected in the chapters in this volume. Each chapter summarized current knowledge about a key topic, and together they provide an understanding of patterns of occurrence of DBD; the likely contributing influences on its emergence, expression, and course; and important avenues for treatment, prevention, and eventual curative efforts. The chapters in this volume also have identified many exciting and important areas for investigation that could substantially advance our knowledge and improve our ability to identify, treat, and ultimately prevent these serious problems of childhood. Here we summarize the overall themes and implications emerging in the areas considered during the symposium.

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-HT2 receptor 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.

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.