DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.

Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.

Attentional set shifting in autism spectrum disorder: differentiating between the role of perseveration, learned irrelevance, and novelty processing.

Autism spectrum disorders (ASD) are associated with impaired attentional set shifting, which may reflect enhanced perseverative responding, enhanced learned irrelevance, and/or reduced novelty processing. We assessed the contribution of these potential error sources in ASD adults. A total of 17 ASD and 19 matched comparison individuals first solved a discrimination learning task. Thereafter, the participants faced three types of attentional shift, specifically designed to isolate the effect of the three possible error sources. ASD participants made more errors than comparison individuals in a shift implying a choice between a novel relevant stimulus attribute and a familiar attribute that was previously relevant but now irrelevant. However, they made fewer errors in a shift involving a choice between a novel irrelevant attribute and a familiar, previously irrelevant but now relevant attribute. The results in combination suggest that the performance difference, at least in the present shift task, is caused by reduced novelty processing in ASD participants.

Diagnosing autism spectrum disorders in elderly people.

BACKGROUND: As autism spectrum disorders (ASD) have largely been neglected in old-age psychiatry, the objective of the present paper is to describe the diagnostic process in elderly patients. METHODS: A systematic review of the literature on ASD in older age was undertaken and illustrated by a case series of three elderly patients first diagnosed with ASD in later life by a tertiary mental health clinic. RESULTS: The search of the literature only yielded three papers on late-life ASD, while the review of the available diagnostic procedures among adults suggests some relevance for screening instruments (Autism Questionnaire), diagnostic instruments (Module 4, Autism Diagnostic Observation Schedule), and neuropsychological examination to profile impairments. Nonetheless, the case reports clearly showed that taking a thorough history with the patient, corroborated and supplemented by a close relative or caregiver who has known the patient for at least ten years, still remains the most important diagnostic tool. CONCLUSION: The three case studies show that in clinical practice ASD can easily be missed in elderly individuals presenting with comorbid psychiatric disorders, potentially causing iatrogenic damage. Although further research on phenotyping and diagnosing ASD in older people is warranted, the most important step at this point is to create a greater awareness of the possibility of ASD in old age among health-care professionals working with people in this age group.

Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3'-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3'-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Cross-validation, predictive validity, and time course of the Benzodiazepine Dependence Self-Report Questionnaire in a benzodiazepine discontinuation trial.

The Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) measures the severity of benzodiazepine (BZ) dependence on four domains: awareness of problematic use, preoccupation with the availability of BZ, lack of compliance with the therapeutic regimen, and withdrawal. Although promising results of the Bendep-SRQ have been obtained in cross-sectional studies, no attention has been paid to its clinical relevance during BZ withdrawal, i.e., predictive validity and time course. We performed cross-validation and evaluated the predictive validity and time course on 180 long-term BZ users who were taking part in a general practice BZ discontinuation trial. Three of the four domains had good scalability. Some concerns arose about the preoccupation scale, which emphasizes the need for cross-validation in clinically relevant populations. All scales showed excellent reliability (subject discriminability, item discriminability), while construct and discriminant validity were adequate. All four scales contributed significantly to the prediction of whether complete abstinence would be achieved directly after taking part in the discontinuation program. This prediction was independent of the other prognostic variables, except for those in the domain problematic use. The scales problematic use and preoccupation showed good sensitivity to changes during follow-up. The insensitivity of the scale, lack of compliance can be explained by low baseline scores in our population, while the insensitivity of the withdrawal scale was probably the result of the study design. In conclusion, our study indicated the clinical relevance of the Bendep-SRQ before and during a BZ discontinuation trial. We recommend the use of the Bendep-SRQ in discontinuation therapy and research into the field of BZ addiction.