Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence

CNS Drugs (2018) 32:47–64 https://doi.org/10.1007/s40263-018-0495-7 REVIEW ARTICLE Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence Anna K. Jönsson1,2 • Johan Schill3 • Hans Olsson3 • Olav Spigset4,5 • Staffan Hägg6 Published online: 8 February 2018 Ó The Author(s) 2018. This article is an open access publication Abstract This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the & Staffan Hägg 1 Department of Drug Research, Section of Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden 2 Department of Forensic Genetics and Forensic Chemistry, National Board of Forensic Medicine, Linköping, Sweden 3 Department of Psychiatry, Region Jönköping County, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden 4 Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway 5 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 6 Futurum, Region Jönköping County, Department of Medical and Health Sciences, Linköping University, Sweden increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE. Key Points Increasing evidence shows an elevated risk of venous thromboembolism (VTE) in antipsychotic drug users. In general, no well-documented differences in the occurrence rate of VTE between first- and secondgeneration antipsychotics or between individual antipsychotic drugs have been shown. The biological mechanisms involved in the pathogenesis of antipsychotic-induced VTE are still largely unknown. Physicians should be aware of this potentially serious adverse drug reaction and consider discontinuing or switching the antipsychotic treatment in patients experiencing VTE. The threshold for considering prophylactic antithrombotic treatment should be low when risk situations for VTE arise in users of antipsychotics. 48 A. K. Jönsson et al. 1 Introduction Venous thromboembolism (VTE) is a multicausal disease encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE) [1, 2]. VTE affects approximately 1.0–1.8 per 1000 adults annually, may lead to complications such as post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTPH), and can produce a considerable burden of morbidity and mortality [1, 2]. The presence of one, or a combination of, components of Virchow’s triad—hypercoagulability, stasis of blood flow and vein wall injury—are fundamental to developing VTE and all known risk factors for VTE are considered to affect at least one of these components [1–3]. Established risk factors are listed in Table 1 and include inherited coagulation abnormalities, malignancies, surgery, pregnancy, and medications such as oral contraceptives and hormone replacement therapy [1–4]. VTE has also been associated with psychiatric disorders and antipsychotic treatment [1–4]. In early, uncontrolled, observational studies [5–10], a relatively high incidence of PE among patients with schizophrenia and related disorders was reported but the Table 1 Major risk factors for VTE [1–4] association was not widely acknowledged. However, in the late 1990s, the association again received attention when an increased mortality rate in PE was reported in current users of clozapine compared with past users in a record linkage study on mortality in clozapine users [11, 12]. A few years later, this potential safety concern was strengthened by the publication of a case series of VTE in clozapine users [12], followed by a large nested case– control study [13] reporting a sevenfold increased risk of VTE in patients currently treated with first-generation antipsychotics (FGAs) relative to non-users. Since then, an increasing number of reports supporting and describing this association have been published. The available evidence on this link has previously been summarised by both us [14–16] and others [17–21], including two meta-analyses [22, 23]. The aim of this article is to update and critically review the available data on incidence, risk factors, characteristics, mechanisms and management of VTE in users of antipsychotics. In October 2017, the PubMed and Scopus databases were searched for relevant articles on antipsychotic medication and VTE. In the PubMed search, the Medical Subject Heading (MeSH) terms ‘embolism and thrombosis’, ‘antipsychotic agents’ and ‘schizophrenia’ were used, Clinical factors Surgical factors Inherited factors Advanced age Central venous access Antithrombin deficiency Hospitalisation for acute medical illness Major surgery Dysfibrinogenemia Long-haul flights (duration[4 h) Orthopaedic surgery Factor V Leiden mutation Obesity Pregnancy, including the post-partum period Trauma or fracture Protein C deficiency Protein S deficiency Prothrombin 20210A mutation Medical diseases Drugs Mixed or unknown factors Antiphospholipid syndrome Congestive heart failure Antiestrogens Antipsychotics Inflammatory bowel disease Chemotherapy Activated protein C resistance in the absence of factor V Leiden mutation Malignancy Heparin-induced thrombocytopenia Myeloproliferative disorders Myocardial infarction Polycythemia vera Previous VTE Sepsis Stroke Varicose veins High-dose therapy with progestogens Hormone replacement therapy Oral contraceptives Vaginal ring for contraception Strontium ranelate Thalidomide and lenalidomide VTE venous thromboembolism Family history of VTE High levels of factor VIII Hyperhomocysteinaemia Lupus anticoagulant VTE and Antipsychotics while in Scopus, the title, abstract and keywords were searched for a combination of one of the following terms: ‘embolism’, ‘thrombosis’ and ‘thromboembolism’ and one of the terms (...truncated)