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The maximum duration of treatment was 9 and 6\u2009months, respectively. Interspecies differences were noted in the response to JNJ\u201037822681 in terms of extrapyramidal (EPS)\u2010like clinical signs and prolactin\u2010mediated tissue changes in the mammary gland. Monkeys showed severe EPS\u2010like clinical signs such as abnormal posture, abnormal eye movements and hallucination\u2010like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ\u201037822681\u2010induced EPS\u2010like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin\u2010related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ\u201037822681. The monkey toxicology studies did not provide an exposure\u2010based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ\u201037822681\u2010associated adverse events in humans than the Sprague\u2013Dawley rat. Copyright \u00a9 2013 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.2916","type":"journal-article","created":{"date-parts":[[2013,10,8]],"date-time":"2013-10-08T11:53:51Z","timestamp":1381233231000},"page":"974-992","source":"Crossref","is-referenced-by-count":5,"title":["Differential responses to JNJ\u201037822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague\u2013Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics"],"prefix":"10.1002","volume":"34","author":[{"given":"Eric J.","family":"de Waal","sequence":"first","affiliation":[{"name":"Janssen Research and Development, a division of Janssen Pharmaceutica NV, Drug Safety Sciences Department of Preclinical Project Development  Turnhoutseweg 30 2340 Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Desmidt","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, a division of Janssen Pharmaceutica NV, Drug Safety Sciences Department of Preclinical Project Development  Turnhoutseweg 30 2340 Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Korte","sequence":"additional","affiliation":[{"name":"Covance Laboratories GmbH  Kesselfeld 29 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Niehoff","sequence":"additional","affiliation":[{"name":"Covance Laboratories GmbH  Kesselfeld 29 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevan","family":"Chase","sequence":"additional","affiliation":[{"name":"Huntingdon Life Sciences Huntingdon Research Centre  Woolley Road, Alconbury, Huntingdon Cambridgeshire PE28 4HS UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Arrowsmith","sequence":"additional","affiliation":[{"name":"Huntingdon Life Sciences Huntingdon Research Centre  Woolley Road, Alconbury, Huntingdon Cambridgeshire PE28 4HS UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Lampo","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, a division of Janssen Pharmaceutica NV, Drug Safety Sciences Department of Preclinical Project Development  Turnhoutseweg 30 2340 Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,9,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(99)00027-2"},{"key":"e_1_2_7_3_1","unstructured":"AnghelescuIG JanssensL KentJ deBoerP TritsmansL DalyEJ vanNuetenL SchmidtME.2012.Does early improvement predict response to the fast\u2010dissociating D2receptor antagonist JNJ\u201037822681 in patients with acute schizophrenia?Eur. 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