Drug Safety

, Volume 31, Issue 8, pp 685–694 | Cite as

Associations Between Venous Thromboembolism and Antipsychotics

A Study of the WHO Database of Adverse Drug Reactions
  • Staffan Hägg
  • Andrew Bate
  • Malin Stahl
  • Olav Spigset
Original Research Article


Background: Concern has been raised about the occurrence of venous thromboembolism (VTE) during treatment with antipsychotics. However, to date, clozapine is the only antipsychotic agent for which recurring evidence supports an association with VTE. Therefore, the aim of this study was to investigate the association between antipsychotic drugs, including clozapine and VTE.

Study design and methods: Data mining of the WHO database of adverse drug reactions (ADRs) using Bayesian statistics is in routine use for early alerting to possible ADRs. An information component measure was used to investigate the association between antipsychotic drugs and VTE reactions in the database.

Results: A total of 754 suspected cases of VTE related to treatment with antipsychotics had been reported. After excluding cases related to clozapine, 379 cases remained. A robust association was found for the second-generation antipsychotics group but not for the high-potency, first-generation antipsychotics group or the low-potency first-generation antipsychotics group. The individual compounds with statistically significant associations were olanzapine, sertindole and zuclopenthixol. A time-dependent analysis showed that the associations were positive for these drugs in 2002, 2001 and 2003, respectively. Case analyses were undertaken after excluding ten suspected duplicate reports. Of the remaining 369 cases, 91 cases were associated with olanzapine, 9 with zuclopenthixol and 6 with sertindole.

Conclusions: VTE was more often reported with the antipsychotic drugs olanzapine, sertindole and zuclopenthixol than with other drugs in the WHO database. Further studies are warranted to explain this disproportional reporting. Since the associations found were based on incomplete clinical data, the results should be considered as preliminary and interpreted cautiously.


Clozapine Olanzapine Antipsychotic Drug Sertindole Information Component 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the national centres that contribute data to the WHO international drug monitoring programme. The opinions and conclusions in this article are, however, not necessarily those of the various national centres or of the WHO. The research was funded by the Swedish Research Council and the WHO Collaborating Centre without other external funding. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors have no conflicts of interest directly relevant to the content of this study.


  1. 1.
    Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications. Drugs 2004; 64: 701–23PubMedCrossRefGoogle Scholar
  2. 2.
    Newcomer JW. Metabolic risk during antipsychotic treatment. Clin Ther 2004; 26: 1936–46PubMedCrossRefGoogle Scholar
  3. 3.
    Hägg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002; 16: 765–76PubMedCrossRefGoogle Scholar
  4. 4.
    Walker AM, Lanza LL, Arellano F, et al. Mortality in current and former users of clozapine. Epidemiology 1997; 8: 671–7PubMedGoogle Scholar
  5. 5.
    Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine. Lancet 2000; 355: 1155–6PubMedCrossRefGoogle Scholar
  6. 6.
    Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000; 356: 1219–23PubMedCrossRefGoogle Scholar
  7. 7.
    Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic medication and venous thrombosis. Br J Psychiatry 2001; 179: 63–6PubMedCrossRefGoogle Scholar
  8. 8.
    Parkin L, Skegg DC, Herbison GP, et al. Psychotropic drugs and fatal pulmonary embolism. Pharmacoepidemiol Drug Saf 2003; 12: 647–52PubMedCrossRefGoogle Scholar
  9. 9.
    Farah RE, Makhoul NM, Farah RE, et al. Fatal venous thromboembolism associated with antipsychotic therapy. Ann Pharmacother 2004; 38: 1435–8PubMedCrossRefGoogle Scholar
  10. 10.
    Liperoti R, Pedone C, Lapane KL, et al. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med 2005; 165: 2677–82PubMedCrossRefGoogle Scholar
  11. 11.
    Hamanaka S, Kamijo Y, Nagai T, et al. Massive pulmonary thromboembolism demonstrated at necropsy in Japanese psychiatric patients treated with neuroleptics including atypical antipsychotics. Circ J 2004; 68: 850–2PubMedCrossRefGoogle Scholar
  12. 12.
    Ray JG, Mamdani MM, Yeo EL. Antipsychotic and antidepressant drug use in the elderly and the risk of venous thromboembolism. Thromb Haemost 2002; 88: 205–9PubMedGoogle Scholar
  13. 13.
    Waage IM, Gedde-Dahl A. Pulmonary embolism possibly associated with olanzapine treatment [letter]. BMJ 2003; 327: 1384PubMedCrossRefGoogle Scholar
  14. 14.
    del Conde I, Goldhaber SZ. Pulmonary embolism associated with olanzapine [letter]. Thromb Haemost 2006; 96: 690–1PubMedGoogle Scholar
  15. 15.
    Kamijo Y, Soma K, Nagai T, et al. Acute massive pulmonary thromboembolism associated with risperidone and conventional phenothiazines. Circ J 2003; 67: 46–8PubMedCrossRefGoogle Scholar
  16. 16.
    Bate A, Lindquist M, Edwards IR, et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54: 315–321PubMedCrossRefGoogle Scholar
  17. 17.
    Bate A, Lindquist M, Orre R, et al. Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol 2002; 58: 483–490PubMedCrossRefGoogle Scholar
  18. 18.
    Lindquist M, Stahl M, Bate A, et al. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 2000; 23: 533–42PubMedCrossRefGoogle Scholar
  19. 19.
    Edwards IR, Olsson S. WHO programme: global monitoring. In: Mann RD, Andrews EB, editors. Pharmacovigilance. London: John Wiley & Sons; 2002: 169–182Google Scholar
  20. 20.
    Orre R, Lansner A. Bayesian neural networks with confidence estimations applied to data mining, Comput Stat Data Anal 2000; 34: 473–493CrossRefGoogle Scholar
  21. 21.
    Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93–102PubMedCrossRefGoogle Scholar
  22. 22.
    WHO Collaborating Centre for Drug Statistics Methodology [online]. Available from URL:[Accessed 2005 May 15]
  23. 23.
    Norén GN, Bate A, Orre R, et al. Extending the methods used to screen the WHO drug safety database towards analysis of complex associations and improved accuracy for rare events. Stat Med 2006; 25: 3740–57PubMedCrossRefGoogle Scholar
  24. 24.
    van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf 2002; 11: 3–10PubMedCrossRefGoogle Scholar
  25. 25.
    Lindquist M, Edwards IR, Bate A, et al. From association to alert: a revised approach to international signal analysis. Pharmacoepidemiol Drug Saf 1999; 8: S15–25PubMedCrossRefGoogle Scholar
  26. 26.
    Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Paroxetine in pregnant women: SSRI and neonatal withdrawal syndrome. Lancet 2005; 365: 482–7PubMedGoogle Scholar
  27. 27.
    Coulter DM, Bate A, Meyboom RH, et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 2001; 322: 1207–9PubMedCrossRefGoogle Scholar
  28. 28.
    Anderson Jr FA, Wheeler HB, Goldberg RJ, et al. The prevalence of risk factors for venous thromboembolism among hospital patients. Arch Intern Med 1992; 152: 1660–4PubMedCrossRefGoogle Scholar
  29. 29.
    ten Ham M. WHO’s role in international ADR monitoring. Post Mark Surveillance 1992; 5: 223–30Google Scholar
  30. 30.
    Hägg S, Tätting P, Spigset O. Olanzapine and venous thromboembolism. Int Clin Psychopharmacol 2003; 18: 299–300PubMedCrossRefGoogle Scholar
  31. 31.
    Axelsson S, Hagg S, Eriksson AC, et al. In vitro effects of antipsychotics on human platelet adhesion and aggregation and plasma coagulation. Clin Exp Pharmacol Physiol 2007; 34: 775–80PubMedCrossRefGoogle Scholar
  32. 32.
    Wagstaff AJ, Bryson HM. Clozapine: a review of its pharmacological properties and therapeutic use in patients with schizophrenia who are unresponsive to or intolerant of classical antipsychotic agents. CNS Drugs 1995; 4: 370–400CrossRefGoogle Scholar
  33. 33.
    Lazarus A. Physical restraints, thromboembolism, and death in 2 patients. J Clin Psychiatry 2001; 62: 207–8PubMedCrossRefGoogle Scholar
  34. 34.
    Hughes JR, Hatsukami DK, Mitchell JE, et al. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 1986; 143: 993–7PubMedGoogle Scholar
  35. 35.
    Beratis S, Katrivanou A, Gourzis P. Factors affecting smoking in schizophrenia. Compr Psychiatry 2001; 42: 393–402PubMedCrossRefGoogle Scholar
  36. 36.
    Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642–5PubMedCrossRefGoogle Scholar
  37. 37.
    Danilenko-Dixon DR, Heit JA, Silverstein MD, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, casecontrol study. Am J Obstet Gynecol 2001; 184: 104–10PubMedCrossRefGoogle Scholar
  38. 38.
    Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610–9PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Staffan Hägg
    • 1
    • 2
  • Andrew Bate
    • 3
  • Malin Stahl
    • 3
  • Olav Spigset
    • 4
    • 5
  1. 1.Division of Clinical PharmacologyLinköping University HospitalLinköpingSweden
  2. 2.Division of Clinical PharmacologySahlgrenska University HospitalGöteborgSweden
  3. 3.Uppsala Monitoring CentreWHO Collaborating Centre for International Drug MonitoringUppsalaSweden
  4. 4.Department of Clinical PharmacologySt Olav University HospitalTrondheimNorway
  5. 5.Department of Laboratory MedicineChildren’s and Women’s Health, Norwegian University of Science and TechnologyTrondheimNorway

Personalised recommendations