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The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.

We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD, their unaffected siblings and controls. Response inhibition is a key executive function deficit of attentiondeficit/hyperactivity disorder (ADHD).To obtain new insight into the biological nature of response inhibition deficits in adolescents with ADHD.We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD (n = 185), their siblings unaffected by ADHD (n = 111) and controls (n = 126). We took fmri measurement while the subjects performed the stop-task; this allowed us to investigate neural activation and neural connectivity.Our results indicate that adolescents with ADHD show reduced brain activation and reduced connectivity in their response inhibition network. Our neural measurements correlated with subjects' performance on the stop-task and with the number of ADHD symptoms in the adolescents with ADHD. Unaffected siblings showed similar but less severe neural deviations but no cognitive deficits; unaffected siblings also showed unique patterns of compensatory connectivity.These results provide new insights into the biological background of response inhibition and of ADHD. Neural measurements can give us a better understanding of the familial patterns of biological alterations, even if no behavioral deficits could be detected in the unaffected siblings. These neural correlates can also help to explain part of the ADHD phenotype.

BACKGROUND: The need for and the interest in non-pharmacological treatments for children with ADHD are increasing. The treatments include electro-encephalogram (EEG) frequency-neurofeedback and Cogmed working memory training. AIM: To investigate the efficacy of frequency-neurofeedback and Cogmed working memory training in children with ADHD. METHOD: Forty-one children with ADHD (aged 8-15 years) were assigned to frequency-neurofeedback or to placebo-neurofeedback in a randomized double-blind trial. We took measurements to find out whether frequency-neurofeedback had reduced the severity of the ADHD-symptoms, and/or had improved neurocognitive ability and global clinical functioning. Fifty-one children with ADHD (aged 5-7 years) were assigned to the active Cogmed JM-working memory training or to the placebo working memory training in a randomised double-blind trial. We took measurements to find out whether Cogmed JM-working memory training had reduced the ADHD symptoms, and/or had improved neurocognitive ability, daily performance and global clinical functioning. RESULTS: The ADHD symptoms and global clinical functioning of the children in both neurofeedback groups improved. However, frequency-neurofeedback did nor produce any significantly better treatment results than did the placebo neurofeedback. At the neurocognitive level, frequency-neurofeedback did not yield any measurements that were significantly superior to those achieved with placebo feedback. Various outcome measurements improved in both groups with memory training. However, the active working memory training was not found to have produced significantly better results than the placebo training with regards to the ADHD symptoms, neurocognitive ability and daily and global functioning. Children from the active working memory training group showed improvements in trained working memory tasks but not on untrained tasks. CONCLUSION: Neither study produced any conclusive evidence for the efficacy of the investigated treatments in children with ADHD. However, both types of treatments can be further improved. Furthermore, the controlled designs may have restricted the embedding of the treatments. Because of possible improvements in the treatments in the future and because of the design restrictions affecting the treatments in their present form, it is still too early to draw any definitive conclusions about the validity and advantages of the two treatment methods.

BACKGROUND: Somatic disorders occur more often in psychiatric patients than in the general population. Somatic symptoms can cause or increase psychiatric symptoms. Psychiatric symptoms and their treatment can have an effect on the physical state of the patient. A pilot study involving an adult outpatient population has demonstrated that 62% of the patients studied had new clinically relevant symptoms. So far, no other data are available relating to somatic screening in child and adolescent psychiatry. AIM: To assess whether somatic screening of children and adolescents newly referred to a department of child and adolescent psychiatry in the Netherlands gives added value to the diagnosis and treatment policy. METHOD: In a pilot study 43 newly referred patients aged between 6 and 18 were screened by means of somatic history, a physical examination and blood parameters. On this basis we could calculate the percentage of somatic symptoms and , where necessary, follow-up treatment could be applied. RESULTS: One or more clinically relevant disorders were found in almost 56% of the children and adolescents investigated. The disorders included dysmorphic anomalies, weight and height deviations, raised thyroid hormone levels, dyslipidaemia, anaemia and vitamin D and B12 deficiency. Advice about a healthy lifestyle was given to 44% of the patients. An antipsychotic medication in 25% of the patients was changed, in the case of 16% of the patients a family doctor was contacted about subsequent treatment and 19% of the patients were referred to a medical specialist. CONCLUSION: Although the results of the pilot study indicate that somatic screening does provide added value, more research is needed in order to optimise the screening procedure.

BACKGROUND: Transparency by means of quality indicators is regarded as a method for monitoring and improving the quality of care. In the Dutch mental health service (GGZ) a generic basic set of indicators has been developed, but it is not clear whether the set is suitable for use in child and adolescent psychiatry. AIM: To assess whether the GGZ Basic Set of performance indicators for 2007-2008 was suitable for use in a child and adolescent psychiatric setting and to detect any omissions in that set. METHOD: A heterogeneous national group of eight health professionals and five 'stakeholders' in child and adolescent mental health judged the existing Basic Set by means of a Delphi procedure consisting of two written rounds and a panel discussion. The experts assessed potential indicators with regard to necessity, validity, clarity and applicability to child and adolescent psychiatry using a scale of 0 to 9. Indicators scoring more than 7 were considered to be appropriate. RESULTS: Only two of the 54 indicators were considered appropriate. A lower cut-off point would leave 16 indicators, of which 10 related to the outcome of treatment. One of the nine proposed innovative indicators was added. CONCLUSION: Very few of the indicators in the Basic Set were considered to be suitable for use in child and adolescent psychiatry. Respondents expressed a preference for a limited number of indicators that emphasised the opinion of the patient and of parents rather than the outcomes of treatment.

The aim of this study was to investigate whether thyroid function and thyroid peroxidase antibodies (TPOAb) are associated with depression, when using both state and trait parameters of depression.In 1125 participants of the Nijmegen Biomedical Study, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and TPOAb were measured twice. The Beck Depression Inventory (BDI), a self-reported lifetime diagnosis of depression, and the neuroticism scale of the Eysenck Personality Questionnaire Revised Short Scale (EPQ-RSS) were used to evaluate the presence of state and trait features of depression.We found no association between TSH and FT4 levels and BDI score, current depression, lifetime diagnosis of depression, and EPQ-RSS neuroticism score. Subjects with TPOAb had higher EPQ-RSS neuroticism scores in comparison with subjects without TPOAb, mean score 4.1 vs. 3.2 (regression coefficient 0.70; 95% CI 0.1-1.3; P-value 0.02 after adjustment for confounders). The prevalence of a lifetime diagnosis of depression was higher in subjects with positive TPOAb in comparison with participants without TPOAb: 24.2% vs. 16.7% (relative risk 1.4; 95% CI 1.0-2.1; P-value 0.04 after adjustment for confounders).Thyroid peroxidase antibodies are positively associated with trait markers of depression. The presence of TPOAb may be a vulnerability marker for depression.

Early infantile autism' as defined by Kanner has grown into a spectrum of autistic disorders. The recognition of Asperger's disorder and of pervasive developmental disorder not otherwise specified (PDD-NOS), has led to increased demand for appropriate diagnostic assessment of autism in adults. The expression ofimpairments in social interaction, communication, imagination and mental flexibility changes during development into adulthood. The diagnostic procedure in adult psychiatry should comprise a collateral developmental interview. Autism spectrum disorders in adults may mimic, or be overshadowed by, other psychiatric disorders. For effective diagnosis, the application of structured interviews, such as the 'Autism diagnostic observation schedule' (ADOS), 'Autism diagnostic interview-revised' (ADI-R) or 'Diagnostic interview for social and communication disorders' (DISCO) is recommended.

Two patients, girls aged 9 and 10 years, were admitted to the paediatric ward due to somatically-unexplained debilitating abdominal pain. Both they and their parents expressed resistance to psychiatric examination before and after admission. After conversations with a psychiatrist and an activation programme, one of the girls recovered and the other family broke the medical contact after having enforced a lot of somatic investigations; when followed up, they stated that the complaints had disappeared. The management of somatically-unexplained abdominal pain in children is not always easy. It is essential to introduce the psychiatrist as an expert in treating the consequences of the complaints rather than an expert in searching for psychiatric causes. Associated impaired functioning is a sign of severe symptoms, which require referral to a psychiatrist or a psychologist.

To determine whether a standard elimination diet can decrease the ADHD-symptoms in a heterogeneous group of young children with ADHD.Open, descriptive.40 children, 36 boys and 4 girls, aged 3-7 (average 4.8 years), who met the DSM-IV-criteria for ADHD, followed their usual diet for two weeks and thereafter for two weeks an elimination diet, based on the few foods diet (rice, turkey, pear and lettuce). The behaviour of the child was evaluated at study entry, after the baseline period and at the end of the diet. Parents completed the 10-item Conners list, the ADHD Rating Scale and a physical complaints list. The teachers completed the 10-item Conners list and the ADHD Rating Scale twice, at the beginning and at the end of the diet.According to the parent-ratings, 25 children (62%) showed an improvement in behaviour of at least 50% on both the Conners list and the ADHD Rating Scale at the end of the elimination diet. Nine children (23%) withdrew from the study because the parents were unable to stick to the diet or because the child fell ill. Among the 15 children with both parent and teacher ratings, 10 responded both at home and in school.In young children with ADHD an elimination diet can lead to a statistically significant decrease in symptoms.

To describe the functioning, comorbidity and treatment of adults with attention deficit hyperactivity disorder (ADHD).Retrospective.In the period 1 May 1995 to 31 January 1998, 141 patients aged 18-54 were diagnosed with ADHD at the Delfland Psychiatric Outpatients' Department, Delft, the Netherlands. For all of these patients, data concerning the functioning, comorbidity, and the response to treatment with clonidine (n = 34) or methylphenidate (n = 99), were collected from anamneses, hetero-anamneses and school reports.The most frequent complaints were: mood-swings, rage-outbursts, sensation-seeking behaviour, sleeping disorders, anxiety and depressive symptoms. In 94% (n = 123) of the cases, childhood onset of ADHD symptoms was confirmed by a family member. The distribution of ADHD subtypes was comparable to the distribution in children. Psychiatric comorbidity was common. Treatment with methylphenidate was more effective and better tolerated than treatment with clonidine.With respect to ADHD subtypes, patterns of comorbidity and effectiveness of medication, ADHD in the adults studied was comparable with what is known about ADHD in children.

This study on children with a Pervasive Developmental Disorder (PDD; N = 32), children with developmental language disorder (N = 22), and normally developing children (N = 28) sought to answer questions concerning attachment and autistic behaviour. We could replicate the finding that children with a PDD are able to develop secure attachment relationships to their primary caregiver. Children with PDD who had an insecure attachment showed fewer social initiatives and responses than children with PDD who had a secure attachment, even when the insecurely and securely attached PDD children were matched on chronological and mental age. Children with both a PDD and mental retardation were more often classified as disorganised. Three findings suggested that a disorganised attachment does not merely reflect the presence of "autistic" behaviour: (1) children with PDD did not reveal higher rates of a disorganised attachment than matched comparison children; (2) having a PDD diagnosis and having a disorganised attachment were found to be associated with opposite effects on an ethological measure of level of behavioural organisation; and (3) a disorganised attachment but not a PDD diagnosis was associated with an increase in heart rate during parting with the caregiver and a decrease in heart rate during reunion.

In the present study it was investigated whether the smaller P3s in attention-deficit hyperactivity disorder (ADHD) children are caused by a shortage of capacity underlying P3 processes or whether they are due to a capacity allocation problem. Also, effects of methylphenidate on these processes were investigated. Performance and event-related potentials (ERPs) of 14 ADHD and 14 control children were measured using an irrelevant-probe technique. Three types of task irrelevant visual probes (standards, deviants, and novels) were presented against the background of two visual tasks that varied in task difficulty. The parietal P3 wave was measured in response to task stimuli and probes. ADHD subjects made significantly fewer correct detections than normal controls in both the easy and the hard tasks. Controls showed an enhanced P3 to task-relevant stimuli in the hard task, whereas ADHD children did not. Probe (novel) P3 amplitudes decreased from the easy to the hard task to the same extent in both groups. Methylphenidate enhanced the percentage of correct responses and task P3 amplitudes in both the easy and the hard task but probe P3 amplitudes were not influenced by methylphenidate. It was concluded that ADHD children do not suffer from a shortage in attentional capacity; rather, the evidence is in favor of a problem with capacity allocation. Furthermore, methylphenidate had enhancing effects on performance and ERPs, but did not improve the capacity-allocation deficit.

Fourteen children with attention-deficit hyperactivity disorder (ADHD) and 14 normal control children were compared with respect to stimulus- and response-related processes. Subjects with ADHD took part in two additional sessions under methylphenidate or placebo. In both experiments, performance and electrophysiological measures such as the P2, N2, and P3 components of event-related potential and electromyogram (EMG) activity were measured during an Eriksen flanker task. In both groups of children, reaction times (RTs) to arrow stimuli incongruent with the target were longer than those to neutral stimuli (response interference), which were again slower than RTs to target-alone stimuli (perceptual interference). Children with ADHD made more errors to incongruent stimuli and showed more response interference. For correct responses, no differences between the groups in response interference effects on reaction time, P2, N2, and P3 latency, or EMG onset were found. Methylphenidate had a general enhancing effect on accuracy but did not specifically reduce interference from the flanking stimuli. Methylphenidate had no effects on RT, N2 and P2 latency, P3 amplitude or latency, or EMG activity. The conclusion that methylphenidate did not influence response processes contrasts sharply with findings reported by authors using the Sternberg memory search task.

This study aimed to explore the boundaries between PDD and related disorders and to develop classificatory algorithms for what is currently called Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). Data collected by means of a standard coding system for the DSM-IV field trial for autistic disorder were used. Information on diagnostic criteria for autistic disorder as listed in ICD-10 and DSM-IV was compared between subjects functioning at least in the mildly retarded range and clinically classified as autistic disorder (n = 205), PDDNOS (n = 80) and other non-PDD disorders (n = 174). Only a limited number of items from the ICD-10 and DSM-IV systems for autistic disorder significantly discriminated the PDDNOS group from other disorders. A scoring rule based on a short set of 7 ICD-10/DSM-IV criteria with a cutoff of 3 items and 1 social interaction item set as mandatory had the best balance between high sensitivity and high specificity in discriminating PDDNOS from non-PDD disorders. These rules yielded a somewhat better prediction than most effective rules based on the full set of 12 criteria for autistic disorder with a cutoff of 4 items and 1 social item as mandatory. Generally accepted and well-validated criteria to identify individuals with PDDNOS should facilitate both research and clinical services.

The stereotypic behavior of children (N = 26) while in a playroom session with their parent was studied. The sample included children with a pervasive developmental disorder, an attention-deficit/hyperactivity disorder, a developmental expressive language disorder, or a developmental receptive language disorder and normally developing children. Stereotypic behaviors associated with distress, elation, and composure were compared on mean duration and form of the stereotypies and heart rate changes around the onset of the stereotypies. Results showed that stereotypies associated with different moods differed in all variables studied. Results confirm that a valid classification scheme for stereotypic behaviors is needed as they indicate different functions of individual stereotypies.

This study was designed to examine the classification performance of diagnostic rules for pervasive developmental disorder not otherwise specified (PDD-NOS) and multiple complex developmental disorder (McDD), with clinical diagnosis as the gold standard. McDD is an heuristic concept of a developmental disorder characterised by social impairments, affective dysregulation, and thought disturbance. Detailed information on the symptoms, reliably extracted from the charts of 103 children with PDD-NOS and McDD, 32 with autistic disorder, and 96 with non-PDD disorders, was used to determine the presence of the DSM-IV criteria of autistic disorder and the criteria of McDD. A scoring rule for PDD-NOS based on a short set of seven DSM-IV criteria with a cut-off point of three items and one social interaction item set as mandatory had the best balance between high sensitivity and high specificity. The most effective and simple rule based on McDD criteria had a cut-off of three items, out of six items of anxieties and thought disturbance.

The aim of the study was to compare social initiatives and gaze behavior in low-functioning children with a pervasive developmental disorder (PDD), high-functioning children with a PDD, children with a language disorder, and normally developing children. Behavior of the children was observed while they watched television and performed a playful task with a parent. Compared to the high-functioning children, the low-functioning children with a PDD showed fewer social initiatives. The high-functioning children with a PDD did not differ from the non-PDD control children in the number of social initiatives and gazes. However, in children with PDD, timing of social gaze proved to be different in that they had lower levels of visual checking before but not after a declarative pointing gesture. Furthermore, they had lower levels of returning gaze.

It has been hypothesized that deficits in theory of mind (ToM) and emotion recognition abilities in subjects with autisticlike disorders are independent. We examined the relationships between deficits in the various social cognitive domains in children with an autistic disorder (N = 20), in children with a pervasive developmental disorder not otherwise specified (PDDNOS) (N = 20), and in psychiatric control (N = 20) and normal children (N = 20). The clinical groups were matched person-to-person on age and verbal IQ. The clinical children were 8-18 years old, the normal children 8-13 years old. The test battery included tasks for the matching and the context recognition of emotional expressions, and a set of first- and second-order ToM tasks. ToM and emotion recognition functioning proved to be better integrated in the non-PDD children than in the PDD children, but also in the PDD children significant correlations were found between ToM and emotion recognition measures.

We compared the predictability of the behaviour of hyperactive children with that of aggressive children, combined hyperactive/aggressive children and normal children. Detailed behaviour measurements relating to each child and an experimenter were recorded during playroom session. Predictability was expressed in information-theoretical measures and data were tested by means of a Multivariate Analysis of Variance (MANOVA) with between-subject factors “hyperactivity” and “aggression”. Hyperactivity was characterised by chaotic social and communicative interaction between child and experimenter and by rigidity in the intra-child transitions of activity states. Aggression on the other hand, was associated with lower predictability of activity behaviours of the child in the context of interaction with the experimenter, which may be due to oppositional features in the child.

Twenty-five adolescents referred to an outpatient clinic because of school refusal in 1985-1986 were followed up after an average of 5 years. DSM-III diagnoses and scores on the Maudsley Symptom Checklist were obtained at initial contact and a follow-up. At follow-up, information was also gathered on psychosocial adjustment, and subjects completed self-ratings of anxiety and depression. At initial contact, school refusal was associated mainly with anxiety symptoms, and to a lesser extent with depressive and somatoform disorders. No specific relationships were found between diagnoses at baseline and at follow-up. About half of the sample still had a psychiatric disorder at follow-up. Outcome was negatively associated with a history of previous psychosocial or psychiatric treatment and a small family size, and positively with a history of frequent somatic complaints.

Self-injurious behaviour (SIB) is a frequently occurring and serious problem in autistic and non-autistic retarded children. This paper first summarizes clinical knowledge on SIB. Attention is paid to the Lesch-Nyhan syndrome and Tourette's syndrome as examples of clinical syndromes that are particularly associated with SIB. Then animal models are reviewed that suggest the involvement of dopaminergic, opioidergic and serotonergic mechanisms in the pathophysiology of SIB. The putative biochemical models of SIB in humans are discussed and pharmacological interventions are briefly outlined.