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P.2.046 Calcium channel blockade changes the effect of haloperidol on alpha1 adrenergic system responsiveness
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P.2 Psychotic disorders and antipsychotics
striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA which displays higher selectivity for A2A receptors than CGS 21680. The effect of CGS 21680 on Fos-like immunoreactivity in the nucleus accumbens shell and medial striatum was counteracted by the selective A2A antagonist SCH 58261 (5 mg/kg). The results show that stimulation of A2A adenosine receptors induces a pattern of Fos-like immunoreactivity similar to that of atypical neuroleptics and that adenosine A2A receptors participate to the induction of Fos-like-immunoreactivity by clozapine, suggesting a possible therapeutic utilization of selective adenosine A2A agonists.
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Calcium channel blockade changes the effect of haloperidol on alpha1 adrenergic system responsiveness
I. Nalepa, G. Kreiner, M. Kowalska. Institute of Pharmacology, Polish Academy of Sciences, 12 Smcma Str., 31-343 Kraktw, Poland The therapeutic action of haloperidol (HAL) and other antipsychotic drugs are believed to be linked predominantly with their acute effect on dopamine D2 receptors that are negatively coupled to adenyl cyclase and cyclic AMP generation. However, the effects of neuroleptics on second messenger systems may be due to their interaction with other than dopamine receptors, while the stimulation of these receptors leads also indirectly to a decrease in intracellular calcium levels and phosphoinositide turnover. It has been reported that a blockade of voltage-dependent Ca 2+ channels by nifedipine (NIF) affects the action of several psychotropic drugs given chronically. Noradrenaline (NA), activating the ~l-adrenoceptors (cq-AR) promotes a hydrolysis of phosphoinositides that is followed by the formation of inositol trisphosphate and diacylglycerol, that releases calcium from the intracellular stores and activates protein kinase C (PKC), respectively. The stimulation of the fl-adrenergic receptor (~-AR) with NA activates adenyl cyclase and increases cyclic AMP generation. The aim of our study was to assess how acute and chronic treatments with HAL given under the conditions of NIF influence the ~I-AR and/5-AR responsiveness in the rat brain cortex. Male Wistar rats were divided into four groups and treated daily for 14 days with saline, NIF (5 mg/kg i.p.), HAL (0.5 mg/kg i.p.) or combination of the neuroleptic and NIF, in which HAL was given 15 min after the injection with NIE The animals were decapitated after 24 h or 2 h ~Yom the last injection, for chronic and acute experiments, respectively. The cortical slices were stimulated with NA (100/~M) to induce inositol phosphate (IP) formation and with NA (100 # M ) or isoproterenol (10 /zM) for cyclic AMP generation. Neither acute nor chronic treatment with NIF changed the adrenergic receptors responsiveness to their agonists. HAL, given acutely significantly enhanced the IP response to NA (5.71 ± 0.77 vs. saline 3.97 ± 0.3), while the pretreatment with NIF counteracted that effect (4.32 ± 0.55 vs. HAL 5.17 ± 0.77). In the contrary, chronic treatment with HAL did not induce any changes in the IP response to NA. However, under the conditions of a calcium channel blockade with NIF, HAL increased the IP accumulation compared to saline control (5.49 ± 0.5 and 4.64 ± 0.34, respectively). The fl AR response stimulated with either NA or ISO was not affected by any treatment. Our results indicate that the presence of NIF can modulate the effects of HAL on the ~el-AR responsiveness. However, several subtypes of otl-AR have been cloned. Among them the cq~ type is known to be responsible for the phosphoinositides hydrolysis and PKC activation while the ~IA, through G protein, may affect L-type calcium channel current. The results suggest that in the presence of a calcium channel blockade chronic treatment with HAL may modulate the possible functional relationship between two subtypes of cq-AR that occurs at the second messenger level.
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5HT2A and DRD4 molecular genotypes in a clinical trial of olanzapine versus risperidone in schizophrenic patients
H. Nicolini, C. Cruz, B. Camarena, H. Ortega. Departamento de
Gen(tica Psiquidtrica Divisidn de Investigaciones Clim!cas, lnstituto Mexicano de Psiquiatr(a, Calzada Mdxico-Xochimilco 101, san Lorenzo Huipulco M(xico D.E 14370, Mexico The description of polymorphisms present in candidate genes from neurobiological systems allow their use as molecular tools in many psychiatric disorders. Recent studies with molecular markers of several of the serotonin and dopamine receptor human genes, relevant to schizophrenia, have shown some interesting results. An European muhicentre study showed a positive association between the disease and the 5HT2A receptor gene I . Additionally, there are reports that show a relationship between clinical response to clozapine and the silent mutation (102T/C) within the coding region of the 5HT2a receptor gene2. Although, other groups have not replicated these results3. This failure for replication h~ts been attributed to sample differences or to differences in psychiatric rating scales. In this study we evaluated molecular variants of the 5HT2a and DRD4 receptor genes in 32 Mexican schizophrenic patients, participants of a clinical trial of efficacy and safety of the "atypical" neuroleptic olam,apine. Methods: All patients were recruited from the Mexican Institute of Psychiatry in Mexico City. Patients who met DSMIV criteria for schizophrenia were included, and randomly assorted to olanzapine or risperidone treatment for 6 weeks. Additional patient ev~Lluationconsisted of CGI, PANSS and DiMascio scales. After informed written consent, venous blood samples were collected and DNA was extracted. The 5HT2a/MspI TI02C polymorphism and the 48-base pair repeat region of DRD4 gene were analyzed after PCR amplification. Clinical variables were compared among patients depending upon their molecular genttype. Allele or genotype frequencies were analyzed as 2 × 2 or 2 × 3 contingency tables using chi-square statistics. A two tailed t-test was used to compared clinical scores and genotypes. Results: There were no differences in age. gender and clinical severity between groups of drug comparison. Clinical improvement or the presence of extrapyramidal symptoms after 6 weeks of treatment were similar among patients regardless drug treatment. However, the two patients with molecular genotype DRD4-77 showed a higher delta of response in PANSS (75%) compared with those individuals bearing: 44 (54%) or 47 (49%) genotypes. Conclusion: The use of molecular genotypes of psychiatric drugs action sites could be a helpful clinical guidance in predicting patient response.
References [1] J Williams et al Lancet 347, 1294-1296, 1996. [2] M Arranz et al., Lancet 346, 281-282, 1995 [3] AK Malhotra et al., Lancet 347, 1830. 1996
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Clozapine and suicide: A case report
N. Ozpoyraz, L. Tamam, M.L. Soylu, M. 0"nat. ~ukurova University,
Faculty of Medicine, Department of Psychiatr3; Adana, 01330, Turkey Introduction: Suicidal ideation, suicide plans, attempted and completed suicide occur frequently in patients with schizophrenia. The suicide rate among schizophrenic patients is more than 20 times higher than that in the general population. About 50 percent of all schizc,phrenic patients attempt suicide, and 10 to 15 percent of schizophrenic patients die by suicide. Clozapine is an atypical antipsychotic drug in the treatment of schizophrenic patients who are resistant or intolerant to conventional anlipsychotics. Additional to its other unique features, clozapine decreases suicidiality in neuroleptic-resistant patients (Meltzer and Okayli 1995). In this case report, a schizophrenic patient who had committed suicide during clozapine treatment is presented. Case Report: IY 36-year-old, male, officer, a college graduate. He has been followed with a psychiatric diagnosis of "'chronic paranoid schizophrenia" for 15 years. He has been on regular treatment of various conventional antipsychotic drugs during this period. No suicidal attempts, plans or ideation has been defined in his psychiatric history.
P.2 Psychotic disorders and antipsychotics
striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA which displays higher selectivity for A2A receptors than CGS 21680. The effect of CGS 21680 on Fos-like immunoreactivity in the nucleus accumbens shell and medial striatum was counteracted by the selective A2A antagonist SCH 58261 (5 mg/kg). The results show that stimulation of A2A adenosine receptors induces a pattern of Fos-like immunoreactivity similar to that of atypical neuroleptics and that adenosine A2A receptors participate to the induction of Fos-like-immunoreactivity by clozapine, suggesting a possible therapeutic utilization of selective adenosine A2A agonists.
•
Calcium channel blockade changes the effect of haloperidol on alpha1 adrenergic system responsiveness
I. Nalepa, G. Kreiner, M. Kowalska. Institute of Pharmacology, Polish Academy of Sciences, 12 Smcma Str., 31-343 Kraktw, Poland The therapeutic action of haloperidol (HAL) and other antipsychotic drugs are believed to be linked predominantly with their acute effect on dopamine D2 receptors that are negatively coupled to adenyl cyclase and cyclic AMP generation. However, the effects of neuroleptics on second messenger systems may be due to their interaction with other than dopamine receptors, while the stimulation of these receptors leads also indirectly to a decrease in intracellular calcium levels and phosphoinositide turnover. It has been reported that a blockade of voltage-dependent Ca 2+ channels by nifedipine (NIF) affects the action of several psychotropic drugs given chronically. Noradrenaline (NA), activating the ~l-adrenoceptors (cq-AR) promotes a hydrolysis of phosphoinositides that is followed by the formation of inositol trisphosphate and diacylglycerol, that releases calcium from the intracellular stores and activates protein kinase C (PKC), respectively. The stimulation of the fl-adrenergic receptor (~-AR) with NA activates adenyl cyclase and increases cyclic AMP generation. The aim of our study was to assess how acute and chronic treatments with HAL given under the conditions of NIF influence the ~I-AR and/5-AR responsiveness in the rat brain cortex. Male Wistar rats were divided into four groups and treated daily for 14 days with saline, NIF (5 mg/kg i.p.), HAL (0.5 mg/kg i.p.) or combination of the neuroleptic and NIF, in which HAL was given 15 min after the injection with NIE The animals were decapitated after 24 h or 2 h ~Yom the last injection, for chronic and acute experiments, respectively. The cortical slices were stimulated with NA (100/~M) to induce inositol phosphate (IP) formation and with NA (100 # M ) or isoproterenol (10 /zM) for cyclic AMP generation. Neither acute nor chronic treatment with NIF changed the adrenergic receptors responsiveness to their agonists. HAL, given acutely significantly enhanced the IP response to NA (5.71 ± 0.77 vs. saline 3.97 ± 0.3), while the pretreatment with NIF counteracted that effect (4.32 ± 0.55 vs. HAL 5.17 ± 0.77). In the contrary, chronic treatment with HAL did not induce any changes in the IP response to NA. However, under the conditions of a calcium channel blockade with NIF, HAL increased the IP accumulation compared to saline control (5.49 ± 0.5 and 4.64 ± 0.34, respectively). The fl AR response stimulated with either NA or ISO was not affected by any treatment. Our results indicate that the presence of NIF can modulate the effects of HAL on the ~el-AR responsiveness. However, several subtypes of otl-AR have been cloned. Among them the cq~ type is known to be responsible for the phosphoinositides hydrolysis and PKC activation while the ~IA, through G protein, may affect L-type calcium channel current. The results suggest that in the presence of a calcium channel blockade chronic treatment with HAL may modulate the possible functional relationship between two subtypes of cq-AR that occurs at the second messenger level.
•
5HT2A and DRD4 molecular genotypes in a clinical trial of olanzapine versus risperidone in schizophrenic patients
H. Nicolini, C. Cruz, B. Camarena, H. Ortega. Departamento de
Gen(tica Psiquidtrica Divisidn de Investigaciones Clim!cas, lnstituto Mexicano de Psiquiatr(a, Calzada Mdxico-Xochimilco 101, san Lorenzo Huipulco M(xico D.E 14370, Mexico The description of polymorphisms present in candidate genes from neurobiological systems allow their use as molecular tools in many psychiatric disorders. Recent studies with molecular markers of several of the serotonin and dopamine receptor human genes, relevant to schizophrenia, have shown some interesting results. An European muhicentre study showed a positive association between the disease and the 5HT2A receptor gene I . Additionally, there are reports that show a relationship between clinical response to clozapine and the silent mutation (102T/C) within the coding region of the 5HT2a receptor gene2. Although, other groups have not replicated these results3. This failure for replication h~ts been attributed to sample differences or to differences in psychiatric rating scales. In this study we evaluated molecular variants of the 5HT2a and DRD4 receptor genes in 32 Mexican schizophrenic patients, participants of a clinical trial of efficacy and safety of the "atypical" neuroleptic olam,apine. Methods: All patients were recruited from the Mexican Institute of Psychiatry in Mexico City. Patients who met DSMIV criteria for schizophrenia were included, and randomly assorted to olanzapine or risperidone treatment for 6 weeks. Additional patient ev~Lluationconsisted of CGI, PANSS and DiMascio scales. After informed written consent, venous blood samples were collected and DNA was extracted. The 5HT2a/MspI TI02C polymorphism and the 48-base pair repeat region of DRD4 gene were analyzed after PCR amplification. Clinical variables were compared among patients depending upon their molecular genttype. Allele or genotype frequencies were analyzed as 2 × 2 or 2 × 3 contingency tables using chi-square statistics. A two tailed t-test was used to compared clinical scores and genotypes. Results: There were no differences in age. gender and clinical severity between groups of drug comparison. Clinical improvement or the presence of extrapyramidal symptoms after 6 weeks of treatment were similar among patients regardless drug treatment. However, the two patients with molecular genotype DRD4-77 showed a higher delta of response in PANSS (75%) compared with those individuals bearing: 44 (54%) or 47 (49%) genotypes. Conclusion: The use of molecular genotypes of psychiatric drugs action sites could be a helpful clinical guidance in predicting patient response.
References [1] J Williams et al Lancet 347, 1294-1296, 1996. [2] M Arranz et al., Lancet 346, 281-282, 1995 [3] AK Malhotra et al., Lancet 347, 1830. 1996
•
]
Clozapine and suicide: A case report
N. Ozpoyraz, L. Tamam, M.L. Soylu, M. 0"nat. ~ukurova University,
Faculty of Medicine, Department of Psychiatr3; Adana, 01330, Turkey Introduction: Suicidal ideation, suicide plans, attempted and completed suicide occur frequently in patients with schizophrenia. The suicide rate among schizophrenic patients is more than 20 times higher than that in the general population. About 50 percent of all schizc,phrenic patients attempt suicide, and 10 to 15 percent of schizophrenic patients die by suicide. Clozapine is an atypical antipsychotic drug in the treatment of schizophrenic patients who are resistant or intolerant to conventional anlipsychotics. Additional to its other unique features, clozapine decreases suicidiality in neuroleptic-resistant patients (Meltzer and Okayli 1995). In this case report, a schizophrenic patient who had committed suicide during clozapine treatment is presented. Case Report: IY 36-year-old, male, officer, a college graduate. He has been followed with a psychiatric diagnosis of "'chronic paranoid schizophrenia" for 15 years. He has been on regular treatment of various conventional antipsychotic drugs during this period. No suicidal attempts, plans or ideation has been defined in his psychiatric history.