AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof of principle study

Schizophrenia Research

Volumn 172, Issue 1-3, 2016, Pages 152-157

  Litman, Robert E ^a,b   Smith, Mark A ^c,d   Doherty, James J ^c,e   Cross, Alan ^c   Raines, Shane ^c,f   Gertsik, Lev ^g   Zukin, Stephen R ^c,h,i  

^a CBH Health   (United States)

^b GEORGETOWN UNIVERSITY   (United States)

^c ASTRAZENECA   (United Kingdom)

^d TEVA PHARMACEUTICALS   (Israel)

^e Sage Therapeutics Inc   (United States)

^f 2b Analytics   (United States)

^g CALIFORNIA CLINICAL TRIALS   (United States)

^h FOREST RESEARCH INSTITUTE   (United States)

ⁱ Haborside Financial Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 METHYL 5 (3 PIPERAZIN 1 YLMETHYL[1,2,4]OXADIAZOL 5 YL) 2 (4 TRIFLUOROMETHOXYBENZYL) 2,3 DIHYDROISOINDOL 1 ONE METHANESULFONATE; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; NEUROLEPTIC AGENT; PLACEBO; RISPERIDONE; UNCLASSIFIED DRUG; AZD8529; INDOLE DERIVATIVE; METABOTROPIC RECEPTOR; OXADIAZOLE DERIVATIVE;

ADULT; ADVERSE OUTCOME; AKATHISIA; ANXIETY DISORDER; AREA UNDER THE CURVE; ARTICLE; CLINICAL EFFECTIVENESS; CLINICAL GLOBAL IMPRESSION SCALE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DYSKINESIA; FEMALE; HEADACHE; HUMAN; INCREASED APPETITE; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NOSE OBSTRUCTION; PARKINSONISM; POSITIVE AND NEGATIVE SYNDROME SCALE; PRIORITY JOURNAL; PRURITUS; RANDOMIZED CONTROLLED TRIAL; SCHIZOPHRENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; VOMITING; ADOLESCENT; ALLOSTERISM; BLOOD; METABOLISM; MIDDLE AGED; PSYCHOLOGICAL RATING SCALE; TREATMENT OUTCOME; YOUNG ADULT;

ADOLESCENT; ADULT; ALLOSTERIC REGULATION; ANTIPSYCHOTIC AGENTS; DOUBLE-BLIND METHOD; FEMALE; HUMANS; INDOLES; MALE; MIDDLE AGED; OXADIAZOLES; PSYCHIATRIC STATUS RATING SCALES; RECEPTORS, METABOTROPIC GLUTAMATE; RISPERIDONE; SCHIZOPHRENIA; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84959104261     PISSN: 09209964     EISSN: 15732509     Source Type: Journal    
DOI: 10.1016/j.schres.2016.02.001     Document Type: Article

References (31)

1. Barnes T.R. A rating scale for drug-induced akathisia. Br. J. Psychiatry 1989, 154:672-676.
2. Bugarski-Kirola D., Wang A., Abi-Saab D., Blattler T. A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia - results from the CandleLyte study. Eur. Neuropsychopharmacol. 2014, 24(7):1024-1036.
3. Chaki S. Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia. Eur. J. Pharmacol. 2010, 639(1-3):59-66.
4. Conn P.J., Lindsley C.W., Jones C.K. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol. Sci. 2009, 30(1):25-31.
5. Coyle J.T. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell. Mol. Neurobiol. 2006, 26(4-6):365-384.
6. Coyle J.T., Balu D., Benneyworth M., Basu A., Roseman A. Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. Dialogues Clin. Neurosci. 2010, 12(3):359-382.
7. Cross A.J. AZD8529 - an mGluR2 positive allosteric modulator for the treatment of schizophrenia. Neuropsychopharmacology 2013, 38(S26).
8. 1H-MRS imaging study. Int. J. Neuropsychopharmacol. 2013, 16(2):471-475.
9. de la Fuente-Sandoval C., Leon-Ortiz P., Azcarraga M., Stephano S., Favila R., Diaz-Galvis L., et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis. JAMA Psychiatry. 2013, 70(10):1057-1066.
10. Demjaha A., Egerton A., Murray R.M., Kapur S., Howes O.D., Stone J.M., McGuire P.K. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol. Psychiatry 2013, 75(5):11-13.
11. Gill K.M., Cook J.M., Poe M.M., Grace A.A. Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr. Bull. 2014, 40(2):341-350.
12. Guy W. Abnormal Involuntary Movements Scale (AIMS). ECDEU Assessment Manual for Psychopharmacology, Revised 1976, 534-537. U.S. Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, Rockville, MD.
13. Guy W. Clinical global impression. ECDEU Assessment Manual for Psychopharmacology, Revised 1976, 217-222. U.S. Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, Rockville, MD.
14. Javitt D.C., Zukin S.R. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 1991, 148(10):1301-1308.
15. Kay S.R., Fiszbein A., Opler L.A. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull. 1987, 13(2):261-276.
16. Kinon B.J., Zhang L., Millen B.A., Osuntokun O.O., Williams J.E., Kollack-Walker S., et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J. Clin. Psychopharmacol. 2011, 31(3):349-355.
17. Koback K.A., Skodol A.E., Bender D.S. Structured clinical interview for DSM-IV Axis I disorders (SCID I). Handbook of Psychiatric Measures 2008, American Psychiatric Publishing, Washington, D.C. second ed. A.J. Rush, M.B. First, D. Blacker (Eds.).
18. Krystal J. Efficacy of an mGluR2 agonist (LY354740) and an mGluR2 positive allosteric modulator (AZD8529) in attenuating ketamine effects in humans. Presented at: American College of Neuropsychopharmacology Annual Meeting; Hollywood, Florida 2013.
19. Krystal J.H., Abi-Saab W., Perry E., D'Souza D.C., Liu N., Gueorquieva R., et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 2005, 179(1):303-309.
20. Kurita M., Holloway T., Garcia-Bea A., Kozlenkov A., Friedman A.K., Moreno J.L., Heshmati M., Golden S.A., Kennedy P.J., Takahashi N., Dietz D.M., Mocci G., Gabilondo A.M., Hanks J., Umali A., Callado L.F., Gallitano A.L., Neve R.L., Shen L., Buxbaum J.D., Han M.-H., Nestler E.J., Meana J.J., Russo S.J., Gonzalez-Maeso J. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat. Neurosci. 2012, 15(9):1245-1254.
21. Li M.L., Hu X.Q., Li F., Gao W.J. Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: still promising or a dead end?. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015, 6:66-76.
22. Lin C.H., Lane H.Y., Tsai G.E. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol. Biochem. Behav. 2012, 100(4):665-677.
23. Moreno J.L., Sealfon S.C., Gonzalez-Maeso J. Group II metabotropic glutamate receptors and schizophrenia. Cell. Mol. Life Sci. 2009, 66(23):3777-3785.
24. Patil S.T., Zhang L., Martenyi F., Lowe S.L., Jackson K.A., Andreev B.V., et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat. Med. 2007, 13(9):1102-1107.
25. Pietrzak R.H., Olver J., Norman T., Piskulic D., Maruff P., Snyder P.J. A comparison of the cogstate schizophrenia battery and the measurement and treatment research to improve cognition in schizophrenia (MATRICS) battery in assessing cognitive impairment in chronic schizophrenia. J. Clin. Exp. Neuropsychol. 2009, 31(7):848-859.
26. Salih H., Anghelescu I., Kezic I., Sinha V., Hoeben E., Van Nueten L., De Smedt H., De Boer P. Pharmacokinetic and pharmacodynamics characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomized, double-blind phase-1 studies. J. Psychopharmacol. 2015, 29(4):414-425.
27. Simpson G.M., Angus J.W. A rating scale for extrapyramidal side effects. Acta Psychiatr. Scand. Suppl. 1970, 45(212):11-19.
28. Stauffer V.L., Millen B.A., Anderson S., Kinon B.J., LaGrandeur L., Lindenmayer J.P., Gomez J.C. Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo. Schizophr. Res. 2013, 150(2-3):434-441.
29. Umbricht D., Alberati D., Martin-Facklam M., Borroni E., Youssef E.A., Ostland M., et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry 2014, 71(6):637-646.
30. Vinson P.N., Conn P.J. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology 2012, 62(3):1461-1472.
31. Wolf D., Ruparel K., Turetsky B., Kohler C., Satterthwaite T., Elliot M., March M., Cross A., Smith M., Zukin S., Gur R.C., Gur R.E. Striatal activation induced by mGluR2 positive allosteric modulation correlates with negative symptom reduction in schizophrenia. Neuropsychopharmacology 2013, 38:S141-S142.