A systematic review and meta-analysis of the long-term overall outcome of autism spectrum disorders in adolescence and adulthood.

OBJECTIVE: A systematic review and meta-analysis of studies reporting on the overall outcome in terms of a global measure of adjustment in children with autistic disorders followed up in adolescence and adulthood. METHOD: PubMed, PsycINFO, and EMBASE were systematically searched on 3rd of August 2015. Included studies were analyzed using random-effects models estimating event rates (%) and 95% confidence intervals (95%CI). RESULTS: From 4350 records identified in the search, 15 studies covering 12 unique samples and a total of N = 828 individuals with autistic disorders were included in the analyses. An estimated 19.7% (95%CI: 14.2-26.6) had a good outcome, 31.1% (95%CI: 23.2-40.4%) a fair outcome, and 47.7% (95%CI: 36.6-59.0) a poor outcome. The meta-analysis showed strong evidence for heterogeneity. The subtype of childhood autism is a significant moderating factor on the risk of having a poor outcome at follow-up, whereas age at follow-up showed statistically significant but inconsistent associations with outcome status. CONCLUSION: The long-term outcome of almost half of all individuals with autistic disorders is poor. The subtype of autism in childhood may be a predictor for specific long-term outcomes, but in general, little is known about the pathways and predictors.

Nationwide time trends in dispensed prescriptions of psychotropic medication for children and adolescents in Denmark.

OBJECTIVE: The analysis of time trends in dispensed prescriptions of psychotropic medications for children and adolescents in Denmark. METHOD: The entire data set of the Danish prescription register covering stimulants, antidepressants, antipsychotics, and anxiolytics used in children and adolescents over a 15-year time span from 1996 to 2010 was analyzed. Both non-adjusted age-standardized prevalence rates and adjusted age-standardized prevalence rates considering the increase in patient numbers over time were calculated, and time trends were assessed based on 105908 patient-years. RESULTS: For stimulants, antidepressants, and antipsychotics, the non-adjusted prevalence rates increased significantly. These trends were strongest for the stimulants. However, all adjusted prevalence rates were much lower with the anxiolytics even declining significantly. The prevalence rates of stimulants and antipsychotics were significantly higher among males than females, whereas females received significantly more antidepressants. The increase in prescription rates for both antidepressants and antipsychotics was mainly due to increased use among the 14- to 17-year-olds. Stratification by diagnoses revealed significantly increasing prevalence rates of dispensed antidepressants and antipsychotics in six major diagnostic indications. CONCLUSION: Although increasing, the unadjusted Danish prevalence rates of dispensed prescriptions of psychotropics for children and adolescents are still lower than in many other Western countries.

Familiality of neural preparation and response control in childhood attention deficit-hyperactivity disorder.

BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). RESULTS: Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. CONCLUSIONS: Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.

Genetic analysis of reaction time variability: room for improvement?

BACKGROUND: Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). RESULTS: Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75-0.83). CONCLUSIONS: Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

European guidelines on managing adverse effects of medication for ADHD.

The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

Predictability of oppositional defiant disorder and symptom dimensions in children and adolescents with ADHD combined type.

BACKGROUND: Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making. METHOD: Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5-17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses. RESULTS: ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension. CONCLUSIONS: The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADHD.

ADHD and DAT1: further evidence of paternal over-transmission of risk alleles and haplotype.

We [Hawi et al. (2005); Am J Hum Genet 77:958-965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3'-UTR VNTR. In the current investigation, we analyzed three new sample comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three-replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3'-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal over-transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.

The heterogeneity of causes and courses of attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit / Hyperactivity Disorder (ADHD) is a frequent mental disorder with onset in childhood and persistence into adulthood in a sizeable number of people. Despite a rather simple clinical definition, ADHD has many facets because of frequent co-morbid disorders and varying impact on psychosocial functioning. Thus, there is considerable heterogeneity in various domains. METHOD: A review of recent research findings in: i) selected domains of aetiology reflecting the role of genes, brain structures and functioning and the interplay of causal factors and ii) clinical heterogeneity in terms of co-morbidities, gender effects, courses and outcomes. RESULTS: Molecular genetic studies have identified a number of candidate genes which have a small effect on behavioural variation in ADHD. In the most recent Genome Scan Meta Analysis of seven ADHD linkage studies, genome-wide significant linkage was identified on chromosome 16. The volume of both the total brain and various regions including the prefrontal cortex, the caudate nucleus and the vermis of the cerebellum is smaller in ADHD. Functional MRI has documented a specific deficit of frontostriatal networks in ADHD. Integrative aetiological models have to take the interaction of gene and environment on various dysfunctions into account. Clinical heterogeneity results from frequent associations with various co-morbidities, the impact of the disorder on psychosocial functioning, and gender effects. Partly, these effects are evident also in the course and outcome of ADHD. CONCLUSION: ADHD is a chronic mental disorder with a complex aetiology. So far, various neurobiological factors have been identified that need to be studied further to better understand their interaction with environmental factors. The clinical presentation and the long-term course of ADHD are manifold.

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD.

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

Association of ADHD with genetic variants in the 5'-region of the dopamine transporter gene: evidence for allelic heterogeneity.

Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.

Differential dopamine receptor D4 allele association with ADHD dependent of proband season of birth.

Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder.

Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases.

The validity and reliability of the diagnosis of hyperkinetic disorders in the Danish Psychiatric Central Research Registry.

OBJECTIVE: To validate the diagnosis of hyperkinetic disorders (HD) in the Danish Psychiatric Central Research Registry (DPCRR) for children and adolescents aged 4 to 15 given in the years 1995 to 2005. METHOD: From a total of 4568 participants, a representative random subsample of n=387 patients were used to validate the diagnosis. Patient files were systematically scored for the presence of ICD-10 criteria for HD and oppositional defiant disorder/conduct disorder (ODD/CD; F91). Further to this, an inter-rater reliability study was also conducted, whereby two experienced child and adolescent psychiatrists who were blind to patients discharge diagnoses, rated a random subsample of n=101 participants. RESULTS: Information was available for 372 out of 387 patients. Out of n=372 available files, n=324 (86.8%) were evaluated to fulfil diagnostic criteria for HD. Due to missing information it was not possible to reach a conclusion for 5.1% of the cases, 3.8% of the diagnoses were registration errors, and in 4.3% of the files the diagnosis had to be rejected. Inter-rater agreement was high (κ=0.83, z=10.9, P<.001). The validity of hyperkinetic disorders, unspecified (F90.9) was lower and comorbid CD/ODD were under-diagnosed in the sample. All participants fulfilling HD criteria also fulfilled DSM-5-criteria for ADHD. CONCLUSION: The risk of misclassification of patients with HD in the DPCRR is relatively low, with the exception of the diagnosis of hyperkinetic disorders, unspecified (F90.9).

Prediction of low body weight at long-term follow-up in acute anorexia nervosa by low body weight at referral.

OBJECTIVE: The authors investigated the hypothesis that in acute anorexia nervosa a low body weight predicts a poor weight prognosis for the future. METHOD: The body mass indexes at referral of 272 female patients were examined in relation to the body mass indexes of these patients after a mean follow-up of 9.5 years. RESULTS: The overall correlation between body mass indexes at referral and at follow-up was r = 0.33. Despite this low correlation, the 100 patients with body mass indexes less than 13 kg/m2 at referral had low weights at long-term follow-up. Eleven of the 12 deceased patients were among these 100 patients, as were 24 of the 46 surviving patients whose body mass indexes were 17.5 kg/m2 or less at follow-up. CONCLUSIONS: For patients with anorexia nervosa, a body mass index less than 13 kg/m2 at referral indicates a substantial risk for chronic anorexia nervosa and death related to emaciation.

Evaluation of inpatient treatment of adolescent anorexic patients.

After some introductory remarks dealing with evaluation research of the course of anorexia nervosa the sample and methodology of the author's prospective study of young anorexic patients are outlined. Selected findings coming from systematic assessment at the time of admission and discharge are presented. Furthermore, findings coming from analyses predicting change during in-patient treatment are reported.

Attitudinal dimensions in adolescent anorexic patients: an analysis of the Goldberg Anorectic Attitude Scale.

An abbreviated version of the Goldberg Anorectic Attitude Scale (GAAS) consisting of seven subscales was analyzed with the aid of a sample of 23 adolescent anorexic patients with early onset of the disease. Intercorrelations indicated that the individual scales were sufficiently independent. A test of convergent validity resulted in substantial correlations of some scales of the GAAS with other scales measuring anorexic behaviour and symptoms. Clinical characteristics of the anorexic syndrome and a number of the background variables had no effect on GAAS scores. The validity of the subscale measuring denial of illness is questionable. On the other hand, there is some indication of clinical utility of the GAAS since it adequately reflects change due to inpatient treatment.

Enuresis in child psychiatric clinic patients.

The clinical profile and the outcome of 386 enuretic children attending a child psychiatric clinic were studied and compared with 2,404 other child psychiatric cases assessed during the same period. The profiles of developmental and family history, psychiatric diagnoses, specific delays in development at assessment, and intelligence resembled each other. The only exceptions were an overrepresentation of delayed developmental milestones in the history and an underrepresentation of neuroses and eating disorders among enuretics.

Elective mutism: an analysis of 100 cases.

OBJECTIVE: An extended series of 100 children with elective mutism (EM) was clinically analyzed. METHOD: The total sample included two subgroups of clinically referred children at different locations and a subgroup of nonreferred children with EM. The study was based on comprehensive item sheets and, in the nonreferred sample only, the Child Behavior Checklist. RESULTS: EM is a rare disorder in the referred child psychiatric samples. It typically starts at preschool age, is more common in girls, and is seen in all social strata. A background of migration and early developmental risk factors is also quite common. Premorbid speech and language disorders play a role in one third of the clientele, and three quarters of children with EM had behavioral abnormalities during infancy and preschool age. School and unfamiliar people create the social context in which children with EM most frequently do not speak. Shyness and internalizing behavior problems are the most common personality features in EM, and comorbid diagnoses are quite frequent. CONCLUSION: This large series of affected children has identified the most typical features of EM and thereby extends the limited knowledge of this rare disorder of childhood.

Long-term psychopathological and cognitive outcome of children with fetal alcohol syndrome.

OBJECTIVE: The long-term outcome of a large cohort of children suffering from fetal alcohol syndrome was studied. METHOD: Structured psychiatric interviews, behavior checklists for parents and teachers, and intelligence tests were used. Assessments took place during preschool age, early school age (6 to 12 years), and late school age (> or = 13 years). RESULTS: There was an excess of psychopathology with a wide variety of psychiatric syndromes in this cohort. Hyperkinetic disorders, emotional disorders, sleep disorders, and abnormal habits and stereotypes persisted over time. Interview findings were largely in accordance with parents' and teachers' questionnaire findings. Intelligence test findings included a large proportion of mentally retarded children and displayed high stability at follow-up. CONCLUSIONS: The development of children suffering from fetal alcohol syndrome is jeopardized by a high rate of persistent psychiatric and cognitive impairments.