Skip to main content
SpringerLink
Log in

Tolerability and Safety Profile of Cariprazine in Treating Psychotic Disorders, Bipolar Disorder and Major Depressive Disorder: A Systematic Review with Meta-Analysis of Randomized Controlled Trials

  • Systematic Review
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Background

Cariprazine is a novel antipsychotic agent recently approved for treating schizophrenia and bipolar mania in the USA. The sample sizes of published randomized controlled trials (RCTs) of the drug are small; previous meta-analyses included few RCTs and did not specifically investigate the tolerability/safety profile of cariprazine.

Objective

Our objective was to conduct a meta-analysis of published RCTs to systematically review the tolerability and safety of cariprazine versus placebo.

Methods

We searched the clinical trial registers (the metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) and electronic databases (PubMed, Embase, PsycINFO and Cochrane library) up to June 2016 to identify phase II/III RCTs of cariprazine in patients with schizophrenia, bipolar disorder or major depressive disorder. We conducted a meta-analysis to investigate outcomes, including risks of discontinuation due to adverse events (AEs), extrapyramidal side effects (EPS) or related events, metabolic syndrome and cardiovascular-related events.

Results

We included nine RCTs, with a total of 4324 subjects. The risk of discontinuation due to AEs for cariprazine was similar to that for placebo (risk ratio [RR] 1.13, 95 % confidence interval [CI] 0.77–1.66). Cariprazine was associated with higher risks of EPS-related events than was placebo, including risk of akathisia (RR 3.92, 95 % CI 2.83–5.43), tremor (RR 2.41, 95 % CI 1.53–3.79) and restlessness (RR 2.17, 95 % CI 1.38–3.40). The cariprazine treatment group was more likely to have clinically significant weight gain (RR 1.68, 95 % CI 1.12–2.52). No statistically significant differences in results were found in other metabolic parameters or cardiovascular-related events.

Conclusion

There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied. Further clinical and post-marketing pharmacovigilance studies are needed to investigate the long-term safety of cariprazine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T. Management of psychosis and schizophrenia in adults: summary of updated NICE guidance. BMJ. 2014;348:g1173. doi:10.1136/bmj.g1173.

    Article  PubMed  Google Scholar 

  2. Kendall T, Morriss R, Mayo-Wilson E, Marcus E, Guideline Development Group of the National Institute for H, Care E. Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ. 2014;349:g5673. doi: 10.1136/bmj.g5673.

  3. Publication No. WO/2009/104739 Published on Aug. 27, Assigned to Mitsubishi Tanabe Pharma for Oral Administration Solid Preparation (Japanese Inventors). US Fed News Service, Including US State News. 3 September 2009.

  4. Nord M, Farde L. Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther. 2011;17(2):97–103. doi:10.1111/j.1755-5949.2010.00222.x.

    Article  PubMed  Google Scholar 

  5. Kusumi I, Boku S, Takahashi Y. Psychopharmacology of atypical antipsychotic drugs: from the receptor binding profile to neuroprotection and neurogenesis. Psychiatry Clin Neurosci. 2015;69(5):243–58. doi:10.1111/pcn.12242.

    Article  CAS  PubMed  Google Scholar 

  6. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10(1):79–104. doi:10.1038/sj.mp.4001556.

    Article  CAS  PubMed  Google Scholar 

  7. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96. doi:10.1176/ajp.156.11.1686.

    CAS  PubMed  Google Scholar 

  8. McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res. 2005;80(1):19–32. doi:10.1016/j.schres.2005.07.014.

    Article  PubMed  Google Scholar 

  9. Henderson DC, Cagliero E, Copeland PM, Borba CP, Evins E, Hayden D, et al. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry. 2005;62(1):19–28. doi:10.1001/archpsyc.62.1.19.

    Article  CAS  PubMed  Google Scholar 

  10. Koro CE, Fedder DO, L’Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry. 2002;59(11):1021–6.

    Article  CAS  PubMed  Google Scholar 

  11. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–28. doi:10.1016/S0140-6736(05)66378-7.

    Article  CAS  PubMed  Google Scholar 

  12. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23. doi:10.1056/NEJMoa051688.

    Article  CAS  PubMed  Google Scholar 

  13. US Department of Health and Human Services; US Food and Drug Administration. FDA approves new drug to treat schizophrenia and bipolar disorder. Available at http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm463103.htm. Accessed 29 Dec 2015.

  14. Kane JM, Zukin S, Wang Y, Lu K, Ruth A, Nagy K, 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):367–73. doi:10.1097/JCP.0000000000000346.

    CAS  PubMed  Google Scholar 

  15. Durgam S, Litman RE, Papadakis K, Li D, Nemeth G, Laszlovszky I. Cariprazine in the treatment of schizophrenia: a proof-of-concept trial. Int Clin Psychopharmacol. 2015;. doi:10.1097/YIC.0000000000000110.

    PubMed  PubMed Central  Google Scholar 

  16. Durgam S, Starace A, Li D, Migliore R, Ruth A, Nemeth G, 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):450–7. doi:10.1016/j.schres.2013.11.041.

    Article  PubMed  Google Scholar 

  17. Durgam S, Cutler AJ, Lu K, Migliore R, Ruth A, Laszlovszky I, 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):e1574–82. doi:10.4088/JCP.15m09997.

    Article  PubMed  Google Scholar 

  18. Sachs GS, Greenberg WM, Starace A, Lu K, Ruth A, Laszlovszky I, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord. 2015;174:296–302. doi:10.1016/j.jad.2014.11.018.

    Article  CAS  PubMed  Google Scholar 

  19. Durgam S, Starace A, Li D, Migliore R, Ruth A, Nemeth G, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord. 2015;17(1):63–75. doi:10.1111/bdi.12238.

    Article  CAS  PubMed  Google Scholar 

  20. Calabrese JR, Keck PE Jr, Starace A, Lu K, Ruth A, Laszlovszky I, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015;76(3):284–92. doi:10.4088/JCP.14m09081.

    Article  PubMed  Google Scholar 

  21. Durgam S, Earley W, Lipschitz A, Guo H, Laszlovszky I, Nemeth G, 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. 2015;. doi:10.1176/appi.ajp.2015.15020164.

    PubMed  Google Scholar 

  22. Durgam S, Earley W, Guo H, Li D, Nemeth G, Laszlovszky I, 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):371–8. doi:10.4088/JCP.15m10070.

    Article  PubMed  Google Scholar 

  23. Gyertyan I, Kiss B, Saghy K, Laszy J, Szabo G, Szabados T, et al. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochemist Int. 2011;59(6):925–35. doi:10.1016/j.neuint.2011.07.002.

    Article  CAS  Google Scholar 

  24. Kiss B, Horvath A, Nemethy Z, Schmidt E, Laszlovszky I, Bugovics G, 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):328–40. doi:10.1124/jpet.109.160432.

    Article  CAS  PubMed  Google Scholar 

  25. Girgis RR, Xu X, Gil RB, Hackett E, Ojeil N, Lieberman JA, et al. Antipsychotic binding to the dopamine-3 receptor in humans: a PET study with [(11)C]-(+)-PHNO. Schizophr Res. 2015;168(1–2):373–6. doi:10.1016/j.schres.2015.06.027.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mizrahi R, Agid O, Borlido C, Suridjan I, Rusjan P, Houle S, et al. Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. Schizophr Res. 2011;131(1–3):63–8. doi:10.1016/j.schres.2011.05.005.

    Article  PubMed  Google Scholar 

  27. Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, et al. The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study With [11C]-(+)-PHNO. Arch Gen Psychiatry. 2009;66(6):606–15. doi:10.1001/archgenpsychiatry.2009.43.

    Article  CAS  PubMed  Google Scholar 

  28. Yildiz A, Nikodem M, Vieta E, Correll CU, Baldessarini RJ. A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania. Psychol Med. 2015;45(2):299–317. doi:10.1017/S0033291714001305.

    Article  CAS  PubMed  Google Scholar 

  29. Citrome L, Durgam S, Lu K, Ferguson P, Laszlovszky I. The effect of cariprazine on hostility associated with schizophrenia: post hoc analyses from 3 randomized controlled trials. J Clin Psychiatry. 2016;77(1):109–15. doi:10.4088/JCP.15m10192.

    Article  PubMed  Google Scholar 

  30. Vieta E, Durgam S, Lu K, Ruth A, Debelle M, Zukin S. Effect of cariprazine across the symptoms of mania in bipolar I disorder: analyses of pooled data from phase II/III trials. Eur Neuropsychopharmacol. 2015;25(11):1882–91. doi:10.1016/j.euroneuro.2015.08.020.

    Article  CAS  PubMed  Google Scholar 

  31. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36(2):375–89. doi:10.1038/npp.2010.192.

    Article  CAS  PubMed  Google Scholar 

  32. Zukin S, Lu K, Ruth A, Debelle M, Durgam S, D’Souza I. Categorical improvement across mania symptoms: pooled analyses of cariprazine phase II/III trials. Bipolar Disord. 2015;17:89.

    Google Scholar 

  33. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed 15 June 2014.

  34. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi:10.1136/bmj.b2535 (Epub 2009/07/23).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed 8 Aug 2014.

  36. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi:10.1136/bmj.d4002.

    Article  PubMed  Google Scholar 

  37. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi:10.1016/j.jclinepi.2010.04.026.

    Article  PubMed  Google Scholar 

  38. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University dbEP, Inc.). Available from gradepro.org.

  39. Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data. Biometrics. 1985;41(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  40. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  41. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  42. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10(1):101–29.

    Article  Google Scholar 

  43. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. doi:10.1136/bmj.327.7414.557 (Epub 2003/09/06).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rosenblad A. Chapter 17: introduction to meta-analysis by Michael Borenstein, Larry V. Hedges, Julian PT Higgins, Hannah R. Rothstein. Int Stat Rev. 2009;77(3):478–9.

    Article  Google Scholar 

  45. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. Wiley Online Library; 2008.

  46. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Stat Soc Ser A. 2009;172(1):137–59. doi:10.1111/j.1467-985X.2008.00552.x.

    Article  Google Scholar 

  47. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

  48. StatsToDo. Computer Program to Combine Means and Standard Deviations from Multiple Groups [cited Jan 2016]. Available from: https://www.statstodo.com/ComMeans_Pgm.php.

  49. US Food and Drug Administration. Full Prescribing information for VRAYLAR (cariprazine). 2015. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf.

  50. Nemeth G, Debelle M, Laszlovszky I, Szalai E, Szatmari B, Harsanyi J, et al. Monotherapy treatment with cariprazine for the treatment of predominant negative symptoms of patients with schizophrenia: a double-blind, active comparator-controlled trial. Eur Psychiatry. 2016;33:S256–7.

    Article  Google Scholar 

  51. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–62. doi:10.1016/S0140-6736(13)60733-3.

    Article  CAS  PubMed  Google Scholar 

  52. De Fruyt J, Deschepper E, Audenaert K, Constant E, Floris M, Pitchot W, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol. 2012;26(5):603–17. doi:10.1177/0269881111408461.

    Article  PubMed  Google Scholar 

  53. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord. 2010;12(2):116–41. doi:10.1111/j.1399-5618.2010.00798.x.

    Article  CAS  PubMed  Google Scholar 

  54. Osby U, Correia N, Brandt L, Ekbom A, Sparen P. Mortality and causes of death in schizophrenia in Stockholm county, Sweden. Schizophr Res. 2000;45(1–2):21–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Ms Lisa Wong, Dr Anthony Wai Yee Tam and Dr Shweta Anand for editing and proof-reading.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, 2/F Laboratory Block FMB, 21 Sassoon Road, Hong Kong SAR, China

      Kim S. J. Lao, Ying He, Ian C. K. Wong & Esther W. Chan

    2. Research Department of Practice and Policy, UCL, School of Pharmacy, London, UK

      Ian C. K. Wong & Frank M. C. Besag

    3. East London NHS Foundation Trust, Bedfordshire, London, UK

      Frank M. C. Besag

    4. Institute of Psychiatry, Psychology and Neuroscience, London, UK

      Frank M. C. Besag

    Authors
    1. Kim S. J. Lao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ying He
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ian C. K. Wong
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Frank M. C. Besag
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Esther W. Chan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Esther W. Chan.

    Ethics declarations

    Funding

    No sources of funding were used to conduct this study or prepare this manuscript.

    Conflicts of Interest

    KSJL, YH, ICKW, FMCB and EWC declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted study.

    Author Contributions

    KSJL, ICKW and EWC had the original idea for this study and contributed to the development of the idea and study design. KSJL and YH independently conducted a systematic review and reviewed the literature for relevance. KSJL and YH undertook the analysis. KSJL, YH, ICKW and EWC contributed to interpretation of the analysis. KSJL and YH wrote the first draft of the paper. KSJL, YH, ICKW and EWC critically reviewed the results and the manuscript. FMCB reviewed the data and presentation of the paper and provided clinical input. ICKW and EWC provided oversight to all aspects of this project. KSJL and EWC are the guarantors. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Additional information

    K. S. J. Lao and Y. He contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 3299 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lao, K.S.J., He, Y., Wong, I.C.K. et al. Tolerability and Safety Profile of Cariprazine in Treating Psychotic Disorders, Bipolar Disorder and Major Depressive Disorder: A Systematic Review with Meta-Analysis of Randomized Controlled Trials. CNS Drugs 30, 1043–1054 (2016). https://doi.org/10.1007/s40263-016-0382-z

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s40263-016-0382-z

    Keywords

    Search

    Navigation