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Olanzapine, a novel atypical antipsychotic, has electrophysiological effects on A9 and A10 dopamine cells similar to clozapine
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Variant forms have differing affinities for the antipsychotic drug clozapine. However, allelic association analyses of the 48 bp repeat and response to clozapine have failed to demonstrate an effect of genotype or response. Simple analysis of these repeat numbers may not be sufficient to tease out relationships with response. The examination of the haplotypes of other polymorphisms within DRD4 may allow detection of effects caused by complex variation in the 48 bp repeats. Three additional polymorphic sites have been found within the DRD4: a mononucleotide repeat within the intron 1, Sinai RFLP and a 12 bp repeat. Kennedy et al. (1994) examined the combination of all four sites in clozapine treated schizophrenic patients and reported that this analysis produces an ability to predict response in 70% of cases. We have studied all four polymorphic sites in 146 European schizophrenic patients treated with clozapine and tested association between these alleles with response to clozapine using the difference in pre- and posttreatment gas scores as a continuous measure of response. We have found no significant association when using a combination of all four polymorphisms, although weak association is detected with one allelic form of the mononucleotide repeat.
OLANZAPINE, A NOVEL ATYPICAL ANTIPSYCHOTIC, HAS ELECTROPHYSIOLOGICAL EFFECTS ON A9 AND A10 DOPAMINE CELLS SIMILAR TO CLOZAPINE Marsha E. Stockton*, Kurt Rasmussen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN46285, USA Chronic administration of classical antipsychotics decreases the number of spontaneously active substantia nigra (A9) and ventral tegmental area (A10) dopamine cells, while chronic administration of atypical antipsychotics (e.g., clozapine) decreases only the number of spontaneously active A10 cells. The effects of antipsychotics on A9 cells may underlie their motor side-effects, while their effects on A10 ceils may underlie their therapeutic action. We examined the effects of olanzapine on the electrophysiological properties of A9 and A 10 dopamine cells in rats. Acute administration of olanzapine (10 and 20 mg/kg) increased the number of spontaneously active A10, but not A9, cells. Similar to clozapine, chronic administration of olanzapine (10 and 20 mg/kg/day x 21 days), decreased the number of spontaneously active A10, but not A9, cells. Administration of the dopamine agonist apomorphine reversed the effects of chronic olanzapine on A10 dopamine cells, indicating that the inhibition of A10 cells may be mediated through depolarization inactivation. Additionally, olanzapine, like clozapine, differentially reversed the inhibitory effects of d-amphetamine on A10 cells vs A9 cells. In conclusion, olanzapine has selective effects on A10 (vs A9) dopamine cells following acute and chronic administration that are similar to those seen with clozapine.
AGGRESSION DURING DRUG-FREE AND ANTIPSYCHOTIC TREATMENT IN INPATIENTS WITH CHRONIC SCHIZOPHRENIA, USING THE OVERT AGGRESSION SCALE T.-P. Su, J. Tuskan, L. Tsao, D. Pickar
Experimental Therapeutics Branch, NIMH, NIH, Bethesda, MD 20892-1380, USA To investigate the relationship between aggression, clinical symptoms and biological parameters in schizophrenia, a retrospective chart review of 48 inpatients on a research ward was conducted. Overt Aggression Scale (OAS) (Yudofsky, 1986) ratings, BPRS ratings, plasma cholesterol, body weight and CSF monoamine levels were collected during three treatment conditions--placebo, fluphenazine and clozapine. Results include: 25 of 48 patients (52%) exhibited aggressive behavior; there were significant decreases in episodes of aggression between placebo (81 episodes), fluphenazine (19 episodes) and clozapine (3 episodes). OAS scores also declined with clozapine treatment (PBO= 11.2___13.7, FLU = 2.9 + 5.7, CLZ=0.36_+l.0, p<0.01); BPRS thought disorder subscale scores correlated with number of aggressive episodes and higher OAS scores during placebo and fluphenazine condition, however, no correlation existed during clozapine treatment; patients with "high resolution" (episodes > 3 or OAS scores > 10) (n = 13) compared to patients with "low aggression" (n=35) demonstrated younger age, lower body weight and significant increases in CSF 5-HIAA from fluphenazine to placebo. These data identify several predictors of aggression in schizophrenia, indicate that clozapine may have a selective effect on aggression and suggest that aggression in schizophrenia may be mediated by different mechanisms than in other psychiatric disorders.
THE RELATIONSHIP OF TREATMENT RESPONSE TO CHRONICITY OF ILLNESS IN A LONG-TERM PROSPECTIVE STUDY OF SCHIZOPHRENIA S. Szymanski*, T. Cannon, F. Gallacher, K. Martin, D. Shastel, C. Heimberg, B. Turetsky, D. Sandefur, N. McGrady, R.E. Gur
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA Schizophrenia is a clinically heterogenous disorder. The relationship of the stage of illness to treatment outcome is unclear. Consequently, the aim of this study was to examine the impact of neuroleptics on short and long-term symptom change in both neuroleptic-naive and previously medicated patients. DSMIIIR schizophreniform and chronic schizophrenic patients were assessed and treated in an open study for two years with periodic behavioral assessments performed.
Variant forms have differing affinities for the antipsychotic drug clozapine. However, allelic association analyses of the 48 bp repeat and response to clozapine have failed to demonstrate an effect of genotype or response. Simple analysis of these repeat numbers may not be sufficient to tease out relationships with response. The examination of the haplotypes of other polymorphisms within DRD4 may allow detection of effects caused by complex variation in the 48 bp repeats. Three additional polymorphic sites have been found within the DRD4: a mononucleotide repeat within the intron 1, Sinai RFLP and a 12 bp repeat. Kennedy et al. (1994) examined the combination of all four sites in clozapine treated schizophrenic patients and reported that this analysis produces an ability to predict response in 70% of cases. We have studied all four polymorphic sites in 146 European schizophrenic patients treated with clozapine and tested association between these alleles with response to clozapine using the difference in pre- and posttreatment gas scores as a continuous measure of response. We have found no significant association when using a combination of all four polymorphisms, although weak association is detected with one allelic form of the mononucleotide repeat.
OLANZAPINE, A NOVEL ATYPICAL ANTIPSYCHOTIC, HAS ELECTROPHYSIOLOGICAL EFFECTS ON A9 AND A10 DOPAMINE CELLS SIMILAR TO CLOZAPINE Marsha E. Stockton*, Kurt Rasmussen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN46285, USA Chronic administration of classical antipsychotics decreases the number of spontaneously active substantia nigra (A9) and ventral tegmental area (A10) dopamine cells, while chronic administration of atypical antipsychotics (e.g., clozapine) decreases only the number of spontaneously active A10 cells. The effects of antipsychotics on A9 cells may underlie their motor side-effects, while their effects on A10 ceils may underlie their therapeutic action. We examined the effects of olanzapine on the electrophysiological properties of A9 and A 10 dopamine cells in rats. Acute administration of olanzapine (10 and 20 mg/kg) increased the number of spontaneously active A10, but not A9, cells. Similar to clozapine, chronic administration of olanzapine (10 and 20 mg/kg/day x 21 days), decreased the number of spontaneously active A10, but not A9, cells. Administration of the dopamine agonist apomorphine reversed the effects of chronic olanzapine on A10 dopamine cells, indicating that the inhibition of A10 cells may be mediated through depolarization inactivation. Additionally, olanzapine, like clozapine, differentially reversed the inhibitory effects of d-amphetamine on A10 cells vs A9 cells. In conclusion, olanzapine has selective effects on A10 (vs A9) dopamine cells following acute and chronic administration that are similar to those seen with clozapine.
AGGRESSION DURING DRUG-FREE AND ANTIPSYCHOTIC TREATMENT IN INPATIENTS WITH CHRONIC SCHIZOPHRENIA, USING THE OVERT AGGRESSION SCALE T.-P. Su, J. Tuskan, L. Tsao, D. Pickar
Experimental Therapeutics Branch, NIMH, NIH, Bethesda, MD 20892-1380, USA To investigate the relationship between aggression, clinical symptoms and biological parameters in schizophrenia, a retrospective chart review of 48 inpatients on a research ward was conducted. Overt Aggression Scale (OAS) (Yudofsky, 1986) ratings, BPRS ratings, plasma cholesterol, body weight and CSF monoamine levels were collected during three treatment conditions--placebo, fluphenazine and clozapine. Results include: 25 of 48 patients (52%) exhibited aggressive behavior; there were significant decreases in episodes of aggression between placebo (81 episodes), fluphenazine (19 episodes) and clozapine (3 episodes). OAS scores also declined with clozapine treatment (PBO= 11.2___13.7, FLU = 2.9 + 5.7, CLZ=0.36_+l.0, p<0.01); BPRS thought disorder subscale scores correlated with number of aggressive episodes and higher OAS scores during placebo and fluphenazine condition, however, no correlation existed during clozapine treatment; patients with "high resolution" (episodes > 3 or OAS scores > 10) (n = 13) compared to patients with "low aggression" (n=35) demonstrated younger age, lower body weight and significant increases in CSF 5-HIAA from fluphenazine to placebo. These data identify several predictors of aggression in schizophrenia, indicate that clozapine may have a selective effect on aggression and suggest that aggression in schizophrenia may be mediated by different mechanisms than in other psychiatric disorders.
THE RELATIONSHIP OF TREATMENT RESPONSE TO CHRONICITY OF ILLNESS IN A LONG-TERM PROSPECTIVE STUDY OF SCHIZOPHRENIA S. Szymanski*, T. Cannon, F. Gallacher, K. Martin, D. Shastel, C. Heimberg, B. Turetsky, D. Sandefur, N. McGrady, R.E. Gur
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA Schizophrenia is a clinically heterogenous disorder. The relationship of the stage of illness to treatment outcome is unclear. Consequently, the aim of this study was to examine the impact of neuroleptics on short and long-term symptom change in both neuroleptic-naive and previously medicated patients. DSMIIIR schizophreniform and chronic schizophrenic patients were assessed and treated in an open study for two years with periodic behavioral assessments performed.