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Exacerbation risk following withdrawal of oral and depot neuroleptic treatment of psychotic patients
169
tion and hypometabolism have been reported in schizophrenic patients. Therefore, this region might be considered a major therapeutic target in treating schizophrenia. Using in vitro receptor autoradiography, we examined changes in dopamine D2-1ike receptor binding in medial prefrontal cortex and other brain regions following 8 months treatment of rats with a typical neuroleptic, haloperidol (1.5mg/kg/day) or two atypical neuroleptics, raclopride (10 mg/kg/day) and clozapine (25 mg/kg/day), using 125I-sulpiride (a dopamine D2 receptor family ligand). Haloperidol treatment significantly increased 125I-sulpiride binding in medial prefrontal cortex [+35%] and caudate putamen [+42%]. Raclopride treatment also elevated ~/51-sulpiride binding in medial prefrontal cortex [+ 33%] and caudate putamen [+ 35%]. Interestingly, chronic clozapine treatment significantly increased ~25I-sulpiride binding in medial prefrontal cortex [+ 24%] only. This suggests that upregulation of dopamine D 2like receptors in the medial prefrontal cortex may be important for mediating some of the antipsychotic effects of typical and atypical neuroleptics. Results using other dopamine receptor radioligands will be reported.
OLANZAPINE: A PROMISING ANTIPSYCHOTIC AGENT
"ATYPICAL"
P.V. Tran*, C.M. Beasley, G.D. Tollefson, J.N. Beuzen, S.L. Holman, T.M. Sanger, W.G. Satterlee Eli Lilly and Company, Lilly Corporate Center, DC 2128. Indianapolis, IN 46285, USA Olanzapine, structurally a thienobenzodiazepine, is a putative "atypical" antipsychotic agent. In vitro studies have indicated that olanzapine has high affinity for 5-HTzA, 5-HT2c, Dz, D1, muscarinic (particularly M1), cq, and H1 receptors. In vivo binding studies, neuroendocrine studies (ratio of blockade of quipazine-stimulated serum corticosterone elevation to blockade of pergolide-stimulated serum corticosterone elevation), and behavioral studies (ratio of blockade of 5-HTP-induced head twitch to blockade of apomorphine-induced climbing behavior) all suggest greater in vivo antagonism of 5-HT, compared to dopamine receptors. Olanzapine selectively diminishes the spontaneous firing rate of Ax0 dopaminergic neurons without decreasing the rate of A 9 n e u r o n s on chronic administration. Olanzapine inhibits avoiding in a conditionedavoidance paradigm but induces catalepsy only at 4-fold higher doses, suggesting antipsychotic activity and low potential for extrapyramidal symptoms. Additionally, unlike typical antipsychotics, olanzapine increases responding during the punished responding component of a conflict test in a way similar to clozapine and substitutes for clozapine in a drug discrimination test. The acute phase (6 weeks) of a large (n=335) double-blind, olanzapine, placebo and haloperidol trial with schizophrenic inpatients in the United States and Canada has recently been completed. The results have been reported elsewhere. The acute phase (6 weeks) of a second large (n=431) double-blind, olanzapine, and haloperidol trial with schizophrenia inpatients
conducted in Europe, Israel, South Africa, and Australia has more recently been completed. Results of this trial will be reported in detail.
EXACERBATION RISK FOLLOWING WITHDRAWAL OF ORAL AND DEPOT NEUROLEPTIC TREATMENT OF PSYCHOTIC PATIENTS Adele C. Viguera*, Ross J. Baldessarini, Daniel P. van K a m m e n McLean Hospital, South Belknap III, 115 Mill Street, Belmont, MA 02178, USA Recurrences in psychotic and major mood disorders are common; while benefits of maintenance treatment are substantial, the significance of interrupting such therapies is not as clear. Our objective was to define risks-over-time of major exacerbation in chronic idiopathic psychotic disorders following abrupt discontinuation of ongoing maintenance neuroleptic treatment in comparison with previously determined risks after stopping lithium in manic-depressive disorders. We searched for studies involving abrupt discontinuation of long-term oral maintenance treatment in schizophrenia that provide data on individual-time-to-recurrence. Survival analysis and curve-fitting were used to compute time-to-50% recurrence (ET5o_+ SEM; median "survival" time). Data concerning 984 subjects withdrawn from oral neuroleptics were compared with 83 stopping depot neuroleptics and 101 bipolar patients withdrawn from lithium. ETso___SE was 4.0_+0.1 (oral), 6.7_+0.3 (depot), and 3.2_+0.2 months (lithium), and 12-month risks for "relapse" were 83%, 59%, and 78%, respectively (oral neuroleptic differed significantly from depot, but not lithium). Risk of psychotic exacerbation is high within the first several months of discontinuing oral neuroleptics, reduced or delayed after long-acting neuroleptics, and similar to that following lithium in bipolar disorder, in which an iatrogenicpharmacodynamic contribution is strongly suspected. The risk rates computed may be informative for the design and interpretation of research protocols as well as in clinical treatment and counseling.
PRELIMINARY DATA ON PATIENTS SUFFERING FROM FIRST EPISODE OF PSYCHOSIS J. Wong*, G. Bean, M. Beiser Clarke Institute of Psychiatry, University of Toronto, 250 College St., Toronto, Ontario M5T I R8, Canada Despite years of research and clinical experience, definite dose-response curves for antipsychotic medication have not been well established. Previous studies comparing high-dose
tion and hypometabolism have been reported in schizophrenic patients. Therefore, this region might be considered a major therapeutic target in treating schizophrenia. Using in vitro receptor autoradiography, we examined changes in dopamine D2-1ike receptor binding in medial prefrontal cortex and other brain regions following 8 months treatment of rats with a typical neuroleptic, haloperidol (1.5mg/kg/day) or two atypical neuroleptics, raclopride (10 mg/kg/day) and clozapine (25 mg/kg/day), using 125I-sulpiride (a dopamine D2 receptor family ligand). Haloperidol treatment significantly increased 125I-sulpiride binding in medial prefrontal cortex [+35%] and caudate putamen [+42%]. Raclopride treatment also elevated ~/51-sulpiride binding in medial prefrontal cortex [+ 33%] and caudate putamen [+ 35%]. Interestingly, chronic clozapine treatment significantly increased ~25I-sulpiride binding in medial prefrontal cortex [+ 24%] only. This suggests that upregulation of dopamine D 2like receptors in the medial prefrontal cortex may be important for mediating some of the antipsychotic effects of typical and atypical neuroleptics. Results using other dopamine receptor radioligands will be reported.
OLANZAPINE: A PROMISING ANTIPSYCHOTIC AGENT
"ATYPICAL"
P.V. Tran*, C.M. Beasley, G.D. Tollefson, J.N. Beuzen, S.L. Holman, T.M. Sanger, W.G. Satterlee Eli Lilly and Company, Lilly Corporate Center, DC 2128. Indianapolis, IN 46285, USA Olanzapine, structurally a thienobenzodiazepine, is a putative "atypical" antipsychotic agent. In vitro studies have indicated that olanzapine has high affinity for 5-HTzA, 5-HT2c, Dz, D1, muscarinic (particularly M1), cq, and H1 receptors. In vivo binding studies, neuroendocrine studies (ratio of blockade of quipazine-stimulated serum corticosterone elevation to blockade of pergolide-stimulated serum corticosterone elevation), and behavioral studies (ratio of blockade of 5-HTP-induced head twitch to blockade of apomorphine-induced climbing behavior) all suggest greater in vivo antagonism of 5-HT, compared to dopamine receptors. Olanzapine selectively diminishes the spontaneous firing rate of Ax0 dopaminergic neurons without decreasing the rate of A 9 n e u r o n s on chronic administration. Olanzapine inhibits avoiding in a conditionedavoidance paradigm but induces catalepsy only at 4-fold higher doses, suggesting antipsychotic activity and low potential for extrapyramidal symptoms. Additionally, unlike typical antipsychotics, olanzapine increases responding during the punished responding component of a conflict test in a way similar to clozapine and substitutes for clozapine in a drug discrimination test. The acute phase (6 weeks) of a large (n=335) double-blind, olanzapine, placebo and haloperidol trial with schizophrenic inpatients in the United States and Canada has recently been completed. The results have been reported elsewhere. The acute phase (6 weeks) of a second large (n=431) double-blind, olanzapine, and haloperidol trial with schizophrenia inpatients
conducted in Europe, Israel, South Africa, and Australia has more recently been completed. Results of this trial will be reported in detail.
EXACERBATION RISK FOLLOWING WITHDRAWAL OF ORAL AND DEPOT NEUROLEPTIC TREATMENT OF PSYCHOTIC PATIENTS Adele C. Viguera*, Ross J. Baldessarini, Daniel P. van K a m m e n McLean Hospital, South Belknap III, 115 Mill Street, Belmont, MA 02178, USA Recurrences in psychotic and major mood disorders are common; while benefits of maintenance treatment are substantial, the significance of interrupting such therapies is not as clear. Our objective was to define risks-over-time of major exacerbation in chronic idiopathic psychotic disorders following abrupt discontinuation of ongoing maintenance neuroleptic treatment in comparison with previously determined risks after stopping lithium in manic-depressive disorders. We searched for studies involving abrupt discontinuation of long-term oral maintenance treatment in schizophrenia that provide data on individual-time-to-recurrence. Survival analysis and curve-fitting were used to compute time-to-50% recurrence (ET5o_+ SEM; median "survival" time). Data concerning 984 subjects withdrawn from oral neuroleptics were compared with 83 stopping depot neuroleptics and 101 bipolar patients withdrawn from lithium. ETso___SE was 4.0_+0.1 (oral), 6.7_+0.3 (depot), and 3.2_+0.2 months (lithium), and 12-month risks for "relapse" were 83%, 59%, and 78%, respectively (oral neuroleptic differed significantly from depot, but not lithium). Risk of psychotic exacerbation is high within the first several months of discontinuing oral neuroleptics, reduced or delayed after long-acting neuroleptics, and similar to that following lithium in bipolar disorder, in which an iatrogenicpharmacodynamic contribution is strongly suspected. The risk rates computed may be informative for the design and interpretation of research protocols as well as in clinical treatment and counseling.
PRELIMINARY DATA ON PATIENTS SUFFERING FROM FIRST EPISODE OF PSYCHOSIS J. Wong*, G. Bean, M. Beiser Clarke Institute of Psychiatry, University of Toronto, 250 College St., Toronto, Ontario M5T I R8, Canada Despite years of research and clinical experience, definite dose-response curves for antipsychotic medication have not been well established. Previous studies comparing high-dose