{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T19:15:32Z","timestamp":1788203732924,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropsychopharm Rep"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D<jats:sub>2<\/jats:sub> receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify<jats:sup>\u00ae<\/jats:sup>). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti<jats:sup>\u00ae<\/jats:sup>), another D<jats:sub>2<\/jats:sub> receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40\u00a0years in the area of antipsychotic drug discovery for dopamine D<jats:sub>2<\/jats:sub> receptor partial agonists.<\/jats:p>","DOI":"10.1002\/npr2.12180","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T00:14:59Z","timestamp":1620519299000},"page":"134-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Discovery research and development history of the dopamine D<sub>2<\/sub> receptor partial agonists, aripiprazole and brexpiprazole"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-7302","authenticated-orcid":false,"given":"Tetsuro","family":"Kikuchi","sequence":"first","affiliation":[{"name":"New Drug Research Division Pharmaceutical Business Division Otsuka Pharmaceutical Co., Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Lead Discovery Research New Drug Research Division Pharmaceutical Business Division Otsuka Pharmaceutical Co., Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikio","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of CNS Research New Drug Research Division Pharmaceutical Business Division Otsuka Pharmaceutical Co., Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Hirose","sequence":"additional","affiliation":[{"name":"New Drug Research Division Pharmaceutical Business Division Otsuka Pharmaceutical Co., Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Futamura","sequence":"additional","affiliation":[{"name":"Department of CNS Research New Drug Research Division Pharmaceutical Business Division Otsuka Pharmaceutical Co., Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"McQuade","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development &amp; Commercialization, Inc.  Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.033175"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2005.02.051"},{"issue":"1","key":"e_1_2_9_4_1","first-page":"329","article-title":"7\u2010{4\u2010[4\u2010(2,3\u2010Dichlorophenyl)\u20101\u2010piperazinyl]butyloxy}\u20103,4\u2010dihydro\u20102(1H)\u2010quinolinone (OPC\u201014597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity","volume":"274","author":"Kikuchi T","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm940608g"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v62n1201"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v63n0903"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.60.7.681"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.11m07530"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2014.12.013"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.213793"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.213819"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568007024606221"},{"issue":"1","key":"e_1_2_9_14_1","first-page":"1","article-title":"Second\u2010generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review","volume":"19","author":"Newcomer JW","year":"2005","journal-title":"CNS Drugs"},{"issue":"2","key":"e_1_2_9_15_1","first-page":"371","article-title":"Regulation of monoamine metabolism in the central nervous system","volume":"24","author":"Carlsson A","year":"1972","journal-title":"Pharmacol Rev"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(88)90493-6"},{"issue":"1","key":"e_1_2_9_17_1","first-page":"11","article-title":"Pathophysiology of schizophrenia and the role of newer antipsychotics","volume":"16","author":"Risch SC","year":"1996","journal-title":"Pharmacotherapy"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2009.02.007"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(01)00263-9"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1592\/phco.29.1.64"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145709000327"},{"issue":"1","key":"e_1_2_9_22_1","first-page":"40","article-title":"Multidimensional assessment of functional outcomes in schizophrenia: results from qualify, a head\u2010to\u2010head trial of aripiprazole once\u2010monthly and paliperidone palmitate","volume":"20","author":"Potkin SG","year":"2017","journal-title":"Int J Neuropsychopharmacol"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e31828ea95c"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881117728428"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbr006"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-9964(03)00050-1"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300203"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/14.2.130"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.05.104"},{"issue":"3","key":"e_1_2_9_30_1","first-page":"373","article-title":"Treatment of neuroleptic induced akathisia with the 5\u2010HT2 antagonist ritanserin","volume":"26","author":"Miller CH","year":"1990","journal-title":"Psychopharmacol Bull"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145713001417"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-977X(99)00053-X"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(00)01025-8"},{"issue":"2","key":"e_1_2_9_34_1","first-page":"145","article-title":"Effect of L\u2010DOPA in schizophrenia","volume":"26","author":"Inanaga K","year":"1972","journal-title":"Folia Psychiatr Neurol Jpn"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2015.1086269"},{"issue":"1","key":"e_1_2_9_36_1","first-page":"25","article-title":"Developing novel antipsychotic drugs: strategies and goals","volume":"2","author":"Miyamoto S","year":"2000","journal-title":"Curr Opin CPNS Invest Drugs"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-25761-2_4"},{"issue":"1","key":"e_1_2_9_38_1","first-page":"137","article-title":"Effects of the novel antipsychotic agent 7\u2010{4\u2010[4\u2010(2,3\u2010dichlorophenyl)\u20101\u2010piperazinyl]butyloxy}\u20103,4\u2010dihydro\u20102(1H)\u2010quinolinone (OPC\u201014597) on prolactin release from the rat anterior pituitary gland","volume":"277","author":"Inoue T","year":"1996","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2003.09.082"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/npr2.12076"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2016.04.013"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0000000000000123"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3371\/CSRP.MCCI.010316"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000000665"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.12682"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.12654"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000000979"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2014.12.014"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2014.06.008"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-008-1240-6"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2019.05.006"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-07-02873.2002"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.pra.0000452561.98286.1e"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2017.11.017"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0852-z"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1177\/1039856219889303"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2011.565333"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12090"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-014-3459-8"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2017.00144"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(03)01308-6"}],"container-title":["Neuropsychopharmacology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/npr2.12180","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/npr2.12180","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/npr2.12180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T07:38:04Z","timestamp":1693381084000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/npr2.12180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,7]]},"references-count":60,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1002\/npr2.12180"],"URL":"https:\/\/doi.org\/10.1002\/npr2.12180","archive":["Portico"],"relation":{},"ISSN":["2574-173X","2574-173X"],"issn-type":[{"value":"2574-173X","type":"print"},{"value":"2574-173X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,7]]},"assertion":[{"value":"2021-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}