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Dopamine transporter gene polymorphism in Tourette's disorder
P.6. Other topics
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Aggression is linked to increased tryptophan catabolism in patients undergoing interferon treatment
S. Russo, I.P. Kema, E.B. Haagsma, J.C. Boon, H.B. Willemse, J.A. Den Boer, E.G.E. De Vries, J. Korf. Uniuersity Hospital
Groningen, Groningen, The Netherlands Subject: Treatment with recombinant interferon is linked to high rates of psychychiatric comorbidity (1). We investigated the relation of catabolism of the essential amino acid tryptophan and psychiatric symptoms in patients undergoing combination treatment of interferon-alpha and ribavirin. Patients: Twenty-one patients suffering from viral hepatitis C were included. Patients were free of psychotropic medication. Methods: A psychiatrist screened patients before and after 2 months of treatment using a structured diagnostical interview. Plasma tryptophan and platelet serotonin levels were measured at each visit(2). Results: Eighteen patients completed the study. At baseline no evident psychopathology was observed in any of the patients. After two months of treatment 10 patients were suffering from increased aggression. No other structm'al psychopathology was observed. The presence of these complaints was highly correlated to decrease of plasma tryptophan levels (p=0.013). For the whole group, plasma tryptophan level was not changed (p=0.21). Platelet serotonin content however was decreased for the whole group (p= 0.002). Discussion: Disorders of aggressive impulse dysregulation are highly prevalent in patients receiving interferon treatment. This is linked to increased tryptophan catabolism and hence decreased cerebral serotonergic neurotransmission.
References [1] Menkes DB, MacDonald JA. Interferons, serotonin and neurotoxicity. Psychol. Med. 2000;30(2):259~fi8. [2] Kema IP, de Vries EG, Schellings AM, Postmus PE, Muskiet FA. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin. Chem. 1992;38(4):534-40.
~ T h e
effect of atomoxetine on the social and family functioning of children and adolescents with attention-deficit/hyperactivity disorder (ADHD)
C. Donnellya , D. Faries2, A. Swensen2, D. Ruff2, D. Michelson2, L. Matza 3, C. Barker 3, A. Rentz 3, D. Revicki3. 1Dartmouth-
Hitchcock Medical Center, Department of Psychiatry, Lebanon, U.S.A.; 2Eli Lilly and Company, Indianapolis, U.S.A.; 3MedTap International, Bethesda, U.S.A. Objective: In addition to the debilitating core symptoms of inattention, hyperactivity, impulsivity and disorganization, ADHD has been associated with decreased social and family functioning. The impact of atomoxetine (previously known as tomoxetine), an investigational non-stimulant pharmacotherapy, on the social and family functioning of children and adolescents with ADHD was assessed in a randomized, placebo-controlled, dose-response study. In order to better understand the clinical importance of the improvement in core ADHD symptoms, the relationship between the social fimctioning and ADHD symptoms was investigated. Methods: Children and adolescents were randomized to either placebo or one of three doses of atomoxetine (0.5, 1.2, or 1.8
$437
mg/kg/day) for eight weeks. The Childhood Health Questionnaire (CHQ), a well-validated quality of life instrument, was administered at baseline and study end. The CHQ subscales measure the patient's mental health, self-esteem, general behavior, as well as the impact of ADHD on the parent's emotional distress or schedule. Correlations between the CHQ and the ADHD-RS (a symptom measure) were calculated. Results: Data were available for 249 children. Statistically significant improvements were observed for all subscales of the CHQ related to social and family functioning. Significant correlations between improvement in the ADHD-RS Total Score and the CHQ psychosocial subscale (1-=-0.55, p<.001) as well as the CHQ self esteem subscale (1"=-0.35, p<.001) were observed. Conclusion: The results of this study suggest that atomoxetine improves both the core-symptoms of ADHD and the social and family functioning of children and adolescents with the disorder. Moreover, ADHD symptom control is related to improvements in psychosocial and family functioning and reduced burden of illness on both the child and parent. Improvement in quality of life for both parent and child is an important benefit deriving from the successful treatment of core ADHD symptoms with atomoxetine.
•
Dopamine transporter gene polymorphism in Tourette's disorder
M. Stamenkovic 1, J. Stastny1, P. Schiissler1, K. Fuchs 2, C. Gebhart 1, E Riederer 1, S.D. Schindler1, E Leisch a, K. Horn& a, W. Siegharta, S. Kasper 1, H.N. Aschauer 1.
1University Hospital for Psychiatry, Department of General Psychiatry, Vienna, Austria; e Uniuersity Hospital for Psychiatry, Department of General Psychiatry and Diuision of Biochemical Psychiatry, Vienna, Austria; 3University of Technology, Department of statistics and probability theory, Vienna, Austria Objectives: The etiopathogenesis of Tourette's Disorder (TD) an neuropsychiatric disorder with genetic contribution is still unclear. Dopamine Systems are hypothetised to play a role in TD developement. Molecular biologic linkage studies showed evidence for exclusion of a major genetic contribution of the dopamine receptor (D1, D2, D3, D4, D5) genes and the dopamine transporter (DAT) gene. Because linkage and association studies differ in methods and theory, the aim of our study was to investigate if alleles and genotypes of DAT are associated with TD. Methods: Seventyseven patients (48 male, 29 female) with the diagnisis of TD according to DSM-IV were enrolled in this study. A healthy sex and age matched control group (N=77) was investigated. Blood samples were drown from patients and controls. DAT polymorphism was assesed using polymerase chain reaction (PCR). The 40 bp variable tandem repeat (VNTR) polymorphism located in the 3' untranslated region of DAT was amplified using the method of Vandenberg et al. Results: By genotyping in our group of TD patients two alleles of DAT were detected (allele 5=440bp, 6=480bp). There were no significant differences between TD patients and controls with respect to distribution of alleles 5 and 6 and genotypes of DAT. Conclusion: Our results are in line with results from Gelernter et al. who also investigated genotypings of DAT but in large pedigree of TD and could not find a linkage ofDAT polymorphism and TD.
P.6. Other topics"
$438
References [1] Vandenberg D, Periso A, Hawkins A et al. (1992) Human dopamine transporter gene (DAT1) maps to Chromosome 5p15.3 and displays a VNTR. Genomics 14:1104-1106 [2] Gelernter J, Vandenberg D, Kruger S e t al. (1995) The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette Syndrome. Genomics 30:459-463
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T
h
e
effects of the adenosinic agonists and antagonists on behaviour and on EEG activity in rats
1. Cristescu, T. Raducanu, A. Zugravu, D. Vasile, S. Stoleru.
Department of Pharmacology, University of Medicine, and Pharmacy Carol Dauila, Bucharest, Romania Purpose: To establish a correlation between the electrical brain activity and the behavioral changes of the acquiring phase of the memorization processes induced by adenosine agonists, antagonists and agonist-antagonist association. Methods: The study used four groups of 10 male Wistar rats each (weight: 200-250 g): control (0.2 ml saline inj i.p.), adenosine (20 ~tg/kgc inj i.p.), adenosine + theophylline (20 ~tg/kgc inj i,p. + 20 ~tg/kgc inj i.p.), theophylline (20 ~tg/kgc inj i.p.). The Dellu test was used for the behavioral study. The test implies the use of an Y-shaped maze with 3 equal-length arms placed at 120 degree angle. The test studies especially the working memory of the animals. It consists of two maze passages per day with a six-hour period in between, for ten consecutive days. For the first passage one of the arms of the maze is closed, so that the animal can explore the other two for a five-minute period of time. For the second passage it was able to freely explore all the three arms also for a five-minute period. The right choice percentage, defined as visit into the new, previously unexplored arm, was measured. The next issues were determined also: percentage of time spent in the unknown arm, total number of visits and the number of visits in the previously unexplored arm. The recording of the surface EEG was made by BIOPAC SYSTEM MP 100, on four channels. After a Fourier fast analysis all the values of the frequency interval 0.5-34 Hz (i.e. 2107 values) were evaluated in Excel. The statistical significance of differences among the comparison groups was tested by a t-test, 1-tailed for the behavioral study and 2-tailed for the EEG. Results: On the behavioral study the results showed an improvement of the exploration activity during the experiment induced by adenosine; theophylline induced an opposite effect, while adenosine + theophylline increased the exploration ability but also induced hypermotility. The EEG's results may indicate the existence of the adenosinic tonus. The study helped to prove that an adenosinic agonist changes the place of the cerebral waves toward lower ranges of frequency, while an antagonist moves them toward higher ranges of frequency. The simultaneous administration of an antagonist and an agonist could not completely antagonize the adenosinic tonus. Conclusions: Adenosine effects on behavior may be explained by the altering the EEG frequency curves toward lower levels. Theophylline effects on behavior may be explained by the altering the EEG frequency curves toward higher levels. Adenosine + theophylline induced altering of EEG frequency curves toward low levels explains the effect on behavior (acquiring phase, without explaining the hypermotility).
•
Nondominant hemisphere dysfunction in Asperger's disorder
S. Isacu, M.-D. Gheorghe, A. Dragan, A. Giosa. Department of Psychiatry, Central Military Hospital Bucharest, Romania
Background: Asperger's disorder has many clinical features in common with acquired right-hemisphere dysfunction and has been postulated to result from a developmental abnormality of the right hemisphere. Studies with adults have suggested that documented right hemisphere damage may lead to deficits in social skills, prosody, spatial orientation, problem solving, and recognition of nonverbal cues. Objective: Possible regional cerebral blood flow abnormalities in Asperger's disorder. Method: The subjects of this study were two males, first 26 years old, lefthanded and the second 23 years old. Both were diagnosed on the basis of the presence of a complete constellation of clinical features (DSM IV, ICD-10, and Gillberg's criteria). Patients were investigated with computed tomographic (CT) scanning, and SPECT scanning. Results: CT revealed in the first subject a discrete enlargement of the left lateral ventricle, reflecting a mild degree of left hemispheric atrophy, the second had a mild degree of frontal atrophy. SPECT scanning demonstrated left hemispheric abnormalities (diffusely decreased left hemispheric uptake, with marked hypoperfusion left inferior frontal and basal ganglia abnormalitiesdecrease uptake on the right side) in the first subject and was normal in the second. Conclusion: Right hemisphere dysfunction is possible to be a nondominant hemisphere dysfunction (we described the same SPECT abnormalities in the left hemisphere to a lefthanded subject). We found also basal ganglia abnormalities, more frequently described in high functioning autism. Continuation of research in Asperger's disorder with various brain imaging techniques in coordination with neuropsychological evaluations in larger samples is clearly needed in this area. References [1] McKelvey J.R., et al., 1995, Right-hemisphere dysfunction in Asperger's Syndrome. Journal of Child Neurology, 10(4):310-314. [2] Sernrud-Clikeman M., Hynd G.W,, 1990, Right hemispheric dysfunction in nonverbal learning disabilities social, academic, and adaptative functioning in adults and children. Psychological Bulletin 107(2):196-209. [3] Berthier M,L., Starkstein S.E., Leiguarda R., 1990, Developmental cortical anomalies in Asperger's syndrome: neuroradiological findings in two patients. Journal of Neuropsychiatry & Clinical Neurosciences 2(2): 197-201.
•
Aggression is linked to increased tryptophan catabolism in patients undergoing interferon treatment
S. Russo, I.P. Kema, E.B. Haagsma, J.C. Boon, H.B. Willemse, J.A. Den Boer, E.G.E. De Vries, J. Korf. Uniuersity Hospital
Groningen, Groningen, The Netherlands Subject: Treatment with recombinant interferon is linked to high rates of psychychiatric comorbidity (1). We investigated the relation of catabolism of the essential amino acid tryptophan and psychiatric symptoms in patients undergoing combination treatment of interferon-alpha and ribavirin. Patients: Twenty-one patients suffering from viral hepatitis C were included. Patients were free of psychotropic medication. Methods: A psychiatrist screened patients before and after 2 months of treatment using a structured diagnostical interview. Plasma tryptophan and platelet serotonin levels were measured at each visit(2). Results: Eighteen patients completed the study. At baseline no evident psychopathology was observed in any of the patients. After two months of treatment 10 patients were suffering from increased aggression. No other structm'al psychopathology was observed. The presence of these complaints was highly correlated to decrease of plasma tryptophan levels (p=0.013). For the whole group, plasma tryptophan level was not changed (p=0.21). Platelet serotonin content however was decreased for the whole group (p= 0.002). Discussion: Disorders of aggressive impulse dysregulation are highly prevalent in patients receiving interferon treatment. This is linked to increased tryptophan catabolism and hence decreased cerebral serotonergic neurotransmission.
References [1] Menkes DB, MacDonald JA. Interferons, serotonin and neurotoxicity. Psychol. Med. 2000;30(2):259~fi8. [2] Kema IP, de Vries EG, Schellings AM, Postmus PE, Muskiet FA. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin. Chem. 1992;38(4):534-40.
~ T h e
effect of atomoxetine on the social and family functioning of children and adolescents with attention-deficit/hyperactivity disorder (ADHD)
C. Donnellya , D. Faries2, A. Swensen2, D. Ruff2, D. Michelson2, L. Matza 3, C. Barker 3, A. Rentz 3, D. Revicki3. 1Dartmouth-
Hitchcock Medical Center, Department of Psychiatry, Lebanon, U.S.A.; 2Eli Lilly and Company, Indianapolis, U.S.A.; 3MedTap International, Bethesda, U.S.A. Objective: In addition to the debilitating core symptoms of inattention, hyperactivity, impulsivity and disorganization, ADHD has been associated with decreased social and family functioning. The impact of atomoxetine (previously known as tomoxetine), an investigational non-stimulant pharmacotherapy, on the social and family functioning of children and adolescents with ADHD was assessed in a randomized, placebo-controlled, dose-response study. In order to better understand the clinical importance of the improvement in core ADHD symptoms, the relationship between the social fimctioning and ADHD symptoms was investigated. Methods: Children and adolescents were randomized to either placebo or one of three doses of atomoxetine (0.5, 1.2, or 1.8
$437
mg/kg/day) for eight weeks. The Childhood Health Questionnaire (CHQ), a well-validated quality of life instrument, was administered at baseline and study end. The CHQ subscales measure the patient's mental health, self-esteem, general behavior, as well as the impact of ADHD on the parent's emotional distress or schedule. Correlations between the CHQ and the ADHD-RS (a symptom measure) were calculated. Results: Data were available for 249 children. Statistically significant improvements were observed for all subscales of the CHQ related to social and family functioning. Significant correlations between improvement in the ADHD-RS Total Score and the CHQ psychosocial subscale (1-=-0.55, p<.001) as well as the CHQ self esteem subscale (1"=-0.35, p<.001) were observed. Conclusion: The results of this study suggest that atomoxetine improves both the core-symptoms of ADHD and the social and family functioning of children and adolescents with the disorder. Moreover, ADHD symptom control is related to improvements in psychosocial and family functioning and reduced burden of illness on both the child and parent. Improvement in quality of life for both parent and child is an important benefit deriving from the successful treatment of core ADHD symptoms with atomoxetine.
•
Dopamine transporter gene polymorphism in Tourette's disorder
M. Stamenkovic 1, J. Stastny1, P. Schiissler1, K. Fuchs 2, C. Gebhart 1, E Riederer 1, S.D. Schindler1, E Leisch a, K. Horn& a, W. Siegharta, S. Kasper 1, H.N. Aschauer 1.
1University Hospital for Psychiatry, Department of General Psychiatry, Vienna, Austria; e Uniuersity Hospital for Psychiatry, Department of General Psychiatry and Diuision of Biochemical Psychiatry, Vienna, Austria; 3University of Technology, Department of statistics and probability theory, Vienna, Austria Objectives: The etiopathogenesis of Tourette's Disorder (TD) an neuropsychiatric disorder with genetic contribution is still unclear. Dopamine Systems are hypothetised to play a role in TD developement. Molecular biologic linkage studies showed evidence for exclusion of a major genetic contribution of the dopamine receptor (D1, D2, D3, D4, D5) genes and the dopamine transporter (DAT) gene. Because linkage and association studies differ in methods and theory, the aim of our study was to investigate if alleles and genotypes of DAT are associated with TD. Methods: Seventyseven patients (48 male, 29 female) with the diagnisis of TD according to DSM-IV were enrolled in this study. A healthy sex and age matched control group (N=77) was investigated. Blood samples were drown from patients and controls. DAT polymorphism was assesed using polymerase chain reaction (PCR). The 40 bp variable tandem repeat (VNTR) polymorphism located in the 3' untranslated region of DAT was amplified using the method of Vandenberg et al. Results: By genotyping in our group of TD patients two alleles of DAT were detected (allele 5=440bp, 6=480bp). There were no significant differences between TD patients and controls with respect to distribution of alleles 5 and 6 and genotypes of DAT. Conclusion: Our results are in line with results from Gelernter et al. who also investigated genotypings of DAT but in large pedigree of TD and could not find a linkage ofDAT polymorphism and TD.
P.6. Other topics"
$438
References [1] Vandenberg D, Periso A, Hawkins A et al. (1992) Human dopamine transporter gene (DAT1) maps to Chromosome 5p15.3 and displays a VNTR. Genomics 14:1104-1106 [2] Gelernter J, Vandenberg D, Kruger S e t al. (1995) The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette Syndrome. Genomics 30:459-463
•
T
h
e
effects of the adenosinic agonists and antagonists on behaviour and on EEG activity in rats
1. Cristescu, T. Raducanu, A. Zugravu, D. Vasile, S. Stoleru.
Department of Pharmacology, University of Medicine, and Pharmacy Carol Dauila, Bucharest, Romania Purpose: To establish a correlation between the electrical brain activity and the behavioral changes of the acquiring phase of the memorization processes induced by adenosine agonists, antagonists and agonist-antagonist association. Methods: The study used four groups of 10 male Wistar rats each (weight: 200-250 g): control (0.2 ml saline inj i.p.), adenosine (20 ~tg/kgc inj i.p.), adenosine + theophylline (20 ~tg/kgc inj i,p. + 20 ~tg/kgc inj i.p.), theophylline (20 ~tg/kgc inj i.p.). The Dellu test was used for the behavioral study. The test implies the use of an Y-shaped maze with 3 equal-length arms placed at 120 degree angle. The test studies especially the working memory of the animals. It consists of two maze passages per day with a six-hour period in between, for ten consecutive days. For the first passage one of the arms of the maze is closed, so that the animal can explore the other two for a five-minute period of time. For the second passage it was able to freely explore all the three arms also for a five-minute period. The right choice percentage, defined as visit into the new, previously unexplored arm, was measured. The next issues were determined also: percentage of time spent in the unknown arm, total number of visits and the number of visits in the previously unexplored arm. The recording of the surface EEG was made by BIOPAC SYSTEM MP 100, on four channels. After a Fourier fast analysis all the values of the frequency interval 0.5-34 Hz (i.e. 2107 values) were evaluated in Excel. The statistical significance of differences among the comparison groups was tested by a t-test, 1-tailed for the behavioral study and 2-tailed for the EEG. Results: On the behavioral study the results showed an improvement of the exploration activity during the experiment induced by adenosine; theophylline induced an opposite effect, while adenosine + theophylline increased the exploration ability but also induced hypermotility. The EEG's results may indicate the existence of the adenosinic tonus. The study helped to prove that an adenosinic agonist changes the place of the cerebral waves toward lower ranges of frequency, while an antagonist moves them toward higher ranges of frequency. The simultaneous administration of an antagonist and an agonist could not completely antagonize the adenosinic tonus. Conclusions: Adenosine effects on behavior may be explained by the altering the EEG frequency curves toward lower levels. Theophylline effects on behavior may be explained by the altering the EEG frequency curves toward higher levels. Adenosine + theophylline induced altering of EEG frequency curves toward low levels explains the effect on behavior (acquiring phase, without explaining the hypermotility).
•
Nondominant hemisphere dysfunction in Asperger's disorder
S. Isacu, M.-D. Gheorghe, A. Dragan, A. Giosa. Department of Psychiatry, Central Military Hospital Bucharest, Romania
Background: Asperger's disorder has many clinical features in common with acquired right-hemisphere dysfunction and has been postulated to result from a developmental abnormality of the right hemisphere. Studies with adults have suggested that documented right hemisphere damage may lead to deficits in social skills, prosody, spatial orientation, problem solving, and recognition of nonverbal cues. Objective: Possible regional cerebral blood flow abnormalities in Asperger's disorder. Method: The subjects of this study were two males, first 26 years old, lefthanded and the second 23 years old. Both were diagnosed on the basis of the presence of a complete constellation of clinical features (DSM IV, ICD-10, and Gillberg's criteria). Patients were investigated with computed tomographic (CT) scanning, and SPECT scanning. Results: CT revealed in the first subject a discrete enlargement of the left lateral ventricle, reflecting a mild degree of left hemispheric atrophy, the second had a mild degree of frontal atrophy. SPECT scanning demonstrated left hemispheric abnormalities (diffusely decreased left hemispheric uptake, with marked hypoperfusion left inferior frontal and basal ganglia abnormalitiesdecrease uptake on the right side) in the first subject and was normal in the second. Conclusion: Right hemisphere dysfunction is possible to be a nondominant hemisphere dysfunction (we described the same SPECT abnormalities in the left hemisphere to a lefthanded subject). We found also basal ganglia abnormalities, more frequently described in high functioning autism. Continuation of research in Asperger's disorder with various brain imaging techniques in coordination with neuropsychological evaluations in larger samples is clearly needed in this area. References [1] McKelvey J.R., et al., 1995, Right-hemisphere dysfunction in Asperger's Syndrome. Journal of Child Neurology, 10(4):310-314. [2] Sernrud-Clikeman M., Hynd G.W,, 1990, Right hemispheric dysfunction in nonverbal learning disabilities social, academic, and adaptative functioning in adults and children. Psychological Bulletin 107(2):196-209. [3] Berthier M,L., Starkstein S.E., Leiguarda R., 1990, Developmental cortical anomalies in Asperger's syndrome: neuroradiological findings in two patients. Journal of Neuropsychiatry & Clinical Neurosciences 2(2): 197-201.