Brilaroxazine (RP5063), a Novel Serotonin-Dopamine Stabilizer, Displays Antipsychotic Efficacy in Rodents

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Laxminarayan Bhat Kouacou Adiey Seema R Bhat Prabhu Mohapatra


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

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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: <>. Date accessed: 29 may 2023. doi:
Research Articles


1. van Os J, Kapur Shitij. Schizophrenia. Lancet. 2009;374(9690):635-645.
2. Bhat L, Cantillon M, Ings R. Brilaroxazine (RP5063) Clinical Experience in Schizophrenia:" A New Option to Address Unmet Needs". J Neurol Neuromedicine. 2018;3(5):39-50.
3. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune System Abnormalities in Schizophrenia: An Integrative View and Translational Perspectives. Front Psychiatry. 2022;13. doi:10.3389/fpsyt.2022.880568
4. Goldsmith DR, Rapaport MH. Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits. Front Psychiatry. 2020;11. doi:10.3389/fpsyt.2020.00046
5. Müller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front Neurosci. 2015;9(OCT). doi:10.3389/fnins.2015.00372
6. Murck H, Laughren T, Lamers F, et al. Taking Personalized Medicine Seriously: Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia. Innov Clin Neurosci. 2015;12:26S-40S.
7. Wang D, Wang Y, Chen Y, et al. Differences in inflammatory marker profiles and cognitive functioning between deficit and nondeficit schizophrenia. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.958972
8. Gobira P.H., Ropke J., Aguiar D.C., Crippa JAS, Moreira FA. Animal models for predicting the efficacy and side effects of antipsychotic drugs. Revista Brasileira de Psiquiatria. 2013;35:132-139.
9. McCutcheon RA, Marques TR, Howes OD. Schizophrenia—an overview. JAMA Psychiatry. 2020;77(2):201-210.
10. Baldwin D., Mayers A. Sexual side-effects of antidepressant and antipsychotic drugs. Advances in Psychiatry Therapy. 2003;9:202-210.
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.
54. Health Information: Schizophrenia. National Institute of Mental Health. Published online 2018.
55. Weinberger D.R. Schizophrenia. . In: Davis K, Charney D., Coyle J.T., Nemeroff C, eds. Neuropsychopharmacology- 5th Generation of Progress. . ANCP; 2002:649-650.
56. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2013;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4.
57. López-Gil X, Artigas F, Adell A. Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action. International Journal of Neuropsychopharmacology. 2009;12(4):487-499.
58. Atkins AL, Helms ML, O.’Toole LA, Belknap JK. Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing. Psychopharmacology (Berl. 2001;157(1):96-104.
59. van den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull. 2010;36(2):246-270.
60. Csomor PA, Preller KH, Geyer MA, Studerus E, Huber T, Vollenweider FX. Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy “low and high gating” humans and relation to psychometry. Neuropsychopharmacology. 2014;Sep;39(10):2485-96. doi:10.1038/npp.2014.102.
61. Swerdlow NR, Light GA, Sprock J, Calkins ME, Green MF, Greenwood TA. Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. Schizophr Res. 2014;152(2-3):503-512. doi:10.1016/j.schres.2013.12.004.
62. Rajagopal L, Kwon S, Huang M, et al. RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia. Behavioural brain research. 2017;332:180-199.
63. Stahl SM, Grady MM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th ed. Cambridge University Press; 2011.
64. Švob Štrac D, Pivac N, Mück-Šeler D. The serotonergic system and cognitive function. Transl Neurosci. 2016;7(1):35-49. doi:10.1515/tnsci-2016-0007.
65. Cantillon M, Ings R, Bhat L. Pharmacokinetics of RP5063 following single doses to normal healthy volunteers and multiple doses over 10 days to stable schizophrenic patients. Clin Transl Sci. 2018;11(4):378-386.

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