Antipsychotics and the risk of venous thromboembolismBMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c4216 (Published 22 September 2010) Cite this as: BMJ 2010;341:c4216
- 1Centro di Medicina dell’Invecchiamento, Dipartimento di Scienze Gerontologiche, Geriatriche e Fisiatriche, Università Cattolica del Sacro Cuore, Largo A Gemelli 8, 00168, Rome, Italy
Patients with schizophrenia have an increased risk of venous thromboembolism (VTE), and this might be associated with the use of antipsychotics, especially low potency drugs such as chlorpromazine and thioridazine.1 Among atypical antipsychotics, clozapine has consistently been associated with VTE in young patients with psychiatric illnesses,2 but evidence from large observational studies has suggested that other atypical antipsychotics carry a similar risk, especially among new users and elderly patients.3 So far, however, the possibility that the underlying psychiatric disorders themselves—and not the antipsychotics—are associated with VTE has never been excluded. This could occur, for example, by the increased concentrations of adrenaline seen during psychotic excitation increasing blood coagulation.4
In the linked study (doi:10.1136/bmj.c4245), Parker and colleagues report a large population based case-control study that included primary care patients aged over 16 who were taking antipsychotics.5 In almost 99% of cases the reason for prescription of antipsychotics could not be ascertained. Most antipsychotics used were conventional agents, with prochlorperazine—probably given for nausea and vomiting—accounting for almost 80% of all prescriptions. The authors found that the use of antipsychotics was associated with a significantly increased risk of VTE (odds ratio 1.32, 95% CI 1.23 to 1.42). The validity of the findings is strengthened by the large sample size and the low potential for exposure and outcome misclassification because of the detailed source of data and adjustment for a large number of confounders.
The highest risks were for quetiapine (nearly fourfold increased risk) and for low potency antipsychotics rather than high potency ones. New users of antipsychotics seemed at greater risk than continuing users, and the effect was not seen in those who stopped taking the drug. These findings indicate that VTE is directly linked to the use of an antipsychotic, and that the risk of VTE increases early after starting the drug.
The mechanisms by which antipsychotics contribute to VTE remain elusive. Venous stasis can be exacerbated by excessive sedation.1 The metabolic abnormalities (dyslipidaemia, increased plasma concentrations of leptin and glucose, hyperhomocysteinaemia, and weight gain) documented especially among users of atypical antipsychotics may be associated with decreased fibrinolytic activity,6 but they take months or years to manifest and occur only in long term users. Patients on conventional antipsychotics and clozapine have shown high levels of circulating lupus anticoagulant and anticardiolipin antibodies, but these are seldom associated with thromboembolism.7
Changes in platelet function, plasma coagulation, or fibrinolysis are likely to be responsible for the increase in thrombotic events because VTE occurred early and during treatment of short duration; in addition, the risk of VTE was higher when antipsychotics were injected. Conventional agents, including chlorpromazine, fluphenazine, flupentixol, trifluoperazine, and haloperidol, have been associated with enhanced aggregation of platelets.8 Inhibition of 5-hydroxytryptamine 2A platelet receptors by clozapine, olanzapine, and risperidone can modulate receptor density and affinity but does not uniformly enhance platelet adhesion and aggregation.9 An effect of antipsychotics on platelets is supported by recent experimental findings.10
Although VTE is treatable it has a three month mortality rate of 15-18%,11 and evidence is accumulating that the use of antipsychotics is an established risk factor for VTE. However, consistent with previous estimates, Parker and colleagues found a low absolute risk of antipsychotic related VTE (four extra cases of VTE per 10 000 patients treated over one year), and doctors should consider this risk when making clinical decisions. The rarity of such adverse events does not justify antithrombotic prophylaxis for patients on antipsychotics without other medical conditions for which such preventive treatment is indicated.
Despite their association with serious risks and few data to support their efficacy antipsychotics are widely used, and in 2008 they became the top selling drug class in the United States, ahead of lipid regulators and proton pump inhibitors.12 Despite efforts to improve non-drug based interventions, antipsychotics are often used, especially for the treatment of agitation in people with dementia.
In clinical practice we need to be able to identify the best candidates for antipsychotic treatment, such as those people with the lowest vascular risk profile who may respond to short term and low dose treatment with antipsychotics because of individual pharmacogenetic characteristics, and those who may be more susceptible to developing side effects as a result of individual vascular risk factors possibly interacting with antipsychotics.
Cite this as: BMJ 2010;341:c4216
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.