Correspondence : Sang Hyuk Lee, MD, Department of Psychiatry, Pochon CHA University College of Medicine, 351 Yatap-dong, Bundang-gu, Seongnam 135-720, Korea
Tel : +82-31-780-5874, Fax : +82-31-780-6135, E-mail : fishnsea@hanmail.net

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depression and anxiety disorders because of their low frequency of adverse side effects. Citalopram is one of the newest SSRIs, and it has a higher affinity for anti-serotoninergic receptors than the other SSRIs. The pharmacological effects of citalopram are almost exclusively ascribed to the S enantiomer, and S-citalopram (escitalopram) was recently introduced as an antidepressant. The most common side effects of escitalopram include nausea, vomiting, constipation, diarrhea, headache, sexual dysfunction, agitation, and restlessness. Escitalopram is also associated with some relatively uncommon adverse reactions including inappropriate antidiuretic hormone secretion syndrome, extrapyramidal symptoms, bleeding complications, cardiac arrhythmias, and the serotonin syndrome (confusion, myoclonus, and gastrointestinal tract activation).¹ In the present study we present a rare and relatively unrecognized case of pulmonary embolism associated with escitalopram.

Case Report

A 70-year-old woman visited a psychiatric outpatient clinic on an ambulatory basis. She had suffered symptoms of a depressive mood, sleep disturbance, loss of appetite, weight loss, fatigue, difficulty concentrating, and hopelessness for three months. She was hospitalized at Bundang CHA General Hospital for further treatment following a diagnosis of major depression. All of the results from a physical examination, several routine laboratory tests (including blood vitamin B12 and folic acid assessments), and microbiological evaluations were found to be within the normal ranges except for the fasting blood sugar level (159 mg/dl). Escitalopram was administered at a 10 mg/day dosage for treatment. She also continued to take the diabetes medication that she had previously been taking. The continuation of the diabetes medication resulted in her blood sugar being relatively well maintained within the normal range.
Her appetite and sleep patterns recovered after the use of the antidepressant medication. The daily dose of escitalopram was increased to 20 mg/day after eight days of treatment. She complained of dyspnea and confusion after waking up on the 10th day of treatment, and she later collapsed. Her arterial oxygen saturation (SaO₂) was 70%, but the application of her O₂ mask did not restore her SaO₂ level to within the normal range. She was therefore transferred to the Department of Pulmonology for further evaluation. Multifocal pulmonary thromboembolism in the distal pulmonary artery, the interlobar pulmonary artery, and segmental and subsegmental pulmonary arteries of both lungs were evident in the chest CT performed on the same day. A pulmonologist reviewed the drug and risk factors contributing to her pulmonary embolism. She was a nonsmoker with no previous history of superficial or deep vein thrombosis (DVT) or of pulmonary embolism. The serum tests for total blood count, renal and hepatic functions, sedimentation rate, homocysteine, and fibrinogen were all normal: protein C, 0.3 (normal range 0.17-0.31) mg/dL; protein S, 2.0 (normal range 0.94-2.14) mg/dL; antithrombin III activity, 117 (normal range 80-125)%, antiphospholipid IgM, (-); antiphospholipid IgG, (-); anti-ds DNA, (-); antinuclear antibody, (-); and prothrombin time, 12.4 (normal range 10.0-12.5) sec; international normalized ratio, 1.11. Factor V Leiden and prothrombin 20210A mutations were also ruled out. Escitalopram was replaced with warfarin at 4 mg per day.

Discussion

Venous thromboembolic disease represents a spectrum of conditions that includes DVT and pulmonary embolism, with an estimated annual incidence of 117 cases per 100,000 persons.² Major risk factors for venous thromboembolic disease include prolonged immobility, surgery, trauma, malignancy, pregnancy, estrogenic medications, hormone therapy, tamoxifen, congestive heart failure, hyperhomocysteinemia, diseases that alter the blood viscosity (e.g., polycythemia, sickle cell disease, and multiple myeloma), and inherited thrombophilia.³
Approximately 75% of patients with venous thromboembolic disease have at least one of the established risk factors, and 50% of all cases of DVT occur in hospitalized patients or nursing-home residents.⁴ Inherited thrombophilias have been identified in 24-37% of patients with DVT and in the majority of patients with familial thrombosis.^5,6
We now consider the possible reasons for the association of pulmonary embolism with escitalopram use in depressive patients. There is considerable evidence that depressive symptoms are associated with hypercoagulability through increased platelet activity. The first piece of evidence is that depressive symptoms may increase the risk of stroke through increased platelet activity due to sympathoadrenal hyperactivity.⁷ In addition, depressed patients exhibit greater platelet activation, as demonstrated by the increased binding of a monoclonal antibody (i.e., annexin V protein) relative to the healthy controls.⁸ Furthermore, the mean plasma levels of platelet factor 4 and β-thromboglobulin are higher in depressed patients with ischemic heart disease than in nondepressed patients with ischemic heart disease and healthy controls.⁹ These findings support the possibility that depression increases the risk of hypercoagulability by increasing platelet aggregation.¹⁰ Drugs affecting neuronal serotonin reuptake are important in the pharmacotherapy of a variety of psychiatric illnesses, including depression. It has been shown that SSRIs not only affect neuronal serotonin uptake, but they also modulate peripheral serotonin. Serotonin is a relatively weak platelet activator on its own; however, it significantly potentiates platelet aggregation in the presence of other proaggregatory factors (e.g., adenosine diphosphate, adrenaline, and collagen).¹¹
Diabetes mellitus (DM), which was present in our patient, is a putative risk factor for pulmonary embolism. Patients with DM have a hypercoagulable state with many coagulations and metabolic abnormalities involving lipids, endothelial dysfunction, fibrinolytic systems, and platelets. Therefore, we can assume that depressed patients with comorbid DM may have an increased risk of being at a hypercoagulable state. However, reports about its link with pulmonary embolism are controversial. Therefore, we could not insist that the DM in our patient primarily contributed to the pulmonary embolism.¹² The temporal relation between the initiation of escitalopram treatment and the appearance of pulmonary embolism in the absence of any other major risk factors, such as smoking, malignancy, varicosity, venous insufficiency, and previous history of superficial vein thrombosis or DVT, prompted us to consider a possible association between escitalopram and this particular adverse event. Since our patient's blood sugar was relatively well maintained within the normal range after she was diagnosed with DM, escitalopram appears to have been the major factor associated with the development of pulmonary embolism in this patient. However, her advanced age may have been another major contributing factor.
There have been many reported cases of increased bleeding tendencies caused by SSRIs,^13,14 but there was only one such case that was reportedly related to thrombosis.15 Those authors suggested that the temporal relation between the use of SSRIs and platelet dysfunction is bidirectional; that is, the immediate and early effects of SSRIs on platelets might increase the tendency for thrombosis, whereas the late effects after repeated dosing might increase the tendency to bleed. In the case presented here, platelet stimulation by escitalopram in the early stage might have increased the tendency for thrombosis. Further evaluations and studies are required to detect the hematologic complications that could be associated with SSRIs, especially escitalopram.

1. Aronson B, Delgado P. Escitalopram. Drugs Today (Barc) 2004;40:121-131.

2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-593.

3. Ramzi DW, Leeper KV. DVT and pulmonary embolism: part I. Diagnosis. Am Fam Physician 2004;69:2829-2836.

4. Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002;162:1245-1248.

5. Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism-results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost 1997;77:444-451.

6. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001;135:367-373.

7. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55:580-592.

8. Musselman DL, Tomer A, Manatunga AK, Knight BT, Porter MR, Kasey S, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996;153:1313-1317.

9. Laghrissi-Thode T, Wagner WR, Pollock BG, Johnson PC, Finkel MS. Elevated platelet factor 4 and β-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997;42:290-295.

10. Ohira T, Iso H, Satoh S, Sankai T, Tanigawa T, Ogawa Y, et al. Prospective study of depressive symptoms and risk of stroke among Japanese. Stroke 2001;32:903-908.

11. Skop BP, Brown TM. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996;37:12-16.

12. Howard BV. Risk factors for cardiovascular disease in individuals with diabetes. The strong heart study. Acta Diabetol 1996;33:180-184.

13. Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, et al. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature. Rev Med Interne 2000;21:152-160.

14. Vandel P, Vandel S, Kantelip JP. SSRI-induced bleeding: two case reports. Therapie 2001;56:445-447.

15. Kurne A, Ertugrul A, Anil Yagcioglu AE, Yazici KM. Venous thromboembolism and escitalopram. Gen Hosp Psychiatry 2004;26:481-483.