Các tiền dược agonist thụ thể glutamate chuyển hóa nhóm II LY2979165 và LY2140023 làm giảm phản ứng hình ảnh chức năng với ketamine ở người khỏe mạnh

Psychopharmacology - Tập 235 - Trang 1875-1886 - 2018
Mitul A. Mehta1, Anne Schmechtig1, Vasileia Kotoula1, Juliet McColm2, Kimberley Jackson2, Claire Brittain2, Sitra Tauscher-Wisniewski, Bruce J. Kinon3, Paul D. Morrison4, Thomas Pollak4, Timothy Mant5, Steven C. R. Williams1, Adam J. Schwarz6
1Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
2Eli Lilly and Company, Windlesham, UK
3Lundbeck LLC, Deerfield, USA
4Psychosis Studies Department, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
5QuintilesIMS, Reading, UK
6Eli Lilly and Company, Indianapolis, USA

Tóm tắt

Sự truyền dẫn tín hiệu glutamate bất thường, đặc biệt là sự rối loạn của thụ thể N-methyl-d-aspartate (NMDAR), đã được liên kết với các rối loạn tâm thần và đại diện cho một mục tiêu điều trị mới. Việc sử dụng ketamine, một chất đối kháng NMDA với liều thấp, trên những người tình nguyện khỏe mạnh tạo ra một tín hiệu hình ảnh phụ thuộc mức độ oxy trong máu (BOLD) mạnh mẽ, có thể bị cản trở bởi việc điều trị trước bằng các liều đơn, có hiệu quả trị liệu của các thuốc đã được thị trường hóa tương tác với hệ thống glutamate. Để kiểm tra sự cản trở tín hiệu BOLD do ketamine gây ra bởi việc điều trị trước bằng either một agonist thụ thể glutamate chuyển hóa (mGluR) 2/3 hoặc một agonist mGluR2 ở những người tình nguyện khỏe mạnh, chúng tôi đã sử dụng một thí nghiệm thách thức ketamine với hình ảnh cộng hưởng từ dược lý (phMRI) để đánh giá hiệu ứng điều chỉnh của các liều đơn cấp tính của LY2140023 (pomaglumetad methionil), tiền dược methionine của agonist mGluR2/3 LY404039 (10, 40 và 160 mg; N = 16 người tham gia) và của LY2979165, cùng với tiền dược alanine của agonist mGluR2 chọn lọc ortho-steric 2812223 (20 và 60 mg; N = 16 người tham gia). Sự giảm tín hiệu phMRI BOLD do ketamine kích thích so với giả dược đã được quan sát thấy ở các liều cao nhất của cả LY2140023 và LY2979165. Một mối quan hệ đã được quan sát giữa sự giảm tín hiệu BOLD và nồng độ plasma của 2812223 tăng lên trong nhóm LY2979165. Những kết quả này xác định các liều hoạt động dược lý của các tiền dược agonist mGluR nhóm II LY2140023 và LY2979165 ở người. Chúng cũng mở rộng các loại hợp chất đã được chứng minh là có thể đảo ngược tín hiệu phMRI do ketamine gây ra ở người, hỗ trợ thêm cho việc sử dụng phương pháp này như một dấu ấn sinh học hình ảnh thần kinh để đánh giá các tác động chức năng.

Từ khóa

#ketamine #thụ thể NMDAR #mGluR #hình ảnh cộng hưởng từ dược lý #BOLD #rối loạn tâm thần

Tài liệu tham khảo

Absalom AR, Lee M, Menon DK, Sharar SR, De Smet T, Halliday J et al (2007) Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers. Br J Anaesth 98(5):615–623. https://doi.org/10.1093/bja/aem063 Adams DH, Kinon BJ, Baygani S, Millen BA, Velona I, Kollack-Walker S, Walling DP (2013) A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry 13(1):143. https://doi.org/10.1186/1471-244X-13-143 Adams DH, Zhang L, Millen BA, Kinon BJ, Gomez JC (2014) Pomaglumetad Methionil (LY2140023 monohydrate) and aripiprazole in patients with schizophrenia: a phase 3, multicenter, double-blind comparison. Schizophr Res Treat 2014:758212–758211. https://doi.org/10.1155/2014/758212 Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ et al (2012) NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A 109(41):16720–16725 Bifone A, Gozzi A (2012) Neuromapping techniques in drug discovery: pharmacological MRI for the assessment of novel antipsychotics. Expert Opin Drug Discov 7(11):1071–1082 Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218 Chaves C, Marque CR, Trzesniak C, Machado de Sousa JP, Zuardi AW, Crippa JAS et al (2009) Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update. Braz J Med Biol Res 42(11):1002–1014 Chaves C, Marque CR, Maia-de-Oliveira JP, Wichert-Ana L, Ferrari TB, Santos AC et al (2015) Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia. Schizophr Res 161(2–3):439–445. https://doi.org/10.1016/j.schres.2014.11.031 De Simoni S, Schwarz AJ, O'Daly OG, Marquand AF, Brittain C, Gonzales C et al (2013) Test-retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers. NeuroImage 64:75–90. https://doi.org/10.1016/j.neuroimage.2012.09.037 Deakin JFW, Lees J, McKie S, Hallak JEC, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine. Arch Gen Psychiatry 65(2):154–164 Dedeurwaerdere S, Wintmolders C, Straetemans R, Pemberton D, Langlois X (2011) Memantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds: exemplified by activity of an mGlu2/3 receptor agonist. Psychopharmacology 214(2):505–514. https://doi.org/10.1007/s00213-010-2052-z Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD (2012) Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 169(11):1203–1210. https://doi.org/10.1176/appi.ajp.2012.12010144 Doyle OM, De Simoni S, Schwarz AJ, Brittain C, O'Daly OG, Williams SC, Mehta MA (2013) Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents. J Pharmacol Exp Ther 345(1):151–160. https://doi.org/10.1124/jpet.112.201665 Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD (2008) Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 33(7):1603–1610. https://doi.org/10.1038/sj.npp.1301531 Duncan GE, Miyamoto S, Leipzig JN, Lieberman JA (1999) Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine. Brain Res 843(1–2):171–183 Egerton A, Stone J (2012) The glutamate hypothesis of schizophrenia: neuroimaging and drug development. Curr Pharm Biotechnol 13(8):1500–1512 Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK, Stone JM (2012a) Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 37(11):2515–2521. https://doi.org/10.1038/npp.2012.113 Egerton A, Fusar-Poli P, Stone J (2012b) Glutamate and psychosis risk. Curr Pharm Des 18(4):466–478 Egerton A, Stone JM, Chaddock CA, Barker GJ, Bonoldi I, Howard RM et al (2014) Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis. Neuropsychopharmacology 39(12):2891–2899. https://doi.org/10.1038/npp.2014.143 Ginovart N, Kapur S (2012) Role of dopamine D(2) receptors for antipsychotic activity. Handb Exp Pharmacol (212):27–52. doi:https://doi.org/10.1007/978-3-642-25761-2_2 Gozzi A, Large CH, Schwarz A, Bertani S, Crestan V, Bifone A (2008) Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33(7):1690–1703. https://doi.org/10.1038/sj.npp.1301547 Hashimoto K (2014) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets 18(9):1049–1063. https://doi.org/10.1517/14728222.2014.934225 Howes O, McCutcheon R, Stone J (2015) Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol 29(2):97–115. https://doi.org/10.1177/0269881114563634 Iwata Y, Nakajima S, Suzuki T, Keefe RS, Plitman E, Chung JK et al (2015) Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. Mol Psychiatry 20(10):1151–1160. https://doi.org/10.1038/mp.2015.68 Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K et al (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3(102):102mr102 Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS et al (2017) Utility of imaging-based biomarkers for glutamate-targeted drug development in psychotic disorders: a randomized clinical trial. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2017.3572 Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157(4):514–520 Kendell SF, Krystal JH, Sanacora G (2005) GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets 9(1):153–168. https://doi.org/10.1517/14728222.9.1.153 Kinon BJ, Gomez JC (2013) Clinical development of pomaglumetad methionil: a non-dopaminergic treatment for schizophrenia. Neuropharmacology 66:82–86. https://doi.org/10.1016/j.neuropharm.2012.06.002 Kinon BJ, Millen BA, Zhang L, McKinzie DL (2015) Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry 78:754–762. https://doi.org/10.1016/j.biopsych.2015.03.016 Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214 Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R et al (2005) Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 179(1):303–309. https://doi.org/10.1007/s00213-004-1982-8 Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19 Large CH (2007) Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol 21(3):283–301. https://doi.org/10.1177/0269881107077712 Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and n-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117(3):697–706. https://doi.org/10.1016/s0306-4522(02)00652-8 Maksymetz J, Moran SP, Conn PJ (2017) Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Mol Brain 10(1):15. https://doi.org/10.1186/s13041-017-0293-z Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150 Mason OJ, Morgan CJ, Stefanovic A, Curran HV (2008) The psychotomimetic states inventory (PSI): measuring psychotic-type experiences from ketamine and cannabis. Schizophr Res 103(1–3):138–142. https://doi.org/10.1016/j.schres.2008.02.020 McColm J, Brittain C, Suriyapperuma S, Swanson S, Tauscher-Wisniewski S, Foster J, Soon D, Jackson K (2017) Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects. Br J Clin Pharmacol 83:1654–1667. https://doi.org/10.1111/bcp.13252 Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK (2016) Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73(7):665–674. https://doi.org/10.1001/jamapsychiatry.2016.0442 Moghaddam B (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281(5381):1349–1352. https://doi.org/10.1126/science.281.5381.1349 Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37(1):4–15. https://doi.org/10.1038/npp.2011.181 Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS et al (2015) Synthesis and pharmacological characterization of C4-(thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY2812223), a highly potent, functionally selective mGlu2 receptor agonist. J Med Chem. https://doi.org/10.1021/acs.jmedchem.5b01124 Northoff G, Richter A, Bermpohl F, Grimm S, Martin E, Marcar VL, Wahl C, Hell D, Boeker H (2005) NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI. Schizophr Res 72(2–3):235–248. https://doi.org/10.1016/j.schres.2004.04.009 Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007 Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV et al (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13(9):1102–1107. https://doi.org/10.1038/nm1632 Poels EM, Kegeles LS, Kantrowitz JT, Slifstein M, Javitt DC, Lieberman JA et al (2014) Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry 19(1):20–29. https://doi.org/10.1038/mp.2013.136 Pollak TA, De Simoni S, Barimani B, Zelaya FO, Stone JM, Mehta MA (2015) Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study. Psychopharmacology 232(24):4515–4524. https://doi.org/10.1007/s00213-015-4078-8 Reid JG, Gitlin MJ, Altshuler LL (2013) Lamotrigine in psychiatric disorders. J Clin Psychiatry 74(7):675–684. https://doi.org/10.4088/JCP.12r08046 Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7(5):426–437. https://doi.org/10.1038/nrd2462 Schizophrenia Working Group of the Psychiatric Genetics Consortium, T (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427. https://doi.org/10.1038/nature13595 Stauffer VL, Millen BA, Andersen S, Kinon BJ, Lagrandeur L, Lindenmayer JP, Gomez JC (2013) Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo. Schizophr Res 150(2–3):434–441. https://doi.org/10.1016/j.schres.2013.08.020 Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ et al (2012) Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol Psychiatry 17(7):664–665. https://doi.org/10.1038/mp.2011.171 Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA (2015) Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. J Psychopharmacol 29:1025–1028. https://doi.org/10.1177/0269881115592337 Zhang W, Mitchell MI, Knadler MP, Long A, Witcher J, Walling D, Annes W, Ayan-Oshodi M (2015) Effect of pomaglumetad methionil on the QT interval in subjects with schizophrenia. Int J Clin Pharmacol Ther 53(6):462–470 Zink M, Correll CU (2015) Glutamatergic agents for schizophrenia: current evidence and perspectives. Expert Rev Clin Pharmacol 8(3):335–352