Department of Psychiatry, Leiden University Medical Center, The Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands
Department of Clinical Epidemiology and Thrombosis and Haemostasis Center, Leiden University Medical Center, The Netherlands
Correspondence: Jan P. Vandenbroucke, Leiden University Medical Center, Department of Clinical Epidemiology, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 5265230; Fax: +3171 5248122; e-mail: vdbroucke{at}mail.medfac.leidenuniv.nl
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To investigate whether antipsychotic medication is a risk factor for venous thrombosis.
Method A description of the 10 psychiatric patients was obtained from the pulmonary emboli autopsy reports. We carried out a brief historic overview of the literature. We re-analysed data from the Leiden Thrombophilia Study (LETS), a casecontrol study on patients with venous thrombosis.
Results In the autopsy reports, five out of 10 psychiatric patients with fatal pulmonary embolism had confirmed use of antipsychotic drugs. After the application of chlorpromazine and its analogues a higher incidence of venous thrombosis in psychiatric patients was described in the German literature between 1953 and 1977. In the re-analysis of the LETS casecontrol study, four patients used antipsychotic drugs versus none in the control group. Recent epidemiological studies of good methodological quality have confirmed these findings.
Conclusions Venous thrombosis appears to be associated with the use of antipsychotic drugs in psychiatric patients.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We present a comprehensive report of the 10 psychiatric patients from the Leiden autopsy reports, and give a brief historic overview of the literature dealing with venous thrombosis in psychiatry. We also present secondary analyses of a case-control study on risk factors for venous thrombosis, the Leiden Thrombophilia Study (LETS; Koster et al, 1993).
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Historic literature overview
Based on our findings in the autopsy record study we searched Medline from
1960 to 1998 for material on the subject of psychiatry and venous thrombosis,
specifically antipsychotic medication and pulmonary embolism.
Casecontrol study
Details about the methodology of the casecontrol study have been
published earlier (Koster et al,
1993). In brief, from 1990 to 1993, 474 incident cases with a
first episode of deep-vein thrombosis, in whom objective tests had confirmed
the diagnoses, were selected from three anticoagulation clinics. In the
Netherlands, anticoagulation clinics monitor coumarin treatment for virtually
all patients diagnosed with venous thrombosis in well-defined geographic
areas. The study was limited to out-patients. Psychiatric in-patients or
general hospital in-patients who were in the hospital at the time of enrolment
were excluded. The patients were asked to find a control subject of the same
gender, about the same age, who was not a biological relative, had no history
of thrombosis or malignant disorders and did not use coumarins. This
population-based casecontrol study was used to estimate the risk of a
first episode of deep-vein thrombosis in relation to several clotting factor
abnormalities (Koster et al,
1993).
Participants were asked to report any medication use. Comorbidity and medical treatments were assessed. Risk factors for thrombosis such as oral contraceptive use, surgery, immobilisation and family history were evaluated extensively. For patients with a first episode of deep-vein thrombosis, medical reports on the admission and treatment were retrieved. Patients older than 70 years of age and patients with malignancies were excluded. Fifty-one patients declined participation and 19 patients were excluded because of psychiatric morbidity which would interfere with participation in the study (Koster et al, 1993).
In the current re-analysis we investigated the frequency of daily use from the available records. First, we investigated the patient and control groups for any daily use of antipsychotics, antidepressants and benzodiazepines (including the index year in which the first episode of deep-vein thrombosis occurred). Second, patients who report usage of these drugs in the same year as the index date of their first thrombosis were excluded to be certain that the medication was used prior to the first thrombosis. Third, we restricted the analyses to those patients with mono-therapeutic medication use, to rule out any interference with comedication and comorbid conditions. Whether patients with a first episode of deep-vein thrombosis used more medication in general, compared with the controls, was checked for other commonly used medications such as beta-blockers and antacids. Odds ratios and 95% confidence intervals were generated through Epi Info 6 (Centers for Disease Control and Prevention & World Health Organization, 1997).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Historical literature overview
The discovery of the antipsychotic qualities of chlorpromazine in 1953 was
soon followed by several case reports in the German literature of fatal
pulmonary embolism related to its use
(Brehmer & Ruckdeschel,
1953; Labhardt,
1954). A first case series, for the period 1954-1957, reported on
11 (3.3%) cases of venous thrombosis and pulmonary embolism in a group of 338
phenothiazine users, compared with one in a non-phenothiazine control group
(Grahmann & Suchenwirth,
1959). In 1963, Mahmodian
(1963) observed a three-fold
increased risk of thrombosis in the period 1958-1961 in psychiatric and
neurological patients compared with the years 1915-1922 (from 6% to 18% in
males and 10% to 29% in females). In 1966, Lal et al
(1966) reported on consecutive
autopsies on 357 psychiatric patients diagnosed mainly with schizophrenia and
a chronic brain syndrome over the period 1961-1964. The prevalence of
pulmonary embolism found in those autopsies was 10%, which was the same as in
all autopsies in the general hospital population
(Lal et al, 1966).
However, the occurrence of pulmonary embolism in the general hospital
population is known to be high; so, the comparability with a general hospital
population in fact points to a high incidence. In a similar study of 343
autopsy reports of psychiatric patients, Kendel & Fodor
(1969) found 98 (29%) cases of
pulmonary embolism, which in 16% was associated with acute psychiatric
symptoms. Scholz (1967)
studied 37 psychiatric patients with a pulmonary embolism as the clinical
cause of death. Twenty-two patients had used antipsychotic drugs. They were
younger and in one-third of the cases there was no explanatory comorbidity.
Ziegler (1977) studied 688
autopsy reports with pulmonary embolism as the sole cause of death.
Twenty-seven (4%) had an underlying psychiatric disorder. Twelve suffered from
schizophrenia and 15 had a depressive illness.
In a large observational study, Meier-Ewert et al (1967) compared two groups between 1953 and 1963: 1092 patients with schizophrenia or depression taking chlorpromazine, amitriptyline or imipramine and a group of 1172 similar psychiatric patients who did not use antipsychotic or antidepressant medication. The frequency of thrombo-embolic complications in the medication group was 2.9% versus 0.59% in the control group. However, 22 of the 34 medication users with a thrombo-embolic complication showed medical comorbidity. An interesting observation was made in 1984: five women with schizophrenia, 33-58 years of age, suffered from deep-venous thrombosis after an acute psychotic phase. They all died from pulmonary embolism without any comorbidity (Hindersin et al, 1984). Apart from general papers dealing with mortality in psychiatric hospitals (Licht et al, 1993; Hewer et al, 1995), until recently this 1984 paper was the last published paper on the specific subject of venous thrombosis in psychiatric patients. However, the subject found new attention in a study of Walker et al (1997) and Hägg et al (2000).
Casecontrol analysis
Baseline characteristics of out-patients with a first episode of venous
thrombosis (n=474) who used antipsychotic drugs, antidepressants or
benzodiazepines and a matched control group (n=474) are reported in
Table 2. A hip operation, heart
valve disease, heart rhythm abnormalities and intravenous heroin use until 1
year prior to the first episode of deep-vein thrombosis was reported as
comorbidity. Medication use concerning five different medication categories
among patients with a first episode of deep-vein thrombosis (n=474)
and the control group (n=474) is shown in
Table 3. In this table the
medication use is reported with increasing restrictiveness: first, all use;
second, use restricted to the year preceding the venous thrombosis; third, use
limited to monotherapy. Four patients used antipsychotic drugs compared with
none in the control group. Their mean age was 42.8 years. One of these
patients also used an antidepressant and a benzodiazepine. The antipsychotic
drugs used were levomepromazine, fluphenazine (both phenothiazines) and
haloperidol. Antidepressant use differed between subjects in the case and
control groups and yielded an odds ratio of 2.3 (95% CI 0.6-10.6). Medication
use in general, such as beta-blocking agents and antacids, did not differ
between patients and controls.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Historical literature overview
Predominantly German literature between 1953 and 1984 confirmed a high
prevalence of thrombosis in psychiatric patients, also with an association
with antipsychotic use. Unfortunately, specific information about the
diagnoses, medication use and physical circumstances under which the
thrombosis occurred were often missing.
Casecontrol analysis
Our findings in the re-analysis of the casecontrol study are
compatible with the hypothesis of antipsychotic drugs as a possible risk
factor for deep-vein thrombosis. Moreover, the original study excluded all
in-patients, also psychiatric in-patients, so that our conclusions relate only
to out-patient antipsychotic drug use. As the numbers are small, confidence
intervals are wide. In consequence the results in themselves are not
conclusive.
Recent literature
Our results are in line with a 1992 publication reporting an impressive
17-fold increase in risk of myocardial infarction observed among young women
using psychotropic drugs and also an almost three-fold increased risk of
venous thrombo-embolism (Thorogood et
al, 1992). A similar recent observation came from a study on
mortality in clozapine users. Among current users of clozapine, 19 cases in 85
399 person-years of fatal pulmonary embolisms were found. This risk was
increased 5.2-fold when compared with the non-use of clozapine
(Walker et al, 1997).
Most recently, Zornberg & Jick
(2000) studied a baseline
population of 29 952 recipients of antipsychotic drugs. They found an odds
ratio of 3.3 for high-potency antipsychotic drugs such as haloperidol and an
odds ratio of 24.1 for low-potency antipsychotic drugs such as
chlorpromazine.
Biological mechanism
The biological mechanism explaining the relation between antipsychotic
drugs and venous thrombosis is unknown. Multiple hypotheses have been
postulated. In the most recent publications of Zornberg & Jick
(2000) and
Hägg et al
(2000) three possible
mechanisms are discussed: antipsychotic drugs enhance aggregation of
platelets; anticardiolipin antibodies are associated with increased risk of
thrombosis and their levels are raised in some patients using chlorpromazine;
and venous stasis is exacerbated by sedation. An alternative explanation can
be found in the article of Hindersin et al
(1984): the acute psychotic
phase is associated with an increase of adrenaline secretion, which enhances
the coagulation mechanism.
Venous thrombosis appears to be associated with the use of antipsychotic drugs in psychiatric patients. Clinicians should be aware of this possible relation when patients using antipsychotic drugs have complaints such as chest pain or dyspnoea. However, it cannot be completely excluded that the findings on antipsychotic drugs are an expression of some other underlying risk factors of the disease itself. Also, the use of these drugs might predispose to venous thrombosis because of other medication effects such as sedation and immobilisation. Because of the clinical implications we conclude that the association between venous thrombosis and psychiatric illness is worthy of renewed investigation, with an emphasis on the mechanisms that might elucidate a direct effect of antipsychotic drugs.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Centers for Disease Control and Prevention & World Health Organization (1997) Epi Info 6. Version 6.04b. A Word Processing Database and Statistical Program for Public Health. Geneva: Centers for Disease Control and Prevention (CDC) USA & World Health Organization.
Grahmann, H. & Suchenwirth, R. (1959) Thrombose hazard in chlorpromazine and reserpine therapy of endogenous psychosis. Nervenarzt, 30, 224-225.
Hägg, S., Spigset, O. & Söderström, T. G. (2000) Association of venous thromboembolism and clozapine. Lancet, 355, 1155-1156.[CrossRef][Medline]
Hewer, W., Rossier, W., Falkenheuer, B., et al (1995) Mortality among patients in psychiatric hospitals in Germany. Acta Psychiatrica Scandinavica, 91, 174-179.[Medline]
Hindersin, P., Siegmund, R. & Körting, H. J. (1984) Thrombophile diathesen als Hämostasestörungen bei akuten psychosen. Psychiatrie, Neurologie und medizinsche Psycholgie, 36, 702-709.
Kendel, K. & Fodor, S. (1969) Pulmonary embolism and symptomatic psychosis. German Medical Monthly, 14, 184-187.[Medline]
Koster, T., Rosendaal, F., Ronde de, H., et al (1993) Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet, 342, 1503-1506.[Medline]
Labhardt, E. (1954) Technik, Nebenerscheinungen und Komplikationen der Largactil Therapie. Schweizer Archives Neurologie und Psychiatrie, 73, 338-344.
Lal, S., Bleiman, M., Brown, B. N., et al (1966) Pulmonary embolism in psychiatric patients. Journal of the American Geriatrics Society, 14, 1138-1143.[Medline]
Licht, R. W., Mortensen, P. B., Gouliaev, G., et al (1993) Mortality in Danish psychiatric long-stay patients, 1972-1982. Acta Psychiatrica Scandinavica, 87, 336-341.[Medline]
Mahmodian, M. H. (1963) Ursachen der Lungenembolie bei psychisch und neurologisch Kranken. Deutsche medizinische Wochenschrift, 204, 229-244.
Meier-Ewert, K., Baumgart, H. H. & Friedenberg, P. (1967) Thromboembolische Komplikationen bei neuround thymoleptischer Behandlung. Deutsche medizinische Wochenschrift, 92, 2174-2178.[Medline]
Scholz, V. (1967) Über thromboembolische Komplicationen unter neuroleptischer Medikation. Nervenartz, 38, 174-177.
Thomassen, R., Vandenbroucke, J. P. & Rosendaal, F. R. (2000) Antipsychotic drugs and venous thromboembolism. Lancet, 365, 252.
Thorogood, M., Cowen, P., Mann, J., et al (1992) Fatal myocardial infarction and use of psychotropic drugs in young women. Lancet, 340, 1067-1068.[Medline]
Vandenbroucke, J. P., Bertina, R. M., Holmes, Z. R., et al (1998) Factor V Leiden and fatal pulmonary embolism. Thrombosis and Haemostasis, 79, 511-516.[Medline]
Walker, A., Lanza, L. & Rothman, K. (1997) Mortality in current and former users of clozapine. Epidemiology, 8, 671-677.[Medline]
Ziegler, H. K. (1977) Lungenembolie aus der sicht des Pathologen. Medizinische Klinik, 72, 1063-1070.[Medline]
Zornberg, G. L. & Jick, H. (2000) Antipsychotic drug use and the risk of first-time idiopathic venous thromboembolism: a casecontrol study. Lancet, 356, 1219-1223.[CrossRef][Medline]
Received for publication July 13, 2000. Revision received January 22, 2001. Accepted for publication January 23, 2001.
Related articles in BJP: