[Biologic aspects of ADHD and conduct disorders in childhood and adolescence, selected preventive aspects]. / Biologické aspekty ADHD (hyperkinetické poruchy) a poruch chování v detském a adolescentním veku, vybrané preventivní aspekty.

Next to environmental factors and problems with interpersonal interaction in family represent developmental findings the basic of understanding these disorders (ADHD, conduct disorders, obsessive-compulsive disorders, tic disorders etc.). Knowledges of neurodevelopment disorders represent new possibilities of prevention and treatment.

Reverse asymmetry and changes in brain structural volume of the basal ganglia in ADHD, developmental changes and the impact of stimulant medications.

We discussed the cross section studies and the meta-analysis of published data in children and adolescents with ADHD (both drug naive and receiving stimulant medications), in comparison with healthy children and adolescents of the same age. In children and adolescents with ADHD the deceleration of the maturation dynamics of discrete CNS structures is found, volume reduction and decreased grey matter in prefrontal and occipital regions, which is accompanied by reverse asymmetry of the basal ganglia volume (putamen, nucleus caudate). The above mentioned developmental characteristics are valid only for the ADHD children, who have not been treated by stimulant medications. The stimulant treatment eliminates the mentioned changes into various extend. These developmental changes of CNS structures volume are missing in girls.

Long term pharmacotherapy by methylfenidate or atomoxetine DAT 1 10/10 ADHD children in correlation with results of the imaging methods.

OBJECTIVES: ADHD is one of the most significant diagnostic units in child and adolescent psychiatry. The occurrence in children is 5-6% and 50-80% continued to adult age. The presence of individual genes (polymorphism) on particular symptoms and processes in ADHD are not known. It is estimated that ADHD symptoms are up to 80% to genetic. The higher density of resultant DAT 1 protein was observed in ADHD patients in comparison with controls. The question was if DAT 1 10/10 predicted bad prognoses in long term therapy. METHODS: We compared 30 ADHD DAT 1 10/10 adolescents treated for 5-6 years. Patients with 30 control adolescents. They were the same age of probands and controls. All these subjects were examined by child psychiatry scales (Conners, Achenbach…). Biological changes were tested by MRI specific CNS volumometry. RESULTS: We didn't confirm bad prognoses in long term therapy with methylphenidate or atomoxetine in ADHD children DAT 1 10/10 in long term therapy. In MRI specific CNS volumometry were not identify any differences in controls and ADHD probands. Gray matter thickness was significantly higher in prefrontal and occipital areas in patients compared to control in prefrontal and occipital areas with cluster-wise p-value<0.05. By this method were not identify any cerebrum damage in long term therapy by methylphenidate and atomoxetine.

A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism.

BACKGROUND: ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. METHODS: A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. RESULTS: We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. CONCLUSIONS: We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.

Circadian rhythms of saliva melatonin in ADHD, anxious and normal children.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders are the most frequent psychiatric disorders in children. Changes in rhythms of symptoms during the day may be influenced by genetic, biological and psychological factors. Some changes of melatonin rhythm may hypothetically change the activity of ADHD by changing arousal or in anxiety children by changing their emotional state. In our present study we identify one group of ADHD children combine type without comorbids, one group of anxiety children and a control group. Most changes of melatonin daily rhythm are supposed in the anxiety group, especially in sleeping time, and more prominent change in the ADHD group with prominent hyperactivity and conduct disorder symptoms. METHODS: Thirty-four ADHD and forty-three control children and eleven anxiety children, all 6-12 years old, participated in the study. The saliva specimens were collected in four different sessions during the school year, around the time of the spring and autumn equinox, when the natural light lasted 11.2 h ± 0.9 h. RESULTS AND CONCLUSIONS: In our study more symptoms of conduct disorder elevated positive or negative correlations between psychopathology and saliva level of melatonin in ADHD and anxiety samples. We hypothesize that co-morbidity of ADHD or anxiety with impulsivity and conduct disorders might have elevated correlations between psychopathology of ADHD or anxiety and plasma melatonin level.

The association between TaqI A polymorphism of ANKK1 (DRD2) gene and ADHD in the Czech boys aged between 6 and 13 years.

OBJECTIVE: The purpose of this study was the correlation of the combined type of ADHD in children and Taq IA polymorphism DRD2 gene. We hypothesized a positive correlation of DRD2 polymorphisms in the combined type of ADHD patients without co-morbidity. PATIENTS AND METHODS: Our research sample included 586 unrelated boys of the Czech origin aged between 6 and 13 years. The ADHD group consisted of 269 boys and the control group consisted of 317 boys. PCR detection of the DRD2 polymorphism was carried out by using primers, described by Grandy (Grandy et al. 1989). RESULTS: The comparison of genotype frequencies showed statistically highly significant difference between the studied groups (p<0.0001). A statistically significant difference was also found when the allelic frequencies between the two groups were compared (p<0.0001), with the A1 allele having a 4.359 fold higher risk of ADHD (Risk Ratio=4.359, 95% CI of RR=3.5753 to 5.3144, Odds Ratio= 7.7824; 95% CI of OR=10.315 to 13.6719). CONCLUSIONS: Our results presented a highly positive correlation between the combined type of ADHD without co-morbidity and ANKK l (DRD2) polymorphism .

ADHD and growth: anthropometric changes in medicated and non-medicated ADHD boys.

BACKGROUND: ADHD children can show changes in growth and development. Many studies describe these changes as a side effect of stimulant medication. However, changes in somatic development can also appear in non-medicated children. This suggests that the changes could be a manifestation of the disorder itself and not just a side effect of the treatment. MATERIAL/METHODS: This study compared anthropometric characteristics in medicated and non-medicated ADHD boys (n=104, age 4-16 years) with the normal non-clinical population. In contrast to most previous studies, complex anthropometrical measurements were used. RESULTS: The results showed significant differences between children with ADHD and those without the diagnosis, the differences found to be statistically significant (p<0.01) being signs of nutrition (percentage of fat, abdominal circumference) and growth suppression (lower body height, smaller head circumference). Differences between the medicated and non-medicated groups corresponded only to a lower value of body fat in the medicated children. CONCLUSIONS: These results suggest that growth changes in ADHD children may be more specific to the disorder itself than to stimulant treatment.

Dopamine beta hydroxylase (DBH) plasma activity in childhood mental disorders.

BACKGROUND: Developmental study of dopaminergic and noradrenergic systems in child psychiatric disorders are rare. DBH activity is one of noradrenergic biochemical marker that is correlate in psychiatry to clinical and genetic data. OBJECTIVES: The main aim of the present study was to measure DBH activity at the onset of acute schizophrenia and depressive disorder in children and adolescents without pharmacological treatment and to compare these values with DBH activity in healthy controls. The authors also investigated untreated ADHD children. METHODS: We examined 42 control healthy children, 15 children non-treated with acute schizophrenia, 15 non-treated children with acute depressive disorders and 30 non-treated ADHD children, all in age 7-14. Plasma DBH level was provided by Nagatsu (1972; 1974). Depressed children were reexamined after clinical remission. RESULTS: DBH activity is statistically significantly decreased in non-treated depressive disorder and ADHD in children and adolescents. DBH activity is normalised during antidepressant therapy in child depression. Child schizophrenia patients present with normal DBH activity. CONCLUSION: These results are similar to the results that have been observed in adult patients with schizophrenia and depression and in previous studies of DBH activity in children with ADHD. These results also indicate hypoactivity of the noradrenergic system in children with ADHD and depression.

Anthropometric changes in non-medicated ADHD boys.

OBJECTIVES: The aim of the study is to compare complex anthropometric characteristics in non medicated boys with ADHD and normal population. METHODS: Complex anthropometric examination of non-medicated ADHD boys (n=46, average age 11.03 years), statistical and clinical comparison to the actual population growth norm. In contrast to the most of the previous studies, which analyzed mostly only BMI or basic signs of growth as height and weight, the presented study operates with a complex anthropometrical measurement and comparison with actual population norm. RESULTS: The results of the study show significant differences in the signs of nutrition (percentage of fat) and growth indicators (lower values of height) between ADHD and non ADHD children. Further anthropometrical parameters show other possible but in the studied sample statistically non-significant differences. CONCLUSION: Many studies analyzed growth relation to medication of ADHD children, but did not consider that the changes could appear also in non-medicated children and thus they might not be only a side effect of the treatment but a manifestation of the disorder itself. Growth changes in non-medicated children are not described well enough, so the presented study was performed to compare anthropometrics characteristics in ADHD boys with norm of nonclinical population and specify the differences. The results points to hypothesis that the growth changes are primarily caused by the disorder itself.

Platelet serotonin uptake in drug-naïve depressive patients before and after treatment with citalopram.

We investigated the kinetic parameters of serotonin (5-HT) uptake into platelets in a group of 26 drug-naïve patients suffering from major depression before and after 3-7 weeks of treatment with citalopram. The degree of depression was rated using the Hamilton Depression Rating Scale (HDRS). The 5-HT uptake characteristics in untreated depressive patients were not significantly different from those of normal subjects. The apparent Michaelis constant (K(M)) was significantly increased, the apparent maximal velocity (V(max)) was not different from baseline, and the uptake efficiency (V(max)/K(M)) was significantly decreased after citalopram treatment. A significantly positive correlation between K(M) and V(max) was found in all groups. There was a significantly lower V(max) and V(max)/K(M) in the female compared with the male depressed patients before citalopram treatment; a hypothesis was supported that lowered 5-HT uptake may reflect a gender-linked vulnerability to a serotonin-related depression. A significant negative correlation between 5-HT uptake efficiency and the initial HDRS score suggests that platelet 5-HT uptake can be used as a marker of effective depressive disorder pharmacotherapy. The initial severity of depression was significantly negatively correlated with V(max), which supported a hypothesis that the initial severity of depressive disorder could be related to the lower V(max).

P300 wave: a comparative study of impulsive aggressive criminals.

Event-Related potentials are a simple non-invasive neurophysiological method enabling to comprehend certain aspects of the cognitive processing of information in humans. The best-known component of Event-Related Potentials is the so-called P3 wave. Alterations in the parameters of P300 wave have been discovered in certain personality disorders and in persons with impulsively aggressive behaviour. The purpose of this study is to investigate the changes of these parameters, especially an amplitude and latency in the place of Pz electrode. We examined 15 persons with the impulsive aggressive behaviour and compared them to a population comparable of normal age, gender and approximate degree of education. We used P300 auditory and a neuropsychological Eysenck IVE battery. The results showed that significantly lower amplitudes had been found in the aggressive impulsive subjects as compared to the control group. No statistically significant differences have been discovered in the latency. These results seem to confirm previous studies.

Some ADHD polymorphisms (in genes DAT1, DRD2, DRD3, DBH, 5-HTT) in case-control study of 100 subjects 6-10 age.

BACKGROUND: Pharmacological approach is the most effective way of treatment of ADHD and its early application prevents from the progress of secondary disorders. The study on present neurotransmitter systems in pathology of ADHD can be helpful in selecting appropriate drug, since there are used various substances with different mechanisms of functioning in treatment of the hyperkinetic syndrome. METHOD: Within our study there were selected the genes of dopaminergic (DRD2, DRD3, DAT1), noradrenergic (DBH) and serotoninergic (5-HTT) systems. With the use of molecular-genetic methods based on association strategy "case-control" there were analysed genes including 11 polymorphisms. The presence of risk alleles was examined in comparison of the sample of 100 ADHD children to a control group of another 100 subjects, who were checked by child psychiatrists and examined with the Conners test in order to exclude eventual cases with ADHD symptoms. RESULTS: Our research suggests the association of some genes with ADHD. It could be concluded: 1) the risk of ADHD is significantly increased in the presence of one risk allele in genes DRD2 (O.R.=7,5), 5-HTT (O.R.=2,7) and DAT1 (O.R.=1,6). 2) The risk of ADHD is significantly increased at homozygotes for risk alleles in genes DRD2 (O.R.=54,8), 5-HTT (O.R.=6,7) and DAT1 (O.R.=6,6). For polymorphisms G444A and C1603T in DBH, which were detected by univariant analysis, haplotype analysis was performed and resulted in conclusion that: 3) the risk of ADHD is significantly increased in the presence of allele DBH +444A as well as in the presence of allele DBH +1603T (O.R.=15).

Psychobiology of dissociation and its clinical assessment.

OBJECTIVE: Dissociation is often defined as partial or total disconnection between memories of the past, awareness of identity and of immediate sensations, and control of bodily movements, often resulting from traumatic experiences, intolerable problems, or disturbed relationships. This type of reaction to a psychological and/or physical trauma has often various neurobiological consequences and its clinical assessment has received enormous interest in recent psychological and neuroscience research. METHODS: Psychometric parameters of the Czech version of the Dissociative Experiences Scale were tested from the viewpoints of internal consistency, validity and factor structure, using data from a sample of n=783 adults, divided into three groups (epilepsy n=243, depression n=357, norm n=183), average age 39 years, SD=13.5. RESULTS: Findings of this study demonstrated that reliability, validity and factor structure of the Czech version of the Dissociative Experiences Scale correspond to those of the original English version. CONCLUSIONS: The Czech version of the questionnaire may be considered a suitable tool for estimating subjectively experienced dissociative symptoms.

Asymmetry of basal ganglia in children with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatry disorder with several key symptoms, such as inattentiveness, impulsivity and hyperactivity. Neuropsychiatry studies have implicated the frontostriatal circuit in the pathological physiology of the disorder. Using magnetic resonance imaging (MRI), we examined the basal ganglia in 13 ADHD patients and eight unaffected comparison children. The volume of caudate, putamen and globus pallidus was measured. In the ADHD patients, we detected an increased left > right asymmetry of the basal ganglia. This reversal of asymmetry in the globus pallidus and caudate nucleus were statistically significant. These finding provide further evidence of morphological brain abnormalities in ADHD.

Polymorphisms and low plasma activity of dopamine-beta-hydroxylase in ADHD children.

Attention-deficit Hyperactivity disorder (ADHD) is a multifactorial disorder clinically characterized by inattentiveness, impulsivity and hyperactivity. The occurrence of this disorder is between 3 and 6% of the children population, with boys predominating over girls at a ratio of 3:1 or more. The research of some candidate genes (DRD4, DAT, DRD5, DBH, 5HTT, HTR1B and SNAP25) brought consistent results confirming the heredity of ADHD syndromes. Dopamine-beta-hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into noradrenaline. Alteration of the dopamine/noradrenaline levels can result in hyperactivity. The DBH protein is released in response to stimulation. DBH activity, derived largely from sympathetic nerves, can be measured in human plasma. Patients with ADHD showed decreased activities of DBH in serum and urine. Low DBH levels correlate indirectly with the seriousness of the hyperkinetic syndrome in children [19,20]. In the DBH gene, the G444A, G910T, C1603T, C1912T, C-1021T, 5 -ins/del and TaqI polymorphisms occur frequently and may affect the function of gene products or modify gene expression and thus influence the progression of ADHD. This article reviews the DBH itself and polymorphisms in the DBH gene that influence the DBH activity in the serum and the CSF level of DBH. All those are evaluated in connection with ADHD.

Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.

OBJECTIVE: To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. METHODS: The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case-control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. RESULTS: Homozygosity for a rare putative promoter variant, -1007C-->T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the -1007T allele compared with -1007C. CONCLUSION: The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.

BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.

Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: a replication study.

Linkage analysis has shown that chromosome 21q22 may contain a candidate gene for bipolar disorder (BPD). One potential 21q22 candidate gene we previously analyzed is SYNJ1, which encodes synaptojanin 1, an inositol 5-phosphatase. Previous mutation screening of SYNJ1 identified three rare functional variants, one of which is a polymorphic variant near the intron 12-oxon 12 border. The rare variants were found only in a total of four BPD patients and no controls, and a trend toward significance was found for the intron 12 polymorphism. In an analysis of a new set of 84 bipolar patients, none of the rare variants were detected. There was an increase in allele 2 for the intron 12 polymorphism, similar to our original study, but the result was not significant. The combined data from both studies continue to show a trend toward significance for allele 2 homozygotes in BPD.

Salivary melatonin rhythm as a marker of the circadian system in healthy children and those with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Problems with sleep structure, efficiency, and timing have been reported in some, but not all, studies on ADHD children. As the sleep-wake cycle belongs to circadian rhythms, the timekeeping circadian system might be involved in ADHD. To assess whether the circadian system of ADHD children differs from that of controls, the rhythm of the pineal hormone melatonin was used as a reliable marker of the system. Saliva from 34 ADHD and 43 control 6- to 12-yr-old children was sampled at 2-h intervals throughout the entire 24-h cycle, and the melatonin profiles of the ADHD and control children were compared. The nocturnal melatonin peaks of the ADHD and control group did not differ significantly. The high nocturnal interindividual variability of the peaks seen in adulthood was present already in the studied children. The 24-h melatonin profiles of all the ADHD subjects did not differ significantly from those of the control subjects. Categorization of subjects according to age, into groups of 6- to 7-yr-old (9 ADHD, 5 control), 8- to 9-yr-old (16 ADHD, 26 control), and 10- to 12-yr-old (9 ADHD, 12 control) children, revealed significant differences between the ADHD and control group in the melatonin rhythm waveform, but not in nocturnal melatonin peaks; the peaks were about the same in both groups and did not change significantly with increasing age. In the oldest, but not in the younger, children, the melatonin signal duration in the ADHD group was shorter than in the control group. The difference might be due to the fact that whereas in the control group both the evening melatonin onset and the morning offset phase delayed in the oldest children relative to those in the youngest children, in the ADHD group only the onset, but not the offset, phase delayed with increasing age. The data may indicate subtle differences between the circadian system of ADHD and control children during development.