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Emerging pharmacological therapies in schizophrenia: what’s new, what’s different, what’s next?

Published online by Cambridge University Press:  03 January 2017

Leslie Citrome
Leslie Citrome*
Affiliation:
Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, New York, USA
*
*Address for correspondence: Leslie Citrome, MD, MPH, 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USA. (Email: citrome@cnsconsultant.com)
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Abstract

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.

Keywords

Aripiprazole lauroxilbrexpiprazolecariprazinedeutetrabenazinelong-acting injectablelumateperonepaliperidone palmitaterisperidonevalbenazine
Type
CME Review Article
Information
CNS Spectrums , Volume 21 , Supplement S1: CME SUPPLEMENT , December 2016 , pp. 1 - 12
Copyright
© Cambridge University Press 2016 

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Footnotes

This activity is supported by an unrestricted educational grant from Intra-Cellular Therapies.

References

1. Leucht, S, Cipriani, A, Spineli, L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013; 382(9896): 951–962.Google Scholar
2. Volavka, J, Citrome, L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother. 2009; 10(12): 1917–1928.Google Scholar
3. Citrome, L, Eramo, A, Francois, C, et al. Lack of tolerable treatment options for patients with schizophrenia. Neuropsychiatr Dis Treat. 2015; 11: 3095–3104.Google Scholar
4. Citrome, L. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Psychiatry. 2014; 75(Suppl 1): 21–26.Google Scholar
5. Aquila, R, Citrome, L. Cognitive impairment in schizophrenia: the great unmet need. CNS Spectr. 2015; 20(Suppl 1): 35–39.Google Scholar
6. Otsuka. REXULTI (brexpiprazole) tablets, for oral use. Prescribing information. Revised September 2016. Available at: https://www.otsuka-us.com/media/static/Rexulti-PI.pdf. Last accessed September 27, 2016.Google Scholar
7. Citrome, L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2015; 69(9): 978–997.CrossRefGoogle ScholarPubMed
8. McEvoy, J, Citrome, L. Brexpiprazole for the treatment of schizophrenia: a review of this novel serotonin-dopamine activity modulator. Clin Schizophr Relat Psychoses. 2016; 9(4): 177–186.Google Scholar
9. Citrome, L, Stensbøl, TB, Maeda, K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother. 2015; 15(10): 1219–1229.Google Scholar
10. Correll, CU, Skuban, A, Ouyang, J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015; 172(9): 870–880.Google Scholar
11. Kane, JM, Skuban, A, Ouyang, J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015; 164(1–3): 127–135.Google Scholar
12. Fleischhacker, WW, Hobart, M, Ouyang, J, et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomised, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. In press. doi: 10.1093/ijnp/pyw076.Google Scholar
13. Kane, JM, Skuban, A, Hobart, M, et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016; 174(1–3): 93–98.Google Scholar
14. Actavis. VRAYLAR (cariprazine) capsules, for oral use. Prescribing Information. Revised September 2015. Available at: http://www.allergan.com/assets/pdf/vraylar_pi. Last accessed September 27, 2016.Google Scholar
15. Citrome, L. Cariprazine for the treatment of schizophrenia: a review of this dopamine D3-preferring D3/D2 receptor partial agonist. Clin Schizophr Relat Psychoses. 2016; 10(2): 109–119.CrossRefGoogle ScholarPubMed
16. Durgam, S, Cutler, AJ, Lu, K, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015; 76(12): e1574–e1582.Google Scholar
17. Kane, JM, Zukin, S, Wang, Y, et al. Efficacy and Safety of cariprazine in acute exacerbation of schizophrenia: results from an international, Phase III clinical trial. J Clin Psychopharmacol. 2015; 35(4): 367–373.Google Scholar
18. Durgam, S, Starace, A, Li, D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014; 152(2–3): 450–457.CrossRefGoogle ScholarPubMed
19. Durgam, S, Earley, W, Li, R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. Schizophr Res. 2016; 176(2–3): 264–271.Google Scholar
20. Alkermes. ARISTADA (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular use. Prescribing information. Revised October 2015. Available at: http://www.alkermes.com/assets/content/files/AristadaPI.pdf. Last accessed September 27, 2016.Google Scholar
21. Citrome, L. Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil. Expert Rev Clin Pharmacol. 2016; 9(2): 169–186.Google Scholar
22. Meltzer, HY, Risinger, R, Nasrallah, HA, et al. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015; 76(8): 1085–1090.Google Scholar
23. Janssen. INVEGA TRINZA (paliperidone palmitate) extended-release injectable suspension, for intramuscular use. Prescribing information. Revised March 2016. Available at: https://www.janssenmd.com/pdf/invega-trinza/INVEGA-TRINZA_PI.pdf. Last accessed September 27, 2016.Google Scholar
24. Berwaerts, J, Liu, Y, Gopal, S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015; 72(8): 830–839.Google Scholar
25. Savitz, AJ, Xu, H, Gopal, S, et al. Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol. 2016; 19(7): pyw018.Google Scholar
26. Citrome, L. The ABC’s of dopamine receptor partial agonists—aripiprazole, brexpiprazole and cariprazine: the 15-min challenge to sort these agents out. Int J Clin Pract. 2015; 69(11): 1211–1220.Google Scholar
27. Kiss, B, Horváth, A, Némethy, Z, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333(1): 328–340.Google Scholar
28. Zimnisky, R, Chang, G, Gyertyán, I, Kiss, B, Adham, N, Schmauss, C. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013; 226(1): 91–100.Google Scholar
29. Citrome, L. Schizophrenia relapse, patient considerations, and potential role of lurasidone. Patient Prefer Adherence. 2016; 10: 1529–1537.CrossRefGoogle ScholarPubMed
30. Otsuka. ABILIFY MAINTENA® (aripiprazole) for extended-release injectable suspension, for intramuscular use. Prescribing information. Revised August 2016. Available at: https://www.otsuka-us.com/media/static/Abilify-M-PI.pdf. Last accessed September 27, 2016.Google Scholar
31. Kane, JM, Sanchez, R, Perry, PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012; 73(5): 617–624.Google Scholar
32. Fleischhacker, WW, Sanchez, R, Perry, PP, et al. Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study. Br J Psychiatry. 2014; 205(2): 135–144.Google Scholar
33. Ishigooka, J, Nakamura, J, Fujii, Y, et al. Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multicenter, randomized, double-blind, non-inferiority study versus oral aripiprazole. Schizophr Res. 2015; 161(2–3): 421–428.Google Scholar
34. Naber, D, Hansen, K, Forray, C, et al. Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res. 2015; 168(1–2): 498–504.CrossRefGoogle ScholarPubMed
35. Citrome, L, Kamat, SA, Sapin, C, et al. Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States. J Med Econ. 2014; 17(8): 567–576.CrossRefGoogle ScholarPubMed
36. Ravenstijn, P, Remmerie, B, Savitz, A, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016; 56(3): 330–339.Google Scholar
37. Janssen. INVEGA SUSTENNA (paliperidone palmitate) extended-release injectable suspension, for intramuscular use. Prescribing information. Revised March 2016. Available at: https://www.invegasustennahcp.com/sites/www.invegasustennahcp.com/files/prescribing-information-invegasustenna.pdf. Last accessed September 27, 2016.Google Scholar
38. Lieberman, JA, Davis, RE, Correll, CU, et al. ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial. Biol Psychiatry. 2016; 79(12): 952–961.Google Scholar
39. Davis, RE, Vanover, KE, O’Gorman, C, et al. ITI-007 for the treatment of schizophrenia: primary & secondary efficacy endpoints and subgroup analyses from two positive randomized, double-blind, placebo-controlled clinical trials. Poster presentation P6-146. Presented at: American Psychiatric Association Annual Meeting; May 14–18, 2016; Atlanta, GA.Google Scholar
40. O’Gorman, C, Vanover, KE, Davis, RE, et al. ITI-007 for the treatment of schizophrenia: safety & tolerability data to date from two double-blind, randomized, placebo-controlled clinical trials. Poster presentation P6-147. Presented at: American Psychiatric Association Annual Meeting; May 14–18, 2016; Atlanta, GA.Google Scholar
41. Snyder, GL, Vanover, KE, Zhu, H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015; 232(3): 605–621.Google Scholar
42. Davis, RE, Correll, CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016; 16(6): 601–614.Google Scholar
43. Intra-Cellular Therapies. Corporate Presentation, 2016. Available at: http://files.shareholder.com/downloads/AMDA-2O83FW/2571108091x0x862131/DF51C35D-C947-4959-B5A6-DC4B9BC3CF76/ITCI_Corporate_Presentation.pdf. Last accessed September 27, 2016.Google Scholar
44. Woods, SW, Morgenstern, H, Saksa, JR, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry. 2010; 71(4): 463–474.Google Scholar
45. Kane, JM. Tardive dyskinesia circa 2006. Am J Psychiatry. 2006; 163(8): 1316–1318.Google Scholar
46. Margolese, HC, Chouinard, G, Kolivakis, TT, Beauclair, L, Miller, R. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. Can J Psychiatry. 2005; 50(9): 541–547.Google Scholar
47. Margolese, HC, Chouinard, G, Kolivakis, TT, Beauclair, L, Miller, R, Annable, L. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry. 2005; 50(11): 703–714.CrossRefGoogle ScholarPubMed
48. Leung, JG, Breden, EL. Tetrabenazine for the treatment of tardive dyskinesia. Ann Pharmacother. 2011; 45(4): 525–531.Google Scholar
49. Müller, T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs. 2015; 24(6): 737–742.Google Scholar
50. Huntington Study Group, Frank, S, Testa, CM, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA. 2016; 316(1): 40–50.Google Scholar
51. Auspex Pharmaceuticals. Treating Hyperkinetic Movement Disorders. December 2014. Available at: http://files.shareholder.com/downloads/AMDA-2IEHYZ/0x0x797219/01a86e01-44d4-4ee0-9fb2-69537c486954/Piper%20Jaffray%20Presentation%2012-2-14.pdf. Last accessed September 27, 2016.Google Scholar
52. Guengerich, FP. Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions. J Labelled Comp Radiopharm. 2013; 56(9–10): 428–431.Google Scholar
53. Anderson, KE, Factor, SA, Hauser, RA, et al. A randomized, double-blind, placebo-controlled trial of deutetrabenazine for the treatment of tardive dyskinesia (ARM-TD). Poster presentation P8-004. Presented at: American Psychiatric Association Annual Meeting; May 14–18, 2016; Atlanta, GA.Google Scholar
54. O’Brien, CF, Jimenez, R, Hauser, RA, et al. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, double-blind, placebo-controlled study. Mov Disord. 2015; 30(12): 1681–1687.Google Scholar
55. Marder, S, Knesevich, MA, Hauser, RA, Liang, GS, O’Brien, CF. KINECT 3: a randomized, double-blind, placebo-controlled Phase 3 trial of valbenazine (NBI-98854) for tardive dyskinesia. Poster presentation P8-082. Presented at: American Psychiatric Association Annual Meeting; May 14–18, 2016; Atlanta, GA.Google Scholar
56. Alkermes. Alkermes submits supplemental new drug application to FDA for two-month dosing option of ARISTADA® for treatment of schizophrenia. Press release. August 8, 2016. Available at: http://investor.alkermes.com/mobile.view?c=92211&v=203&d=1&id=2193630. Last accessed September 27, 2016.Google Scholar
57. Gomeni, R, Heidbreder, C, Fudala, PJ, Nasser, AF. A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone. J Clin Pharmacol. 2013; 53(10): 1010–1019.Google Scholar
58. Laffont, CM, Gomeni, R, Zheng, B, Heidbreder, C, Fudala, PJ, Nasser, AF. Population pharmacokinetics and prediction of dopamine D2 receptor occupancy after multiple doses of RBP-7000, a new sustained-release formulation of risperidone, in schizophrenia patients on stable oral risperidone treatment. Clin Pharmacokinet. 2014; 53(6): 533–543.Google Scholar
59. Laffont, CM, Gomeni, R, Zheng, B, Heidbreder, C, Fudala, PJ, Nasser, AF. Population pharmacokinetic modeling and simulation to guide dose selection for RBP-7000, a new sustained-release formulation of risperidone. J Clin Pharmacol. 2015; 55(1): 93–103.Google Scholar
60. Nasser, AF, Henderson, DC, Fava, M, et al. Efficacy, safety, and tolerability of RBP-7000 once-monthly risperidone for the treatment of acute schizophrenia: an 8-week, randomized, double-blind, placebo-controlled, multicenter Phase 3 study. J Clin Psychopharmacol. 2016; 36(2): 130–140.Google Scholar
61. Isitt, JJ, Nadipelli, VR, Kouassi, A, Fava, M, Heidbreder, C. Health-related quality of life in acute schizophrenia patients treated with RBP-7000 once monthly risperidone: an 8-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study. Schizophr Res. 2016; 174(1–3): 126–131.CrossRefGoogle ScholarPubMed