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Olanzapine: a basic science update

Published online by Cambridge University Press:  06 August 2018

Franklin Bymaster ,
Kenneth W. Perry ,
David L. Nelson ,
David T. Wong ,
Kurt Rasmussen ,
Nick A. Moore  and
David O. Calligaro
Franklin Bymaster*
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
Kenneth W. Perry
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
David L. Nelson
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
David T. Wong
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
Kurt Rasmussen
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
Nick A. Moore
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
David O. Calligaro
Affiliation:
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, IN, USA
*
Correspondence: F. Bymaster, Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285 0510, USA
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Abstract

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype; and α1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5 -HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas ofthe brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 174 , Issue S37: Focus on schizophrenia , February 1999 , pp. 36 - 40
Copyright
Copyright © The Royal College of Psychiatrists, 1999 

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References

Bymaster, F. P., Calligaro, D. O., Marsh, R. D., et al (1996a) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology, 14, 87–96.CrossRefGoogle ScholarPubMed
Bymaster, F. P., Hemrick-Luecke, S. K., Perry, K. W., et al (1996b) Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, 0,-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology, 124, 87–94.CrossRefGoogle Scholar
Bymaster, F. P., Nelson, D. L., DeLapp, N. W., et al (1996c) The atypical antipsychotic olanzapine is an antagonist at dopamine, serotonin and muscarinic receptor subtypes. Schizophrenia Research, 18, 139.CrossRefGoogle Scholar
Bymaster, F. P., Bymaster, L., Bymaster, X.-M., Carter, P. A., et al (1997a) Olanzapine increases extracellular dopamine release and blocks dopamine, serotonin and muscarinic receptors in vivo. Schizophrenia Research, 24, 74.CrossRefGoogle Scholar
Bymaster, F. P., Rasmussen, K., Calligaro, D. O., et al (1997b) In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug. Journal of Clinical Psychiatry, 58 (suppl. 10), 28–36.Google ScholarPubMed
Calligaro, D., Fairhurst, J., Hotten, T. M., et al (1996) The synthesis and biological activity of some known metabolites of the atypical antipsychotic agent olanzapine (LY170053). Biorganic Medicinal Chemistry Letters, 7, 25–30.CrossRefGoogle Scholar
Deutch, A. Y. (1992) The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. Journal of Neural Transmission, 36 (suppl.), 61–89.Google ScholarPubMed
Fuller, R. W. & Snoddy, H. D. (1992) Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine, an antipsychotic drug candidate. Research Communications in Chemical Pathology and Pharmacology, 77, 87–93.Google ScholarPubMed
Li, X.-M., Perry, K.W., Wong, D. T., et al (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology, 136, 153–161.CrossRefGoogle ScholarPubMed
Lucaites, V. L., Bymaster, F. P., Wainscott, D. B., et al (1995) Olanzapine exhibits similar activities to clozapine at cloned human serotonin 2A, 2B, 2C and muscarinic receptors. Society of Neuroscience Abstracts, 21, 1125.Google Scholar
Robertson, G. S. & Fibiger, H. C. (1992) Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience, 46, 315–328.CrossRefGoogle ScholarPubMed
Robertson, G. S. & Fibiger, H. C. (1996) Effects of olanzapine on regional c-fos expression in rat forebrain. Neuropsychopharmacology, 14, 105–110.CrossRefGoogle ScholarPubMed
Roth, B. L., Craigo, S. C., Choudhary, M. S., et al (1994) Binding of typical and atypical antipsychotic agents to (5-hydroxytryptamine)6 and (5-hydroxytryptamine)7 receptors. Journal of Pharmacology and Experimental Therapeutics, 268, 1403–1410.Google Scholar
Schickler, E. & Marr, I. (1996) The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics. Naunyn-Schmiedebergs Archives of Pharmacology, 353, 290–294.Google Scholar
Schotte, A., Janssen, P. F. M., Gommeren, W., et al (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology, 124, 57–73.CrossRefGoogle ScholarPubMed
Skarsfeldt, T. (1995) Differential effects of repeated administration of novel antipsychotic drugs on the activity of midbrain dopamine neurons in the rat. European Journal of Pharmacology, 281, 289–294.CrossRefGoogle ScholarPubMed
Stockton, M. E. & Rasmussen, K. (1996) Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons. Neuropsychopharmacology, 14, 97–104.CrossRefGoogle ScholarPubMed
Zeng, P. X., Le, F. & Richelson, E. (1997) Muscarinic M4 receptor activation by some atypical antipsychotic drugs. European Journal of Pharmacology, 321, 349–354.CrossRefGoogle ScholarPubMed
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