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While risperidone is very often used in clinical practice, the most efficient known anti\u2010psychotic drug is clozapine (CLO). However, the biochemical background of CLO's action still remains elusive. In this study, we performed comparative proteomic analysis of rat cerebral cortex following chronic administration of these two drugs. We observed significant changes in the expression of cytoskeletal, synaptic, and regulatory proteins caused by both antipsychotics. Among other proteins, alterations in collapsin response mediator proteins,<jats:styled-content style=\"fixed-case\">CRMP<\/jats:styled-content>2 and<jats:styled-content style=\"fixed-case\">CRMP<\/jats:styled-content>4, were the most spectacular consequences of treatment with both drugs. Moreover, risperidone increased the level of proteins involved in cell proliferation such as fatty acid\u2010binding protein\u20107 and translin\u2010associated factor X. CLO significantly up\u2010regulated the expression of visinin\u2010like protein 1, neurocalcin \u03b4 and mitochondrial, stomatin\u2010like protein 2, the calcium\u2010binding proteins regulating calcium homeostasis, and the functioning of ion channels and receptors.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13007-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p>Using two\u2010dimensional differential electrophoresis, we demonstrate that chronic treatment the healthy rats with anti\u2010psychotics, clozapine and risperidone, induce changes in expression of cytoskeletal, synaptic, and regulatory proteins in the cerebral cortex. 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