Olanzapine - Focus on the Cardiometabolic Side Effects

Open access


In this article, we review the recent findings concerning weight gain, diabetes mellitus (DM), hyperlipidemia, cardiovascular side effects in patients receiving olanzapine. It will consider the OLZ is associated with an increase in metabolic syndrome or cardiovascular events, and knowledge of these risks is crucial for further monitoring of patients with OLZ-treatment. Although it is one of the most commonly prescribed and effective AATPs, olanzapine causes the most weight gain and metabolic impairments in humans. As noted with glucose abnormalities and antipsychotics, olanzapine has the greatest propensity for causing proatherogenic hyperlipidemia. The mechanism of dyslipidemia with OLZ is poorly understood, but OLZ has been shown to increase lipogenesis, reduce lipolysis, and enhance the antilipolytic effects of insulin in adipocytes. Olanzapine can induce cardiomyopathy in selected patients.

Taken together, all mentioned data indicate that interventions aimed at the amelioration of obesity and cardiovascular illness need to be as multipronged and complex as the contributing psychosocial, behavioural, and biological factors that make obesity and cardiovascular illness more likely in patients with severe mental illness, including schizophrenia.

1. Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs. 2006;20:389-409.

2. Gex-Fabry M, Balant-Gorgia AE, Balant LP. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit. 2003;25:46-53.

3. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, et al. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry. 1998;155:921-8.

4. Kassahun K, Mattiuz E, Nyhart E Jr, Obermeyer B, Gillespie T, Murphy A, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos. 1997;25: 81-93.

5. Kelleher JP, Centorrino F, Albert MJ, Baldessarini RJ. Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drugs. 2002;16:249-61.

6. Kelly DL, Conley RR, Tamminga CA. Differential olanzapine plasma concentrations by sex in a fixeddose study. Schizophr Res. 1999;40:101-14.

7. McCormack PL, Wiseman LR. Olanzapine: a review of its use in the management of bipolar disorder. Drugs. 2004;64:2709-26.

8. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Molecular Psychiatry. 2005;10:79–104.

9. Stockton ME, Rasmussen K. Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons. Neuropsychopharmacology.1996;14:97-104.

10. D. Vancampfort, K. Vansteelandt, C.U. Correll, A.J. Mitchell, A. De Herdt, P. Sienaert, M. Probst, M. De Hert, Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators, Am. J. Psychiatry 170 (2013) 265–274.

11. F.C. Cohen, Entry order as a consideration for innovation strategies, Nat. Rev.Durg Discovery (2006).

12. M. Leonhauser, 2012. Antisychotics: multiple indications help drive growth. Pm 360 marjet watch: the essential source for pharma marketers, 1, 22–24.

13. Davis H, Attia E. Pharmacotherapy of eating disorders. Curr Opin Psychiatry. 2017; doi: 10.1097/YCO.0000000000000358.

14. Lord CC, Wyler SC, Wan R, Castorena CM, Ahmed N, Mathew D, Lee S, Liu C, Elmquist JK. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest. 2017. pii: 93362. doi: 10.1172/JCI93362.

15. Bymaster FP, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14(2):87–96.

16. Meltzer HY, Huang M. In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res. 2008;172:177–197.

17. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A. 2007;104(9):3456–3459.

18. Bymaster FP, et al. Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro. Schizophr Res. 1999;37(1):107–122.

19. Cooper GD, Pickavance LC, Wilding JP, Harrold JA, Halford JC, Goudie AJ. Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities. J Psychopharmacol. 2007;21(4):405–413.

20. Lett TA, Wallace TJ, Chowdhury NI, Tiwari AK, Kennedy JL, Müller DJ. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry. 2012;17(3):242–266.

21. Fang F, Wang Z, Wu R, Calabrese JR, Gao K. Is there a ‘weight neutral’ second-generation antipsychotic for bipolar disorder? Expert Rev Neurother. 2017;17(4):407-418.

22. Rojo LE, Gaspar PA, Silva H, Risco L, Arena P, Cubillos-Robles K, Jara B. Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology. Pharmacol Res. 2015;101:74-85.

23. Himmerich H, Minkwitz J, Kirkby KC. Weight Gain and Metabolic Changes During Treatment with Antipsychotics and Antidepressants. Endocr Metab Immune Disord Drug Targets. 2015;15(4):252-60.

24. Datta SS, Kumar A, Wright SD, Furtado VA, Russell PS. Evidence base for using atypical antipsychotics for psychosis in adolescents. Schizophr Bull. 2014;40(2):252-4.

25. Bartoli F, Lax A, Crocamo C, Clerici M, Carrà G. Plasma adiponectin levels in schizophrenia and role of second-generation antipsychotics: a meta-analysis. Psychoneuroendocrinology. 2015;56:179-89.

26. Hirsch L, Yang J, Bresee L, Jette N, Patten S, Pringsheim T. Second-Generation Antipsychotics and Metabolic Side Effects: A Systematic Review of Population-Based Studies. Drug Saf. 2017; doi: 10.1007/s40264-017-0543-0.

27. Allison D, Mentore J, Heo M, Chandler L, Cappelleri J, Infante M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96.

28. RummelKluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotisc in the treatment of schizophrenia: a systematic review and meta analysis. Schizophr Res. 2010;123(2–3):225–33.

29. Fuller M, Shermock K, Secic M, Grogg A. Comparative study of the development of type 2 diabetes in patients taking risperidone and olanzapine. Pharmacotherapy. 2003;23(8):1037–43.

30. Kessing LV, Thomsen AF, Mogensen UB, Andersen M. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. 2010;197(4):266–71.

31. Werner FM, Covenas R. Safety of antipsychotic drugs: focus on therapeutic and adverse effects. Expert Opin Drug Saf. 2014;13(8):1031–42.

32. Potkin SG, Phiri P, Szegedi A, et al. Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis. Schizophr Res.2013;150(2–3):442–9.

33. Lehman AF, Lieberman JA, Dixon LB, et al. American Psychiatric Association practice guideline for the treatment of patients with schizophrenia, 2nd edn. 2004. http://psychiatryonline.org. Accessed 17 Aug 2017.

34. Lauriello J, Lambert T, Andersen S, et al. An 8-week, doubleblind, randomized, placebo-controlled study of olanzapine longacting injection in acutely ill patients with schizophrenia. J Clin Psychiatry. 2008;69:790-799.

35. Dixon L, Perkins D, Calmes C. American Psychiatric Association guideline watch (September 2009): practice guideline for the treatment of patients with schizophrenia. 2009. http://psychiatryonline.org. Accessed 17 Aug 2017.

36. De Hert M, Guiraud-Diawara A, Marre C. Comparison of metabolic syndrome incidence among schizophrenia patients treated with asenapine versus olanzapine [abstract no. 2584]. Eur Psychiatry. 2013;28(Suppl 1).

37. Simpson GM, Weiden P, Pigott T, et al. Six-month, blinded, multicenter continuation study of ziprasidone versus olanzapine in schizophrenia. Am J Psychiatry. 2005;162:1535-1538.

38. Zhang Q, Deng C, Huang XF. The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology. 2013;38(11):2423-38.

39. Aguilar E, Coronas R, Caixàs A. [Metabolic syndrome in patients with schizophrenia and antipsychotic treatment]. Med Clin (Barc). 2012;139(12):542-6.

40. Olfson M, Marcus SC, Corey-Lisle P, et al. Hyperlipidemia following treatment with antipsychotic medications. Am J Psychiatry 2006; 163:1821–1825.

41. Raedler TJ. Cardiovascular aspects of antipsychotics. Curr Opin Psychiatry. 2010;23(6):574-81.

42. Brown S. Excess mortality of schizophrenia: a meta-analysis. Br J Psychiatry 1997; 171:502–508.

43. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225–235.

44. Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA 2007; 298:1794–1796.

45. Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry 2007; 68 (Suppl 4):8–13.

46. Halpert S, McFarlane SI. When the heart and the mind collide: cardiovascular risk factors and antipsychotic use in the schizophrenic population. J Cardiometab Syndr 2009; 4:1–5.

47. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004; 24:62–69.

48. Bresee LC, Majumdar SR, Patten SB, et al. Prevalence of cardiovascular risk factors and disease in people with schizophrenia: a population-based study. Schizophr Res 2010; 117:75–82.

49. Morissette P, Hreiche R, Mallet L, Vo D, Knaus EE, Turgeon J. Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. J Psychopharmacol. 2007;21(7):735-41.

50. Correll CU, Frederickson AM, Kane JM, et al. Metabolic syndrome and the risk of coronary heart disease in 367 patients treated with second-generation antipsychotic drugs. J Clin Psychiatry 2006; 67:575–583.

51. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of secondgeneration antipsychotic medications during first-time use in children and adolescents. JAMA 2009; 302:1765–1773.

52. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005;20(5):243-51.

53. Czekalla J, Kollack-Walker S, Beasley CM Jr. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry. 2001;62 Suppl 2:35-40.

54. Puttegowda B, Theodore J, Basappa R, Nanjappa MC. Olanzapine Induced Dilated Cardiomyopathy. Malays J Med Sci. 2016;23(2):82-4.

55. Belhani D, Frassati D, Mégard R, Tsibiribi P, Bui-Xuan B, Tabib A, Fanton L, Malicier D, Descotes J, Timour Q Exp Toxicol Pathol. 2006; 57(3):207-12.

56. Kataoka H, Kajiwara H, Yano E. Psychotropic drug-associated electrocardiographic presentation of diffuse J-waves in hypothermia: case report and literature review. Heart Vessels. 2016;31(6):996-1002.

57. Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334–1349.

58. Manu P, Dima L, Shulman M, Vancampfort D, De Hert M, Correll CU. Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management. Acta Psychiatr Scand. 2015;132(2):97-108.

59. A. Zuddas, R. Zanni, T. Usala, Second generation antipsychotics (SGAS) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies, Eur. Neuropsychopharmacol. 21 (2011) 600–620.

60. D. Vancampfort, K. Vansteelandt, C.U. Correll, A.J. Mitchell, A. De Herdt, P. Sienaert, M. Probst, M. De Hert, Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators, Am. J. Psychiatry 170 (2013) 265–274.

Serbian Journal of Experimental and Clinical Research

The Journal of Faculty of Medical Sciences, University of Kragujevac

Journal Information

CiteScore 2017: 0.21

SCImago Journal Rank (SJR) 2017: 0.126
Source Normalized Impact per Paper (SNIP) 2017: 0.081


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 129 129 12
PDF Downloads 99 99 7