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Novelty seeking predicts relapse in detoxified male alcohol dependents
P.5 Addiction
$336
At the 21 st day, the levels were tended to be low, but that did not reach to statistical significance. In hippocampus, 5-HIAA levels were significantly higher than control at 10th day of ethanol consumption. Increased 5-HIAA level returned to control values at the 21 st day of ethanol consumption. No significant changes were observed in DA, DOPAC and HVA levels of the brain regions during chronic ethanol exposure. Conclusion: Decreased 5-HT levels in cerebral cortex and corpus striatnm at 10th day of ethanol consumption could be have an important role for developing physical dependence to ethanol. At 21 st day of ethanol consumption, lost of these significant changes in brain 5-HT levels may indicate development of tolerance to the effects of ethanol. According to our results, 5-HT, but not DA, clearly seems to play a critical role in brain at 10th and 21 st days of chronic ethanol consumption The data also support the hypothesis that low 5-HT turnover may predispose an individual to consume and/or abuse ethanol. Acknowledgements: This study was supported by TI]BITAK (grant no: SBAG-AYD-107).
References [1] Cloninger,C.R., (1987) Neurogeneticand adaptive mechanisms in alcoholism. Science 236, 41(~416. [2] Uzbay, i.T. Usanmaz, S., Tapanyi~it, E.E., Aynacio~lu, S., Akarsu, E.S. (1998) Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs, et al. (1998) Drug Alcohol Depend. 53, 39-47. [3] Uzbay, i.T. and Kayaalp, S.O. (1995) A modified liquid diet of chronic ethanol administration: Validationby ethanol withdrawal syndrome in rats. Pharmacol. Res. 31, 37-42.
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Novelty seeking predicts relapse in detoxifled male alcohol dependents
H.N. Aschauer 1, K. Meszaros 1, E. Lenzin~er1, K. Hornik 2, T. Fiireder2, U. Willinger 1, G. Fischer 1, G. Sch6nbeck'. The European Fluvoxamine
in Alcoholism Study Group; 1Department of General Psychiatry, Univ. Vienna; 2Institut J~r Statistik und Wahrscheinlichkeitstheorie, Technische Universit~it, Austria Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire (TPQ), which measures the three personality dimensions novelty seeking (NS), harm avoidance (HA) and reward dependence (RD) as introduced by C. R. Cloninger, in a multi-center study (11 centers in United Kingdom, Eire, Switzerland and Austria) with detoxified alcohol dependent patients (N = 521,388 males, 133 females, age between 19 and 72 years, mean age 41.7) with a diagnosis of alcohol dependence according to DSM-III-R. NS refers to a heritable tendency toward exploratory activity and intensive excitement in response to novel, reflcting the activity o f the dopaminergic system. The TPQ was administered to patients at baseline. The study was a placebo-controlled, double blind, prospectively randomized trial with the objective of investigating the efficacy of fluvoxamine in reducing the number of detoxified alcohol dependents relapsing to uncontrolled drinking over a 1-year period. Only patients who never reported relapse and missed no visit (weeks 2, 4, 6, 8, 12, 16, 24, 32, 40 and 52 after baseline) were considered as "non-relapsers". The objective of our presented analysis here was to evaluate a possible predictive value of these three personality dimensions (NS, HA, RD) on relapse to uncontrolled drinking over a one year follow up period (Meszaros et al., Alcoholism Clin. Exp. Res., submitted). A logistic regression analysis showed that NS is a strong predictor for relapse in detoxified male alcoholics (p = 0.0007; p-values adjusted for treatment), but not in females. In both sexes, HA and RD were of no predictive value. However, we found a trend for significance of HA for predicting "early" relapse (4 weeks) in females (p = 0.074). Fluvoxamine was not superior to placebo to prevent relapse to uncontrolled drinking over one year (data not shown in detail). Our results show that TPQ personality traits have direct clinical applications for prediction of relapse in detoxified alcohol
dependents and indicate the necessity of additional therapeutic treatment in risk groups. Acknowledgement: The work was financially supported by Solvay Pharma GmbH.
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Effect of acamprosats on the hypothalamicpituitary-adrenal (HPA) system in early abstinent alcoholics
U. Zimmermann, W. Hundt, A. Grabner, K. Hahn, E Holsboer. Max-
Planck-Institute of Psychiatry, Kraepelinstr. 10, 80804 Munich, Germany Purpose: Acamprosate decreases relapse rates in alcoholics by approximately 20% within the first year after detoxification. One strongly suspected mechanism of action involves brain-site specific modulation of excitatory NMDA receptor-mediated neurotransmission. NMDA receptor stimulation in rats I as well as alcohol withdrawal in alcohol dependent patients activates the HPA system with abnormally high cortisol secretion in the in the first days of abstinence. We investigated whether acamprosate normalizes HPA hyperactivity in alcoholics within the first 2 weeks after withdrawal, employing the combined dexamethasonecorticotrophin releasing hormone (Dex-CRH)-test. Methods: 17 alcoholic subjects were tested one week after withdrawal signs had disappeared. In 8 patients (mean + SD age, 48.5 + 12.7), 1992 mg/d of acamprosate was administered orally and a second Dex-CRH test was performed one week later. In the other 9 patients (age 47.8 -+7.1), acamprosate was administered only after the second test. For DexCRH testing, 1.5 mg Dex was administered orally at 11 p.m., followed by 100 ktg hCRH i.v. at 3.00 p.m. the next day. Plasma ACTH and Cortisol was determined at 0, 30, 45, 60 and 75 minutes after CRH. Unstimulated hormone levels and gross and net area under the secretion curve (AUC) after CRH were compared to that of 17 healthy subjects matched for age and sex. Statistical testing was done employing the Wilcoxon and the Mann-Whitney-U-test. Results: Patients before treatment exhibited higher unstimulated cortisol levels compared to healthy controls (mean + SD, 25.8 5:17.7 vs. 8.5 + 5.0 ng/ml, p < 0.001). One week later, unstimulated cortisol was still elevated in both treated (24.5 + 8.6 vs. 9.4 + 6.5 ng/ml, p < 0.01) and untreated patients (14.9 + 8.2 vs. 7.6 + 3.4 ng/ml, p < 0.05). Compared to before treatment, there was a trend for decreased net cortisol AUC (2207 + 2580 vs. 996 -4- 2430 ng.min/ml, p < 0.069) after one week of acamprosate, and the ratio of gross cortisol to gross ACTH AUC (4.5 + 2.2 vs. 3.3 4- 1.9 ng/pg, p < 0.05) was reduced. In the patients left without medication during the week between the tests, these parameters did not change (net cortisol AUC, 1197 + 1766 vs. 1343 4- 2244 ng.min/ml and ratio of cortisol to ACTH AUC, 2.7 4- 1.3 vs. 2.6 4- 2.0 ng/pg). Conclusions: Employing the combined Dex-CRH-test, we could replicate earlier findings of HPA system dysregulation in recently withdrawn alcoholics. These abnormalities were attenuated to a greater extent after one week of acamprosate treatment than after one week without treatment. However, this effect was small and is possibly attributable to greater initial HPA pathology in the acamprosate group. Therefore, our preliminary results need substantiation by a greater sample size before clear conclusions concerning acamprosate's action on HPA hyperactivity after alcohol withdrawal can be drawn.
References [1] Jezova D, Tokarev D, Rusnak M. Endogenous excitatory amino acids are involved in stress-induced adrenocorticotropin and catecholamine release. Neuroendocrinology 1995; 62:326-332
$336
At the 21 st day, the levels were tended to be low, but that did not reach to statistical significance. In hippocampus, 5-HIAA levels were significantly higher than control at 10th day of ethanol consumption. Increased 5-HIAA level returned to control values at the 21 st day of ethanol consumption. No significant changes were observed in DA, DOPAC and HVA levels of the brain regions during chronic ethanol exposure. Conclusion: Decreased 5-HT levels in cerebral cortex and corpus striatnm at 10th day of ethanol consumption could be have an important role for developing physical dependence to ethanol. At 21 st day of ethanol consumption, lost of these significant changes in brain 5-HT levels may indicate development of tolerance to the effects of ethanol. According to our results, 5-HT, but not DA, clearly seems to play a critical role in brain at 10th and 21 st days of chronic ethanol consumption The data also support the hypothesis that low 5-HT turnover may predispose an individual to consume and/or abuse ethanol. Acknowledgements: This study was supported by TI]BITAK (grant no: SBAG-AYD-107).
References [1] Cloninger,C.R., (1987) Neurogeneticand adaptive mechanisms in alcoholism. Science 236, 41(~416. [2] Uzbay, i.T. Usanmaz, S., Tapanyi~it, E.E., Aynacio~lu, S., Akarsu, E.S. (1998) Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs, et al. (1998) Drug Alcohol Depend. 53, 39-47. [3] Uzbay, i.T. and Kayaalp, S.O. (1995) A modified liquid diet of chronic ethanol administration: Validationby ethanol withdrawal syndrome in rats. Pharmacol. Res. 31, 37-42.
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Novelty seeking predicts relapse in detoxifled male alcohol dependents
H.N. Aschauer 1, K. Meszaros 1, E. Lenzin~er1, K. Hornik 2, T. Fiireder2, U. Willinger 1, G. Fischer 1, G. Sch6nbeck'. The European Fluvoxamine
in Alcoholism Study Group; 1Department of General Psychiatry, Univ. Vienna; 2Institut J~r Statistik und Wahrscheinlichkeitstheorie, Technische Universit~it, Austria Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire (TPQ), which measures the three personality dimensions novelty seeking (NS), harm avoidance (HA) and reward dependence (RD) as introduced by C. R. Cloninger, in a multi-center study (11 centers in United Kingdom, Eire, Switzerland and Austria) with detoxified alcohol dependent patients (N = 521,388 males, 133 females, age between 19 and 72 years, mean age 41.7) with a diagnosis of alcohol dependence according to DSM-III-R. NS refers to a heritable tendency toward exploratory activity and intensive excitement in response to novel, reflcting the activity o f the dopaminergic system. The TPQ was administered to patients at baseline. The study was a placebo-controlled, double blind, prospectively randomized trial with the objective of investigating the efficacy of fluvoxamine in reducing the number of detoxified alcohol dependents relapsing to uncontrolled drinking over a 1-year period. Only patients who never reported relapse and missed no visit (weeks 2, 4, 6, 8, 12, 16, 24, 32, 40 and 52 after baseline) were considered as "non-relapsers". The objective of our presented analysis here was to evaluate a possible predictive value of these three personality dimensions (NS, HA, RD) on relapse to uncontrolled drinking over a one year follow up period (Meszaros et al., Alcoholism Clin. Exp. Res., submitted). A logistic regression analysis showed that NS is a strong predictor for relapse in detoxified male alcoholics (p = 0.0007; p-values adjusted for treatment), but not in females. In both sexes, HA and RD were of no predictive value. However, we found a trend for significance of HA for predicting "early" relapse (4 weeks) in females (p = 0.074). Fluvoxamine was not superior to placebo to prevent relapse to uncontrolled drinking over one year (data not shown in detail). Our results show that TPQ personality traits have direct clinical applications for prediction of relapse in detoxified alcohol
dependents and indicate the necessity of additional therapeutic treatment in risk groups. Acknowledgement: The work was financially supported by Solvay Pharma GmbH.
•
Effect of acamprosats on the hypothalamicpituitary-adrenal (HPA) system in early abstinent alcoholics
U. Zimmermann, W. Hundt, A. Grabner, K. Hahn, E Holsboer. Max-
Planck-Institute of Psychiatry, Kraepelinstr. 10, 80804 Munich, Germany Purpose: Acamprosate decreases relapse rates in alcoholics by approximately 20% within the first year after detoxification. One strongly suspected mechanism of action involves brain-site specific modulation of excitatory NMDA receptor-mediated neurotransmission. NMDA receptor stimulation in rats I as well as alcohol withdrawal in alcohol dependent patients activates the HPA system with abnormally high cortisol secretion in the in the first days of abstinence. We investigated whether acamprosate normalizes HPA hyperactivity in alcoholics within the first 2 weeks after withdrawal, employing the combined dexamethasonecorticotrophin releasing hormone (Dex-CRH)-test. Methods: 17 alcoholic subjects were tested one week after withdrawal signs had disappeared. In 8 patients (mean + SD age, 48.5 + 12.7), 1992 mg/d of acamprosate was administered orally and a second Dex-CRH test was performed one week later. In the other 9 patients (age 47.8 -+7.1), acamprosate was administered only after the second test. For DexCRH testing, 1.5 mg Dex was administered orally at 11 p.m., followed by 100 ktg hCRH i.v. at 3.00 p.m. the next day. Plasma ACTH and Cortisol was determined at 0, 30, 45, 60 and 75 minutes after CRH. Unstimulated hormone levels and gross and net area under the secretion curve (AUC) after CRH were compared to that of 17 healthy subjects matched for age and sex. Statistical testing was done employing the Wilcoxon and the Mann-Whitney-U-test. Results: Patients before treatment exhibited higher unstimulated cortisol levels compared to healthy controls (mean + SD, 25.8 5:17.7 vs. 8.5 + 5.0 ng/ml, p < 0.001). One week later, unstimulated cortisol was still elevated in both treated (24.5 + 8.6 vs. 9.4 + 6.5 ng/ml, p < 0.01) and untreated patients (14.9 + 8.2 vs. 7.6 + 3.4 ng/ml, p < 0.05). Compared to before treatment, there was a trend for decreased net cortisol AUC (2207 + 2580 vs. 996 -4- 2430 ng.min/ml, p < 0.069) after one week of acamprosate, and the ratio of gross cortisol to gross ACTH AUC (4.5 + 2.2 vs. 3.3 4- 1.9 ng/pg, p < 0.05) was reduced. In the patients left without medication during the week between the tests, these parameters did not change (net cortisol AUC, 1197 + 1766 vs. 1343 4- 2244 ng.min/ml and ratio of cortisol to ACTH AUC, 2.7 4- 1.3 vs. 2.6 4- 2.0 ng/pg). Conclusions: Employing the combined Dex-CRH-test, we could replicate earlier findings of HPA system dysregulation in recently withdrawn alcoholics. These abnormalities were attenuated to a greater extent after one week of acamprosate treatment than after one week without treatment. However, this effect was small and is possibly attributable to greater initial HPA pathology in the acamprosate group. Therefore, our preliminary results need substantiation by a greater sample size before clear conclusions concerning acamprosate's action on HPA hyperactivity after alcohol withdrawal can be drawn.
References [1] Jezova D, Tokarev D, Rusnak M. Endogenous excitatory amino acids are involved in stress-induced adrenocorticotropin and catecholamine release. Neuroendocrinology 1995; 62:326-332