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5-HT1A receptors, alcoholism and suicidal behavior
43
P Poster Presentations tients. Finally, there are few in vivo data concerning the role of hepatic cytochrome P450. such as CYP2D6 and CYP2C I9. in the metabolism of trimipramine. We have developed an enantioselective HPLC method which allows the measurement of the concentrations of the enantiomers of TRI and its metabolites in plasma. It is based on the use of a chiral cyclodextrin column (acetylated I Cyclobond) connected to a sensitive coulometric detector. presently being used to dose plasma TRI from CYP2D6 and CYP2C19 phenotyped patients. As an example, the concentrations of the (L)- and (D)-forms of 2-hydroxy desmethylTRI, 2-hydroxy TRI. desmethylTRI and TRI measured in an extensive metabolizer of debrisoquine patient who received 400 mg of TRI per day for one month were as follows: 82 and 69; 17 and 7; 63 and 100; 153 and 109 ng/ml, respectively. Preliminary results show an enantioseJectivity in the metabolism of TRI, which indicates that the concentrations of the enantiomers should be taken into account when trying to correlate plasma concentrations and clinical outcome.
IP-2-29I
Plasma Alpha-One Acid Glycoprotein (AAG) and Halo-Peridol (H) Concentrations in Schizophrenic Patients B.G. Augustin. M.W.Jann, B.L. Crabtree. W.M. Pitts. J.G. Carter. Mercer Univers ity and University ofMississippi
This study reports the impact of H upon AAG plasma concentrations (Cps) in schizophrenic patients. AAG Cps were previously reported to be elevated in depressed patients. AAG (mg/dL) and H (ng/ml) Cps were measured in schizophrenic patients over a 6 week time period. Patients were randomly assigned to receive H (N = 18) or placebo (P, N = 18). BPRS assessments and blood samples were obtained at baseline and at weeks 2. 4. and 6. The results and presented below: Mean AAG Cps Group H P
Mean
Baseline 156.2 158.9 H Cps
Week 2
Week 4
Week 6
121.2 131.5
113.8 144.0 12.1
115.0 143.0 12.9
10.8
A gradual and significant (p < 0.05) in AAG Cps were observed with the H group. AAG Cps in the P group did not significantly decrease from baseline to week 6. BPRS scores significantly decreased during H therapy but not with P. Mean HL Cps were within therapeutic range of 10- 12 ng/ml. H binds to AAG where a decrease in AAG Cps over time could result in the increased availability of unbound H. Elevated AAG Cps could partially explain the higher drug doses needed sometimes in the initial treatment phase of acute psychosis.
IP-3 -1 I An Association Study between the ADH2 Gene, the ALDH2 Gene and Alcoholism
Y. Kono, H. Yoneda, H. Imamichi I. T. Sakai. A. Uchida 2, K. Suzuki 2, Y. Mizoi 2. Dept. Neuropsychiatry, Osaka Med. Coil.. Takatsuki, Osaka, Japan; 2 Dept. Legal Medicine, Osaka Med. Coll., Takatsuki, Osaka. Japan ; 1 Sin-abuyama Hospital, Takatsuki, Osaka, Japan
Human alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, show polymorphisms. We examined the allelic association of the ADH2 gene and ALDH2 gene with alcoholism in 99 unrelated Japanese alcoholics and 157 unrelated controls. Diagnosis was made according to DSM-III-R for alcohol dependence. Genomic DNAs were prepared from peripheral white blood cells using standard method. We investigated ADH2 and ALDH2 polymorphisms by using PCR-RFLP methods. We found an apparent excess of the ADH2 heterozygote in the normal controls when we used primer sets reported by Harada and Xu for PCR-RFLP assay of ADH2 polymorphism. The excess was likely to be ascribed to inevident amplification of other ADH sequences, particularly ADHI and ADH3. Therefore we designed a new pair of primers for amplification of ADH2. The 3' ends of the primers were mismatched with the ADH3 sequence in the upstream and with the ADH] sequence in the downstream. The alcoholics had significantly higher frequencies of ADH2'1 and ALDH2'1 alleles than the controls. These results suggest that genetic variation in both ADH and ALDH, by modulating the rate
of metabolism of ethanol and acetaldehyde. influences drinking behavior and the risk of developing alcoholism.
I P-3- 2IS-HT1A Receptors, Alcoholism and Suicidal Behavior W. Pitchot. M. Ansseau, A. Gonzalez Moreno. M. Hansenne. Psychiatric Unit, CHU du San Tilman. B-4000 Liege, Belgium
Several preclinical evidence support the hypothesis of a serotonergic dysfunction in alcohol preference. In human, some studies have demonstrated a serotonergic hypoactivity in alcoholism. The serotonergic abnormalities observed in alcoholics could be related to impulsive aggressive and suicidal behaviors. In 1989, Coccaro et al. studying the prolactin (PRL) response to fenfluramine reported that the strongest behavioral correlate of a reduced serottonergic function is the dimension of irritable impulsive aggression. However, little is known about the role of 5-HTIA receptors, In the present study. we assessed the hormonal (cortisol. ACTH, growth hormone (GH), PRL) and temperature responses to flesinoxan, a highly potent and selective 5-HT IA agonist, in 10 patients meeting DSM-m-R criteria for alcohol dependence, and subgrouped into suicide attempters (n = 5) and nonattempters (11 = 5). The patients were assessed more than 3 weeks after the last reported use of alcohol. A significant effect of suicide class on delta temperature values was apparent among these patients with a history of alcohol dependence: mean delta temperature values, 0.24 ± 0.16 ' C in alcoholic patients with a history of suicide attempt vs 0.61 ± 0.15 C C ill alcoholics without history of suicidal behavior (F = 13.8, P = 0.006). No significant group differences were observed with regard to cortisol. PRL, GH or ACTH. Hormonal and temperature responses to flesinoxan were not correlated with PFAV or SR scale scores. In conclusion, the results of the present study support the implication of the serotonergic system, and particularly of 5-HTI A receptors, in the control of self-directed aggressive behavior in alcoholism. [I] Coccaro EF, Siever U , Klar HM, Maurer G, Cochran K,Cooper TB. Mohs ac, Davis KL. Arch. Gen. Psychiatry 46 (1989)587-599.
I P-3-3! Risperdal Reduces Alcohol Use in Dual Disabled Schizophrenia Patients C.c. Huang. Dept. of Psych., Med. Col. of WI, Milwaukee, U.S.A.
The dual disabled schizophrenia patient is very difficult to treat because of the complications of alcohol use. Seven schizophrenia patients with alcohol dependency (5 male. 2 female, age 23 to 44) were chosen for this study. Their psychoses were stabilized with ordinary neuroleptics, but they continued having drinking problems. The number of days of alcohol use of each patient in one month was used as a parameter to measure the severity of patient's alcohol use. Every patient was allowed to continue his ordinary neuroleptics throughout the course of study, then Risperdal I mg bid medication was added. 3 month average of the monthly parameters prior to Risperdal was compared with the 3 month average of the monthly parameters after the Risperdal. The results show a statistically significant difference (p = 0.05). The means are 7.25 versus 2.90. The exact reason for improvement is unknown. Dopamine malfunction and Serotonergic dysfunction are linked to alcoholism. Risperdal does act on both dopamine D2 and Serotonin 5-HT2 receptors and might have anti-alcoholism effect 3 patients said Risperdal interfered with their drinking. One patient said Risperdal reduced his anxiety. I P-3-4 1
Acamprosate in the Relapse Prevention of Alcohol Dependence
A.B. Whitworth, w.w. Fleischhacker. Dept. ofBiological Psychiatry, lnn sbruck, Austria
The efficacy and tolerance of acamprosate to maintain abstinence was examined in a multicenter double-blind placebo-controlled study of 448 alcohol dependent patients. The treatment lasted for I year after alcohol withdrawal. Patients were followed-up for an additional year. All efficacy analyses were carried OUI on an intention-to-treat basis. In a survival analysis, acamprosate with a one-year rate of 18.3% was significantly better (p = 0.07) than placebo (7.1%). Several other approaches to
P Poster Presentations tients. Finally, there are few in vivo data concerning the role of hepatic cytochrome P450. such as CYP2D6 and CYP2C I9. in the metabolism of trimipramine. We have developed an enantioselective HPLC method which allows the measurement of the concentrations of the enantiomers of TRI and its metabolites in plasma. It is based on the use of a chiral cyclodextrin column (acetylated I Cyclobond) connected to a sensitive coulometric detector. presently being used to dose plasma TRI from CYP2D6 and CYP2C19 phenotyped patients. As an example, the concentrations of the (L)- and (D)-forms of 2-hydroxy desmethylTRI, 2-hydroxy TRI. desmethylTRI and TRI measured in an extensive metabolizer of debrisoquine patient who received 400 mg of TRI per day for one month were as follows: 82 and 69; 17 and 7; 63 and 100; 153 and 109 ng/ml, respectively. Preliminary results show an enantioseJectivity in the metabolism of TRI, which indicates that the concentrations of the enantiomers should be taken into account when trying to correlate plasma concentrations and clinical outcome.
IP-2-29I
Plasma Alpha-One Acid Glycoprotein (AAG) and Halo-Peridol (H) Concentrations in Schizophrenic Patients B.G. Augustin. M.W.Jann, B.L. Crabtree. W.M. Pitts. J.G. Carter. Mercer Univers ity and University ofMississippi
This study reports the impact of H upon AAG plasma concentrations (Cps) in schizophrenic patients. AAG Cps were previously reported to be elevated in depressed patients. AAG (mg/dL) and H (ng/ml) Cps were measured in schizophrenic patients over a 6 week time period. Patients were randomly assigned to receive H (N = 18) or placebo (P, N = 18). BPRS assessments and blood samples were obtained at baseline and at weeks 2. 4. and 6. The results and presented below: Mean AAG Cps Group H P
Mean
Baseline 156.2 158.9 H Cps
Week 2
Week 4
Week 6
121.2 131.5
113.8 144.0 12.1
115.0 143.0 12.9
10.8
A gradual and significant (p < 0.05) in AAG Cps were observed with the H group. AAG Cps in the P group did not significantly decrease from baseline to week 6. BPRS scores significantly decreased during H therapy but not with P. Mean HL Cps were within therapeutic range of 10- 12 ng/ml. H binds to AAG where a decrease in AAG Cps over time could result in the increased availability of unbound H. Elevated AAG Cps could partially explain the higher drug doses needed sometimes in the initial treatment phase of acute psychosis.
IP-3 -1 I An Association Study between the ADH2 Gene, the ALDH2 Gene and Alcoholism
Y. Kono, H. Yoneda, H. Imamichi I. T. Sakai. A. Uchida 2, K. Suzuki 2, Y. Mizoi 2. Dept. Neuropsychiatry, Osaka Med. Coil.. Takatsuki, Osaka, Japan; 2 Dept. Legal Medicine, Osaka Med. Coll., Takatsuki, Osaka. Japan ; 1 Sin-abuyama Hospital, Takatsuki, Osaka, Japan
Human alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, show polymorphisms. We examined the allelic association of the ADH2 gene and ALDH2 gene with alcoholism in 99 unrelated Japanese alcoholics and 157 unrelated controls. Diagnosis was made according to DSM-III-R for alcohol dependence. Genomic DNAs were prepared from peripheral white blood cells using standard method. We investigated ADH2 and ALDH2 polymorphisms by using PCR-RFLP methods. We found an apparent excess of the ADH2 heterozygote in the normal controls when we used primer sets reported by Harada and Xu for PCR-RFLP assay of ADH2 polymorphism. The excess was likely to be ascribed to inevident amplification of other ADH sequences, particularly ADHI and ADH3. Therefore we designed a new pair of primers for amplification of ADH2. The 3' ends of the primers were mismatched with the ADH3 sequence in the upstream and with the ADH] sequence in the downstream. The alcoholics had significantly higher frequencies of ADH2'1 and ALDH2'1 alleles than the controls. These results suggest that genetic variation in both ADH and ALDH, by modulating the rate
of metabolism of ethanol and acetaldehyde. influences drinking behavior and the risk of developing alcoholism.
I P-3- 2IS-HT1A Receptors, Alcoholism and Suicidal Behavior W. Pitchot. M. Ansseau, A. Gonzalez Moreno. M. Hansenne. Psychiatric Unit, CHU du San Tilman. B-4000 Liege, Belgium
Several preclinical evidence support the hypothesis of a serotonergic dysfunction in alcohol preference. In human, some studies have demonstrated a serotonergic hypoactivity in alcoholism. The serotonergic abnormalities observed in alcoholics could be related to impulsive aggressive and suicidal behaviors. In 1989, Coccaro et al. studying the prolactin (PRL) response to fenfluramine reported that the strongest behavioral correlate of a reduced serottonergic function is the dimension of irritable impulsive aggression. However, little is known about the role of 5-HTIA receptors, In the present study. we assessed the hormonal (cortisol. ACTH, growth hormone (GH), PRL) and temperature responses to flesinoxan, a highly potent and selective 5-HT IA agonist, in 10 patients meeting DSM-m-R criteria for alcohol dependence, and subgrouped into suicide attempters (n = 5) and nonattempters (11 = 5). The patients were assessed more than 3 weeks after the last reported use of alcohol. A significant effect of suicide class on delta temperature values was apparent among these patients with a history of alcohol dependence: mean delta temperature values, 0.24 ± 0.16 ' C in alcoholic patients with a history of suicide attempt vs 0.61 ± 0.15 C C ill alcoholics without history of suicidal behavior (F = 13.8, P = 0.006). No significant group differences were observed with regard to cortisol. PRL, GH or ACTH. Hormonal and temperature responses to flesinoxan were not correlated with PFAV or SR scale scores. In conclusion, the results of the present study support the implication of the serotonergic system, and particularly of 5-HTI A receptors, in the control of self-directed aggressive behavior in alcoholism. [I] Coccaro EF, Siever U , Klar HM, Maurer G, Cochran K,Cooper TB. Mohs ac, Davis KL. Arch. Gen. Psychiatry 46 (1989)587-599.
I P-3-3! Risperdal Reduces Alcohol Use in Dual Disabled Schizophrenia Patients C.c. Huang. Dept. of Psych., Med. Col. of WI, Milwaukee, U.S.A.
The dual disabled schizophrenia patient is very difficult to treat because of the complications of alcohol use. Seven schizophrenia patients with alcohol dependency (5 male. 2 female, age 23 to 44) were chosen for this study. Their psychoses were stabilized with ordinary neuroleptics, but they continued having drinking problems. The number of days of alcohol use of each patient in one month was used as a parameter to measure the severity of patient's alcohol use. Every patient was allowed to continue his ordinary neuroleptics throughout the course of study, then Risperdal I mg bid medication was added. 3 month average of the monthly parameters prior to Risperdal was compared with the 3 month average of the monthly parameters after the Risperdal. The results show a statistically significant difference (p = 0.05). The means are 7.25 versus 2.90. The exact reason for improvement is unknown. Dopamine malfunction and Serotonergic dysfunction are linked to alcoholism. Risperdal does act on both dopamine D2 and Serotonin 5-HT2 receptors and might have anti-alcoholism effect 3 patients said Risperdal interfered with their drinking. One patient said Risperdal reduced his anxiety. I P-3-4 1
Acamprosate in the Relapse Prevention of Alcohol Dependence
A.B. Whitworth, w.w. Fleischhacker. Dept. ofBiological Psychiatry, lnn sbruck, Austria
The efficacy and tolerance of acamprosate to maintain abstinence was examined in a multicenter double-blind placebo-controlled study of 448 alcohol dependent patients. The treatment lasted for I year after alcohol withdrawal. Patients were followed-up for an additional year. All efficacy analyses were carried OUI on an intention-to-treat basis. In a survival analysis, acamprosate with a one-year rate of 18.3% was significantly better (p = 0.07) than placebo (7.1%). Several other approaches to