Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology (original) (raw)
ABSTRACT
Aripiprazole (Abilify®) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G‐protein coupled receptors (GPCRs) [especially dopamine (D2) and 5‐HT1A] and antagonistic action at others (especially 5‐HT2A). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short‐term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and Schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long‐term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time‐to‐relapse.
Aripiprazole represents the first functionally selective atypical antipsychotic drug.
Keywords: Aripiprazole, Atypical antipsychotics, Bipolar disorder, Schizophrenia
Full Text
The Full Text of this article is available as a PDF (217.7 KB).
Disclosure. Dr. Bryan L. Roth served as a consultant for Bristol‐Myers Squibb, Otsuka Pharmaceuticals, Eli Lilly, Pfizer, Neotherapeutics, Arena Pharmaceuticals, Memory Pharmaceuticals, SK Corporation and Forest Pharmaceuticals. SK Corporation and Forest Pharmaceuticals.
REFERENCES
- 1.Abou‐Gharbia N, Saba AR, Iwamoto T, _et al._Meta‐analysis of prolactin effects with aripiprazole. Schizophr Res 2003;60:350. [Google Scholar]
- 2.Aihara K, Shimada J, Miwa T, _et al._The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenyl cyclase activity and prolactin release. Brain Res 2004;1003:9–17. [DOI] [PubMed] [Google Scholar]
- 3.Allison DB, Mentore JL. Moonseong H, _et al_Antipsychotic‐induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999;156:1686–1696. [DOI] [PubMed] [Google Scholar]
- 4.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th Ed., Washington , D.C. : American Psychiatric Association, 1994. [Google Scholar]
- 5.Archibald DG, Manos G, Tourkodimitris S, _et al._Reduction in negative symptoms of schizophrenia during long‐term therapy with aripiprazole. Schizophr Res 2003;60:271. 12591589 [Google Scholar]
- 6.Argo TR, Carnaham RM, Perry PJ. Aripiprazole, a novel atypical antipsychotic drug. Pharmacotherapy 2004;24:212–228. [DOI] [PubMed] [Google Scholar]
- 7.Attia E. Atypical antipsychotic medication in anorexia nervosa. Crisp.cit.nih.gov.
- 8.Auby P, Saha A, Ali M, _et al._Safety and tolerability of aripiprazole at doses higher than 30 mg. Eur Neuro-psychopharmacol 2002;12(Suppl 3):S288. [Google Scholar]
- 9.Blumer JL. Aripiprazole to control effect of TBI in Children (ACT). Crisp.cit.nih.gov.
- 10.Bourin M, Auby P, Swanik S, _et al._Aripiprazole vs. haloperidol for maintained treatment effect in acute mania. Eur Neuropsychopharmacol 2003;12(Suppl 4):S333. [Google Scholar]
- 11.Bowles TM, Levin GM. Aripiprazole: A new atypical antipsychotic drug. Ann Pharmacother 2003;37:687–694. [DOI] [PubMed] [Google Scholar]
- 12.Bramer S, Shoaf S, Dalazar D, _et al._Lack of effect of renal and hepatic impairment on the pharmacokinetics of aripiprazole. Eur Neuropsychopharmacol 2003;13(Suppl 4):S333. [Google Scholar]
- 13.Bristol‐Myers Squibb Company and Otsuka America Pharmaceutical, Inc. Abilify (aripiprazole) tablets package insert, 2004.
- 14.Brown D, McEvoy J, Saha R, _et al._Aripiprazole in patients with first episode schizophrenia. Schizophr Res 2003;60:275. [Google Scholar]
- 15.Burris KD, Molski TF, Xu C, _et al._Aripiprozole, a novel antipsychotic, is a high‐affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002;302:381–389. [DOI] [PubMed] [Google Scholar]
- 16.Byars A, Burris K, Jordan S, _et al._Aripiprazole: A dopamine‐serotonin system stabilizer. Eur Neuropsychopharmacol 2002;12(Suppl3):S290–291. [Google Scholar]
- 17.Carson W, Cornblatt B, Saha A, _et al._Neurocognitive benefits of aripiprazole versus olanzapine in stable psychosis. Eur Neuropsychopharmacol 2002;12(Suppl 3):S291. [Google Scholar]
- 18.Carson W, McQuade R, Saha A, _et al._Aripiprazole versus placebo for relapse prevention in patients with chronic schizophrenia. Eur Neuropsychopharmacol 2002;12(Suppl 3):S288. [Google Scholar]
- 19.Carson WH, Kane JM, Ali M, _et al._Efficacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. Eur Neuropsychopharmacol 2000; 10(Suppl 3):309–310. [Google Scholar]
- 20.Carson WH, Saha AR, String fellow JC, _et al._Meta‐analysis of the efficacy of aripiprazole in schizophrenia. Schizophr Res 2003;60:276. [Google Scholar]
- 21.Casey DE, Carson WH, Saba AR, _et al._Aripiprazole Study Group. Switching patients to aripiprazole from other antipsychotic agents: A multicenter randomized study. Psychopharmacology 2003;166:391–399. [DOI] [PubMed] [Google Scholar]
- 22.Curran MP and Perry CM. Amisulpride: A review of its use in the management of schizophrenia. Drugs 2001;61:2123–2150. [DOI] [PubMed] [Google Scholar]
- 23.Daniel DG, Saha AR, Ingenito G, _et al._Aripiprazole, a novel antipsychotic: Overview of a phase II study result. Int J Neuropsychopharmacol 2000;3(Suppl 1):S157. [Google Scholar]
- 24.De Deyn PP, Jeste D, Aubrey P, _et al._Aripiprazole treatment of psychosis in patients with Alzheimer's disease. Eur Neuropsychopharmacol 2003;12(Suppl 4):S325. [Google Scholar]
- 25.DeLeon J. Atypical antipsychotic dosing: The effect of co‐medication with anticonvulsants. Psychiatr Serv 2000;55:125–128. [DOI] [PubMed] [Google Scholar]
- 26.DeQuardo JR. Worsened agitation with aripiprazole: Adverse effect of dopamine partial agonism J Clin Psychiatry 2004;65:132–133. [DOI] [PubMed] [Google Scholar]
- 27.Duggal HS. Aripiprazole‐induced improvement in tardive dyskinesia. Can J Psychiatry 2003;48:771–772. [DOI] [PubMed] [Google Scholar]
- 28.Emsley R, Oosthuizen P. Evidence‐based pharmacotherapy of schizophrenia. Int J Neuropsychopharmacol 2004;7:219–238. [DOI] [PubMed] [Google Scholar]
- 29.Farde L, Nordstrom AL, Wiesel FA, _et al._Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: Relation to extra‐pyramidal side effects. Arch Gen Psychiatry 1992;49:538–544. [DOI] [PubMed] [Google Scholar]
- 30.Findling RL, Blumer JL, Kauffman R, _et al._Aripiprazole in pediatric‐conduct disorder: A pilot study. Eur Neuropsychopharmacol 2003;12(Suppl 4):S335. [Google Scholar]
- 31.Fleischhacker WW. New developments in the pharmacotherapy of schizophrenia. J Neural Transm Suppl 2003;64:105–117. [DOI] [PubMed] [Google Scholar]
- 32.Goodnick PJ, Jerry JM. Aripiprazole: Profile on efficacy and safety. Expert Opin Pharmacother 2002;3:1773–1781. [DOI] [PubMed] [Google Scholar]
- 33.Goodnick PJ, Jerry JM, Parra F. Psychotropic drugs and the ECG: Focus on the QTc interval. Expert Opin Pharmacother 2002;3:479–498. [DOI] [PubMed] [Google Scholar]
- 34.Goodnick PJ, Rodriquez L, Santana O. Antipsychotics: Impact on prolactin levels. Expert Opin Pharmacother 2002;3:1381–1391. [DOI] [PubMed] [Google Scholar]
- 35.Green B. Focus on aripiprazole. Curr Med Res Opin 2004;20:207–213. [DOI] [PubMed] [Google Scholar]
- 36.Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: Occupancy is not just antagonism. Arch Gen Psychiatry 2003;60:974–977. [DOI] [PubMed] [Google Scholar]
- 37.Inoue T, Domae M, Yamada K_et al._Effects of the novel antipsychotic agent 7–(4–[4–(2,3–dichlorophenyl)‐1–piperazinyl]butyloxy)‐3,4–dihydro‐2(1H)‐quinolinone (OPC‐14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther 1996;277:137–143. [PubMed] [Google Scholar]
- 38.Inoue A, Miki S, Seto M, _et al._Aripiprazole, a novel antipsychotic drug, inhibits quinpirole‐evoked GTPase activity but does not up‐regulate dopamine D2 receptor following repeated treatment in the rat striatum. Eur J Pharmacol 1997;321:105–111. [DOI] [PubMed] [Google Scholar]
- 39.Jody D, Carson WH, Iwamoto T, _et al._Meta‐analysis of weight effects with aripiprazole. Eur Neuropsychopharmacol 2002;12(Suppl 3):S290. [Google Scholar]
- 40.Jordan S, Koprivica V, Chen R, _et al._The antipsychotic aripiprazole is a potent, partial agonist at the human 5–HT1A receptor. Eur J Pharmacol 2002;441:137–140. [DOI] [PubMed] [Google Scholar]
- 41.Jordan S, Koprvica V, Dunn R, et al. In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol 2004;483:45–53. [DOI] [PubMed] [Google Scholar]
- 42.Kalkman HO, Loetscher E. α2C‐Adrenoceptor blockade by clozapine and other antipsychotic drugs. Eur J Pharmacol 2003;462:33–40. [DOI] [PubMed] [Google Scholar]
- 43.Kane JM, Carson WH, Saha AR, _et al._Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–771. [DOI] [PubMed] [Google Scholar]
- 44.Kasper S, Lerman MN, McQuade RD, _et al._Efficacy and safety of aripiprazole vs. haloperidol for long‐term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 2003;6:325–337. [DOI] [PubMed] [Google Scholar]
- 45.Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical anti‐psychotics: Anew hypothesis. Am J Psychiatry 2001;158:360–369. [DOI] [PubMed] [Google Scholar]
- 46.Keck PE Jr, Marcus R, Tourkodimitris S, _et al._A placebo‐controlled, double‐blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003;160:1651–1658. [DOI] [PubMed] [Google Scholar]
- 47.Keltner NL, Johnson V. Biological perspectives. Aripiprazole: A third generation of antipsychotics begins Perspect Psychiatr Care 2002;38:157–159. [DOI] [PubMed] [Google Scholar]
- 48.Kenakin T. Efficacy at G‐protein‐coupled receptors. Nature Rev Drug Discovery 2002;1:103–110. [DOI] [PubMed] [Google Scholar]
- 49.Kikuchi T, Tottori K, Uwahodo Y, _et al._7‐(4‐[4‐(2,3‐Dichlorophenyl)‐1‐piperazinyl]butyloxy)‐3,4‐dihydro‐2(1H)‐quinolinone (OPC‐14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 1995;274:329–336. [PubMed] [Google Scholar]
- 50.Kostic D, Saha AR, Brunell R, _et al._Meta‐analysis of cardiac safety with aripiprazole. Schizophr Res 2003;60:359. [Google Scholar]
- 51.Kroeze WK, Hufeisen SJ, Popadak BA, _et al._H1‐histamine receptor affinity predicts short‐term weight gain from typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003;28:519–526. [DOI] [PubMed] [Google Scholar]
- 52.Kujawa M, Saha AR, Ali MW, _et al._Switching to aripiprazole monotherapy. Schizophr Res 2003;60:290. [Google Scholar]
- 53.Lam S, Carson WH, Stock E, _et al._Safety and tolerability of aripiprazole in patients with schizophrenia stratified by race. Schizophr Res 2003;60:291. [Google Scholar]
- 54.Lawler CP, Prioleau C, Lewis M, _et al._Interactions of the novel antipsychotic aripiprazole (OPC‐14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999;20:612–627. [DOI] [PubMed] [Google Scholar]
- 55.Lieberman JA. Dopamine partial agonists: Anew class of antipsychotic. CNS Drugs 2004;18:251–267. [DOI] [PubMed] [Google Scholar]
- 56.Lindsey RL, Kaplan D, Koliatsos V, _et al._Aripiprazole and extrapyramidal symptoms. J Am Acad Child Adolesc Psychiatry 2003;42:1268–1269. [DOI] [PubMed] [Google Scholar]
- 57.Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 2004;44:179–187. [DOI] [PubMed] [Google Scholar]
- 58.Marcus R, Jody D, Carson WH, _et al._Aripiprazole versus placebo in acute mania. Eur Neuropsychopharmacol 2002;12(Suppl3):S289. [Google Scholar]
- 59.Marder SR, McQuade RD, Stock E, _et al._Aripiprazole in the treatment of schizophrenia: Safety and tolerability in short‐term, placebo‐controlled trials. Schizophr Res 2003;61:123–136. [DOI] [PubMed] [Google Scholar]
- 60.Marona‐Lewicka D, Nichols DE. Aripiprazole (OPC‐14597) fully substitutes for the 5‐HT1A‐receptor agonist LY293284 in the drug discrimination assay in rats. Psychopharmacology 2004;172:415–421. [DOI] [PubMed] [Google Scholar]
- 61.McGavin JK, Goa KL. Aripiprazole. CNS Drugs 2002:16:779–786; discussion 787–788. [DOI] [PubMed] [Google Scholar]
- 62.Meltzer HY, Li Z, Kaeda Y, _et al._Serotonin receptors: Their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:1159–1172. [DOI] [PubMed] [Google Scholar]
- 63.Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D‐1, D‐2 and serotonin 2 p_K_ i values. J Pharmacol Exp Ther 1989;251:238–246. [PubMed] [Google Scholar]
- 64.Nakai S, Hirose T, Uwahodo Y, _et al._Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone. Eur J Pharmacol 2003;472:89–97. [DOI] [PubMed] [Google Scholar]
- 65.NIMH Psychoactive Drug Screening Program , http://www.kidb.cwru.edu.
- 66.Oshiro Y, Sato S, Kurahashi N, _et al._Novel antipsychotic agents with dopamine autoreceptor agonist properties: Synthesis and pharmacology of 7‐[4‐(4‐phenyl‐1‐piperazinyl)butoxy]‐3,4–dihydro‐2(1H)‐quinolinone derivatives. J Med Chem 1998;41:658–667. [DOI] [PubMed] [Google Scholar]
- 67.Petrie JL, Saha AR, McEvoy JP. Aripiprazole, a new typical antipsychotic: Phase 2 clinical trial result. Eur Neuropsychopharmacol 1997;7(Suppl 2):S227. [Google Scholar]
- 68.Pigott TA, Carson WH, Saha AR, _et al._Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: A placebo‐controlled 26–week study. J Clin Psychiatry 2003;64:1048–1056. [DOI] [PubMed] [Google Scholar]
- 69.Potkin SG, Kujawa M, Carson WH, _et al._Aripiprazole and risperidone versus placebo in schizophrenia and schizoaffective disorder. Schizophr Res 2003;60:300. [Google Scholar]
- 70.Potkin SG, Saha AR, Kujawa MJ, _et al._Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2003;60:681–690. [DOI] [PubMed] [Google Scholar]
- 71.Rivas‐Vazquez R A. Aripiprazole: A novel antipsychotic with dopamine stabilizing properties. Prof Psychol Res Pract 2003;34:108–111. [Google Scholar]
- 72.Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: Selectively non‐selective drugs for mood disorders and schizophrenia. Nature Rev Drug Discovery 2004;4:353–359. [DOI] [PubMed] [Google Scholar]
- 73.Roth BL, Sheffler D, Potkin SG. Atypical antipsychotic drug actions: Unitary or multiple mechanisms for “atypicality” Clin Neurosci Res 2003;3:108–117. [Google Scholar]
- 74.Sanchez R, Bourin M, Auby P, _et al._Aripiprazole vs. haloperidol for maintained treatment effect in acute mania. Proc Intern Conf Bipolar Disord 2003;5:80–81. [Google Scholar]
- 75.Sajatovic M. Treatment for mood and anxiety disorders: Quetiapine and aripiprazole. Curr Psychiatry Rep 2003;5:320–326. [DOI] [PubMed] [Google Scholar]
- 76.Schoemaker GH, Claustre Y, Fage D, _et al._Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 1997;280:83–97. [PubMed] [Google Scholar]
- 77.Schonfeldt‐Lecuona C, Connemann BJ. Aripiprazole and Parkinson's Disease Psychosis. Am J Psychiatry 2004;161:373–374. [DOI] [PubMed] [Google Scholar]
- 78.Seeman P, Lee T, Chau‐Wong M, _et al._Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976;261:717–719. [DOI] [PubMed] [Google Scholar]
- 79.Semba J, Watanabe A, Kito S, _et al._Behavioural and neurochemical effects of OPC‐14597, a novel antipsychotic drug, on dopaminergic mechanisms in rat brain. Neuropharmacology 1995;34:785–791. [DOI] [PubMed] [Google Scholar]
- 80.Shapiro DA, Renock S, Arrington E, _et al._Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003;28:1400–1411. [DOI] [PubMed] [Google Scholar]
- 81.Sikich L. Treatment of Psychotic Disorders in Youth. Crisp.cit.nih.gov.
- 82.Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, Part 2: Illustrating their mechanism of action. J Clin Psychiatry 2001;2:923–924. [DOI] [PubMed] [Google Scholar]
- 83.Staller JA. Aripiprazole in an adult with Asperger disorder. Ann Pharmacother 2003;37:1628–1631. [DOI] [PubMed] [Google Scholar]
- 84.Stock E, Marder SR, Jody D, _et al._Plasma lipids levels and glycemic control in long‐term treatment with aripiprazole. Eur Neuropsychopharmacol 2003; 12(Suppl 4):S327. [Google Scholar]
- 85.Stock E, Marder ST, Saha AR. Safety and tolerability of aripiprazole in schizophrenia. Int J Neuropsychopharmacol 2002;5(Suppl):S184. [Google Scholar]
- 86.Sugiyama A, Satoh Y, Hashimoto K.In vivo canine model comparison of cardiohemodynamic and electro‐physiological effects of a new antipsychotic drug aripiprazole (OPC‐14597) to haloperidol. Toxicol Appl Pharmacol 2001;173:120–128. [DOI] [PubMed] [Google Scholar]
- 87.Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411–420. [DOI] [PubMed] [Google Scholar]
- 88.Tamminga CA. Similarities and differences among antipsychotics. J Clin Psychiatry 2003;64(Suppl 17):7–10. [PubMed] [Google Scholar]
- 89.Tamminga CA, Carlsson A. Partial dopamine agonists and dopaminergic stabilizers, in the treatment of psychosis. Curr Drug Target CNS Neurol Disord 2002;2:141–147. [DOI] [PubMed] [Google Scholar]
- 90.Taylor DM. Aripiprazole: A review of its pharmacology and clinical use. Int J Clin Pract 2003;57:49–54. [PubMed] [Google Scholar]
- 91.Winans E. Aripiprazole. Am J Health Syst Pharm 2003;60:2437–2445. [DOI] [PubMed] [Google Scholar]
- 92.Yokoi F, Grunder G, Biziere K, _et al._Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): A study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 2002;27:248–259. [DOI] [PubMed] [Google Scholar]
- 93.Zhang JY, Nawoschik S, Kowal D, _et al._Characterization of the 5–HT6 receptor coupled to Ca2+ signaling using an enabling chimeric G‐protein. Eur J Pharmacol 2003;472:33–38. [DOI] [PubMed] [Google Scholar]