Abstract
Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 – 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.
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References
Barbier P, Colelli A, Maggio R, Bravi D, Corsini GU . (1997): Pergolide binds tightly to dopamine D2 short receptors and induces receptor sequestration. J Neural Transm 104: 867–874
Barton AC, Black LE, Sibley DR . (1991): Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. Mol Pharmacol 39: 650–658
Bench CJ, Lammertsma AA, Dolan RJ, Grasby PM, Warrington SJ, Gunn K, Cuddigan M, Turton DJ, Osman S, Frackowiak RS . (1993): Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059–01: A study using positron emission tomography and 11C-raclopride. Psychopharmacology (Berl) 112: 308–314
Bergstrom M, Eriksson L, Bohm C, Blomqvist G, Litton J . (1983): Correction for scattered radiation in a ring detector positron camera by integral transformation of the projections. J Comput Assist Tomogr 7: 42–50
Burris KD, Molski TF, Ryan E, Xu C, Tottori K, Kikuchi T, Yocca FD, Molinoff PB . (2000): Aripiprazole is a high affinity partial agonist at human D2 dopamine receptors. International Journal of Neuropsychopharmacology 3(Suppl 1): LS129
Burt DR, Creese I, Snyder SH . (1977): Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science 196: 326–328
Carson WH, Kane JM, Ali M, Dunbar GC, Ingenito G . (2000): Efficacy of aripiprazole in psychotic disorders: Comparison with haloperidol and placebo. Eur Neuropsychopharmacol 10(Suppl 3): S309–S310
Chugani DC, Ackermann RF, Phelps ME . (1988): In vivo [3H]spiperone binding: evidence for accumulation in corpus striatum by agonist-mediated receptor internalization. J Cereb Blood Flow Metab 8: 291–303
Clow A, Jenner P, Theodorou A, Marsden CD . (1979): Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months. Nature 278: 59–61
Clow A, Theodorou A, Jenner P, Marsden CD . (1980): Changes in rat striatal dopamine turnover and receptor activity during one year's neuroleptic administration. Eur J Pharmacol 63: 135–144a
Clow A, Theodorou A, Jenner P, Marsden CD . (1980): Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration. Eur J Pharmacol 63: 145–157b
Creese I, Burt DR, Snyder SH . (1996): Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. J Neuropsychiatry Clin Neurosci 8 (2): 223–226
Daniel DG, Saha AR, Ingenito G, Carson WH, Dunbar G . (2000): Aripiprazole, a novel antipsychotic: Overview of a phase II study result. International Journal of Neuropsychopharmacology 3(Sup 1): S157
Delforge J, Syrota A, Bendriem B . (1996): Concept of reaction volume in the in vivo ligand-receptor model. J Nucl Med 37: 118–125
Ehrin E, Farde L, de Paulis T, Eriksson L, Greitz T, Johnstrom P, Litton JE, Nilsson JL, Sedvall G, Stone-Elander S . (1985): Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: Preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot 36 (4): 269–273
Farde L, Wiesel FA, Halldin C, Sedvall G . (1988): Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45 (1): 71–76
Farde L, Eriksson L, Blomquist G, Halldin C . (1989): Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET: A comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9: 696–708
Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C, Sedvall G . (1992): Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 49 (7): 538–544
Gründer G, Wetzel H, Hammes E, Benkert O . (1993): Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression. Psychopharmacology (Berl) 111 (1): 123–126
Gründer G, Wetzel H, Hillert A, Jochum E, Hiemke C, Benkert O . (1995): The neuroendocrinological profile of roxindole, a dopamine autoreceptor agonist, in schizophrenic patients. Psychopharmacology (Berl) 117 (4): 472–478
Gründer G, Müller MJ, Andreas J, Wetzel H, Heydari N, Schlösser R, Schlegel S, Nickel O, Eissner D, Benkert O . (1999): Occupancy of striatal D2-like dopamine receptors after treatment with the sigma ligand EMD 57445, a putative atypical antipsychotic. Psychopharmacology (Berl) 146: 81–86
Guo N, Waterhouse RN, Hwang DR, Zea-Ponce Y, Huang Y, Simpson N, Castrillon J, Abi-Dargham A, Laruelle M . (2000): Effect of endogenous dopamine on in vivo binding of dopamine D1 and D2 radiotracers. NeuroImage 11 (Part 2): S4
Hirschowitz J, Hitzemann R, Vallabhajosula S . (1997): SPECT studies of D2 occupancy in low-dose haloperidol treatment. Am J Psychiatry 154 (5): 715–716
Ichise M, Ballinger JR, Golan H, Vines D, Luong A, Tsai S, Kung HF . (1996): Noninvasive quantification of dopamine D2 receptors with iodine-123-IBF SPECT. J Nucl Med 37 (3): 513–520
Inoue T, Domae M, Yamada K, Furukawa T . (1996): 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 277: 137–144
Inoue A, Miki S, Seto M, Kikuchi T, Morita S, Ueda H, Misu Y, Nakata Y . (1997): 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 321: 105–111
Ito K, Haga T, Lameh J, Sadee W . (1999): Sequestration of dopamine D2 receptors depends on coexpression of G-protein-coupled receptor kinases 2 or 5. Eur J Biochem 260: 112–119
Kane J, Ingenito G, Ali M . (2000): Efficacy of aripiprazole in psychotic disorders: Comparison with haloperidol and placebo. Schizophrenia Res 41: 38
Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, Zipursky R . (1996): High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: A PET study. Am J Psychiatry 153 (7): 948–950
Kapur S, Zipursky RB, Remington G . (1999): Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156: 286–293
Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P . (2000): A positron emission tomography study of quetiapine in schizophrenia: A preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57: 553–559
Kapur S, Seeman P . (2001): Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158: 360–369
Kendler KS, Bracha HS, Davis KL . (1982): Dopamine autoreceptor and postsynaptic receptor blocking potency of neuroleptics. Eur J Pharmacol 79: 217–223
Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S . (1995): 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 274: 329–336
Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, Frackowiak RS . (1996): Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 16 (1): 42–52
Lammertsma AA, Hume SP . (1996): Simplified reference tissue model for PET receptor studies. NeuroImage 4 (3 Pt 1): 153–158
Laruelle M, D'Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fingado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis RB . (1997): Imaging D2 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology 17: 162–174
Laruelle M . (2000): Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. J Cereb Blood Flow Metab 20: 423–451
Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB . (1999): Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacol. 20: 612–627
Maloteaux JM, Gossuin A, Waterkeyn C, Laduron PM . (1983): Trapping of labelled ligands in intact cells: A pitfall in binding studies. Biochem Pharmacol 32: 2543–2548
Maloteaux JM, Hermans E . (1994): Agonist-induced muscarinic cholinergic receptor internalization, recycling and degradation in cultured neuronal cells. Cellular mechanisms and role in desensitization. Biochem Pharmacol 47: 77–88
Murugaiah K, Theodorou A, Clow A, Jenner P, Marsden CD . (1985): Effects of discontinuous drug administration on the development of dopamine receptor supersensitivity during chronic trifluoperazine or cis-flupenthixol administration to rats. Psychopharmacology (Berl) 86 (1–2): 228–232
Nordström A-L, Farde L, Halldin C . (1992): Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology (Berl) 106: 433–438
Nordström A-L, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, Uppfeldt G . (1993): Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: A double-blind PET study of schizophrenic patients. Biol Psychiatry 33: 227–235
Peroutka SJ, Snyder SH . (1980): Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry 137 (12): 1518–1522
Petrie JL, Saha AR, McEvoy JP . (1997): Aripiprazole, A new atypical antipsychotic: Phase 2 clinical trial result. Eur Neuropsychopharmacol 7(Suppl 2): S227
Roth RH, Elsworth JD . (1995): Biochemical pharmacology of midbrain dopamine neurons. In Bloom FE, Kupfer DJ (eds), Psychopharmacology: The fourth Generation of Progress. New York, Raven Press, pp. 227–244
Sanger DJ, Depoortere R, Perrault G . (1997): Discriminative stimulus effects of apomorphine and 7-OH-DPAT: A potential role for dopamine D3 receptors. Psychopharmacology (Berl) 130: 387–395
Seeman P, Lee T, Chau-Wong M, Wong K . (1976): Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 24;261 (5562): 717–719.
Smith M, Wolf AP, Brodie JD, Arnett CD, Barouche F, Shiue CY, Fowler JS, Russell JA, MacGregor RR, Wolkin A, Angrist B, Rotrosen J, Peselow E . (1988): Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients. Biol Psychiatry 23: 653–663
Sternini C, Brecha NC, Minnis J, D'Agostino G, Balestra B, Fiori E, Tonini M . (2000): Role of agonist-dependent receptor internalization in the regulation of mu opioid receptors. Neuroscience 98: 233–241
Theodorou A, Gommeren W, Clow A, Leysen J, Jenner P, Marsden CD . (1981): Chronic neuroleptic treatment specifically alters the number of dopamine receptors in rat brain. Life Sci 6;28 (14): 1621–1627
Vickery RG, von Zastrow M . (1999): Distinct dynamin-dependent and –independent mechanisms target structurally homologous dopamine receptors to different endocytic membranes. J Cell Biol 144: 31–43
Wetzel H, Hillert A, Gründer G, Benkert O . (1992): Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenia. Am J Psychiatry 151: 1499–1502
Wolkin A, Barouche F, Wolf AP, Rotrosen J, Fowler JS, Shiue CY, Cooper TB, Brodie JD . (1989): Dopamine blockade and clinical response: Evidence for two biological subgroups of schizophrenia. Am J Psychiatry 146: 905–908
Wong DF, Gjedde A . (1996): Compartments and reaction volumes of brain fluid spaces: shaken, not stirred. J Nucl Med 37: 126–127
Wong DF, Sølling T, Yokoi F, Gjedde A . (1998): A quantification of extracellular dopamine release in schizophrenia and cocaine use by means of tremble. In Carson RE, Daube-Witherspoon ME, Herscovitch P (eds), Quantitative Functional Brain Imaging with Positron Emission Tomography. New York, Academic Press, pp. 463–468
Wong DF . (2002): In vivo imaging of D2 dopamine receptors in schizophrenia: the ups and downs of neuroimaging research, commentary. Arch Gen Psychiatry 59: 31–34
Young LT, Wong DF, Goldman S, Minkin E, Chen C, Matsumura K, Scheffel U, Wagner HN Jr . (1991): Effects of endogenous dopamine on kinetics of [3H]N-methylspiperone and [3H]raclopride binding in the rat brain. Synapse 9: 188–194
Acknowledgements
We gratefully acknowledge the support of Yun Zhou, Ph.D., Elias Shaya, M.D., Charles Hong, M.D., Ph.D., Boon Chan, Anqing Chen, Andrew H. Crabb, Abdul Kalaff, and David N. Krasenbaum, and all of Johns Hopkins University. We also thank Robert McQuade, PhD, of Bristol Myers Squibb for his comments. This study was supported in part by Otsuka America Pharmaceutical, Inc., USA, and by PHS grants MH42821, DA09482, and HD24448.
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Yokoi, F., Gründer, 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. Neuropsychopharmacol 27, 248–259 (2002). https://doi.org/10.1016/S0893-133X(02)00304-4
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DOI: https://doi.org/10.1016/S0893-133X(02)00304-4
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