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Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (OR MET , 95% CI; 1.27 (1.10–1.47); OR MET/MET , 95% CI; 1.67 (1.19–2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.

Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes ( ROBO1 , KIAA0319 , KIAA0319L , S100B , DOCK4 , FMR1 , DIP2A , GTF2I , DYX1C1 and DCDC2 ) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes ( SLIT2 , HMGB1 and VAPA ) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network.

The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of γ -aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. National Institute of Mental Health.

The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children. The Impact of Nutrition on Children with ADHD (INCA) study was a randomised controlled trial that consisted of an open-label phase with masked measurements followed by a double-blind crossover phase. Patients in the Netherlands and Belgium were enrolled via announcements in medical health centres and through media announcements. Randomisation in both phases was individually done by random sampling. In the open-label phase (first phase), children aged 4–8 years who were diagnosed with ADHD were randomly assigned to 5 weeks of a restricted elimination diet (diet group) or to instructions for a healthy diet (control group). Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child's individual IgG blood test results) were added to the diet. During the first phase, only the assessing paediatrician was masked to group allocation. During the second phase (challenge phase), all persons involved were masked to challenge allocation. Primary endpoints were the change in ARS score between baseline and the end of the first phase (masked paediatrician) and between the end of the first phase and the second phase (double-blind), and the abbreviated Conners' scale (ACS) score (unmasked) between the same timepoints. Secondary endpoints included food-specific IgG levels at baseline related to the behaviour of the diet group responders after IgG-based food challenges. The primary analyses were intention to treat for the first phase and per protocol for the second phase. INCA is registered as an International Standard Randomised Controlled Trial, number ISRCTN 76063113. Between Nov 4, 2008, and Sept 29, 2009, 100 children were enrolled and randomly assigned to the control group (n=50) or the diet group (n=50). Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23·7 (95% CI 18·6–28·8; p<0·0001) according to the masked ratings. The difference between groups in the mean ACS score between the same timepoints was 11·8 (95% CI 9·2–14·5; p<0·0001). The ARS total score increased in clinical responders after the challenge by 20·8 (95% CI 14·3–27·3; p<0·0001) and the ACS score increased by 11·6 (7·7–15·4; p<0·0001). In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels. There were no harms or adverse events reported in both phases. A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged. Foundation of Child and Behaviour, Foundation Nuts Ohra, Foundation for Children's Welfare Stamps Netherlands, and the KF Hein Foundation.

AbstractAutism is characterized by an impaired development in social interaction and communication and a markedly restricted repertoire of activities and interests. This paper summarizes the research into the social abnormalities in autism, and reviews the empirical support for two behavioural hypotheses on autism, i.e. that autism results from impaired attachment, or from intense and prolonged approach-avoidance conflicts. The core social impairment of autistic subjects seems to be a deficit in attunement and timing of actions and reactions rather than a difference in frequencies of behaviours. Attachment behaviour of most, if not all autistic children tends to be disorganized; nevertheless, they do form attachment relationships in terms of preferential proximity seeking or reunion behaviour in the Strange Situation Test. Attachment studies performed sofar however have methodological limitations ; particularly the study of maternal-infant attunement and reciprocity has been neglected. Empirical evidence fails to support the presence of approach-avoidance conflicts in autistic subjects, and is further at variance with the predicted consequences of such conflicts. Insufficient attention has hitherto been paid to the clinical heterogeneity of autism in behavioural studies. A promising approach to deepen our understanding of the development of the autistic symptomatology is the early detection and subsequent behavioural study of 1-2 year old children at high-risk for autism. Finally, behaviour observation studies in autistic subjects are likely to benefit from the concurrent assessment of physiological indices of arousal, and from the integrated measurement of social-cognitive processes.

Background: Persistent attention deficit hyperactivity disorder (ADHD) and a history of conduct disorder (CD) are highly prevalent among patients with substance use disorders (SUD). We examined the influence of both diagnoses on problem severity, psychiatric comorbidity, and quality of life in methadone-maintained patients. Methods: 193 patients in long-term methadone maintenance treatment (MMT) were assessed for ADHD through a semi-structured interview. Psychiatric disorders and SUD were assessed with the MINI, the CIDI-SAM, and the SIDP-IV. Results: Childhood ADHD was diagnosed in 68 (35.2%) patients; 48 (24.9%) had persisting ADHD; a CD history was present in 116 (60.1%). Patients with adult ADHD had significantly higher problem severity scores, lower quality of life scores, more comorbid SUD and more psychiatric comorbidity. Although both ADHD and CD contributed to problem severity, addictive pathology and psychopathology, ADHD was found to substantially increase the risk of psychiatric comorbidity, independent of CD. Conclusion: ADHD in MMT patients is characterised by greater addiction severity and more comorbid psychopathology, only partly explained by the influence of a coexisting CD. The presence of ADHD in a substantial minority of patients accentuates the need for early detection and treatment of this complicating disorder.

Attention deficit/hyperactivity disorder (ADHD), a common behavioural disorder in children, may be associated with comorbid physical and sleep complaints. Dietary intervention studies have shown convincing evidence of efficacy in reducing ADHD symptoms in children. In this pilot study, we investigated the effects of an elimination diet on physical and sleep complaints in children with ADHD. A group of 27 children (3.8–8.5 years old), who all met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD, were assigned randomly to either a diet group (15/27) or a control group (12/27). The diet group followed a 5-week elimination diet; the control group adhered to their normal diet. Parents of both groups had to keep an extended diary and had to monitor the behaviour and the physical and sleep complaints of their child conscientiously. The primary endpoint was the clinical response, i.e. a decrease of physical and sleep complaints, at the end of the trial, based on parent ratings on a Physical Complaints Questionnaire. The number of physical and sleep complaints was significantly decreased in the diet group compared to the control group ( p  < 0.001), with a reduction in the diet group of 77% ( p  < 0.001, effect size = 2.0) and in the control group of 17% ( p  = 0.08, effect size = 0.2). Specific complaints that were significantly reduced were in three domains: headaches or bellyaches, unusual thirst or unusual perspiration, and sleep complaints. The reduction of complaints seemed to occur independently of the behavioural changes ( p  = 0.1). However, the power of this comparison was low. A positive correlation existed between the reduction of physical and behavioural symptoms ( p  < 0.01). The reduction did not differ between children with or without an atopic constitution ( p  = 0.7). An elimination diet may be an effective instrument to reduce physical complaints in children with ADHD, but more research is needed to determine the effects of food on (functional) somatic symptoms in children with and without ADHD. This trial was registered as an International Standard Randomised Controlled Trial, ISRCTN47247160.

The foreword focuses on the three main critical questions within the political debate: (1) Is ADHD a psychiatric disorder? (2) Is there over-diagnosis and overtreatment of ADHD? (3) Are psychostimulants dangerous drugs? After discussing the problems within the context of general scientific and merely European political context, the authors conclude with a positive outlook comprising (1) step-up of research in ADHD, (2) exercised control over diagnosis and treatment, (3) the need for training and continuous personal development for doctors, and (4) Improvement of information to teachers and parents. The presented supplement on \"ADHD -- beyond core symptoms. Not only a European perspective\" underlines this perspective and reflects a broad spectrum of ADHD-related activities currently underway in Europe while having the worldwide development of the field in mind.