title: A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia.
abstract: Cariprazine is a potential antipsychotic awaiting approval from the US Food and Drug Administration. It is a dopamine D2- and D3-receptor partial agonist, with higher affinity for D3 receptors, as opposed to the D2 antagonism of most older antipsychotic agents. Like most lipophilic antipsychotics, it undergoes extensive hepatic metabolism by cytochrome P450 (CYP), mainly the highly variable 3A4, with the formation of active metabolites. However, the parent compound - particularly its active didesmethyl derivative - is cleared very slowly, with elimination half-lives in schizophrenic patients ranging from 2-5 days for cariprazine to 2-3 weeks for didesmethyl-cariprazine. Exposure to the latter was several times that for cariprazine, although didesmethyl-cariprazine did not reach steady state within the 3 weeks of 12.5 mg/day dosing. Preliminary information on its therapeutic role comes from press releases and a few abstracts presented at scientific meetings. In short-term controlled trials, it was more effective than placebo in reducing positive and negative symptoms of schizophrenia, with an effective dose range of 1.5-12 mg/day. Although cariprazine was associated with a higher incidence of akathisia and extrapyramidal side effects than placebo, it did not cause weight gain, metabolic abnormalities, prolactin increase, or corrected QT prolongation. Similarly, cariprazine's efficacy and tolerability for the treatment of bipolar disorder (manic/mixed and depressive episodes) was established in the dose range of 3-12 mg/day, although again no long-term data are available. Well-designed clinical trials, mainly direct "head-to-head" comparisons with other second-generation antipsychotic agents, are needed to define the therapeutic role and safety profile of cariprazine in schizophrenia and bipolar mania.
authors: IRCCS-istituto di Ricerche Farmacologiche Mario Negri, Milan, italy.
authors: Silvio
authors: S
authors: Caccia
authors: Roberto William
authors: RW
authors: Invernizzi
authors: Alessandro
authors: A
authors: Nobili
authors: Luca
authors: L
authors: Pasina
keywords: antipsychotic; cariprazine; efficacy; pharmacokinetics; pharmacology; safety
references: Curr Opin Investig Drugs. 2010 Jul;11(7):823-32
references: 20571978
references: Adv Ther. 2013 Feb;30(2):114-26
references: 23361833
references: Expert Opin Drug Metab Toxicol. 2011 Jul;7(7):829-46
references: 21476873
references: Bipolar Disord. 2015 Feb;17(1):63-75
references: 25056368
references: Adv Ther. 2013 Feb;30(2):102-13
references: 23361832
references: Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):9-19
references: 17269891
references: Pharmacogenomics. 2010 Nov;11(11):1561-71
references: 21121776
references: Int J Clin Pract. 2009 Dec;63(12):1762-84
references: 19840150
references: J Psychopharmacol. 2005 Nov;19(6 Suppl):16-27
references: 16280334
references: Bioorg Med Chem Lett. 2012 May 15;22(10):3437-40
references: 22537450
references: Am J Psychiatry. 2004 Mar;161(3):414-25
references: 14992963
references: Psychopharmacology (Berl). 2011 Dec;218(3):579-87
references: 21625907
references: Neuropsychiatr Dis Treat. 2012;8:155-68
references: 22570547
references: Drug Discov Today. 2005 Jul 1;10(13):917-25
references: 15993811
references: J Clin Psychiatry. 2007;68 Suppl 1:20-7
references: 17286524
references: Intern Med J. 2008 Jul;38(7):602-6
references: 18715305
references: Eur J Pharmacol. 2011 Oct 15;668(3):355-65
references: 21816144
references: J Pharm Biomed Anal. 2008 Sep 29;48(2):388-97
references: 18242914
references: J Pharmacol Exp Ther. 2010 Apr;333(1):328-40
references: 20093397
references: Pharmacogenomics. 2011 Aug;12(8):1193-211
references: 21843066
references: Circulation. 2000 Dec 5;102(23):2836-41
references: 11104741
references: Int J Neuropsychopharmacol. 2017 Oct 1;20(10):788-796
references: 28531264
references: Psychopharmacology (Berl). 2011 Apr;214(3):625-37
references: 21049266
references: Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206
references: 23320989
references: Science. 1983 Sep 9;221(4615):1054-7
references: 6136093
references: J Psychiatr Res. 2013 Feb;47(2):149-54
references: 23131856
references: Psychoneuroendocrinology. 2003 Jan;28 Suppl 1:9-26
references: 12504069
references: Drug Des Devel Ther. 2010 Feb 18;4:33-48
references: 20368905
references: Expert Rev Neurother. 2012 Dec;12(12):1383-97
references: 23237346
references: J Neurosci. 1983 Aug;3(8):1607-19
references: 6135762
references: Psychopharmacology (Berl). 2011 Apr;214(3):639-52
references: 21052982
references: Expert Opin Pharmacother. 2006 Sep;7(13):1739-48
references: 16925501
references: Synapse. 2013 May;67(5):258-64
references: 23238770
references: Psychopharmacology (Berl). 2011 Aug;216(4):451-73
references: 21394633
references: CNS Drugs. 2007;21(11):911-36
references: 17927296
references: Mol Psychiatry. 2007 Aug;12(8):707-47
references: 17549063