Issues in Pharmacotherapy Practice

Is There an Association between Antipsychotic Medications and Venous Thromboembolism?

Colette Raymond, B.Sc.(Pharm), Pharm.D.1,2
1
Pharmaceutical Sciences Clinical Service Unit, Vancouver Hospital & Health Sciences Center, Vancouver, BC, Canada 
2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
E-mail: coletter@interchange.ubc.ca


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Abstract

Background: Antipsychotic agents are widely used medications.  An association between antipsychotic agents and venous thromboembolism has been proposed in the literature. 
Methods: A literature search was conducted using MEDLINE, EMBASE, PubMed, and national and international adverse drug reaction reporting programs. 
Results: Several case reports, case series, observational and retrospective studies have been published.  Investigators of a large case control study involving 30,000 current antipsychotic users found an increased risk of venous thromboembolism OR 7.1 (95% confidence interval 2.3-21.97).  Agents most commonly implicated include low potency conventional antipsychotics and clozapine. Proposed mechanisms include drug-induced effects of platelet aggregation, anticardiolipin antibodies or weight gain, sedation and diabetes.
Conclusion: A possible association between antipsychotics and venous thromboembolism, although rare, does exist.  Clinicians should be aware of this potential adverse drug reaction.

J Inform Pharmacother 2003;12:300.

Background

Antipsychotic agents are widely used for many indications in medicine and psychiatry with therapeutic indications ranging from treatment of nausea to refractory schizophrenia.  Patients receiving antipsychotics are usually monitored closely for many known adverse effects including movement disorders, seizures and blood dyscrasias. (1)  Case reports, retrospective analyses of cause of death in psychiatric patients and national adverse drug reaction reporting programs suggest that an association between antipsychotic medications and venous thromboembolism (VTE) may exist. The purpose of this paper is to review and summarize the published literature regarding this apparently rare, but potentially dangerous drug reaction.

Methodology

Searches through MEDLINE (1966 - April 2002) and EMBASE (1980 - April 2002), were conducted using the search terms "antipsychotic, antipsychotics, neuroleptic, neuroleptics, antipsychotic agents" and "thrombosis, venous thrombosis, thromboembolism" and "pulmonary embolism."  Observational studies (cohort and case control) and randomized controlled trials reporting VTE outcome data with exposure to antipsychotics were sought. References from articles identified through the MEDLINE search were manually reviewed to identify for further reports.

Results

Several reports suggesting a possible association between antipsychotic medications and VTE have been published (Table 1).  Cases involved different types, doses and durations of exposure to antipsychotics.  Where possible, (2-17) cases were evaluated using a standard method for estimating the probability of adverse drug reactions. (18)  Reported cases were considered to reflect a possible association between antipsychotic drug ingestion and the development of VTE.  While many cases (2-17) appeared to involve objective confirmation of the diagnosis, none involved a drug rechallenge procedure.

One case series identified 49 cases of VTE (3.1%) in 1,590 patients treated with antipsychotics from 1958-61 at a single centre, as compared to 20 cases (0.3%) of VTE in patients on very low doses or no antipsychotics. (19)  This report raised the possibility of a higher than expected incidence of VTE in this population.  Like other reported cases, many patients were elderly with concomitant medical conditions or medications.  Although a comparator group was indicated, it was not stated if the controls were matched for any characteristics.  "Low dose" antipsychotic exposure was not defined or described, thus limiting the utility of the control group and the interpretation of this report.

Retrospective cohort analyses of autopsies have also suggested an increased incidence of VTE in patients with psychosis, and patients treated with antipsychotics. (20-26)  In a study that compared causes of death in 67,072 current and former users of clozapine, it was noted that current clozapine use was associated with an increased risk of pulmonary embolism (RR 5.2 for current compared with past clozapine use). (20)  At a hospital in the Netherlands a review of 14,000 autopsies showed that 10 of 27 patients with idiopathic pulmonary embolism were psychiatric patients (21) and five were treated with antipsychotics. (26)

Several national adverse drug reaction (ADR) reporting programs have described reports of VTE possibly associated with antipsychotics.  Twelve cases of VTE (5 fatal) associated with clozapine that were reported to the Swedish Adverse Reactions Advisory Committee from 1989-2000 are described in Table 1. (17)  Based on an estimate derived from Swedish pharmacy statistics, the authors proposed an incidence of VTE associated with clozapine of 0.017 - 0.05%. (17)  A German ADR surveillance program that assessed severe ADRs in all inpatients of psychiatric hospitals in Switzerland and Germany (103,000 patients from 1993-99), reported that the incidence of VTE was 0.038%, 0.029% and 0.026% in patients treated with clozapine, other antipsychotics and no antipsychotics, respectively, although there was no statistically significant difference between the relative incidences of VTE in these groups. (27)  From 1990-99, the Food and Drug Administration (FDA) in the United States received 99 reports of VTE (39 with objectively confirmed diagnosis) possibly associated with clozapine. (28) From 1964 to 2002, 27 cases of VTE (13 fatal) associated with clozapine and one case of VTE associated with risperidone were reported to the Canadian Adverse Drug Reactions Database (CADRAMP). (29)  From 1988 to 1998 there were 137 reports of VTE associated with antipsychotics made to the World Health Organization (WHO) database of ADRs (clozapine 111, chlorpromazine 4, haloperidol 18, thioridazine 4). (30)  It is possible that due to the spontaneous nature of adverse drug reaction reporting programs that these cases represent a duplication of previously published reports.

A recent study assessed the incidence of VTE in a group of nearly 30,000 patients prescribed an antipsychotic from 1991-8. (31)  The patients were part of the UK based General Practice Research Database, a computerized database of physician visits.  Data were collected at the point of visit including: patient demographics, characteristics, symptoms, medical diagnoses, hospital admissions and prescriptions.  Patients had used at least one antipsychotic during the study period, and were followed for a minimum of six months.  Cases had objectively diagnosed first-time VTE, were admitted to hospital and treated with anticoagulants (identified through computer recorded medical diagnosis and confirmed by discharge records).  All patients were less than 60 years and free of medical conditions potentially associated with VTE including: history of VTE, trauma, pregnancy or surgery within six months, history of an acute psychotic episode within two months, or history of coagulopathy, congestive heart failure, myocardial infarction, cancer, renal failure, epilepsy, diabetes mellitus, cystic fibrosis, multiple sclerosis, alcohol and substance use disorders.  For each case, four controls were matched for age, sex, general practitioner and years in the database.

During a mean follow-up of 6.8 years, 42 cases of idiopathic VTE were identified.  The odds ratio (OR) for VTE (adjusted for smoking, body mass index, hypertension, estrogen and antidepressant use) for current antipsychotic use (within 60 days) was 7.1 (2.3-21.9). The OR for VTE was for recent use (61-120 days) was not significant 2.1 (0.4-11.8). The OR for VTE was greater for low potency agents (chlorpromazine, thioridazine, mesoridazine, pericyazine, methotrimeprazine, pipothiazine, sulpiride) as compared to high potency agents (haloperidol, benperidol, pimozide, trifluoperazine, fluphenazine, perphenaxine, zuclopenthixol, flupenthixol, thiothixene, lozapine); 24.1 (3.3-172.7) and 3.3 (0.8-13.2) for low and high potency agents, respectively. The OR for VTE was 12.4 (3.2-48.3) and 2.3 (0.4-14.9) for doses less than and greater than 100 mg chlorpromazine equivalents, respectively. The OR for VTE was 28.7 (4.9-169.5) and 1.0 (0.1-7.3) for use within 11 months, or greater than or equal to 12 months, respectively.  There was no difference between phenothiazines, thiothixines and heterocyclic agents.  There were no cases of VTE reported with use of atypical antipsychotics (quetiapine, olanzapine clozapine and risperidone), although only 3% of the patients were actually receiving these agents. Patients and controls were well matched for factors including body mass index, smoking status, history of diabetes or hypertension, estrogen and antidepressant use. Stratification for age, sex and outcome did not change the study results.  The authors proposed an incidence for VTE associated with antipsychotic use of 0.14%. (31)  Although case reports and autopsy data suggest there may be an association with clozapine and VTE, (9,12-17,27-30), the results of this study do not add to the available literature as only 3% of patients were taking atypical antipsychotics and no VTE occurred in these patients. 

The following case control studies add to the results of earlier observational studies in Germany. (32-34)  One study identified an increased incidence of VTE (3.3%) among 338 phenothiazine users between 1954-57, as compared to a non-phenothiazine control group (< 0.5%). (32)  The scarce available information about patient diagnoses, medical conditions and medications limits the interpretation of this study.  Another study has reported an increased incidence of VTE in psychiatric and neurological patients from 1958-61(following the introduction of chlorpromazine) as compared to historical controls from 1915-22 (18% vs. 6% in males and 29% vs. 10% in females). (33)  The use of historic controls, as well as minimal reported patient information, limits the interpretation of this study.  An early case control study, assessed 2,344 psychiatric patients and noted an increased incidence of VTE in patients treated with antipsychotic or antidepressant medications (chlorpromazine, amitriptyline, imipramine) as compared to patients with similar psychiatric patients who did not take these medications (2.9% vs. 0.6%). (34)  Most (22/34) patients with VTE had concurrent medical conditions, limiting the interpretation of this data.

Table 1: Case reports of venous thromboembolism associated with antipsychotic medications.

Author (Year)

# pts

Age, sex

Type of report

Drug

Event (Outcome)

Exposure

Naranjo
Score*

Comments

Singer (1975)2

1

59 F

Case report

Chlorpromazine 600 mg/d

PE (Recovery)

6 weeks

4

Also taking clomipramine

Mueh (1980)3

3

37 M



37 F


66 M

Case report

Case 1:  Haloperidol, thioridazine


Case 2:  Fluphenazine

Case 3:  Phenothiazine

Case 1: DVT (Recovery)


Case 2: PE (Unknown)

Case 3: CVA (Unknown)

All cases: many years

4



4


3

Case 1: Lupus anticoagulant positive.  Platelet count 68 000/mm3.  Antinuclear antibody positive 1:20.

Case 2.  Lupus anticoagulant positive.



Case 3: Lupus anticoagulant positive.  Also had polycythemia rubra vera.

Varia (1983)4

3

37 M



64 M


81 M

Case report

Case 1: Chlorpromazine 800 mg/d

Case 2:Thioridazine 20 mg bid

Case 3: Thioridazine 50 bid, 25 qid prn

DVT

(Recovery)

Case 1: 2 wks


Case 2: 15 d

Case 3: 60 d

4



4


4

 

Kelley (1985)5

1

52 M

Case report

Fluphenazine 10 mg bid

CVA (Recovery)

6 yrs

4

Also took benztropine 2 mg bid.  History of treatment with chlorpromazine.  Partial thromboplastin time prolonged (61.3 seconds). Antinuclear antibody positive, 1:40 (lupus anticoagulant positive).

El-Mallakh (1988)6

1

35 F

Case report

Chlorpromazine 800 mg/d, perphenazine 16-24 mg/d, haloperidol 5-30 mg/d

CVA (Recovery)

1 mo

3

Smoker.   Anticardiolipin assay positive (1:1.33) normal = 1:1.13. Antinuclear antibody titre 1:64.

Roche- (1990)7

1

38 F

Case report

Chlorpromazine 50-100 mg/d

PE (Recovery)

~ 20 yrs

4

Pulmonary artery thrombi led to pulmonary hypertension and right ventricular failure.  Positive anticardiolipin antibody.  Positive antiprothrombinase-type anticoagulant.

Metzer (1994)8

1

54 M

Case report

Fluphenazine decanoate

CVA (Unknown)

~ 20 yrs

4

Antiphospholipid and anticardiolipin antibodies measured and found to be normal.

Clardy (1995)9

2

 

Case report

Clozapine 450-700 mg/d

PE (Death)

Not reported

3, 3

Obese patients.

Pantel (1997)10

2

71M


72 M

Case report

Case 1: Zotepine 150 mg/d

Case 2: Zotepine 150 mg/d
 

DVT (Recovery)

Case 1:  17 d

Case 2: 3d

4


4

Case 1 also taking paroxetine 40 mg/d, metoprolol 190 mg/d, digitoxin 0.1 mg/d.

Case 2 also taking paroxetine 40 mg/d, theophylline 675 mg/d, verapamil 120 mg/d.

Ducloux (1999)11

1

25 F

Case report

Chlorpromazine

PE, renal artery and IVC thrombosis (Recovery)

5 yrs

4

Anticardiolipin antibody strongly positive. Chlorpromazine was withdrawn and 6 months later, anticardiolipin antibodies were negative.

Lacika (1999)12

1

71 F

Case report

Clozapine 200 mg/d

PE (Recovery)

4 yrs

3

Patient was wheelchair bound.  Also had Parkinson’s disease.  Other medications included benztropine, clonazepam, furosemide, ranitidine, docusate, domperidone, acetaminophen.

Coodin (2000)13

1

30 M

Case report

Clozapine 75 mg bid

PE (Recovery)

12 d

3

Patient was obese. 6 year history of antipsychotic exposure.

Maynes (2000)14

1

30 M

Case report

Clozapine 400 mg/d

PE (Recovery)

5 mo

3

Patient was obese.  Concomitant medications included sertraline 150 mg/d. 10 year history of antipsychotic exposure.  Increased level of anticardiolipin antigen.

Suttmann (2000)15

1

33 F

Case report

Clozapine 250 mg/d

PE (Recovery)

12 d

3

Patient had factor V Leiden mutation. 

Ihde-Sholl (2001)16

1

29 M

Case report

Clozapine 300 mg/d

PE (Death)

6 wks

3

Pt non-obese.  Also took clonazepam and venlafaxine.  No known risk factors for thromboembolism.

Hagg (2000)17

12

59 M

Case series

Clozapine 300 mg/d

PE (Death)

14 d

3

Also took phenoxymethypenicillin.  Also had myocardial infarction on necropsy.

    26 M   Clozapine 500 mg/d PE (Death) 20 mo 4 Also took cyproterone acetate. Also had myocarditis on necropsy.
    38 F   Clozapine 150 mg/d, haloperidol PE (Death) 14 d
4  
    53 M   Clozapine 100 mg/d PE (Death) Not known 4 Also took clomipramine.  Also had thrombosis in paraprostatic vein plexus.
    33 M   Clozapine 200 mg/d PE (Death) 3 mo 4 Also took lactulose, propantheline.
    36 M   Clozapine 200 mg/d PE (Acute recovery) 2 mo 4 Also took erythromycin.  PE was bilateral.
    54 M   Clozapine 500 mg/d, perphenazine DVT (Recovery) 15 d 4 Also took levomepromazine, amitriptyline.  Also had diabetes mellitus.
    37 F   Clozapine 300 mg/d IJ thrombosis (Unknown) 3 wks 4 Also took zolpidem.
    29 M   Clozapine 400 mg/d DVT/PE (Recovery) 3 wks 4 Also took clonazepam, carbamazepine.
    30 M   Clozapine 200 mg/d, thioridazine DVT (Unknown) 3 mo 4 Also took orphenadrine, carbamazepine.
    25 F   Clozapine 400 mg/d DVT (Recovered) Not known 3 Also took levonorgestrel, ethinylestradiol, diazepam, terbutaline, budesonide.
    42 M    Clozapine 75 mg/d, flupenthixol DVT (Recovered) 2 yrs 4 Also took biperiden, lorazepam, clomipramine.  Also had agranulocytosis.

Hafner
(1965)19

49

31-70 yrs (Mean 48 yrs)
n=34F

Case series

Chlorpromazine equivalents 300-650 mg/d

9 fatal

1-13 wks

-

4 fatal cases verified by autopsy. 15 cases pts also took potentiating drugs (sedatives, hypnotics)

Zornberg
(2000)31 

42 

20-59 yrs (Mean 44.2 yrs)
n=32F 

Case control 

None, or past use 28 (67%)
Current use:
0-99 mg Chlorpromazine equivalents 11 (26%)
> 100 mg Chlorpromazine equivalents 3 (7%)

 

2 fatal

None, or past use 28 (67%)

Current use:
0-11 mo 12 (29%)
> 12 mo 2 (5%)

-

Current use of antipsychotics associated with VTE (odds ratio 7.1 (95% confidence interval 2.3-21.97)

* From Naranjo CA, Busto U, Sellers EM, et al. Clin Pharmacol Ther 1981;30:239-45.  Naranjo score 1-4 suggest possible association between drug and adverse reaction.

Discussion

The mechanism for antipsychotic-induced VTE is unclear, although several mechanisms have been proposed.  One hypothesis is based upon an enhanced platelet response to 5-hydroxytriptamine in the presence of antipsychotics. (35)  An alternate hypothesis suggests that increased anticardiolipin (Ac) levels increase the risk of VTE. (14)  However, Ac antibodies have heterogeneous specificity (36), may be associated with psychosis (37), and are not clearly associated with antipsychotics (38) or thrombosis. (36)  A third hypothesis suggests that venous stasis secondary to antipsychotic associated sedation or weight gain causes VTE. (9,14,19,31)  Finally, obesity (39) and diabetes (40) are possible adverse effects associated with atypical antipsychotics, and have been identified as important risks for venous thrombosis. (41)  These hypotheses lend biological plausibility to a possible association.  Only one large well designed case control study suggests an association between VTE and antipsychotic use.  Although this study suggested an incidence of VTE associated with antipsychotics is to be 0.14%, (33) the relative risk observed was 7.1 (2.3-21.9) for current antipsychotic use as compared to no antipsychotic use.  The magnitude of the OR is suggestive of an association between VTE and antipsychotics.  The objective nature of the mode of VTE diagnosis, as well as the systematic collection of patient data make it unlikely that cases would be missed or that prescriptions for antipsychotics would be undetected.  Selection bias was thus minimized.  There may have been differences between cases and controls with respect to unmeasured coagulation abnormalities, stress (42), alcohol (42), sedation (43), or immobility related to psychiatric illness. (43)

Although case reports suggest that VTE can occur after taking antipsychotics for many years (3,5,7,8,11,12), the risk for VTE was increased only during the first two months of therapy in the UK case control study. (31)  This is suggestive of a temporal association.  Further support of an association is offered by the objective diagnostic criteria for acute VTE, which minimized the likelihood that VTE may have occurred before exposure to antipsychotics.

There does not appear to be a relationship between antipsychotic dose and incidence of VTE.  The OR for VTE at doses of antipsychotic greater than 100 mg of chlorpromazine equivalents was not statistically significant. (31)  This argues against an association between antipsychotics and VTE. (31,42,43)  Only a small number of cases were identified, suggesting that the study may not have had enough cases to detect differences that may exist between different classes of antipsychotics. Additionally, only small numbers of patients were taking atypical antipsychotics in this study, The association between these agents and VTE thus remains uncertain.

Many case reports, adverse drug reaction monitoring system reports and retrospective autopsy data suggest that there is an increased risk of VTE with clozapine. (9,12-17,27-30)  This might be explained by weight gain, sedation or diabetes associated with clozapine, or that these patients are followed very closely due to the clozapine-associated risk of agranulocytosis.  There are no formal observational studies assessing the potential for VTE associated with clozapine or other atypical antipsychotics.  The proposed association between clozapine and VTE has some biological plausibility and temporal correlation, but lacks consistent assessment of data, controlled studies, or obvious relation to clozapine dose.

It is important for clinicians to be aware of the possibility of VTEs associated with antipsychotic use. Current manufacturer labeling for clozapine includes VTE as a possible adverse effect. (44)  Management of patients who have experienced VTE associated with antipsychotics should be evaluated on an individual basis. One author has suggested discontinuing the antipsychotic should a patient develop VTE. (17)  Most authors offered no management suggestions. For any case of VTE potentially associated with antipsychotics, it would seem reasonable to reassess the risks and benefits of continued therapy with antipsychotic medication for that patient in light of an increased thrombotic risk. Consideration should be made for other causes of a hypercoagulable state, both congenital and acquired. (45)  Although there is no information to suggest an effect of estrogen use, smoking, obesity or physical activity on VTE risk reduction in this patient population, it would be prudent to suggest modification of existing risks for VTE if therapy with antipsychotic medication is to be continued. Any cases of VTE possibly associated with antipsychotics should be reported to an ADR reporting program.

Although rare, it seems that a possible association between antipsychotics and VTE exists.  While suggestive of an association, the available published data suffers from methodological limitations.  Case reports, retrospective cohorts and spontaneous adverse drug reaction reporting databases lack control groups, and therefore the ability to draw firm conclusions about an association between drug and adverse effect.  This association for conventional antipsychotics is supported by one large case control study, and for clozapine by case reports and retrospective data.  Further study of atypical antipsychotics is warranted.

Authors Competing Interests

None declared.

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