A Case Report of Chronic Thromboembolic Pulmonary Hypertension after Long-Term Use of Risperidone and Paliperidone

INTRODUCTION

Chronic thromboembolic pulmonary hypertension (CTEPH) is a group of pulmonary hypertension characterized by microvascular thrombosis in pulmonary arteries as a consequence of pulmonary embolism.¹ The cumulative incidence of CTEPH within the first 2 years after a symptomatic pulmonary embolism event is 0.1-9.1%.² There has been studies suggest an increased risk of venous thromboembolism with antipsychotics drugs, including both first- and second-generation antipsychotics.^3-5 However, no report has addressed the association between CTEPH and antipsychotics drugs. In the present article, we describe a case of CTEPH most likely related to long-term use of second-generation antipsychotics.

CASE

A 62-year-old female without significant medical illness has been diagnosed with schizoaffective disorder since 2011. She was initially treated with risperidone 3-6 mg/day. Her treatment was switched to paliperidone 3 mg/day in 2014 due to persistent auditory hallucinations. Patient was admitted to the hospital with wheezing and productive cough in January 2016. Acute bronchitis was impressed and was treated with a short-course of bronchodilator and corticosteroid. After discharge, she visited cardiology clinic for follow-up. Pulmonary function test did not show any obstructive lung disease. Echocardiogram showed preserved left ventricular systolic and diastolic function but peak tricuspid regurgitation velocity of 3.2 m/sec. No valvular heart disease was impressed. However, the peak tricuspid regurgitation velocity was progressively increased to 5.2 m/sec within a year, accompanying with D-shaped left ventricle (eccentric index 1.2), severe right ventricular dilatation and dysfunction, right atrial dilatation (end-systolic right atrial area 26.44 cm²), and a N-terminal pro-brain natriuretic peptide (NT-pro BNP) of 2930 pg/mL (reference range < 125 pg/mL). A computed tomography of the chest showed engorged pulmonary arteries with small, suspicious thrombi in the distal segments. No emphysema or interstitial lung disease was impressed. The d-dimer was 2.72 ug/mL. Therefore, rivaroxaban was initiated for pulmonary embolism. Few months later, patient was admitted to the hospital for hemoptysis, lower extremities edema, and progressive dyspnea. Her oxygen saturation with ambient air was 80%. Lung perfusion scan showed multiple wedge-shaped, mismatched perfusion defects at bilateral lung fields, which demonstrated high probability of CTEPH (Figure 1). Patient underwent a right heart catheterization that demonstrated an elevated mean pulmonary arterial pressure of 74 mmHg, pulmonary capillary wedge pressure of 19 mmHg, pulmonary vascular resistance of 1023 dynes/sec/cm^-5, right atrial pressure of 20 mmHg and cardiac index of 2.7 L/min/m² (reference range 2.5-5 L/min/m²). A 6-minute walk distance test was performed with the result of 129.25 meters. Patient had no history of recent surgery or trauma, vascular diseases, and cancer. She was not obese (body mass index 24.9 kg/m²) and had never been on hormone therapy. Anti-cardiolipin, lupus anticoagulant, and anti-beta2-glycoprotein were negative. Protein C and protein S were within normal range (83.8% and > 130.0%, respectively). Patient had normal platelet count (165 × 10^3 /uL), normal renal function (serum creatinine 1.0 mg/dl) with proteinuria (urine protein 300 mg/dl). She had no other known risk factors for venous thromboembolism except the use of antipsychotic drug. Because of suspicion of antipsychotic-induced CTEPH, paliperidone was discontinued and changed to aripiprazole. Since her CTEPH was involved in distal segments of pulmonary arteries and she refused pulmonary endarterectomy, she was started on riociguat and life-long anticoagulant. Three months later, her dyspnea and lower extremities edema were resolved. Her oxygen saturation with ambient air was improved to 92%. The 6-minute walk distance had increased to 300.13 meters. The peak tricuspid regurgitation velocity turned to be 4.6 m/sec. Despite optimal medical treatment, subsequent echocardiogram still indicated persistent pulmonary hypertension. Therefore, pulmonary angiography was performed and showed multiple hypoperfused areas (Figure 2). Balloon pulmonary angioplasty was performed successfully on right distal segments and patient was discharged home without complications.

Figure 1.

The anterior (A) and posterior (B) views of lung perfusion scan showed multiple wedge-shaped, mismatched perfusion defects at bilateral lung fields, specifically at right middle and left lower lobes (black arrow).

Figure 2.

The right upper (A), right lower (B), left upper (C), and left lower (D) views of pulmonary angiography showed multiple hypoperfused areas (black arrow), suggesting chronic thromboembolic disease.

DISCUSSION

CTEPH is an uncommon condition that may occur after overt pulmonary embolism, typically followed by a honeymoon period.¹ During the honeymoon period, symptoms usually are absent despite the onset of pulmonary hypertension.¹ Therefore, CTEPH is oftentimes not detected until pulmonary hypertension worsens and causes dyspnea, hypoxemia, and right ventricular dysfunction.¹ The risk of the development of CTEPH is increased in patients with chronic inflammatory disorders, cancer, and coagulopathy.¹ In the present case, patient had no known risk factors for CTEPH. Paliperidone is the active metabolite of risperidone, and both paliperidone and risperidone have thrombotic risk.^3-6 A 5-year exposure to drugs with thrombotic risk might contribute to her CTEPH.

The prevalence of schizophrenia in patients with CTEPH was more than 10-times higher than general population based on a retrospective study in Japan.⁷ One of the possible reasons for this phenomenon is the use of antipsychotics. To our knowledge, this is the first case report indicating possible relation between antipsychotic drugs and CTEPH. As thrombosis is the triggering factor of the development of CTEPH, antipsychotic drugs have been associated with increased risk of venous thromboembolism.^3-6 In addition, nitric oxide may play an important role in the pathophysiology of CTEPH as reduced endogenous nitric oxide levels were found in patients with CTEPH.⁸ Studies have suggested that antipsychotic drugs may affect plasma nitrates level and decrease expression of endothelial nitric oxide synthase.^9,10 Antipsychotics drugs may facilitate the development of CTEPH by altering nitric oxide availability in pulmonary vascular endothelium.

While most of the antipsychotics are associated with increased risk of pulmonary embolism, a retrospective analysis showed that quetiapine and aripiprazole were not significantly correlated with increased risk of pulmonary embolism.³ In the present case, paliperidone was discontinued after the diagnosis of CTEPH and changed to aripiprazole.

Due to absence of symptoms of deep vein thrombosis, we did not perform venogram or doppler ultrasonography of lower extremities in this case. However, in clinical practice, a comprehensive investigation of deep vein thrombosis will provide clinicians more insights on the etiology of CTEPH.

LEARNING POINTS

The present case observed a progressive pulmonary hypertension during the use of second-generation anti-psychotics. CTEPH should be considered in schizophrenic patients who receive anti-psychotics and present with undetermined cause of cardiopulmonary symptoms.

CONFLICT OF INTEREST

All authors have no conflict of interest to declare.