Deep venous thrombosis and pulmonary embolism in psychiatric settings

 

 

Els G. Van Neste, Ward Verbruggen, Mark Leysen

Psychiatric Hospital Sint-Amedeus, Antwerp. BELGIUM

Address for correspondence

 

 

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ABSTRACT

Background and objectives: Deep venous thrombosis and pulmonary embolism are serious, possibly life-threatening events which are often ignored in psychiatric settings. This article investigates which psychiatric patients are at increased risk of developing a venous thromboembolism. To our knowledge we are the first to perform a literature review of clinical studies relating venous thrombosis and pulmonary embolism to psychotropic drugs and mental disorders.
Methods: A Medline search for English studies using the appropriate search terms was performed. In addition, cross references of the relevant articles` literature references were considered. We withheld 12 observational studies, 29 case-reports and one review-article.
Results: We found evidence that low potency antipsychotic drugs like chlorpromazine and thioridazine, and clozapine for treatment of resistant schizophrenia have an increased risk of venous thromboembolism. There is no evidence that antidepressants, benzodiazepines or mood stabilizers have a similar effect. Also psychiatric conditions like physical restraint, catatonia and neuroleptic malignant syndrome are related to a higher incidence of deep venous thrombosis.
Conclusions: Limitations of the studies and hypotheses about underlying biological mechanisms are reviewed. The rationale for prophylactic measures is discussed and recommendations to prevent deep venous thrombosis and pulmonary embolism are given.

Key words: Venous thrombosis; Pulmonary embolism; Mental disorders; Antipsychotic drugs.

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Introduction

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are frequent illnesses with an annual incidence of more than 1 per 1000 persons and a mortality rate above 15% in the first 3 months after diagnosis¹. Both illnesses have a common pathogenesis and are referred to as venous thromboembolism (VTE). Many studies about this subject have been performed in medical and surgical settings. In psychiatric settings this problem is often ignored.

Known risk factors for development of DVT and PE during medical and surgical hospitalisations include congenital factors (i.e. hereditary thrombophilia like Factor V Leiden, prothrombin deficiency...) and acquired factors (advanced age, obesity, former DVT or PE, surgery, trauma, neoplasms, heart-, kidney-, and bowel diseases, oestrogen hormone therapy, tamoxifen, dehydration, immobilisation...). These risk factors can induce the formation of a DVT by three mechanisms described as Virchow’s triad: slowing down of the blood velocity, damage to the vessel wall and hypercoagulability².

The aim of this literature review is to examine if psychotropic medication or specific psychiatric conditions give a higher risk of developing DVT or PE. Moreover we aim to investigate the underlying biological mechanisms or risk factors and give recommendations to prevent DVT and PE in psychiatric patients.

 

Method

A Medline search (1956- march 2008), for English studies using a combination of the following Mesh terms: “Venous Thrombosis”, “Pulmonary Embolism” “Psychotropic drugs”, “Mental Disorders” was performed. In addition, cross references of the relevant articles` literature references were considered. For each study or case-report, we defined study design, authors, study group and control group (if present), diagnosis, risk factors, treatment and results. We withheld 12 observational studies, 29 case-reports and one review-article. Studies were classified according to their link with either psychotropic drugs (antipsychotic drugs, antidepressants, benzodiazepines and mood stabilizers) or psychiatric conditions (physical restraint, catatonia, neuroleptic malignant syndrome).

 

Results

Psychotropic drugs

The association between conventional antipsychotics and VTE was investigated in 8 observational studies, listed in Table I^3-10. Two studies suggest a positive association between conventional antipsychotics and VTE but are inconclusive (due to small numbers of patients)^3,8. The data of 5 out of 6 remaining observational studies from large databases support the association between antipsychotic drugs and VTE for conventional antipsychotics^4,5,7,9-10. Especially low potency antipsychotics such as chlorpromazine and thioridazine and to a lesser extent high potency antipsychotics such as haloperidol show a strong association with VTE^7,9. More specifically an increased risk has been observed with phenothiazines, butyrophenones and benzamides were found^5,7,10. Only the study of Liperoti et al. didn’t find an increased risk⁶. In this study, low doses of antipsychotic agents were in accordance with recommendations for use in elderly people but were substantially lower than those previously prescribed in the study of Zornberg et al.³. The risk for VTE was highest during the first few months of conventional antipsychotic drug use³. Psychiatric conditions as schizophrenia⁶, an acute psychotic episode^7,9,10, dementia^6,10 and alcohol or substance misuse⁷ were often not included in the study. Only in the study of Parkin et al.⁶ and Hamanaka et al.⁴ the study focused on patients with severe psychiatric conditions as schizophrenia and bipolar disorder.

Other risk factors and protective factors for VTE were controlled in all studies by excluding them. Immobilisation as a risk factor was eliminated by excluding patients with an acute psychotic episode that can require fixation and sedations^7,9,10, hospitalised patients⁵ and patients with low cognitive and daily functioning⁶. In all the studies, the diagnosis of DVT or PE was confirmed by objective standards such as dopplerultrasonography, ventilation perfusion scintigraphy, CT scan or autopsy^3-10.

Two retrospective studies and 11 case reports highlighted the association between clozapine and VTE (Table II)^11-23. Patients using regular doses of clozapine for treating resistant schizophrenia seem to have an increased risk to develop VTE in the first months of clozapine treatment^12,15-20,23. Also, more men developed VTE during clozapine treatment although the prescription and reporting rate seems to be similar for both sexes¹². The diagnosis was confirmed with appropriate technical investigations or autopsy in all studies^11-23.

On the association between VTE and other atypical antipsychotic drugs, 4 case-reports (Table II)^24-27 and 3 previously mentioned studies^4-6 were found. The study of Hamanaka et al. was based on small numbers (4 patients)⁴ and Parkin et al.⁹ didn’t find an increased risk. Only Liperoti et al. found a mild increased risk for atypical antipsychotic drugs⁶.

The literature review revealed one case report of fluoxetine²⁸ and one of escitalopram²⁹ in association with VTE. In the previously mentioned studies of Ray et al., Zornberg et al., Parkin et al. and Lacut et al. (Table I)^5,7,9,10, only the study of Parkin et al. found an increased risk (odds ratio of 4.9 (95% CI: 1.1 -22.5) for current use of antidepressants⁹. Recently, a nested case-control study, based on the United Kingdom General Practice Research database, found that amitriptyline, particularly at high doses, conferred an increased risk of VTE (odds ratio of 1.7 (95% CI 1.2-2.4)³⁰.

There were no relevant studies found on benzodiazepines.

The only relevant study about mood stabilisers showed an excess mortality by pulmonary embolism in 405 bipolar and 92 unipolar patients who attended the same out-patient lithium clinic for up to 30 years³¹.

Psychiatric conditions

The literature search revealed three psychiatric conditions with an increased risk of DVT or PE: physical restraint, catatonia, neuroleptic malignant syndrome (Table III)^32-45.

In the English literature we found 6 cases of patients who developed a DVT or PE during physical restraint, listed in Table III^32-35. Physical restraint was usually applied in a suspine position with a waist belt or four-point restraint of the wrists and ankles. PE during physical restraint covered all age categories but was mainly present in men. The duration of restraint was long, between 3 to 13 days. In most of the cases risk factors other than physical restraint for VTE were present, with exception of the case report of Laursen et al.³⁵. In two cases, the patients were complaining of chest pain or respiratory difficulties for several days, ascribed to anxiety or psychosis, before the correct diagnosis was made^32,35. Two patient collapsed shortly after the restraints were removed^32,34 and one patient died 24 hours after removal of the restraints³³. Antipsychotic medication was often given to sedate the patient during restraint.

Five case reports and one review of 20 autopsy case-reports of PE in severe catatonia with psychomotor retardation are shown in Table III^36-41. Immobility and refusal of fluids were always present as risk factors. The study of McCall et al.³⁶ suggested death from PE would occur after the second week of catatonic symptoms and often occurred without warning. But in the case-report of Woo⁴¹, PE was diagnosed during the first week of catatonia. Antipsychotic drugs, antidepressants and benzodiazepines were given shortly before or during the catatonic state.

Six cases of patients who died from a PE during neuroleptic malignant syndrome have been described (Table III)^42-45. Neuroleptic malignant syndrome is characterized by severe rigidity, fever, altered mental status and autonomic dysfunction. Rhabdomyolysis was sometimes present in the reported cases.

In all case-reports the diagnosis of VTE was confirmed with appropriate technical investigations or autopsy^32-45.

 

Discussion

Limitations

The data demonstrate an association between antipsychotic drugs and VTE for conventional antipsychotics^4,5,7,9-10 and clozapine^11-23. The risk was highest during the first few months of antipsychotic drug use and also applies to less affected patients.

Most observational studies on conventional antipsychotics were based on large databases with a control group^5,6,7,9,10 and one study was a prospective study¹⁰. However, most studies were not mentioning the dose of antipsychotic drugs and concomitant use of medication^3,4,5,8,9,10. Most risk factors were controlled in the studies but only the recent study of Lacut et al excluded the congenital risk factors, factor V Leiden and prothrombin deficiency¹⁰. Although special attention was paid to avoid recall bias, it can not be completely ruled out.

Both retrospective studies on clozapine were not controlling other risk factors for VTE^11,12. In most case-reports other risk factors were present but not examined or mentioned completely^13-23. Further observational studies should ideally include a control group.

Findings on atypical antipsychotic drugs other than clozapine were few and discordant^4-6.

There is only few or no evidence that antidepressants, benzodiazepines or mood stabilizers give an increased risk of VTE^{5,7,9,10,28-31}.

Physical restraint, catatonia and neuroleptic malignant syndrome predispose to VTE with possibly fatal outcome. These findings are based on numerous case-reports (Table III)^32-45. The common denominator in all three conditions is immobility. The case reports perform an important role in highlighting the risk of immobility in these psychiatric conditions. Other risk factors for developing VTE were not examined completely. Antipsychotic drugs had often been used in this patients although stopped in catatonia and neuroleptic malignant syndrome. This can be a confounding factor. Observational studies might be difficult to design for severe catatonia and neuroleptic malignant syndrome since they are relatively rare conditions.

There are two important limitations of this literature review: language bias and diagnosis bias. Exclusion of papers published in non-English languages might have limited the total number of cases available for inclusion. Secondly, pulmonary embolism is often misdiagnosed as sudden cardiac death. Ten of 27 cases of fatal pulmonary embolism were diagnosed in psychiatric patients only at autopsy⁴⁶. This makes it possible that some cases of PE are missed and without autopsy are ascribed to other fatal conditions.

Underlying biological mechanisms

Serveral underlying mechanisms have been proposed to explain the association between antipsychotic drugs and VTE. Sedation induced by antipsychotic drugs, can increase venous stasis. Hypercaogulability via an enhanced aggregation of platelets with conventional antipsychotics has been suggested in previous studies^47,48 or via hyperprolactinemia in an indirect pathway more recently⁴⁹. Another hypothesis is the increased levels of lupus anticoagulant and anticaridiolipin antibodies induced by conventional antipsychotic agents and clozapine^50,51. Finally, hyperhomocysteinemia was also suggested as a plausibel underlying mechanism but is probably more related to the psychiatric disorder itself^52,53.

Immobilisation is regarded as an important risk factor for surgical and bedridden patients⁵⁴ but also for healthy persons on long distances air travels⁵⁵ or in persistent sitting position⁵⁶. In conditions like physical restraint, severe catatonia and neuroleptic malignant syndrome immobilisation, causing slowing down of the bloodstream, seems the common risk factor for the development of VTE. Additional risk factors for VTE inherent to the specific psychiatric conditions are: heavy resistance during physical restraint situations (damage to the vessel wall), lack of fluid intake in severe catatonia (hypercoagulability) and fever and rhabdomyolysis in the neuroleptic malignant syndrome (hypercoagulability)⁵⁷. Three factors can cause delay in medical attention. Firstly, the patient may due to his illness not be able to communicate leg pain from DVT or chest pain or respiratory difficulties from PE³⁹. Secondly, there is a risk that these physical complaints are ascribed to anxiety or psychosis and are not taken seriously^32,35. Thirdly, PE can occur without warning signs and sometimes patients collapsed when ambulation was restarted which may activate silent cloths³³.

The studies on antipsychotic drugs ruled out the influence of immobility by exclusion. During physical restraint, severe catatonic states or neuroleptic malignant syndrome, antipsychotic drugs are often used before or during the illness. But in catatonia and neuroleptic malignant syndrome antipsychotics are mostly stopped.

Prophylaxis and treatment

DVT and PE are life threatening illnesses. Prophylactic measures for VTE in medical and surgical settings are physical excercise, placement of elastic stockings, use of pneumatic compression and administration of subcutaneous heparin⁵⁸. This review raises the question if patients on antipsychotic agents or during physical restraint, severe catatonic state or neuroleptic malignant syndrome should receive prophylactic measures against VTE.

Although VTE prophylaxis for all patients taking antipsychotic drugs is inappropriate, we have to consider the fact that the risk of VTE increases significantly if several risk factors are present at the same time⁵⁹. Screening patients for additional risk factors of DVT and PE seems advisable to identify those patients that would benefit from prophylaxis. Prophylaxis proposed by some authors to prevent VTE in patients during prolonged restraint or with severe catatonia, range from a higher awarness of VTE, conducting frequent physical examinations, physical excercise, until anticoagulation^34,37-40. Some authors suggest anticoagulation therapy during immobility due to neuroleptic malignant syndrome for al such patients^42,45. There is one report on a prophylaxis scheme in a mental hospital in the Czech Republic but this is not based on scientific evidence⁶⁰. Until there is more evidence from prospective observational and randomized controlled studies recommendations based on prophylactic measures taken in medical and surgical settings⁵⁸ seems appropriate.

If a psychiatric patient is identified as having an increased risk for VTE the following prophylactic measures should be considered. Firstly, avoidance of strict bedrest or immobility and an increased amount of exercise is for most patients sufficient but often ignored. Also sufficient hydration is of importance. Secondly, complaints such as swelling, pain or discolouring of the leg, chest pain or dyspnoea merit special attention. Conducting physical examinations focusing on this complaints is essential. Further technical investigations as Doppler ultrasound of the lower extremity to diagnose DVT or ventilation-perfusion scan or spiral CT of the chest to diagnose for PE is necessary. Thirdly, the implementation of other deep venous thrombosis prophylactic measures (i.e. placement of elastic stockings, use of pneumatic compression or administration of subcutaneous heparin) should be considered in high risk patients. We consider patients taking antipsychotics combined with multiple other risk factors, physical restraint for long periods, persistent immobility due to severe catatonia and neuroleptic malignant syndrome at high risk for VTE.

 

Conclusion

Psychiatric patients taking conventional antipsychotic drugs or clozapine, under physical restraint or suffering from severe catatonia or neuroleptic malignant syndrome seem to have an increased risk to develop deep venous thrombosis and pulmonary embolism which are potentially life-threatening events. A double blind study in the psychiatric population is needed in order to refine the subgroups of our patients who would benefit from DVT prophylaxis.

 

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Address for correspondence:
Dr. Els G. Van Neste
Isabellalei 22
28180 Ekeren (Antwerp) Belgium
Tel. +32 (0) 486 409938
Fax +32 (0) 323 33110
E-mail: elsvanneste@hotmail.com

Received 16 May 2008
Accepted 8 January 2009