Case Report

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American Journal of Emergency Medicine

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American Journal of Emergency Medicine 32 (2014) 814.e1-814.e2

Pulmonary thromboembolism due to paliperidone: report of 2 cases

Abstract

venous thromboembolism is serious medical condition, which might be caused by psychotropic medications. Previously, antipsychotic-induced VTE due to olanzapine, risperidone, clozapine, and amisulpiride was reported. In this report, we present 2 cases of paliperidone-induced VTE.

Massive pulmonary thromboembolism (PTE) is a potentially fatal cardiovascular disease frequently encountered in the emergency department (ED) [1]. venous thromboembolism is a common condition, with an annual incidence of more than 1 per 1000. Risk factors can be divided into congenital, such as hereditary thrombo- philia, and acquired, including advanced age, obesity, surgery, malignancies, and estrogen therapy [2]. Recent research has focused on increased risk of VTE in psychiatric settings. psychiatric conditions, which have been found dangerous in this regard, are physical restraint, catatonia, and neuroleptic malignant syndrome. Possible underlying mechanisms are immobilization and dehydration in all 3 conditions, plus vessel injury in the situation of physical restraint, due to heavy resistance of the patient, or fever and rhabdomyolysis in the case of neuroleptic malignant syndrome [3]. Higher risk of VTE has also been reported for specific classes of psychotropic drugs, most consistently for antipsychotics. Exact mechanisms have not been elucidated yet, and only recently, increased prolactin has been implicated as a potential contributing factor [4]. In the present article, we describe 2 cases of pulmonary embolism (PE) most probably related to paliperidone treatment.

A 28-year-old man, engineer, single, was admitted to hospital due to first-episode psychotic disorder. Treatment with palliperidone (3 mg/d) was started, and the dose was gradually increased to 9 mg/d. After 8 weeks of treatment, the patient applied to emergency service with complaints of respiratory pain and hemoptysis. Clinical exam- ination did not show auscultator findings, dyspnea, tachypnea, and fever. Blood pressure and heart rate were in reference range. The patient was referred to the department of chest diseases. blood analysis showed raised concentrations of C-reactive protein 121 mg/L (reference range, b 10 mg/L), fibrinogen (600 g/L [reference range, 2-4 g/L]), and D-dimer (0.89 mg/L [b 0.50 mg/L]). Liver and renal function tests as well as cardiac enzymes were normal. His prolactin level was high, 45 mg/dL. Spiral computed tomography showed a PE in the left lower lobe. Standard anticoagulant treatment was started, and the patient recovered immediately.

A 40-year-old man, medical doctor, married, got a son. He had been treated with 8 mg/da risperidone for 3 years with a diagnosis of psychotic disorder. Six months ago, his treatment was changed to paliperidone 6 mg/d due to complaints of drowsiness. He was seen in the emergency service with fever, irritability, and mild dyspnea during

the last 4 days. The patient was referred to the department of chest diseases urgently. His plasma D-dimer level is 1.2 mg/L (b 0.50 mg/L); C- reactive protein level, 155 mg/L (reference range, b 10 mg/L); and Fibrinogen level, 970 g/L (reference range, 2-4 g/L). Liver and renal function tests as well as cardiac enzymes were normal. His prolactin level was also normal. Computed tomographic pulmonary angiogra- phy revealed left lobar pulmonary Artery thrombosis, regional consolidation, and atelectasis with infection in the left lower lobe and a small pleural effusion. Based on the history and aforemen- tioned results, the diagnosis of PE was established. Standard anticoagulant treatment was started, and the patient recovered.

Two patients had no history of recent surgery or trauma, peripheral vascular diseases, cancer, or cardiovascular diseases. physical activity and body mass index were normal. Case 1 never smoked and did not use illicit drugs or alcohol. Case 2 consumed 1 bottle of wine per week and 20 cigarettes per day. A full workup for coagulopathy (Factor V Leiden, prothrombin deficiency, protein C and S deficiency, antiphospholipid antibodies, activated protein C resis- tance, elevated Factor VIII, and hyperhomocysteinemia) did not show any abnormalities for 2 patients.

Case 1 continued taking heparin for 6 months, and case 2, for 1 year. They did not have another thromboembolic episode during the follow-up period. Case 1 was followed up for 1 year. His paliperidone treatment was discontinued and changed to aripiprazole 10 mg/d. Case 2 was followed up for 3 years, and the dose of paliperidone was tapered to 3 mg/d. His prolactin level is normal. Both patients’ professional and social functioning are relatively good.

Antipsychotic treatment has been linked to higher risk of VTE by most studies [4,5]. In a recent report, both typical and atypical antipsychotics were associated with higher risk of PE (odds ratio [OR], 1.17), depending on the specific drug used; the highest OR was found for clozapine (OR, 1.47), followed by ziprasidone, risperidone, and olanzapine. On the other hand, aripiprazole and quetiapine were not found to increase the risk [6]. There are also case reports associating olanzapine [7,8], risperidone [8], sertindole [9], and amisulpride [10] with higher risk of VTE, but to our knowledge, no data for palliperidone have been reported. The biological mechanism explain- ing the relation between antipsychotic drugs and venous thrombosis is unknown. Multiple hypotheses have been developed. Mechanisms involved in the thrombotic complications associated with antipsy- chotic drugs, such as the lupus-like syndromes induced by phenothi- azines or aTypical antipsychotic drugs, have been suggested [11]. However, Canoso and de Oliviera [14] followed up Psychiatric patients treated in the long term with chlorpromazine in which concentrations of antiphospholipid antibodies were elevated and could not find an increase in the incidence of thrombosis [12]. In other studies, anticardiolipin antibody could not be detected in the cases of PTE involving antipsychotic drugs.

0735-6757/(C) 2014

814.e2 M.C.B. Sengul et al. / American Journal of Emergency Medicine 32 (2014) 814.e1-814.e2

Atypical antipsychotic drugs have an affinity for the type 2A serotonin receptor (5HT2A) that is greater than type 2 dopamine

Atakan Yilmaz, MD

Department of Emergency Medicine

receptor. It has been suggested that 5HT2A-induced platelet aggre- gation might be affected in patients receiving olanzapine, risperidone, or clozapine. It has been suggested that platelet aggregation is enhanced via 5HT2A antagonism by second generation antipsychotics or due to hyperhomocysteinemia [13].

The other studies suggest that hyperprolactinemia is an important novel risk factor for PTE in patients on antipsychotic drugs and that the thrombogenic effect is caused by adenosine diphosphate- stimulated platelet activation [14]. Hamanaka et al [17] did not examine the prolactin concentrations in their study, and they wish to further investigate the hormonal effects in cases of PTE associated with antipsychotic drugs [15]. As plasma prolactin level of the first patient was elevated but the second patient’s plasma prolactin level was not high at the time of hospital admission, palliperidone-related hyperprolactinemia was a probable factor contributing to PE in these many patients. In a study of PE depending on amilsulpirid, predis- posing factors have suggested hyperprolactinemia. In the same case, other than paroxetine and alprozolam, use of aripiprazole was drawn to amilsulpirid unlike 5HT2A affinity [10]. Nonetheless, aripiprazole has been reported not to raise the risk of VTE [8,14]. The same is suggested for antidepressants (and certain case reports), in support of some association with VTE [14].

The biological mechanisms involved in the pathogenesis of this possible adverse reaction are largely unknown, but several hypoth- eses have been suggested such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinemia, and hyperprolactinemia. The association may also be related to underlying risk factors present in psychotic patients. The risk factors for antipsychotic-related throm- bolembolic events include recently started antipsychotic therapy (within the past 3 or 12 months), higher doses of drug, concomitant multiple antipsychotic therapy, intravenous or intramuscular admin- istration of drug, and use of second-generation antipsychotics, particularly clozapine [16,18]. Physicians need to be aware of this possible Adverse drug reaction.

This case report suggests that clinicians should consider antipsychotic drugs as a potential risk factor of VTE. Controlled studies are needed to further elucidate this adverse effect and to determine the possible Predisposing factors and the biological mechanisms involved.

Melike Ceyhan Balci Sengul, MD Department of Psychiatry, Pamukkale University School of Medicine, Denizli, Turkey

Kemal Kaya, MD

Department of Psychiatry Isparta State Hospital, Isparta, Turkey

Tekirdag State Hospital, Tekirdag, Turkey

Cem Sengul, MD Department of Psychiatry, Pamukkale University School of Medicine, Denizli, Turkey

Mustafa Serinken, MD

Department of Emergency Medicine

Pamukkale University School of Medicine, Denizli, Turkey

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2013.12.038

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