Is there an association between clozapine and venous thromboembolism?

An increasing body of literature suggests first or second-generation antipsychotic medications may predispose individuals to a slightly higher risk of venous thromboembolism (VTE). A meta-analysis including seven case-control studies found a 2.4-fold greater risk of VTE in people taking antipsychotics (Zhang et al. 2011). A subsequent meta-analysis including 17 studies (including cohort and case control studies) found individuals who received an antipsychotic medication were significantly more likely to develop VTE (adjusted odds ratio (AOR) 1.54, 95% confidence interval 1.28-1.86) than those who were not prescribed an antipsychotic (Barbui, Conti, and Cipriani 2014).

What about clozapine, specifically?  In a study of 67,072 deceased former and current clozapine users, current users were found to have a five-fold increased mortality rate from pulmonary embolus compared to previous users (Walker et al. 1997). Then, in an analysis from a large US hospital database of 450,951 antipsychotic-treated patients, clozapine had the highest AOR (1.46) in comparison to other antipsychotics, although this study was not sufficiently powered to differentiate between agents (Allenet et al. 2012). In the Barbui meta-analysis described above (three studies related to clozapine), the AOR for clozapine was 1.53 with a 95% confidence interval of 0.94-2.52.  In a systematic review of 34 cases of pulmonary embolism associated with clozapine, 77% occurred within the first six months clozapine was prescribed, and 9 cases were associated with <200 mg/day of clozapine or less, and 13 cases were associated with >300 mg/day or more (Poudyal and Lohani 2019). In sum, given that VTE is an uncommon event and extremely large sample sizes are needed to draw comparisons, at present there is insufficient evidence to differentiate risk between specific antipsychotic medications, including clozapine from others (Jönsson et al. 2018).



  • Allenet B, Schmidlin S, Genty C, Bosson JL: Antipsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf 21:42-48, 2012
  • Barbui C, Conti V, Cipriani A: Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta-analysis of observational studies. Drug Saf 37:79-90, 2014
  • Jönsson AK, Schill J, Olsson H, et al: Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence. CNS Drugs 32:47-64, 2018
  • Poudyal R, Lohani S: Clozapine associated pulmonary embolism: systematic review. J Community Hosp Intern Med Perspect 9:300-304, 2019
  • Walker AM, Lanza LL, Arellano F, Rothman KJ: Mortality in current and former users of clozapine. Epidemiology 8:671-677, 1997
  • Zhang R, Dong L, Shao F, et al: Antipsychotics and venous thromboembolism risk: a meta-analysis. Pharmacopsychiatry 44:183-188, 2011
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