Brilaroxazine (RP5063), a Novel Serotonin-Dopamine Stabilizer, Displays Antipsychotic Efficacy in Rodents
Main Article Content
Abstract
Introduction: Brilaroxazine (RP5063) displays high affinity for serotonin (5-HT) 1A/2A/2B/7 and dopamine (D) 2/3/4 and moderate affinity for D1, serotonin transporter (SERT), and nicotinic acetylcholine receptor, α4β2. These receptors are associated with multiple psychological disorders.
Methods: The pre-clinical assessment involved three standard models emulating human schizophrenia symptoms. The apomorphine climbing test (Protais et al., 1976), in 5 groups of 10 NMRI mice, compared brilaroxazine (1, 3, and 10 mg/kg i.p.), haloperidol (0.5 mg/kg i.p.), and vehicle. The apomorphine-induced deficit in prepulse inhibition (PPI) (Geyer et al., 2001), in 5 groups of 15 Wistar rats, compared brilaroxazine (3, 10, and 30 mg/kg i.p.), haloperidol (1 mg/kg), and vehicle. The dizocilpine effect on locomotion, stereotypy, and rearing (Rung et al. 2005), in 6 groups of 10 Wistar rats, compared brilaroxazine (3, 10, and 30 mg/kg i.p.), olanzapine (6 mg/kg i.p.) and vehicle with (and without) induction.
Results: Brilaroxazine decreased apomorphine-induced climbing across the 1, 3, and 10 mg/kg doses versus controls (p<0.001). This compound dose-dependently reversed the apomorphine-induced PPI effects- 10 mg/kg at 87 dB (p<0.05) and 30 mg/kg at all levels (p<0.01). In the dizocilpine-induced model, it decreased versus vehicle controls: (1) spontaneous locomotor activity by 15% (p<0.05, 3 mg/kg), 40% (p<0.001, 10 mg/kg) and 30% (p<0.01, 30 mg/kg); (2) induced locomotion by 25% (p<0.05, 3 mg/kg), 49% (p<0.01, 10 mg/kg), and 47% (p<0.01, 30 mg/kg), (3) stereotypy by 51% and 58% (p<0.001, 10- and 30-mg/kg, respectively), and rearing (only 10 mg/kg, NS).
Conclusion: Brilaroxazine showed animal proof-of-concept activity by mitigating pharmacologically induced behaviors in rodents reflecting psychotic symptoms in humans.
Keywords:
Antipsychotic, Brilaroxazine, Dizocilpine (MK-801)-induced model, Prepulse inhibition test, Rodent models of schizophrenia, RP5063, Schizophrenia
Article Details
How to Cite
BHAT, Laxminarayan et al.
Brilaroxazine (RP5063), a Novel Serotonin-Dopamine Stabilizer, Displays Antipsychotic Efficacy in Rodents.
Medical Research Archives, [S.l.], v. 11, n. 4, may 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3834>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3834.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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11. Hansen T.E., Casey DE., Hoffman W.F. Neuroleptic intolerance. Schizophr Bull. 1997;23(4):567-582.
12. Meltzer H.Y., Risinger R., Nasrallah H.A., du Y., Zummo J., Corey L. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015;76(8):1085-1090. doi:10.4088/JCP.14m09741.
13. Üçok A., Gaebel W. Side effects of atypical antipsychotics: a brief overview. World Psychiatry. 2008;7:58-62.
14. Henna Neto J, Elkis H. Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study. Brazilian Journal of Psychiatry. 2007;29:228-232.
15. Kane JM. Clinical efficacy of clozapine in treatment-refractory schizophrenia: an overview. The British Journal of Psychiatry. 1992;160(S17):41-45.
16. Elkis H, Meltzer HY. Refractory schizophrenia. Brazilian Journal of Psychiatry. 2007;29:S41-S47.
17. Pierre JM, Wirshing DA, Wirshing WC, et al. High-dose quetiapine in treatment refractory schizophrenia. Published online 2005.
18. Lindenmayer JP. Treatment refractory schizophrenia. Psychiatric Quarterly. 2000;71(4):373-384.
19. Frankel J, Schwartz T. Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol. 2017;7(1):29-41. doi:10.1177/2045125316672136.
20. Ascher-Svanum H, Zhu B, Faries D, Landbloom R, Swartz M, Swanson J. Time to discontinuation of atypical versus typical antipsychotics in the naturalistic treatment of schizophrenia. BMC Psychiatry. 2006;6:8. doi:10.1186/1471-244X-6-8.
21. Cramer J, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv. 1998;49(2):196-201.
22. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Published online 2008.
23. Kroken AR, Kjelby E, Wentzel-Larsen T, Mellesdal SS, Jørgensen AH, Johnsen E. Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: influence of current treatment strategies. Ther Adv Psychopharmacol. 2014;4(6):228-239. doi:10.1177/2045125314545614.
24. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;3):CD006654. doi:10.1002/14651858.CD006626.pub2.
25. Levine SZ, Goldberg Y, Samara M, Davis JM, Leucht S. Joint modeling of dropout and outcome in three pivotal clinical trials of schizophrenia. Schizophr Res. 2015;164(1-3):122-126. doi:10.1016/j.schres.2015.02.021.
26. Leucht S, Heres S, Hamann J, Kane JM. Methodological issues in current antipsychotic drug trials. Schizophr Bull. 2008;34(2):275-285.
27. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE. Investigators N Engl J Med. 2005;353(12):1209-1223.
28. Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E. 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(7):681-690.
29. Carpenter WT, Koenig JI. The evaluation of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology. 2008;33:2061-2079.
30. Kemmler G, Hummer M, Widschwendter C, Fleischhacker WW. Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs: a meta-analysis. Arch Gen Psychiatry. 2005;Dec;62(12):1305-12.
31. Rabinowitz J, Davidov O. A composite approach that includes dropout rates when analyzing efficacy data in clinical trials of antipsychotic medications.Schizophr Bull. Published online 2008.
32. Cantillon M, Prakash A, Alexander A, Ings R, Sweitzer D, Bhat L. Dopamine Serotonin Stabilizer RP5063: A Randomized, Double-blind, Placebo-controlled Multicenter Trial of Safety and Efficacy in Exacerbation of Schizophrenia or Schizoaffective Disorder. Schizophr Res. 2017;189:126-133. doi:10.1016/j.schres.2017.01.043.
33. Koester LS, Carbon M, Correll CU. Emerging drugs for schizophrenia: an update. Expert Opin Emerg. 2014;Drugs.19(4:511-531. doi:10.1517/14728214.2014.958148.
34. Belgamwar RB, El-Sayeh HG. Aripiprazole versus placebo for schizophrenia. Cochrane Database Syst Rev. 2011;8.
35. Hirose T, Kikuchi T. Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J Med Investig. 2005;52:284-290.
36. Kiss B, Horvath A, Nemethy Z, Schmidt E, Laszlovszky I, Bugovics G. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3/D2 dopamine receptor antagonist–partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010;333(1):328-340. doi:10.1124/jpet.109.160432.
37. Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulators. J Pharmacol Exp Ther. 2014;350:589-604. doi:10.1124/jpet.114.213793.
38. Cantillon M, Ings R, Bhat L. Initial clinical experience of RP5063 following single doses in normal healthy volunteers and multiple doses in patients with stable schizophrenia. Clin Transl Sci. Published online 2018. doi:10.1111/cts.12545.
39. Bhat L, Hawkinson J, Cantillon M, et al. RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats. Eur J Pharmacol. 2017;810:92-99.
40. Bhat L, Hawkinson J, Cantillon M, et al. RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia–induced pulmonary arterial hypertension in rats. Eur J Pharmacol. 2017;810:83-91.
41. Bhat L, Bhat SR, Nault MC, Biernat M, Labbe SM. Evaluation of Brilaroxazine (RP5063) in a Bleomycin-Induced Rodent Model of Idiopathic Pulmonary Fibrosis. Medical Research Archives (Accepted). Published online 2023.
42. Bhat L, Bhat SR, Ramakrishna A, Amirthalingam M. Brilaroxazine Topical Liposomal-gel Formulation Displays Efficacy in the Imiquimod-induced Psoriatic BALB/c Mouse Model. In: International Societies for Investigative Dermatology. International Societies for Investigative Dermatology; 2023.
43. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. Front Psychiatry. 2022;13.
44. Protais P, Costentin J, Schwartz JC. Climbing Behavior Induced by Apomorphine in Mice. a simple test for the study of dopamine receptors in striatum. Psychopharmacology (Berl). 1976;50:1-6.
45. Geyer MA, Moghaddam AB. Chapter 50: Animal Models Relevant to Schizophrenia Disorders. In: K.L. D, D. C, J.T C, C N, eds. Neuropsyopharmacology: The Fifth Generation of Progress Geyer Psycho-Pharmacology. ; 2002:117-154.
46. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl. 2001;Jul;156(2-3):117-54.
47. Rung JP, Carlsson A, Rydén Markinhuhta K, Carlsson ML. MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(5):827-832.
48. Jahkel M, Rilke O, Koch R, Oehler J. Open field locomotion and neurotransmission in mice evaluated by principal component factor analysiseffects if housing condition, individual activity disposition and psychotropic drugs. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24:61-84.
49. Carrey N, McFadyen PM, Brown RE. Effects of chronic methylphenidate administration on the locomotor and exploratory behavior of prepubertal mice. J Child Adolesc Psychopharmacol. 2000;10:277-286.
50. Burton N. Psychiatry. 2nd ed. Wiley-Blackwell; 2010.
51. Carli M, Invernizzi RW. Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task. Front Neural Circuits. 2014;8(58). doi:10.3389/fncir.2014.00058.
52. Rolland B, Jardri R, Amad A, Thomas P, Cottencin O, Bordet R. Pharmacology of hallucinations: several mechanisms for one single symptom? Biomed Res Int. 2014;2014(307106). doi:10.1155/2014/307106.
53. Matthews M., Tesar G., Fattal O., Muzina D.J. Schizophrenia and Acute Psychosis. . Published 2013. Accessed January 20, 2023. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/psychiatry-psychology/schizophrenia-acute-psychosis/.
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