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Metabolite alterations in the basal ganglia associated with methamphetamine-related psychiatric symptoms: A proton MRS study
246 limbic blood flow in schizophrenia. Neuroreport 6:869-872. Work supported by MIND Institute
METABOLITE ALTERATIONS IN THE BASAL GANGLIA AS S OCIATED WITH METHAMPHETAMINE-RELATED PSYCHIATRIC SYMPTOMS: A PROTON MRS STUDY Y. Sekine,* K. Nakamura,Y. Minabe, M. Kawai, K. Suzuki, K. Takebayashi, N. Takei, N. Mori
Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One of the reasons may be the persistence of metabolite abnormalities in the brains of abstinent methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and eholine-contaiaing compounds (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users, and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and the comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia. This work was supported by a Grant-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant for Scientific Research from the Ministry of Health and Welfare of Japan, a grant for Target-Oriented Research and Development from the Ministry of Science and Technology of Japan, and the Stanley Foundation.
PET IMAGING OF DOPAMINE D 1 AND D 2 RECEPTORS IN PATIENTS TREATED WITH CLOZAPINE, OLANZAPINE, QUETIAPINE, OR RISPERIDONE J. Tauscher,* T. Hussain, O. Agid, R Barsoum, D. Hussey, A. A. Wilson, S. Houle, R. B. Zipursky, S. Kapur
Dept. of General Psychiatry, University of Vienna, Austria, Vienna, Vienna, Austria Even though there are several new atypical antipsychotics, clozapine remains unique in its efficacy in refractory schizophrenia. Thus far, neither clozapine's affinity for the dopamine D 4 receptor, its serotonin 5-HT2A receptor antagonism, its robust alterations of noradrenergic biochemistry, nor its relatively moderate occupancy of D 2 receptors provided a convincing explanation for its unique actions. In vitro, clozapine uniquely shows a relatively high affinity for D 1 receptors together with its moderate affinity for D 2 receptors. Dopamine D 1 receptors mediate reward related functions, a mechanism centrally relevant to the anti-"psychotic" action of antipsychotics. Therefore, the objective of this study was to compare atypical antipsychotics on their relative actions on the dopamine D 1 vs.
15. Neuroimaging, Neurochemical D 2 receptors in patients. We used PET and the D 1 receptor antagonist radioligand [ 11C]SCH23390 as well as the D 2 receptor antagonist radioligand [1 lC]raclopride ' respectively, to investigate striatal and frontal D 1 as well as striatal D 2 receptor occupancy. Twentyfive patients with schizophrenia were scanned during treatment with clozapine 400-600 mg/d (N=7), olanzapine 15-22.5 mg/d (N=6), quetiapine 300-700 mg/d (N=5), and risperidone 3-6 mg/d (N=7), and their D 1 and D 2 receptor occupancy was calculated using baseline binding potentials obtained in untreated healthy controls. Mean striatal D 1 occupancies ranged from 54% with clozapine to 12% with quetiapine, with the following rank-order: clozapine>olanzapine>risperidone>quetiapine (p<0.05). Striatal D 2 occupancy ranged from 81% (SD=4) with risperidone to 38% (SD=8) with quetiapine and the following rank-order: risperidone>olanzapine>clozapine>quetiapine (p<0.01). The ratio of striatal D l/D2 occupancy as an index for a balanced action at D 1 and D 2 receptors was significantly higher with clozapine (0.88) than with olanzapine (0.54; p=0.001), quetiapine (0.41; p=0.024), or risperidone (0.31; p<0.001). This PET study in schizophrenic patients is consistent with the theory that clozapine has a unique interaction with the D1/D 2 system, and with data from animal models. The balanced D1/D 2 antagonism may explain the clinical uniqueness of clozapine in patients with refractory symptoms. These cross-sectional data provide a strong impetus for prospective clinical studies focussing on the role of dopamine D 1 receptors, along with moderate D 2 antagonism as a means for enhanced therapeutic efficacy against psychosis.
PROTON MAGNETIC RESONANCE SPECTROSCOPY (1H-MRS) IN ADOLESCENTS AT RISK FOR SCHIZOPHRENIA: THE EDMONTON HIGH RISK PROJECT R Tibbo,* P. Allen, C. Hanstock, A. Valiakalayil, L. Paulson
Psychiatry, University of Alberta, Edmonton, AB, Canada The purpose of this study is to investigate brain metabolite changes longitudinally with 1H-MRS between non-psychotic adolescents at high risk for schizophrenia (HR) and normal adolescent controls to detect vulnerability markers for schizophrenia. Non-psychotic HR adolescents having a parent with schizophrenia (n=20, mean age=16.4) and adolescent controls (n=22, mean age=16.7) between the ages of 13-19 were recruited and examined at baseline. To date, follow-up 1H-MRS at a mean of 18.3 months includes 8 HR (mean age 17.8) and 8 controls (mean age 18.3). 1H-MRS consisted of choline (Cho), N-acetylaspartate (NAA), inositol (Ino) and glutamate/ glutamine (Glx). Data was acquired using a 3 Tesla scanner with a 2.5cm3 voxel placed over the right frontal lobe. Significantly higher levels of Glx were seen at baseline in non-psychotic HR adolescents compared to controls (1.86 +/- 0.46; 1.53 +/- 0.39) p=0.016. Results for NAA (1.74 +/- 0.2; 1.67 +/- 0.2) p=0.27, Cho (0.96 +/0.11; 0.96 +/- 0.12) p=0.89, and Ino (0.78 +/- 0.17; 0.76 +/- 0.18) p=0.77 were not significant. Results of repeat testing are currently non-significant. Significant 1H-MRS results in Glx levels for adolescents at risk for schizophrenia may represent a potential genetic vulnerability marker for schizophrenia. The longitudinal significance will be determined as sample size of the repeat testing increases. The relevance of the Glx findings in this non-psychotic HR cohort will be discussed in the context of the glutamate hypothesis for schizophrenia.
International Congress on Schizophrenia Research 2003
METABOLITE ALTERATIONS IN THE BASAL GANGLIA AS S OCIATED WITH METHAMPHETAMINE-RELATED PSYCHIATRIC SYMPTOMS: A PROTON MRS STUDY Y. Sekine,* K. Nakamura,Y. Minabe, M. Kawai, K. Suzuki, K. Takebayashi, N. Takei, N. Mori
Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One of the reasons may be the persistence of metabolite abnormalities in the brains of abstinent methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and eholine-contaiaing compounds (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users, and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and the comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia. This work was supported by a Grant-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant for Scientific Research from the Ministry of Health and Welfare of Japan, a grant for Target-Oriented Research and Development from the Ministry of Science and Technology of Japan, and the Stanley Foundation.
PET IMAGING OF DOPAMINE D 1 AND D 2 RECEPTORS IN PATIENTS TREATED WITH CLOZAPINE, OLANZAPINE, QUETIAPINE, OR RISPERIDONE J. Tauscher,* T. Hussain, O. Agid, R Barsoum, D. Hussey, A. A. Wilson, S. Houle, R. B. Zipursky, S. Kapur
Dept. of General Psychiatry, University of Vienna, Austria, Vienna, Vienna, Austria Even though there are several new atypical antipsychotics, clozapine remains unique in its efficacy in refractory schizophrenia. Thus far, neither clozapine's affinity for the dopamine D 4 receptor, its serotonin 5-HT2A receptor antagonism, its robust alterations of noradrenergic biochemistry, nor its relatively moderate occupancy of D 2 receptors provided a convincing explanation for its unique actions. In vitro, clozapine uniquely shows a relatively high affinity for D 1 receptors together with its moderate affinity for D 2 receptors. Dopamine D 1 receptors mediate reward related functions, a mechanism centrally relevant to the anti-"psychotic" action of antipsychotics. Therefore, the objective of this study was to compare atypical antipsychotics on their relative actions on the dopamine D 1 vs.
15. Neuroimaging, Neurochemical D 2 receptors in patients. We used PET and the D 1 receptor antagonist radioligand [ 11C]SCH23390 as well as the D 2 receptor antagonist radioligand [1 lC]raclopride ' respectively, to investigate striatal and frontal D 1 as well as striatal D 2 receptor occupancy. Twentyfive patients with schizophrenia were scanned during treatment with clozapine 400-600 mg/d (N=7), olanzapine 15-22.5 mg/d (N=6), quetiapine 300-700 mg/d (N=5), and risperidone 3-6 mg/d (N=7), and their D 1 and D 2 receptor occupancy was calculated using baseline binding potentials obtained in untreated healthy controls. Mean striatal D 1 occupancies ranged from 54% with clozapine to 12% with quetiapine, with the following rank-order: clozapine>olanzapine>risperidone>quetiapine (p<0.05). Striatal D 2 occupancy ranged from 81% (SD=4) with risperidone to 38% (SD=8) with quetiapine and the following rank-order: risperidone>olanzapine>clozapine>quetiapine (p<0.01). The ratio of striatal D l/D2 occupancy as an index for a balanced action at D 1 and D 2 receptors was significantly higher with clozapine (0.88) than with olanzapine (0.54; p=0.001), quetiapine (0.41; p=0.024), or risperidone (0.31; p<0.001). This PET study in schizophrenic patients is consistent with the theory that clozapine has a unique interaction with the D1/D 2 system, and with data from animal models. The balanced D1/D 2 antagonism may explain the clinical uniqueness of clozapine in patients with refractory symptoms. These cross-sectional data provide a strong impetus for prospective clinical studies focussing on the role of dopamine D 1 receptors, along with moderate D 2 antagonism as a means for enhanced therapeutic efficacy against psychosis.
PROTON MAGNETIC RESONANCE SPECTROSCOPY (1H-MRS) IN ADOLESCENTS AT RISK FOR SCHIZOPHRENIA: THE EDMONTON HIGH RISK PROJECT R Tibbo,* P. Allen, C. Hanstock, A. Valiakalayil, L. Paulson
Psychiatry, University of Alberta, Edmonton, AB, Canada The purpose of this study is to investigate brain metabolite changes longitudinally with 1H-MRS between non-psychotic adolescents at high risk for schizophrenia (HR) and normal adolescent controls to detect vulnerability markers for schizophrenia. Non-psychotic HR adolescents having a parent with schizophrenia (n=20, mean age=16.4) and adolescent controls (n=22, mean age=16.7) between the ages of 13-19 were recruited and examined at baseline. To date, follow-up 1H-MRS at a mean of 18.3 months includes 8 HR (mean age 17.8) and 8 controls (mean age 18.3). 1H-MRS consisted of choline (Cho), N-acetylaspartate (NAA), inositol (Ino) and glutamate/ glutamine (Glx). Data was acquired using a 3 Tesla scanner with a 2.5cm3 voxel placed over the right frontal lobe. Significantly higher levels of Glx were seen at baseline in non-psychotic HR adolescents compared to controls (1.86 +/- 0.46; 1.53 +/- 0.39) p=0.016. Results for NAA (1.74 +/- 0.2; 1.67 +/- 0.2) p=0.27, Cho (0.96 +/0.11; 0.96 +/- 0.12) p=0.89, and Ino (0.78 +/- 0.17; 0.76 +/- 0.18) p=0.77 were not significant. Results of repeat testing are currently non-significant. Significant 1H-MRS results in Glx levels for adolescents at risk for schizophrenia may represent a potential genetic vulnerability marker for schizophrenia. The longitudinal significance will be determined as sample size of the repeat testing increases. The relevance of the Glx findings in this non-psychotic HR cohort will be discussed in the context of the glutamate hypothesis for schizophrenia.
International Congress on Schizophrenia Research 2003