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Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study

  • Andrew J. Cutler (a1), Suresh Durgam (a2), Yao Wang (a3), Raffaele Migliore (a2), Kaifeng Lu (a2), István Laszlovszky (a4) and György Németh (a4)...

Abstract

Objective

Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.

Methods

This was a multicenter, open-label, flexible-dose study of cariprazine 3–9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3–9 mg/d) and 4 weeks of safety follow-up.

Results

A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.

Conclusions

Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.

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Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

*Address correspondence to: Andrew J. Cutler, Chief Medical Officer, Meridien Research Inc., 8043 Cooper Creek Boulevard, Bradenton, Florida 34201, USA. (Email: acutler@meridienresearch.net)

References

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1. Dixon, L, Postrado, L, Delahanty, J, Fischer, PJ, Lehman, A. The association of medical comorbidity in schizophrenia with poor physical and mental health. J Nerv Ment Dis. 1999; 187(8): 496502.
2. Weber, NS, Cowan, DN, Millikan, AM, Niebuhr, DW. Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge Survey. Psychiatr Serv. 2009; 60(8): 10591067. Available at: http://ps.psychiatryonline.org/doi/pdf/10.1176/ps.2009.60.8.1059.
3. De Hert, MA, van Winkel, R, Van Eyck, D, et al. Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res. 2006; 83(1): 8793.
4. Laursen, TM, Munk-Olsen, T, Vestergaard, M. Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry. 2012; 25(2): 8388.
5. Leucht, S, Pitschel-Walz, G, Abraham, D, Kissling, W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizophr Res. 1999; 35(1): 5168.
6. Weiden, PJ. EPS profiles: the atypical antipsychotics are not all the same. J Psychiatr Pract. 2007; 13(1): 1324.
7. Lieberman, JA, Stroup, TS, McEvoy, JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353(12): 12091223. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa051688.
8. Durgam, S, Earley, W, Lipschitz, A, et al. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry. 2016; 173(3): 271281.
9. Durgam, S, Earley, W, Guo, H, et al. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry. 2016; 77(3): 371378.
10. Németh, G, Laszlovszky, I, Czobor, P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017; pii: S0140-6736(17): 30060-0. Epub ahead of print Feb 6.
11. Kiss, B, Horváth, A, Némethy, Z, et al. 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): 328340. Available at: http://jpet.aspetjournals.org/content/333/1/328.
12. Kiss, B, Horti, F, Bobok, A. Cariprazine, a D3/D2 dopamine receptor partial agonist antipsychotic, displays greater D3 receptor occupancy in vivo compared with other antipsychotics. Schizophr Res. 2012; 136(8 Suppl 1): S190.
13. Slifstein, M, Abi-Dargham, A, D’Souza, DC, et al. Cariprazine demonstrates high dopamine D3 and D2 receptor occupancy in patients with schizophrenia: a clinical PET study with [11C]–(+)–PHNO. Neuropsychopharmacology. 2013; 38: S520S521.
14. Seneca, N, Finnema, SJ, Laszlovszky, I, et al. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography. Psychopharmacology (Berl). 2011; 218(3): 579587. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210913/.
15. 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): 450457. Available at: http://www.schres-journal.com/article/S0920-9964(13)00658-0/pdf.
16. Durgam, S, Cutler, AJ, Lu, K, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase III, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015; 76(12): e1574e1582. Available at: http://www.psychiatrist.com/jcp/article/Pages/2015/v76n12/v76n1201.aspx.
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): 367373.
18. Durgam, S, Greenberg, W, Li, D, et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl). 2017; 234(2): 199209. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203812/.
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM–IV–TR). Washington, DC: American Psychiatric Association; 2000.
20. Kay, SR, Opler, LA, Spitzer, RL, Williams, JB, Fiszbein, A, Gorelick, A. SCID–PANSS: two-tier diagnostic system for psychotic disorders. Compr Psychiatry. 1991; 32(4): 355361.
21. Kay, SR, Fiszbein, A, Opler, LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2): 261276.
22. Guy, W. The Clinician Global Severity and Impression Scales: ECDEU Assessment Manual for Psychopharmacology. DHEW Publication no. 76-338. Rockville, MD: National Institute of Mental Health; 1976: 218222.
23. Posner, K, Brown, GK, Stanley, B, et al. The Columbia–Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168(12): 12661277. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893686/.
24. Guy, W. The Abnormal Movement Scale: ECDEU Assessment Manual for Psychopharmacology. DHEW Publication no. 76-338. Rockville, MD: National Institute of Mental Health; 1976: 218222.
25. Barnes, TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989; 154: 672676.
26. Simpson, GM, Angus, JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970; 212: 1119.
27. Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Washington, DC: U.S. Department of Health and Human Services; 2009. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf.
28. Chrzanowski, WK, Marcus, RN, Torbeyns, A, Nyilas, M, McQuade, RD. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology (Berl). 2006; 189(2): 259266.
29. Cutler, AJ, Kalali, AH, Mattingly, GW, Kunovac, J, Meng, X. Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial. CNS Spectr. 2013; 18(1): 4354.
30. Kane, JM, Fleischhacker, WW, Hansen, L, Perlis, R, Pikalov, A 3rd, Assunção-Talbott, S. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009; 70(5): 627643.
31. Keks, NA, Ingham, M, Khan, A, Karcher, K. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder: randomised, controlled, open-label study. Br J Psychiatry. 2007; 191(2): 131139. Available at: http://bjp.rcpsych.org/content/191/2/131.
32. Arato, M, O’Connor, R, Meltzer, H, ZEUS Study Group. A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) Study. Int Clin Psychopharmacol. 2002; 17(5): 207215.
33. Fleischhacker, WW, McQuade, RD, Marcus, RN, Archibald, D, Swanink, R, Carson, WH. A double-blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiatry. 2009; 65(6): 510517.
34. Stahl, SM, Cucchiaro, J, Simonelli, D, Hsu, J, Pikalov, A, Loebel, A. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: a 6-month, open-label, extension study. J Clin Psychiatry. 2013; 74(5): 507515. Available at: http://www.psychiatrist.com/JCP/article/Pages/2013/v74n05/v74n0516.aspx.
35. Citrome, L, Cucchiaro, J, Sarma, K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol. 2012; 27(3): 165176.
36. Newcomer, JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007; 8(Suppl 1): 2027.
37. McEvoy, JP, Lieberman, JA, Perkins, DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007; 164(7): 10501060. Available at: http://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.2007.164.7.1050.
38. Lee, SY, Park, MH, Patkar, AA, Pae, CU. A retrospective comparison of BMI changes and the potential risk factors among schizophrenic inpatients treated with aripiprazole, olanzapine, quetiapine or risperidone. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(2): 490496.

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