and pulmonary embolism: is there an association? Y. Alvarez1, M. Farre1, M. Carrasco2, C. Pedro2, C. Garcia-Ribera3 , A. Ruiz-Ripoll3.

1Clinical Pharmacology Unit, IMIM,Barcelona, Spain; 2Department of Hematology, Hospital del Mar, IMAS, Barcelona, Spain; 3Department of Psychiatry, Hospital del Mar, IMAS, Barcelona, Spain.

Statement of the study

The use of antipsychotics is considered a risk factor for venous thromboembolism. Clozapine has been Objectives. To report a case of pulmonary embolism temporally associated with olanzapine administration. related to an increased risk of death from pulmonary embolism. Olanzapine belongs to the In addition we summarise the literature and analyse factors associated for venous thromboembolism thienobenzodiazepine class, and its chemical structure is similar to clozapine. in the context of olanzapine treatment. Case-report

A 45-year-old man was admitted to the hospital because of acute dyspnea and chest pain. He was a of the lung and pulmonary angiography confirmed pulmonary thrombosis. Doppler ultrasonography of non-smoker and was not overweight. He had a 10-year history of schizophrenia and was in chronic his legs did not show deep venous thrombosis. Coagulation tests revealed prothrombin 20210 G/A treatment with paroxetine and fluphenazine decanoate; olanzapine was added to the treatment two heterozygous mutation with normal prothrombin concentration; and mildly elevated plasma level of months prior to event. During the last months he presented paranoid delusions, remained in a social homocysteine associated to vitamin B12 deficiency. withdrawal state lying in bed with very poor food intake. Nuclear ventilation-perfusion (V/Q) scanning A Medline search was done to collect previous literature, which was used to obtain new references. Results

We found eight cases, five males and three women. Half of them had developed deep venous thrombosis The possible increased risk of thromboembolism associated to olanzapine is at present poorly understood. and/or pulmonary embolism during the first weeks after starting the olanzapine treatment. Most of them It may be related to drug-induced sedation, weight gain, hyperleptinaemia and metabolic syndrome; or were in concomitant treatment with others psychotropics drugs and had others risk factors. In our case, to hyperprolactinemia that enhances platelet activation. genetic and metabolic factors could be relevant.

Sex and age Psychiatric diagnosis Dose olanzapine Other treatments Diagnosis Time to event Complementary Abnormal values and Test for coagulation Risk factors Outcomes (mg/d) (mg/d) (d) imaging techniques Other diagnosis disorder

Lazarus M Schizophrenia 20 haloperidol (20), PTE - Chest x-ray, brain computed Temperature of 37.5 ºC, - Physical restraint Death 2001 37 divalproex sodium (1500) tomographic scan were normal dehydratation during 8 days Autopsy: extensive bilateral JCP benztropine (2) WBC 20.5 *109/L pulmonary emboli F Bipolar disorder 5 lithium (900), PTE - Chest x-ray was normal Temperature of 37.6 ºC, - Physical restraint Death 70 nortriptyline (75) dehydratation during 3 days Autopsy: pulmonary olanzapine (5), WBC 20.5 *109/L thromboemboli levothyroxine (50 ug/d) Li 2.1 mEq/L simvastatin (10) Hypothyroidism hydrochlorothiazide (25) triamterene (37.5) Waage M Psychotic disorder 30 levomepromazine (50) PTE 70 Spiral computed tomography - Tests for coagulation Overweight Alive 2003 28 (10) disorders were normal BMJ (1 ) Hägg M Dementia 5 haloperidol (1-3 ) PTE suspected 39 Phlebography: DVT - - Age Death 2003 89 hydroxyzine (25-50 ) ICP clomethiazole (600 ) venlafaxine (75 ) M Dementia 5 acetylsalisylic acid (75 ) DVT 42 Phlebography - - Age, heart failure Alive 78 digoxin (0.13 ) clomethiazole (600 ) valproic acid (900 ) F 5 tamoxifen (49) PTE suspected 11 Sonography: DVT Dehydration - Breast cancer, tamoxifen, Death 84 Delusional disorder, mirtazapine (30) age, DM, heart failure. depressive symptoms oxazepam (30) furosemide(40) spironolactone (25) Toki F Schizoaffective disorder 20 haloperidol (12) PTE 120 Pulmonary ventilation / Hyperprolactinemia 863 mU/L Hyperprolactinemia Alive 2004 54 levomepromazine (125) perfussion scan (normal level, <400) Tests for coagulation JCP lithium (600) disorders were normal (2) biperiden (6) promethazine (75) Alvarez M Schizophrenia 10 paroxetine (20) PTE 90 Pulmonary ventilation / - Homocysteine 27.7 mol/l Genetic and metabolic factors Alive 2006 45 fluphenazine(1) perfusion scan, AngioTAC (range: 5-15), Clinophilia Vit B12 235 pg/ml Low intake (range: 270-730) Prothrombin 20210 G/A heterozygous mutation

PTE: Pulmorary Thromboembolism DVT: Deep Venous Thrombosis Conclusions

Olanzapine seems to share with other antipsychotics a risk for thromboembolism. The risk appears greatest during the initial months of treatment. Periodic monitoring of serum prolactin level is advisable. We recommend vigilance for clotting abnormalities, especially when physical restraint is indicated.

References

Lazarus A. Physical restraints, thromboembolism, and death in 2 patients. J Clin Psychiatry 2001;62:207- Waage IM,Gedde-Dahl A. Pulmonary embolism possibly associated with olanzapine treatment. BMJ 208. 2003;327:1384. Hägg S, Tätting P, Spigset O. Olanzapine and venous thromboembolism. Int Clin Psychopharmacol Toki S, Morinobu S, Yoshino A, Yamawaki S. A case of venous thromboembolism probably associated 2003;18:299-300. with hyperprolactinemia after the addition of olanzapine to typical antipychotics. J Clin Psychiatry 2004; 65:1576-2577.

Institut d’Atenció Psiquiàtrica: Salut Mental i Toxicomanies Hospital del Mar