Sir:Although there are several reports of venous thromboembolic complications in patients on treatment with clozapine, 1-4 an association does not constitute proof of a causal relationship. The following history, however, may support causality.Case report. Mr. A, a 28-year-old man with a 3-year history of schizophrenia (DSM-IV criteria), was admitted for evaluation of his unresponsiveness to several neuroleptics. He started with clozapine and received no other medication. Ten days later, he developed acute dyspnea and fever. At that time, he was taking clozapine, 225 mg/day, and his level of physical activity was normal: he did not stay in bed during the daytime and participated normally in the ward activities. The clinical suspicion of pulmonary embolism was confirmed by ancillary investigations (i.e., perfusion-ventilation lung scan, ventilation scan, arterial blood gases), and standard anticoagulant treatment was initiated promptly. He recovered well, from his psychosis as well as from the pulmonary embolism. Further investigation showed that he had no known risk factors for venous thromboembolism (VTE). He was not obese, he had not undergone a recent trauma, and his family history for VTE was negative. He had no medical disorder associated with an increased risk for VTE (e.g., inflammatory bowel disease, congestive heart failure, malignancy, myeloproliferative disorder). Laboratory investigations ruled out deficiencies of antithrombin III, proteins C and S, and the factor V Leiden mutation. Serious consideration was given to the possibility that the use of clozapine had caused the pulmonary embolism, but in view of this excellent response and the lack of good evidence for the relationship, his treatment with clozapine (400 mg/day) was continued. Oral anticoagulants (acenocoumarol) were stopped after 9 months.Twenty-six months after discontinuation of his anticoagulant treatment, Mr. A was admitted for a new episode of chest pain and dyspnea. Perfusion-ventilation lung scanning revealed the presence of several new pulmonary emboli. Treatment with anticoagulants was resumed, and he recovered again. He has now been on treatment with clozapine (400 mg/day) and acenocoumarol for 4 years, and no new episodes of VTE have occurred. (Two years after the second episode, Mr. A.'s blood was examined for IgG and IgM antibodies against phospholipids; the negative results made an antiphospholipid syndrome unlikely.) The risks associated with long-term treatment with oral anticoagulants were explained to him, and a switch to another atypical neuroleptic was advised. However, he refused to stop his treatment with clozapine, because there is no guarantee that other drugs will be as effective and he is very concerned about a return of his auditory hallucinations.A recognized approach to examine a presumed adverse reaction to a particular drug is discontinuation, which is usually followed by a disappearance of the reaction. A reappearance of the side effect upon re-administration of the drug provides evidence for a causal relat...

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