Current Treatment Options in Psychiatry

, Volume 6, Issue 2, pp 154–163 | Cite as

New-generation Antipsychotics and Cardiovascular Risk

  • Aishwarya K. Rajagopalan
  • William K. Bache
  • Serena Z. Chen
  • Ermal Bojdani
  • Kevin J. LiEmail author
Schizophrenia and Other Psychotic Disorders (J Csernansky, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Schizophrenia and Other Psychotic Disorders


Purpose of Review

To critically review the current landscape of literature on cardiotoxicity of “new-generation antipsychotics,” defined as those approved by the Food and Drug Administration in the last 10 years.

Recent Findings

There is a paucity of data regarding the cardiovascular risks of these medications. Based on the investigations that have been published, iloperidone appears to be the greatest risk of corrected QT prolongation followed by asenapine whereas lurasidone, cariprazine, and brexpiprazole were not found to have significant effects on corrected QT. However, the evidence was low quality. In terms of metabolic effects, asenapine, iloperidone, cariprazine, and brexpiprazole all had mild to moderate effects whereas lurasidone had no significant effects observed.


Further investigation is warranted for all of these medications to better understand their cardiovascular effects.


Antipsychotics Cardiotoxicity Brexpiprazole Cariprazine Asenapine Iloperidone 



We would like to acknowledge Elaine Alligood for her assistance in literature search and article access.

Compliance with Ethical Standards

Conflict of Interest

Aishwarya K. Rajagopalan, William K. Bache, Serena Z. Chen, Ermal Bojdani, and Kevin J. Li declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Simeone JC, Ward AJ, Rotella P, Collins J, Windisch R. An evaluation of variation in published estimates of schizophrenia prevalence from 1990 horizontal line 2013: a systematic literature review. BMC Psychiatry. 2015;15:193. Scholar
  2. 2.
    Remington G, Addington D, Honer W, Ismail Z, Raedler T, Teehan M. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatr. 2017;62(9):604–16. Scholar
  3. 3.•
    Zhang Y, Liu Y, Su Y, You Y, Ma Y, Yang G, et al. The metabolic side effects of 12 antipsychotic drugs used for the treatment of schizophrenia on glucose: a network meta-analysis. BMC Psychiatry. 2017;17(1):373. non-industry sponsored network meta-anaylsis that compares the metabolic effects of 12 different antipsychotic medications.
  4. 4.
    Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Kissling W, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull. 2012;38(1):167–77. Scholar
  5. 5.•
    Stoner SC. Management of serious cardiac adverse effects of antipsychotic medications. Ment Health Clin. 2017;7(6):246–54. but thorough education focused article centered on treatment of antipsychotic related cardiovacsular toxicity.
  6. 6.
    Polcwiartek C, Kragholm K, Schjerning O, Graff C, Nielsen J. Cardiovascular safety of antipsychotics: a clinical overview. Expert Opin Drug Saf. 2016;15(5):679–88. Scholar
  7. 7.
    Vieta E, Montes JM. A review of asenapine in the treatment of bipolar disorder. Clin Drug Investig. 2018;38(2):87–99. Scholar
  8. 8.•
    Durgam S, Landbloom RP, Mackle M, Wu X, Mathews M, Nasrallah HA. Exploring the long-term safety of asenapine in adults with schizophrenia in a double-blind, fixed-dose, extension study. Neuropsychiatr Dis Treat. 2017;13:2021–35. industry sponsored, this study with 120 patients across multiple sites compares tolerability of low-dose asenapine, high-dose asenapine, and olanzapine.
  9. 9.
    Potkin SG. Asenapine: a clinical overview. J Clin Psychiatry. 2011;72(Suppl 1):14–8. Scholar
  10. 10.
    Chapel S, Hutmacher MM, Haig G, Bockbrader H, de Greef R, Preskorn SH, et al. Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation. J Clin Pharmacol. 2009;49(11):1297–308. Scholar
  11. 11.
    Kotasek F, Tibrewal P, Dhillon R. QTc prolongation with asenapine. Aust N Z J Psychiatry. 2014;48(10):961. Scholar
  12. 12.
    Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry. 2007;68(10):1492–500.Google Scholar
  13. 13.
    Gill JS, Sulaiman AH. QTc prolongation and ventricular trigemini with asenapine: a case report. Turk Psikiyatri Derg. 2018;29(1):67–8.Google Scholar
  14. 14.
    Grossini E, Gramaglia C, Farruggio S, Camillo L, Mary D, Vacca G, et al. Asenapine modulates nitric oxide release and calcium movements in cardiomyoblasts. J Pharmacol Pharmacother. 2016;7(1):6–14. Scholar
  15. 15.
    Grossini E, Gramaglia C, Farruggio S, Bellofatto K, Anchisi C, Mary D, et al. Asenapine increases nitric oxide release and protects porcine coronary artery endothelial cells against peroxidation. Vasc Pharmacol. 2014;60(3):127–41. Scholar
  16. 16.
    Lim X, Tibrewal P, Dhillon R, Bastiampillai T, Chen L, Lin A. Can asenapine cause myocarditis? Asian J Psychiatr. 2015;14:78–9. Scholar
  17. 17.
    Kemp DE, Zhao J, Cazorla P, Landbloom RP, Mackle M, Snow-Adami L, et al. Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder. J Clin Psychiatry. 2014;75(3):238–45. Scholar
  18. 18.
    Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106–15. Scholar
  19. 19.
    Stepanova E, Grant B, Findling RL. Asenapine treatment in pediatric patients with bipolar I disorder or schizophrenia: a review. Paediatr Drugs. 2018;20(2):121–34. Scholar
  20. 20.
    Mathis MV. FDA Summar Review: Iloperidone. In: (FDA) FaDA, editor.2009. p. 1–21.
  21. 21.
    Kane JM, Lauriello J, Laska E, Di Marino M, Wolfgang CD. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol. 2008;28(2 Suppl 1):S29–35. Scholar
  22. 22.
    Tonin FS, Wiens A, Fernandez-Llimos F, Pontarolo R. Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy. Core Evid. 2016;11:49–61. Scholar
  23. 23.
    Weiden PJ, Manning R, Wolfgang CD, Ryan JM, Mancione L, Han G, et al. A randomized trial of iloperidone for prevention of relapse in schizophrenia: the REPRIEVE study. CNS Drugs. 2016;30(8):735–47. Scholar
  24. 24.
    Rado JT, Janicak PG. Long-term efficacy and safety of iloperidone: an update. Neuropsychiatr Dis Treat. 2014;10:409–15. Scholar
  25. 25.
    Cutler AJ. Iloperidone: a new option for the treatment of schizophrenia. Expert Rev Neurother. 2009;9(12):1727–41. Scholar
  26. 26.
    Citrome L. Iloperidone: a clinical overview. J Clin Psychiatry. 2011;72(Suppl 1):19–23. Scholar
  27. 27.
    Citrome L. Iloperidone redux: a dissection of the Drug Approval Package for this newly commercialised second-generation antipsychotic. Int J Clin Pract. 2010;64(6):707–18. Scholar
  28. 28.
    Citrome L, Weiden PJ, Alva G, Glick ID, Jackson R, Mattingly G, et al. Switching to iloperidone: an omnibus of clinically relevant observations from a 12-week, open-label, randomized clinical trial in 500 persons with schizophrenia. Clin Schizophr Relat Psychoses. 2015;8(4):183–95. Scholar
  29. 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):43–54. Scholar
  30. 30.
    Mathis MV. FDA Summary review: lurasidone. In: (FDA) FaDA, editor. 2010.
  31. 31.
    Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs. 2009;18(11):1715–26. Scholar
  32. 32.
    Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(6):829–36. Scholar
  33. 33.
    Ogasa M, Kimura T, Nakamura M, Guarino J. Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study. Psychopharmacology. 2013;225(3):519–30. Scholar
  34. 34.
    Mathis MV. FDA summary review: cariprazine. 2015.
  35. 35.
    Girgis RR, Slifstein M, D’Souza D, Lee Y, Periclou A, Ghahramani P, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO. Psychopharmacology. 2016;233(19–20):3503–12. Scholar
  36. 36.
    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. Scholar
  37. 37.
    Lao KS, He Y, Wong IC, Besag FM, Chan EW. 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. 2016;30(11):1043–54. Scholar
  38. 38.
    Durgam S, Greenberg WM, Li D, Lu K, Laszlovszky I, Nemeth G, 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. 2017;234(2):199–209. Scholar
  39. 39.
    Cutler AJ, Durgam S, Wang Y, Migliore R, Lu K, Laszlovszky I, et al. Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr. 2018;23(1):39–50. Scholar
  40. 40.
    Nasrallah HA, Earley W, Cutler AJ, Wang Y, Lu K, Laszlovszky I, et al. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry. 2017;17(1):305. Scholar
  41. 41.
    Vieta E, Earley WR, Burgess MV, Durgam S, Chen C, Zhong Y, et al. Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder. Int Clin Psychopharmacol. 2019;34(2):76–83. Scholar
  42. 42.
    Mathis MV. FDA summary review: brexpiprazole. 2015. p. 1–17.Google Scholar
  43. 43.
    Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879–911. Scholar
  44. 44.
    Stahl SM. Mechanism of action of brexpiprazole: comparison with aripiprazole. CNS Spectr. 2016;21(1):1–6. Scholar
  45. 45.
    Aronow WS, Shamliyan TA. Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders. Ann Transl Med. 2018;6(8):147. Scholar
  46. 46.
    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):978–97. Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  • Aishwarya K. Rajagopalan
    • 1
    • 2
    • 3
  • William K. Bache
    • 1
    • 2
    • 3
  • Serena Z. Chen
    • 1
    • 2
    • 3
  • Ermal Bojdani
    • 1
    • 2
    • 3
  • Kevin J. Li
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Veterans AffairsBrocktonUSA
  2. 2.Harvard South Shore Psychiatry Residency Training ProgramBrocktonUSA
  3. 3.Harvard Medical SchoolBostonUSA

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