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Mechanisms of action of clozapine in the treatment of neuroleptic-resistant and neuroleptic-intolerant schizophrenia

Published online by Cambridge University Press:  16 April 2020

AY Deutch
AY Deutch*
Affiliation:
Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT06510, USA, and Psychiatry Service, Department of Veterans'Affairs Medical Center, West Haven, CT, USA
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Summary

The mechanisms of action which account for the effectiveness of clozapine as a pharmacotherapy for the treatment of neuroleptic non-responders and neuroleptic intolerant schizophrenic subjects remain elusive. We review recent data concerning the actions of clozapine in laboratory animals, and discuss the likely sites of action of clozapine and the receptors through which clozapine acts. We suggest that actions at dopamine D2 receptors in the caudate nucleus and putamen underlie the extrapyramidal side effects of conventional neuroleptics. In contrast, we propose that clozapine acts in the prefrontal cortex, specifically targeting an as yet unidentified DA receptor of the D2 family, to exert therapeutic actions in neuroleptic non-responders. We suggest that the ability of clozapine to augment extracellular dopamine levels in the prefrontal cortex may represent a key mechanism contributing to the therapeutic effects of this drug, and suggest some alternative approaches which might be expected to result in effects similar to those of clozapine.

Keywords

antipsychotic drugsdopamineimmediate-early geneprefrontal cortexstriatum
Type
Research Article
Information
European Psychiatry , Volume 10 , Issue S1 , 1995 , pp. 39s - 46s
Copyright
Copyright © Elsevier, Paris 1995

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References

Akbarian, SBunney, WE JrPotkin, SGWigal, SBHagman, JOSandman, CAJones, EGAltered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances in cortical development. Arch Gen Psychiat 1993; 50: 169–77CrossRefGoogle ScholarPubMed
Anderson, PHComparison of the pharmacological characteristics of [3H] raclopride and [3H]SCH 23390 binding to dopamine receptors in vitro in mouse brain. Eur J Pharmacol 1988; 146: 113–CrossRefGoogle Scholar
Baldessarini, RJFrankenburg, FRClozapine: A novel antipsychotic drug. N Engl J Med 1991; 324: 746–54Google Scholar
Beaudet, ADescarries, LFine structure of monoamine axon terminals in cerebral cortex. In: Descarries, LReader, TRJasper, HHMonoamine innervation of the cerebral cortex New York: Alan R. Liss, Inc, 1984 77–93Google Scholar
Benes, FMMcSparren, JBird, EDSanGiovanni, JPVincent, SLDeficits in small interneurons in prefrontal and cingulate cortex of schizophrenic and schizoaffective patients. Arch Gen Psychiat 1991; 48: 996–1001CrossRefGoogle ScholarPubMed
Berman, KFWeinberger, DThe prefrontal cortex in schizophrenia and other neuropsychiatric diseases: in vivo physiological correlates of cognitive deficits. Prog Brain Res 1990; 85: 521–38CrossRefGoogle ScholarPubMed
Brown, KWWhite, TThe association among negative symptoms, movement disorders, and frontal lobe psychological deficits in schizophrenic patients. Biol Psychiatry 1991; 30: 1182–90CrossRefGoogle ScholarPubMed
Bunney, BSAghajanian, GKDopamine and norepinephrine innervated cells in the rat prefrontal cortex: pharmacological differentiation using microiontophoretic techniques. Life Sci 1976; 19: 1783–92CrossRefGoogle ScholarPubMed
Carelli, RMWest, MORepresentation of the body by single neurons in the dorsolateral striatum of the awake, unrestrained rat. J Comp Neurol 1991; 309: 231–49CrossRefGoogle ScholarPubMed
Clark, JDeutch, AYGallipoli, PZAmara, SFunctional expression and CNS distribution of aβ-alanine-sensitive neuronal GABA transporter. Neuron 1992; 9: 337–48CrossRefGoogle ScholarPubMed
Claus, ABollen, JDe Cuyper, HEneman, MMalfroid, MPeuskens, JHeylen, SRisperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicenter double-blind comparative study. Acta Psychiatr Scand 1990; 85: 295–305CrossRefGoogle Scholar
Davis, KKahn, RSKo, GDavidson, MDopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1992; 148: 1474–86Google Scholar
Deutch, AYThe regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia J Neural Transm 1992; 36 (suppl) 61–89Google ScholarPubMed
Deutch, AYIdentification of the neural systems subserving clozapine's actions: clues from c-fos expression J Clin Psychiatry 1994; 55 (suppl B) 37–42Google Scholar
Deutch, AYCameron, DSPharmacological characterization of dopamine systems in the nucleus accumbens core and shell. Neuroscience 1992; 46: 49–56CrossRefGoogle ScholarPubMed
Deutch, AYDuman, RS The effects of antipsychotic drugs on prefrontal cortical fos expression: cellular localization and pharmacological characterization. Neuroscience, in pressGoogle Scholar
Deutch, AYLee, MCIadorola, MJRegionally specific effects of atypical antipsychotic drugs on striatal Fos expression: the nucleus accumbens shell as a locus of antipsychotic action. Mol Cell Neurosci 1992; 3: 332–41CrossRefGoogle ScholarPubMed
Deutch, AYLewis, DAWhitehead, RECameron, DSRedmond, DE JrRoth, RHNeuroleptics increase fos expression in the striatal complex and temporal cortex of non-human primates. Soc Neurosci Abstr 1993a; 19: 134Google Scholar
Deutch, AYZahm, DSBourdelais, AJThe nucleus accumbens core and shell: delineation of corticostriatal circuits and their functional attributes.Kalivas, PWBarnes, CDLimbic Motor Circuits and Neuropsychiatry Boca Raton, FL: CRC Press, 1993b; 45–88Google Scholar
Dragunow, MFaull, RThe use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 1989; 29: 261–5CrossRefGoogle ScholarPubMed
Dragunow, MRobertson, GSFaull, RLMRobertson, HAJansen, KD2 dopamine receptor antagonists induce Fos and related proteins in striatal neurons. Neuroscience 1990; 37: 287–94CrossRefGoogle ScholarPubMed
Friedman, LKnutson, LShurell, MMeltzer, HYPrefrontal sulcal prominence is inversely related to response to clozapine in schizophrenia. Biol Psychiatry 1991; 29: 865–77CrossRefGoogle Scholar
Ganzini, LHeintz, RTHoffman, WFCasey, DEPrevalence of tardive dyskinesia in neuroleptic-treated diabetics: a controlled study. Arch Gen Psychiatry 1991; 48: 259CrossRefGoogle ScholarPubMed
Gellman, RLAghajanian, GKPyramidal cells in piriform cortex receive a convergence of inputs from monoamine activated GABAergic interneurons. Brain Res 1993; 600: 63–73CrossRefGoogle ScholarPubMed
Goldman-Rakie, PSLeranth, CWilliams, SMMons, NGeffard, MDopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proc Natl Acad Sci USA 1989; 86: 9015–9CrossRefGoogle Scholar
Goldstein, MDeutch, AYDopaminergic mechanisms in the pathogenesis of schizophrenia. FASEB J 1992; 6: 2413–21CrossRefGoogle ScholarPubMed
Grobin, ACDeutch, AYApomorphine increases extracellular GABA levels in the prefrontal cortex of the freely-moving, concious rat. Soc Neurosci Abstr 1994; 20: 1154Google Scholar
Kane, JMHonigfeld, FSinger, JMeltzer, H the Clozaril ® Collaborative Study Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 1988; 45: 789–96CrossRefGoogle ScholarPubMed
Kish, SJShannak, KHornykiewicz, OUneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease: pathophysiologic and clinical implications. N Engl J Med 1988; 318: 876–80CrossRefGoogle ScholarPubMed
Levin, SFrontal lobe dysfunctions in schizophrenia. II: impairments of psychological and brain functions. J Psychiat Res 1984; 18: 57–72CrossRefGoogle ScholarPubMed
Lewander, TWestebergh, SEMorrison, DClinical profile of remoxipride—a combined analysis of a comparative double-blind multicentre trial programme Acta Psychiatry Scand 1990; 82 (suppl 358) 92–8CrossRefGoogle Scholar
Leysen, JEJanssen, PMFGommeren, WWynants, JPauwels, PJJanssen, PAJIn vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. J Pharmacol Exp Ther 1992; 41: 494–508Google ScholarPubMed
Makra, BBond, ALader, MComparative psychotropic effects of metoclopromide and prochlorperazine in normal subjects. J Clin Pharmacol 1975; 15: 449–54Google Scholar
Mansour, AWatson, SJDopamine receptor expression in the CNSBloom, FKupfer, DPsychopharmacology: The Fourth Generation of Progress New York: Raven Press, 1995 207–19Google Scholar
Martin, LJBlackstone, CDLevey, AIHuganair, RLPrice, DLAMPA glutamate receptor subunits are differentially distributed in rat brain. Neuroscience 1993; 53: 327–58CrossRefGoogle ScholarPubMed
Meador-Woodruff, JH Neuroanatomy of dopamine receptor gene expression: potential substrates for neuropsychiatric illness Clin Neuropharmacol 1995;in press.CrossRefGoogle Scholar
Meador-Woodruff, JHGrandy, Dvan Tol, HHMDamask, SPLittle, KYCivelli, OWatson, SJDopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacol 1994; 10: 239–48CrossRefGoogle ScholarPubMed
Meltzer, HYMatsubara, SLee, JCClassification of typical and atypical antipsychotic drugs on the basis of D1, D2, and serotonin2 pKi values. J Pharmacol Exp Ther 1989; 251: 238–46Google ScholarPubMed
Miller, JCInduction of c-fos mRNA expression in rat striatum by neuroleptic drugs. J Neurochem 1990; 54: 1453–5CrossRefGoogle ScholarPubMed
Miller, LGJankovic, JMetoclopromide-induced movement disorders. Clinical findings with a review of the literature. Arch Int Med 1989; 149: 2486–92CrossRefGoogle Scholar
Moghaddam, BBunney, BSAcute effect of typical and atypical antipsychotic drugs on the release of dopamine from the prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J. Neurochem 1990; 54: 1755–60CrossRefGoogle Scholar
Morgan, JICurran, TThe role of ion flux in the control of c-fos. Nature 1989; 322: 552–5CrossRefGoogle Scholar
Morilak, DAGarlow, SJCiaranello, RDImmunocytochemical localization and description of neurons expressing 5-HT2 receptors in the rat brain. Neuroscience 1993; 54: 701–17CrossRefGoogle Scholar
Nguyen, TVKasofsky, BBirnbaum, RCohen, BHyman, SEDifferential expression of c-fos and Zif 268 in rat striatum following haloperidol, clozapine, and amphetamine. Proc Natl Acad Sci USA 1991; 89: 4270–4CrossRefGoogle Scholar
Palmer, MRHoffer, BJCatecholamine modulation of enkephalin-induced electrophysiological responses in cerebral cortex. J Pharmacol Exp Ther 1980; 213: 205–15Google ScholarPubMed
Peterson, OTSt Mary, JSHarding, NRCis-flupenthixol antagonism of the rat prefrontal cortex neuronal response to apomorphine and ventral tegmental area input. Brain Res Bull 1987; 18: 723–9CrossRefGoogle ScholarPubMed
Pisa, MSchranz, JADissociable motor roles of the rat's striatum conform to a somatotopic model. Behav Neurosci 1988; 102: 429–40CrossRefGoogle ScholarPubMed
Reader, TAFerron, ADescarries, LJasper, HHModulatory role for biogenic amines in the cerebral cortex: microiontophoretic studies. Brain Res 1979; 160: 217–29CrossRefGoogle ScholarPubMed
Retaux, SBesson, MJPenit-Soria, JOpposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortical slices. Neuroscience 1991; 42: 61–71CrossRefGoogle Scholar
Robertson, GSFibiger, HCNeuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 1992; 46: 315–28CrossRefGoogle ScholarPubMed
Roth, RHWolf, MEDeutch, AYThe neurochemistry of midbrain dopamine systemsMeltzer, HYPsychopharmacology: The Third Generation of Progress New York: Raven Press, 1987 81–94Google Scholar
Sagar, SMSharp, FRCurran, TExpression of c-fos protein in brain: metabolic mapping at the cellular level. Science 1994; 240: 1328–31CrossRefGoogle Scholar
Sesack, SRBunney, BSPharmacological characterization of the receptor mediating electro-physiological responses to dopamine in the rat medial prefrontal cortex: a microiontophoretic study. J Pharmacol Exp Ther. 1989; 248: 1323–33Google Scholar
Sheng, MGreenberg, METhe regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 1990; 4: 477–85CrossRefGoogle ScholarPubMed
Smiley, JFGoldman-Rakic, PSHeterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver enhanced diaminobenzidine sulfide (SEDS) immunolabelling technique. Cerebral Cortex 1993; 3: 223–38CrossRefGoogle Scholar
Sokoloff, PGiros, BMartres, M-PBouthenet, M-LSchwartz, J-CMolecular cloning and characterization of a novel dopamine receptor (D3) as a target for neurolpetics. Nature 1990; 347: 146–50CrossRefGoogle Scholar
Stanley, MLautin, ARotrosen, JGershon, SKleinberg, DMetoclopramide: antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology 1980; 71: 219–25CrossRefGoogle ScholarPubMed
Thierry, AMGodbut, RMantz, JGlowinski, JInfluence of the ascending monoaminergic systems on the activity of the rat prefrontal cortex. Prog Brain Res 1990; 85: 366–77Google ScholarPubMed
Thierry, AMLe Douarin, CPenit, JFerron, AGlowinski, JVariation in the ability of neuroleptics to block the inhibitory influence of dopaminergic neurons on the activity of cells in the rat prefrontal cortex. Brain Res Bull 1986; 16: 155–60CrossRefGoogle ScholarPubMed
Van Eden, CGHoomeman, EMDBuijs, RMMatthijssen, MAHGeffard, MUylings, HBMImmunocytochemical localization of dopamine in the prefrontal cortex of the rat at light and electron microscopic level. Neuroscience 1987; 22: 849–62CrossRefGoogle Scholar
Van Tol, HHMBunzow, JRGuan, H-CSunahara, RKSeeman, PNiznik, HBCivelli, OCloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991; 350: 610–4CrossRefGoogle ScholarPubMed
Yamamoto, BKPehek, EAA neurochemical heterogeneity of the rat striatum as measured by in vivo electrochemistry and dialysis. Brain Res. 1990; 506: 236–42CrossRefGoogle Scholar
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