[ADHD: Burden of Disease According to Subtypes in Adult Patients]. / Der Einfluss des ADHS-Subtyps auf den Leidensdruck bei erwachsenen ADHS-Patienten.

OBJECTIVES: In consideration of ADHD subtype we assessed burden of disease of adult ADHD patients and neuroticism. METHODS: 511 adult ADHD patients were enrolled in the study. We measured ADHD symptoms categorically and dimensionally by the "Homburger ADHS-Skalen für Erwachsene (HASE)". All participants rated their ADHD associated level of suffering. To assess personality traits, the psychometric instrument NEO-PI-R was used. RESULTS: In patients with higher levels of neuroticism, there was no significant difference in the level of suffering between the ADHD subtypes. In the group of ADHD patients which scored low on the neuroticism scale, ADHD combined patients are significant more affected compared to the predominantly hyperactive-impulsive or the predominantly inattentive type. CONCLUSIONS: These results underline the hypothesis that the burden of disease is not only related to the level of ADHD symptoms and subtype but also moderated by neuroticism.

Assessment of post-excitatory long-interval cortical inhibition in adult attention-deficit/hyperactivity disorder.

In order to further examine cortical impairment in adult ADHD patients and to test the hypothesis of a disturbed neuronal inhibition in adults with ADHD, late auditory evoked potentials were measured. By using paired-chirp auditory late responses, we compared 15 adults with ADHD with 15 control subjects, focusing on the inhibition elicited by the stimuli. Besides amplitude measurements, a time-frequency phase coherence study using the wavelet phase synchronization stability (WPSS) was performed. ADHD was diagnosed according to DSM-IV criteria. All ADHD subjects were without medication and did not suffer from any further axis I disorder. WPSS analysis revealed impaired auditory inhibition for ADHD patients for interstimulus intervals (ISI) between 500 and 1,100 ms as compared with healthy controls. By analyzing the WPSS in the interval from 80 ms to 220 ms, mean inhibition of the test chirp was found to be 6% in the ADHD group and 38.5% in the control subjects (p = 0.01). Moreover, overall smaller amplitudes in the N100 and P200 waves at all ISI were found (p = 0.04 and p = 0.02). However, reproducibility indices in the amplitude measurements were low, thus supporting the use of the instantaneous phase-based analysis method. The results support the hypothesis of reduced intracortical inhibition as a correlate of disturbed brain function in adults with ADHD.

Reduced cortical inhibition in violent offenders: a study with transcranial magnetic stimulation.

BACKGROUND: Aggression and violent behaviour are often regarded as a threat to society. Therefore, understanding violent behaviour has high social relevance. We performed a study with transcranial magnetic stimulation on a sample of violent offenders in order to measure cortical inhibition in the motor neuron system that is part of the frontal cortex. METHODS: To investigate intracortical inhibition and intracortical facilitation, we conducted paired-pulse stimulation according to the technique of Kujirai and his group (see Method). The investigation sample comprised 62 right-handers: 32 prisoners who had committed severe violent crimes and 30 controls with no history of violence. All subjects were male and matched for age. RESULTS: Using the paired-pulse paradigm with interstimulus intervals (ISI) of 1-15 ms, a reduced cortical inhibition (ISI: 3 ms) was found in the left cortex of violent offenders compared with control subjects. CONCLUSIONS: These findings corroborate the hypothesis of inhibition deficits and frontal cortex dysfunction in violent offenders when compared with non-violent control subjects.

Epigenetic dysregulation of dopaminergic genes in eating disorders.

OBJECTIVE: The pathophysiology of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN) has been linked to an impaired dopaminergic neurotransmission, still the origin of this disturbance remains unknown. The aim of the present study was, therefore, to evaluate whether the expression of dopaminergic genes is altered in the blood of patients suffering from eating disorders and if these alterations can be explained by changes in the promoter specific DNA methylation of the genes. METHOD: We used quantitative real-time PCR to measure both the expression and the promoter specific DNA methylation of the dopamine transporter (DAT), and the D2 (DRD2) and D4 receptor (DRD4) gene in the blood of 46 patients (22 AN, 24 BN) and 30 healthy controls. RESULTS: Patients showed an elevated expression of DAT mRNA when compared with the controls and a downregulation of the DRD2 expression. The upregulation of the DAT gene was accompanied by a hypermethylation of the gene's promoter in the AN and BN group while a significant hypermethylation of the DRD2 promoter was only present in the AN group. No differences in expression or methylation were found for the other dopamine receptors investigated. DISCUSSION: Our study shows a disturbed expression of dopaminergic genes that is accompanied by a dysregulation of the epigenetic DNA methylation. Further studies are necessary to provide more insight into the epigenetic dysregulation of the dopaminergic neurotransmission in the pathophysiology of eating disorders.

Alpha-synuclein mRNA levels correspond to beck depression inventory scores in females with eating disorders.

Alpha-synuclein (alpha-Syn) is a neuronal protein involved in the regulation of brain serotonin and dopamine levels. We analyzed the peripheral expression of alpha-Syn mRNA and Beck Depression Inventory scores in female patients suffering from anorexia nervosa (n = 18) or bulimia nervosa (n = 24). We found a significant positive association between alpha-Syn mRNA expression and the total scores of the Beck Depression Inventory (linear regression; R(2) = 0.20; p = 0.003). alpha-Syn may play a pathophysiological role in depressive symptoms associated with eating disorders. Further investigations in patients with depression as a sole diagnosis are needed to support its role in the pathogenesis of major depression.

[Examination of fitness to drive]. / Abklärung der Fahreignung.

Driving a car in public traffic requires a high performance that is often underestimated owing to daily habit. Fitness to drive can be impaired temporary or permanently because of taking substances declining the performance and because of various somatic diseases and psychic disorders. To check the fitness to drive is the responsibility of medical examination in terms of road traffic. This is supposed to be an individual examination corresponding to acknowledged guidelines by an experienced expert in order to keep away dangerous drivers from road traffic but not to reduce excessively the personal freedom of those drivers, who do not endanger road traffic considerably.

Epigenetic downregulation of atrial natriuretic peptide but not vasopressin mRNA expression in females with eating disorders is related to impulsivity.

Disturbances of volume-regulating mechanisms have already been implicated in the pathophysiology of eating disorders like anorexia or bulimia nervosa with the peptide hormones vasopressin and atrial natriuretic peptide (ANP) being of special interest. Aim of the present study was to investigate, whether the expression of the corresponding genes was altered and if so, if these changes could be explained by epigenetic mechanisms such as DNA methylation. We analyzed blood samples of 46 women suffering from anorexia (n=22) or bulimia nervosa (n=24) as well as of 30 healthy controls. Peripheral mRNA expression and DNA methylation of the vasopressin and the ANP precursor genes were assessed using real-time PCR. We found significantly lower levels of ANP mRNA in patients with eating disorders. This downregulation was accompanied by a hypermethylation of the ANP gene promoter in the bulimic subgroup. We did not find differences regarding expression or methylation of the vasopressin gene. ANP mRNA expression was inversely associated with impaired impulse regulation. We conclude that epigenetic mechanisms may contribute to the known alterations of ANP homeostasis in women with eating disorders.

Depressive symptoms may explain elevated plasma levels of homocysteine in females with eating disorders.

Elevated plasma homocysteine levels have been found in different psychiatric disorders, including major depression and eating disorders. The aim of the present study was to evaluate whether presence of depression or depressive symptoms is associated with elevated homocysteine levels in patients with eating disorders. Total plasma homocysteine levels were assessed in 44 females with anorexia nervosa (n = 21) or bulimia nervosa (n = 23). Comorbid major depressive disorder (MDD) was diagnosed according to DSM-IV criteria using a semi-structured interview (SCID-I). Furthermore, depressive symptoms were assessed using Beck's depression inventory (BDI). Presence of MDD was not associated with elevated homocysteine levels (t-test: T = 0.42; df = 42; P = 0.68). However, self-rated presence of clinically relevant depressive symptoms (BDI score18) was associated with elevated homocysteine (T = -2.8; df = 42; P = 0.008). Presence of depressive symptoms may explain elevated homocysteine levels previously reported in patients with eating disorders or vice versa. Longitudinal studies are needed to unravel this hen or egg problem.

Association of catecholamine-O-methyltransferase and 5-HTTLPR genotype with eating disorder-related behavior and attitudes in females with eating disorders.

OBJECTIVE: There is growing evidence, that genetic variants contribute to the pathogenesis of anorexia nervosa and bulimia nervosa. Genetic studies have revealed candidate genes, but no satisfactory associations with the disorders have been found so far. The aim of the present study was to evaluate, whether behavioral and attitudinal traits of the disorders can serve as phenotypes with a possible association with two common functional polymorphisms of the monoaminergic pathways. METHOD: Forty-five female in-patients of a specialized hospital for eating disorders were included into the study. Eating disorder symptomatology was assessed using the Eating Disorder Inventory-2. The functional catecholamine-O-methyltransferase (COMT) 158 Val-->Met polymorphism and the deletion/insertion polymorphism of the serotonin transporter promoter 5-HTTLPR were determined. RESULTS: Carriers of at least one Met-allele of the COMT gene had significantly higher total scores of the Eating Disorder Inventory-2, as well as significantly higher scores on the subscales bulimia, ineffectiveness, interoceptive awareness, maturity fears and impulse regulation. Carriers of the deletion of the 5-HTTLPR had significantly higher scores on the subscales drive for thinness and body dissatisfaction. CONCLUSION: We found associations between the COMT and the 5-HTTLPR polymorphisms and specific clinical, behavioral and attitudinal traits of eating disorders. These polymorphisms may predispose their carriers to exhibit certain symptoms of eating disorders or confer a general risk for more severe forms of these disorders.

Glutamate and the glutamate receptor system: a target for drug action.

Glutamate is the most important excitatory neurotransmitter in the central nervous system. In the process, glutamate fulfills numerous physiological functions, but also plays an important role in the pathophysiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs. Under certain conditions, glutamate has a toxic action resulting from an activation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Such mechanisms are currently under discussion in acute neuronal death within the context of hypoxia, ischaemia and traumas, as well as in chronic neurodegenerative or neurometabolic diseases, idiopathic parkinsonian syndrome, Alzheimer's dementia and Huntington's disease. It is hoped that glutamate antagonists will lead to novel therapies for these diseases, whereby the further development of glutamate antagonists for blocking disease-specific subtypes of glutamate receptors may be of major importance in the future.

[Glutamate--a transmitter in the tensionfield between toxin and trophine]. / Glutamat--Ein Transmitter im Spannungsfeld zwischen Toxin und Trophin.

Glutamate is the most important excitatory transmitter in the central nervous system. A tremendous complexity in the actions of this excitatory transmitter was found and an equally great complexity in the molecular structures of the receptors activated by glutamate. The glutamate receptor system influences nearly all other neurotransmitter systems. Glutamate also plays a central role in important processes of the central nervous system like the long-term potentiation in the hippocampus and the central sensitization for pain stimuli in the spinal cord, which is predominantly mediated by NMDA-receptors. But there are actions of glutamate beyond its function as an excitatory transmitter. Glutamate also has a trophic influence on neurons--depending upon the developmental stage. The excitotoxicity of glutamate mediated by NMDA-receptors is the common ultimate mechanism of acute and chronic nerve cell death and plays an important role in many acute neurologic diseases. The modulation of the glutamate system for example by antagonist of the glutamate-receptors might be a possible way in therapy of many different diseases of the central nervous system.