Skip to main content
SpringerLink
Log in

Antipsychotic-Induced Venous Thromboembolism

A Review of the Evidence

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

Abstract

Psychiatric disorders themselves and treatment with conventional antipsychotic medications have in a number of early studies been associated with venous thromboembolism. In general, information on the relationship between antipsychotics and this possible adverse effect is in the form of case reports and open cross-sectional studies. However, recently the association between conventional antipsychotics and venous thrombosis has been strengthened as a result of the publication of a large, nested, case-control study. In this study, low-potency antipsychotic drugs were more strongly associated with venous thrombosis than high-potency drugs. In addition, recent epidemiological data support an association between the atypical antipsychotic agent clozapine and venous thromboembolism. The risk for venous thromboembolism seems to be highest during the initial months of treatment with antipsychotics.

The biological mechanisms responsible for this possible adverse drug reaction are unknown, but a number of hypotheses have been suggested. The increased risk may be the result of drug-induced sedation, obesity, hyperleptinaemia, anti-phospholipid antibodies and increased activity in the coagulation system. The association could also be related to underlying risk factors present in patients with psychosis such as smoking.

Despite the limitations of present knowledge, clinicians should be aware of this possible adverse drug reaction and should consider interrupting or changing the antipsychotic regimen in patients in whom this reaction is suspected. More studies are needed in order to further elucidate this adverse effect, particularly to determine the incidence rate, possible predisposing factors and the biological mechanisms involved.

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

Table I
Table II

Similar content being viewed by others

References

  1. Goldhaber SZ. Clinical overview of venous thromboembolism. Vasc Med 1998; 3: 35–40

    PubMed  CAS  Google Scholar 

  2. Kahn SR, Solymoss S, Lamping DL, et al. Long-term outcomes after deep vein thrombosis: postphlebitic syndrome and quality of life. J Gen Intern Med 2000; 15: 425–9

    Article  PubMed  CAS  Google Scholar 

  3. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610–9

    PubMed  CAS  Google Scholar 

  4. Motykie GD, Zebala LP, Caprini JA, et al. A guide to venous thromboembolism risk factor assessment. J Thromb Thrombolysis 2000; 9: 253–62

    Article  PubMed  CAS  Google Scholar 

  5. Brehmer G, Ruckdeschel KT. Zur technik der Winterschlafbehandlung. Dtsch Med Wochenschr 1953; 78: 1724–5

    Article  PubMed  CAS  Google Scholar 

  6. Labhardt E. Technik, nebenerscheinungen und komplikationen der Largactil therapie. Schweiz Arch Neurol Psychiatr 1954; 73: 338–44

    PubMed  CAS  Google Scholar 

  7. Lunel G, Noble Y, Arne L. The thrombogenic role of neuroleptic agents (apropos of 2 cases) [in French]. Bord Med 1972; 5: 121–6

    PubMed  CAS  Google Scholar 

  8. Ruh-Bernhardt D, Finance F, Rohmer F, et al. Influence of psy-chotropic therapy on thrombogenesis and platelet functions: a propos of 4 cases of thromboembolic accidents occurring in patients treated by neuroleptics and antidepressants [in French]. Encephale 1976; 2: 239–55

    PubMed  CAS  Google Scholar 

  9. Singer L, Finance F, Ruh D. Pulmonary embolisms occurring in 1 month in 3 aged women with manic-depressive psychoses. Discussion: etiopathogenic role or psychiatric treatment [in French]. Ann Med Psychol (Paris) 1975; 1: 256–63

    CAS  Google Scholar 

  10. Varia I, Krishnan RR, Davidson J. Deep-vein thrombosis with antipsychotic drugs. Psychosomatics 1983; 24: 1097–8

    Article  PubMed  CAS  Google Scholar 

  11. Maurice H. Des complications phlepitiques au cours des traitements par les neuroleptiques. Encephale 1956; 51: 797–801

    Google Scholar 

  12. Grahmann H, Suchenwirth R. Thrombose hazard in chlorpromazine and reserpine therapy of endogenous psychosis [in German]. Nervenarzt 1959; 30: 224–5

    PubMed  CAS  Google Scholar 

  13. Hafner H, Brehm I. Thromboembolic complications in neuroleptic treatment. Compr Psychiatry 1965; 6: 25–34

    Article  Google Scholar 

  14. Meier-Ewert K, Baumgart HH, Friedenberg P. Thromboembolism complications in neuro- and thymoleptic therapy [in German]. Dtsch Med Wochenschr 1967; 92: 2174–8

    Article  PubMed  CAS  Google Scholar 

  15. Scholtz V. Concerning the thromboembolic complications from neuroleptic drugs [in German]. Nervenarzt 1967; 38: 174–7

    Google Scholar 

  16. Lal S, Bleiman M, Brown BN. Pulmonary embolism in psychiatric patients. J Am Geriatr Soc 1966; 14: 1138–43

    PubMed  CAS  Google Scholar 

  17. Mahmodian MH. Ursachen der lungenembolie bei psychisch und neurologisch Kranken. Arch Psychiatr Nervenkr 1963; 204: 229–44

    Article  Google Scholar 

  18. Kendel K, Fodor S. Pulmonary embolism and symptomatic psychosis. Ger Med Mon 1969; 14: 184–7

    PubMed  CAS  Google Scholar 

  19. Ziegler HK. Lungenembolie aus der sieht des pathologen. Med Klin 1977; 72: 1063–70

    PubMed  CAS  Google Scholar 

  20. Walker AM, Lanza LL, Arellano F, et al. Mortality in current and former users of clozapine. Epidemiology 1997; 8: 671–7

    PubMed  CAS  Google Scholar 

  21. Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine. Lancet 2000; 355: 1155–6

    Article  PubMed  Google Scholar 

  22. Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000; 356: 1219–23

    Article  PubMed  CAS  Google Scholar 

  23. Modai I, Hirschmann S, Rava A, et al. Sudden death in patients receiving clozapine treatment: a preliminary investigation. J Clin Psychopharmacol 2000; 20: 327–37

    Article  Google Scholar 

  24. Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic medication and venous thrombosis. Br J Psychiatry 2001; 179: 63–6

    Article  PubMed  CAS  Google Scholar 

  25. Lilleng P, Morild I, Hope M. Clozapine and myocarditis [in Norwegian]. Tidsskr Nor Laegeforen 1995; 115: 3026–7

    PubMed  CAS  Google Scholar 

  26. Vogel U, Jurgeleit MP, Bultmann B. The economy class syndrome. Deep vein thrombosis and pulmonary embolism after air travel: neuroleptic therapy a risk factor? [in German]. Munch Med Wochenschr 1998; 140: 421–3

    Google Scholar 

  27. Lacika S, Cooper JP. Pulmonary embolus possibly associated with clozapine treatment [letter]. Can J Psychiatry 1999; 44: 396–7

    PubMed  CAS  Google Scholar 

  28. Suttmann I, Dittert S, Landgraf R, et al. Clozapine and sudden death [letter]. Lancet 2000; 355: 842–3

    Article  PubMed  CAS  Google Scholar 

  29. Maynes D. Bilateral pulmonary embolism in a patient on clozapine therapy [letter]. Can J Psychiatry 2000; 45: 296–7

    PubMed  CAS  Google Scholar 

  30. Coodin S, Ballegeer T. Clozapine therapy and pulmonary embolism [letter]. Can J Psychiatry 2000; 45: 395

    PubMed  CAS  Google Scholar 

  31. Ihde-Scholl T, Rolli ML, Jefferson JW. Clozapine and pulmonary embolus [letter]. Am J Psychiatry 2001; 158: 499–500

    Article  PubMed  CAS  Google Scholar 

  32. Ösby U, Correia N, Brandt L, et al. Time trends in schizophrenia mortality in Stockholm County, Sweden: cohort study. BMJ 2000; 321: 483–4

    Article  PubMed  Google Scholar 

  33. Brown S. Excess mortality of schizophrenia: a meta-analysis. Br J Psychiatry 1997; 171: 502–8

    Article  PubMed  CAS  Google Scholar 

  34. Dukes MNG, Aronson JK, editors. Meyler’s side effects of drugs. 14th rev. ed. Amsterdam: Elsevier, 2000

    Google Scholar 

  35. Vandenbroucke JP, Bertina RM, Holmes ZR, et al. Factor V Leiden and fatal pulmonary embolism. Thromb Haemost 1998; 79: 511–6

    PubMed  CAS  Google Scholar 

  36. Thorogood M, Cowen P, Mann J, et al. Fatal myocardial infarction and use of psychotropic drugs in young women. Lancet 1992; 340: 1067–8

    Article  PubMed  CAS  Google Scholar 

  37. Knudson JF, Kortepeter C, Dubitsky GM, et al. Antipsychotic drugs and venous thromboembolism [letter]. Lancet 2000; 356: 252–3

    Article  PubMed  CAS  Google Scholar 

  38. Wolstein J, Grohmann R, Ruther E, et al. Association of venous thromboembolism and clozapine [letter]. Lancet 2000; 356: 252

    Article  PubMed  CAS  Google Scholar 

  39. Clardy J, Gale RH. Mortality risk and clozapine [letter]. Am J Psychiatry 1995; 152: 651

    PubMed  CAS  Google Scholar 

  40. Pantel J, Schroder J, Eysenbach K, et al. Two cases of deep vein thrombosis associated with a combined paroxetine and zotepine therapy. Pharmacopsychiatry 1997; 30: 109–11

    Article  PubMed  CAS  Google Scholar 

  41. McCall WV, Mann SC, Shelp FE, et al. Fatal pulmonary embolism in the catatonic syndrome: two case reports and a literature review [letter]. J Clin Psychiatry 1995; 56: 21–5

    PubMed  CAS  Google Scholar 

  42. Sukov RJ. Thrombophlebitis as a complication of severe catatonia [letter]. JAMA 1972; 24: 587–8

    Article  Google Scholar 

  43. Hindersin P, Siegmund R. Körting HJ. Thrombophilic diatheses as hemostasis disorders in acute psychoses [in German]. Psychiatr Neurol Med Psychol (Leipz) 1984; 36: 702–9

    CAS  Google Scholar 

  44. Lazarus A. Physical restraints, thromboembolism, and death in 2 patients [letter]. J Clin Psychiatry 2001; 62: 207–8

    Article  PubMed  CAS  Google Scholar 

  45. Hem E, Steen O, Opjordsmoen S. Thrombosis associated with physical restraints. Acta Psychiatr Scand 2001; 103: 73–5

    Article  PubMed  CAS  Google Scholar 

  46. 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: 370–400

    Article  CAS  Google Scholar 

  47. Owens DG. Adverse effects of antipsychotic agents: do newer agents offer advantages? Drugs 1996; 51: 895–930

    Article  PubMed  CAS  Google Scholar 

  48. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686–96

    PubMed  CAS  Google Scholar 

  49. Eckel RH. Obesity and heart disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1997; 96: 3248–50

    Article  PubMed  CAS  Google Scholar 

  50. Rexrode KM, Manson JE, Hennekens CH. Obesity and cardiovascular disease. Curr Opin Cardiol 1996; 11: 490–5

    Article  PubMed  CAS  Google Scholar 

  51. Timar O, Sestier F, Levy E. Metabolic syndrome X: a review. Can J Cardiol 2000; 16: 779–89

    PubMed  CAS  Google Scholar 

  52. de Courten M, Zimmet P, Hodge A, et al. Hyperleptinaemia: the missing link in the, metabolic syndrome? Diabet Med 1997; 14: 200–8

    Article  PubMed  Google Scholar 

  53. Söderberg S, Olsson T, Eliasson M, et al. Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women. J Intern Med 1999; 245: 533–43

    Article  PubMed  Google Scholar 

  54. Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348–53

    Article  PubMed  CAS  Google Scholar 

  55. Schwartz M, Rochas M, Toubi E, et al. High association of anticardiolipin antibodies with psychosis. J Clin Psychiatry 1998; 59: 20–3

    Article  PubMed  CAS  Google Scholar 

  56. Canoso RT, de Oliveira RM. Chlorpromazine-induced anticardiolipin antibodies and lupus anticoagulant: absence of thrombosis. Am J Hematol 1988; 27: 272–5

    Article  PubMed  CAS  Google Scholar 

  57. Canoso RT, de Oliveira RM, Nixon RA. Neuroleptic-associated autoantibodies: aprevalence study. Biol Psychiatry 1990; 27: 863–70

    Article  PubMed  CAS  Google Scholar 

  58. Metzer WS, Canoso RT, Newton JEO. Anticardiolipin antibodies in a sample of chronic schizophrenics receiving neuroleptic therapy. South Med J 1994; 87: 190–2

    Article  PubMed  CAS  Google Scholar 

  59. Steen VD, Ramsey-Goldman R. Phenothiazine-induced systemic lupus erythematosus with superior vena cava syndrome: case report and review of the literature. Arthritis Rheum 1988; 31: 923–6

    Article  PubMed  CAS  Google Scholar 

  60. el-Mallakh RS, Donaldson JO, Kranzler HR, et al. Phenothiazine-associated lupus anticoagulant and thrombotic disease. Psychosomatics 1988; 29: 109–13

    Article  PubMed  CAS  Google Scholar 

  61. Ayuso JL, Ruiz JS. Neuroleptic-induced antinuclear antibodies [letter]. Eur Psychiatry 1996; 11: 378–9

    Article  PubMed  CAS  Google Scholar 

  62. Davis S, Kern HB, Asokan R. Antiphospholipid antibodies associated with clozapine treatment [letter]. Am J Hematol 1994; 46: 166–7

    Article  PubMed  CAS  Google Scholar 

  63. Chengappa KN, Carpenter AB, Keshavan MS, et al. Elevated IGG and IGM anticardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol Psychiatry 1991; 30: 731–5

    Article  PubMed  CAS  Google Scholar 

  64. Firer M, Sirota P, Schild K, et al. Anticardiolipin antibodies are elevated in drug-free, multiply affected families with schizophrenia. J Clin Immunol 1994; 14: 73–8

    Article  PubMed  CAS  Google Scholar 

  65. Roche-Bayard P, Rossi R, Mann JM, et al. Left pulmonary artery thrombosis in chlorpromazine-induced lupus [letter]. Chest 1990; 98: 1545

    Article  PubMed  CAS  Google Scholar 

  66. Boullin DJ, Woods HF, Grimes RPJ, et al. Increased platelet aggregation responses to 5-hydroxytryptamine in patients taking chlorpromazine. Br J Clin Pharmacol 1975; 2: 29–35

    PubMed  CAS  Google Scholar 

  67. Boullin DJ, Grahame-Smith DG, Grimes RPJ, et al. Inhibition of 5-hydroxytryptamine-induced human blood platelet aggregation by chlorpromazine and its metabolites. Br J Pharmacol 1975; 53: 121–5

    Article  PubMed  CAS  Google Scholar 

  68. Boullin DJ, Knox JM, Peters JR, et al. Platelets aggregation and chlorpromazine therapy [letter]. Br J Clin Pharmacol 1978; 6: 538–40

    Article  PubMed  CAS  Google Scholar 

  69. Orr MW, Boullin DJ. The relationship between changes in 5-HT induced platelet aggregation and clinical state in patients treated with fluphenazine. Br J Clin Pharmacol 1976; 3: 925–8

    Article  PubMed  CAS  Google Scholar 

  70. Orr MW, Knox JM, Allen R, et al. The effects of neuroleptic drugs on 5-hydroxytryptamine induced platelet aggregation in schizophrenic patients. Br J Clin Pharmacol 1981; 11: 255–9

    Article  PubMed  CAS  Google Scholar 

  71. Hughes JR, Hatsukami DK, Mitchell JE, et al. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 1986; 143: 993–7

    PubMed  CAS  Google Scholar 

  72. Beratis S, Katrivanou A, Gourzis P. Factors affecting smoking in schizophrenia. Compr Psychiatry 2001; 42: 393–402

    Article  PubMed  CAS  Google Scholar 

  73. Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642–5

    Article  PubMed  CAS  Google Scholar 

  74. Danilenko-Dixon DR, Heit JA, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, case-control study. Am J Obstet Gynecol 2001; 184: 104–10

    Article  PubMed  CAS  Google Scholar 

  75. Anello C, O’Neill R. Does research synthesis have a place in drug regulatory policy? Synopsis of issues: assessment of safety and postmarketing surveillance. Clin Res Regul Aff 1996; 13: 13–21

    Article  Google Scholar 

  76. Venning G. Identification of adverse reactions to new drugs. IV: verification of suspected adverse reactions. BMJ 1983; 286: 544–7

    CAS  Google Scholar 

  77. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527–35

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Sahlgrenska Hospital/Sahlgrenska, S-413 45, Göteborg, Sweden

    Staffan Hägg

  2. Department of Clinical Pharmacology, St Olav’s University Hospital, Trondheim, Norway

    Olav Spigset

Authors
  1. Staffan Hägg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olav Spigset
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Staffan Hägg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hägg, S., Spigset, O. Antipsychotic-Induced Venous Thromboembolism. Mol Diag Ther 16, 765–776 (2002). https://doi.org/10.2165/00023210-200216110-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-200216110-00005

Keywords

Search

Navigation