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

In the early 1950s, a few years after the discovery of chlorpromazine, some cases of fatal PE during treatment with antipsychotics were reported [24, 25]. Thereafter, case reports [26, 27], case series [5‐10, 28‐30] and observational studies [31, 32] describing VTE in FGA users were published, suggesting a link between VTE and psychosis; however, these studies were inconclusive as they lacked control groups or did not have detailed information about possible confounders. Thus, the association fell into oblivion until 1997 when it was again reported [11]. Thereafter, an increasing body of evidence has been reported in the literature supporting a relationship between VTE and antipsychotics. The current systematic observational data for the risk of VTE among users of antipsychotics are summarised in Table 2 (case–control studies) and Table 3 (cohort studies and drug surveillance studies).

A meta-analysis of seven case–control studies [22], involving 31,095 cases and 143,472 controls, was published in 2011. In this analysis, a 2.4-fold overall increased risk (95% CI 1.7–3.4) of VTE was reported in users of antipsychotics. Although the reported risks were higher in SGA users (odds ratio [OR] 2.20, 95% CI 1.22–3.96) than in FGA users (OR 1.72, 95% CI 1.31–2.24) and higher in low-potency FGA users (OR 2.91, 95% CI 1.80–4.71) than in high-potency FGA users (OR 1.58, 95% CI 1.50–1.67), the wide and overlapping CIs, uncertainties regarding drug classification, and the heterogeneity in methodologies used, make the observed differences difficult to interpret.

In a meta-analysis of 17 case–control and cohort studies published in 2014 [23], antipsychotic use was associated with a 1.5-fold increased risk of VTE (95% CI 1.28–1.86). Increased VTE risks were revealed in FGA users (OR 1.74, 95% CI 1.28–2.37; six studies) and SGA users (OR 2.07, 95% CI 1.74–2.52; five studies). No significantly increased risk of PE could be verified in antipsychotic users (OR 4.90, 95% CI 0.77–30.98; three studies). However, after adding the results of a recent case–control study [40], an updated meta-analysis could reveal a statistically increased risk of PE (OR 3.68, 95% CI 1.22–11.07; four studies) [40].

Despite different methodologies, study populations and antipsychotic drug use patterns, most observational studies demonstrate an increased risk for VTE in users of antipsychotics. As case–control studies in general are known to overestimate risks, additional cohort studies are therefore important to verify and confirm results from case–control studies. Regarding the link between VTE and antipsychotics, cohort studies have reported similar findings as case–control studies, and there is also a consistency in overall results across different studies.

The highest VTE risk can be observed in present users of antipsychotics [36‐39], especially the first 3 months of treatment [12, 36‐39], suggesting that the medication rather than the underlying disease is the most important factor. Based on available data, it is complicated to determine which antipsychotic drug type carries the highest risk of VTE. In the meta-analysis from 2011 [22], pooled estimates showed that low-potency FGA had the highest risk, followed by SGA, but with overlapping CIs. In the meta-analysis published in 2014 [23], the risk of VTE was slightly higher in SGA users than in FGA users, but, again, CIs were overlapping. In these two meta-analyses, only a few of the included studies provided data on individual drugs, and pooled estimates of the VTE risk were therefore uncertain. More recently, a few larger studies [36, 39, 46, 52] have been able to study the risk of VTE related to single compounds, but current data can neither conclusively verify the existence of a difference between individual compounds nor identify the antipsychotic drug(s) having the lowest risk of VTE. Therefore, additional, even larger studies should be carried out, especially prospective cohort studies having valid information on already known risk factors for VTE, thereby being able to control for all potentially confounding factors.

The biological mechanisms responsible for the observed increased risk of VTE in antipsychotic drug users are not known and no single biological mechanism is likely to explain this adverse reaction. Several hypotheses have been put forward and proposed mechanisms are related to factors of the antipsychotic drug, the underlying disease, or a combination of these.

Drug-related factors include the frequently observed adverse drug reactions sedation, weight gain and hyperprolactinaemia. Sedation and weight gain pave the way to immobilisation and venous stasis in the lower extremities, thus increasing the risk of VTE [59, 60]. Prolactin is a potent platelet aggregation co-activator and the release of this hormone is inhibited by continuous dopamine release in the pituitary [61, 62]. This effect is mediated via dopamine D₂ receptors. As antipsychotics are D₂ receptor antagonists [63], prolactin increase is a prominent adverse effect, particularly for high-potency FGAs and risperidone. Aripiprazole and clozapine, which show partial agonistic activity and low affinity for dopamine D₂ receptors, respectively, show less or no prolactin increase [64]. Nonetheless, also clozapine is associated with an increased risk of VTE. Conflicting evidence regarding platelet adhesion and aggregation in vitro for clozapine and other antipsychotics make the clinical impact of these findings unclear [14, 65, 66]; it should also be noted that these platelet effects would be expected to cause arterial rather than venous thromboembolic events.

Antiphospholipid antibodies (APLs), including anticardiolipin antibodies and lupus anticoagulants, have been shown to be increased in patients using FGA and clozapine [67‐76]. An enhanced level of APLs is an established risk factor for VTE. However, the clinical impact of a high level of APLs is uncertain since a high level has also been shown in patients not using antipsychotics and only few cases of VTE in patients treated with antipsychotics have been associated with high levels of APLs [73, 75, 77]. Two more recent studies did not find any association between antipsychotic treatment and APL levels [78, 79].

A few well-established risk factors for VTE (Table 1), such as obesity and sedentary lifestyle, are abundant in people with psychotic disorders. Besides being a risk factor by its own, obesity increases thrombin formation and decreases fibrinolytic activity [4]. Obesity is also linked to myocardial infarction and congestive heart failure, conditions associated with VTE. Patients with psychoses clearly have a more sedentary lifestyle than age- and sex-matched controls from the general population, and their often low socioeconomic status and income may reduce the practical possibilities to make healthy lifestyle choices [80].

In the acute phase of a psychotic illness, physical restraint due to uncontrollable behaviour may also increase the risk of VTE. In a case series [81], 22 patients with PE related to catatonic syndrome were described, suggesting that certain psychiatric symptoms may have an increased risk of VTE. Of women admitted to a US hospital, two of four women with the catatonic type of schizophrenia developed VTE, compared with none of 168 women not having this type of schizophrenia [82]. The incidence of VTE was investigated in a Japanese study by means of routine Doppler ultrasound scanning in 79 catatonic patients who were involuntarily hospitalised and 292 non-catatonic physically restrained patients [83]. The incidence of VTE was significantly higher in the catatonic patients (25%) compared with the restrained non-catatonic patients (11%).

High-sensitive C-reactive protein (CRP) and other inflammatory markers are increased in a subgroup of patients with acute psychosis [84], and inflammation parameters have been shown to increase initially when starting treatment with clozapine and haloperidol [85, 86]; however, an increase in inflammatory response would be expected to cause arterial rather than venous thromboembolic events, rendering the clinical importance of this observation uncertain. In addition, markers of thrombogenesis, e.g. platelet activation (P-selectin) and coagulation (D-dimer and factor VIII), are triggered in acute psychosis, suggesting the disease itself may increase the risk of VTE [87]. Increased homocysteine levels have been under debate and have been proposed to increase the risk of VTE, and hyperhomocysteinaemia has been observed in patients with schizophrenia, as well as with the metabolic syndrome, which is an established adverse reaction of antipsychotic drug treatment [88, 89]. However, lifestyle factors such as a poor diet, cigarette smoking and high coffee and tea consumption may cause the observed increase in homocysteine seen in the group, rather than the antipsychotic drug or the disease itself [90].

In conclusion, although several mechanisms have been proposed to date, no clear-cut causal relationships between the mechanisms of action or other biological effects of antipsychotic drugs and VTE have been established.

Due to the increased risk of thromboembolic events in users of antipsychotic medications, individual risk factors for VTE should be assessed and high-risk situations should be identified. The importance of identifying early signs of VTE in antipsychotic users is stressed by the relatively high risks for fatal VTE and PE in antipsychotic users [44, 45] compared with the general increased risk of VTE in antipsychotic users (Tables 2, 3). Moreover, as the risk is dynamic, the risk should be re-evaluated when clinical circumstances change; for example, in situations with reduced mobility, infections, surgery and hospitalisation. In high-risk situations, appropriate prevention measures should be considered, i.e. reducing modifiable risk factors and commencing prophylactic antithrombotic treatment in line with guidelines [91]. To improve adherence to relevant guidelines, interventions such as medical education [92], computer-based alerts [93], and didactic lectures [94] have been suggested. Risk-assessment models (RAMs) have been advocated as instruments to ensure objective risk assessments and to support evidence-based clinical decisions in management of the risk [95, 96]. However, risk predictors differ across RAMs and several of them do not take antipsychotic treatment as a risk factor into consideration, possibly because limited evidence exists regarding how the increased risk of VTE due to antipsychotic agents should be handled in clinical practice.

Attempts to compile algorithms for the primary prevention of VTE for psychiatric inpatients have been made (Table 4). In the algorithm by Malý et al. [18], which is based on an algorithm by Cohen et al. [97], the patients’ risk of VTE is assessed and preventive measures suggested. Prophylactic treatment with low-molecular weight heparin is suggested in hospitalised patients with reduced mobility until they are fully mobilised. Liu et al. [98] adopted the scoring system from Malý et al. [18] to assess the VTE risk in psychogeriatric inpatients. Here, oral contraceptive use was removed, as was laboratory thrombophilia, which would rarely be checked in an elderly patient. The presence of acute renal failure was added as a proxy for dehydration. Patients were classified as having low (score 0–3), medium (4–7) and high risk (≥ 8), as in the scoring system by Malý et al. [18]. Those assessed to be at medium risk had a significantly increased rate of VTE and therefore the authors proposed prophylaxis to be prescribed for psychogeriatric inpatients assessed to be at medium and high risk. Nevertheless, the threshold for prophylactic treatment should also be low in situations with VTE risk factors that are not included in the algorithm. If no contraindications to low-molecular weight heparins are present, the prevention of VTE with such drugs is generally considered safe and effective. No data exist on the use of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban and edoxaban, in this situation. In patients not suitable for treatment with low-molecular weight heparins, DOACs could be considered as an alternative. In such cases, it seems reasonable to use these drugs in low doses, e.g. the doses approved for VTE prophylaxis after hip or knee replacement surgery.

High-risk individuals using antipsychotics should be informed of the symptoms of DVT and PE, as well as the importance of seeking medical care immediately. A manifest VTE or PE in a patient using an antipsychotic agent should be managed in accordance with current guidelines [91]. After diagnosis, the indication of the antipsychotic treatment should be re-evaluated and treatment suspended if possible. Both Malý et al. [18] and Liu et al. [98] recommend that if there is a strong indication for treatment, switching to an antipsychotic with a possibly lower association with VTE should be considered; however, they do not specify which antipsychotics should be preferred (or avoided) in patients with a high risk of VTE. Although solid evidence is lacking, it could be speculated that the risk of VTE might be higher for clozapine than for other SGAs [46, 52]. Separating the other SGAs regarding the risk of VTE is not possible based on available data. As psychotic disorders as such have been associated with VTE, it is possible that the underlying condition may have contributed in the etiology of VTE. When choosing an antipsychotic drug for a patient, it seems reasonable to consider not only drug-specific risk factors for VTE but also patient-specific risk factors. Clinical recommendations for the prevention and management of VTE in users of antipsychotics are summarised in Box 1.

Increasing evidence points towards an increased risk of VTE in patients using antipsychotics. The association is mainly supported on observational data. Even though individual studies have a number of methodological shortcomings, the overall picture suggests that the observed higher risk is related to the antipsychotic medications as such. The risk seems to be highest during the first 3 months of treatment. The currently available literature does not document any clear-cut differences in the risk of VTE between FGA and SGA or between individual antipsychotic drugs, and the biological mechanisms underlying the increased risk are still largely unknown.

In patients developing VTE, adequate antithrombotic treatment should be started and consideration should be given to discontinuing or switching the antipsychotic treatment. Even though solid evidence is lacking, it might be pertinent to avoid clozapine if possible, but giving advice regarding which drug(s) to prefer or avoid among the other SGAs is not possible. Prophylactic antithrombotic treatment should be given liberally to patients concomitantly having other risk factors of developing VTE, e.g. in line with the algorithm outlined in Table 4.