Psychosomatics 44:259-260, June 2003
© 2003 The Academy of Psychosomatic Medicine
Paradoxical Reaction to Fluoxetine
Muhammad N. Momen, M.D.,
C. Simon Sebastian, M.D., and
Peter F. Buckley, M.D., Augusta, Ga.
TO THE EDITOR: A patient with chronic renal insufficiency developed new-onset recurrent venous thrombotic episodes and pulmonary embolism after 6 weeks of fluoxetine therapy, which resolved after drug discontinuation. Endothelial injury and peripheral serotonergic system dysfunction secondary to uremia may have predisposed this patient to thromboembolic complications. Fluoxetine therapy, which does not down-regulate serotonin 5-HT2A receptors and is likely to increase plasma serotonin, was a contributing factor.
Case Report
Ms. A, a 48-year-old woman with chronic renal disease, was admitted to our intensive care unit in critical condition. Psychiatric consultation was requested because of her history of depression. Her problems included metabolic acidosis, confusion, pulmonary embolism with hypoxia, and deep venous thrombosis of the left lower extremity. Ms. A also had had an unexplained low-grade fever for more than 3 weeks. The results of repeated pan cultures were negative. A ventilation perfusion scan suggested pulmonary embolism, and an ultrasound examination showed a mural thrombosis in the left lower leg. Her prothrombin time (11.4 seconds) and partial thromboplastin time (30.5 seconds) were within normal limits. Her D-dimer (a protein released into circulation during profibrin blood clot breakdown and an indicator of blood clot formation) level was positive. Her regular medications included calcitriol, 0.5 µg/day; spironolactone, 25 mg b.i.d.; fluoxetine, 30 mg/day; and oxycodone, 1 tablet every 6 hours as needed for bone pain.
Ms. A was treated with a bicarbonate drip, aggressive electrolyte replacement, empirical antibiotics, heparin, and warfarin. After initial stabilization, she developed massive gastrointestinal bleeding due to a duodenal ulcer. Anticoagulants were discontinued, and therapy for the duodenal ulcer was initiated with tetracycline, metronidazole, and omeprazole. Her fever never remitted completely, and her D-dimer level remained persistently positive, indicating possible ongoing occult thrombosis.
Despite physical prophylactic measures, Ms. A developed new thromboses in subclavian and leg veins. An inferior vena caval filter was placed to prevent pulmonary embolism.
An extensive review revealed rare adverse events (less than one in 1,000), including thrombosis, thrombophlebitis, and fever during preintroductory U.S. clinical trials of fluoxetine on 10,782 patients.1 To our knowledge, there have been no such reports in the postintroductory period. We recommended the immediate discontinuation of fluoxetine. For the first time in over 5 weeks, Ms. A's fever completely resolved, and she suffered no more episodes of thrombosis. She remained afebrile, without any further episodes of venous thrombosis for 18 months, despite chronic renal disease (but in the absence of any serotonergic medication).
Discussion
Selective serotonin reuptake inhibitors (SSRIs) decrease intraplatelet serotonin concentrations, thereby reducing platelet plug formation. This may cause a tendency toward bleeding. Therefore, thrombus formation in response to fluoxetine appears to be a paradoxical reaction.
One contributing factor to this phenomenon is the apparent paradoxical down-regulation of 5-HT2A receptors in response to fluoxetine. SSRIs have varying effects on 5-HT2A receptor down-regulation. Depending on the study, fluoxetine has been reported either to have no effect on 5-HT2A receptor number or to actually increase receptor number.2 Thus, the absence of 5-HT2A receptor down-regulation in response to fluoxetine could contribute to greater platelet aggregation and thrombogenesis. The patient's uremic state was another contributory factor to the proposed paradoxical reaction to fluoxetine. Platelet serotonin content and uptake have been shown to be lower in uremic patients, whereas plasma serotonin is higher than in healthy comparison subjects.3,4 Vascular responses to serotonin depend on the integrity of the endothelial lining. If the latter is intact, serotonin reaching 5-HT1 receptors on the endothelial cells trigger the release of endothelial-derived relaxing factor. In addition, endothelial cells take up the monoamine to degrade or store it. Uremia is associated with vascular damage, as reflected by a high plasma level of von Willebrand factor antigen. A higher level of plasma serotonin, together with endothelial damage or dysfunction, might provide conditions for exaggerated serotonergic amplification, influencing platelet aggregation and persistence of vasoconstriction, and thereby contribute to thromboembolic complications.4,5
REFERENCES
- Physicians Desk Reference, 56th ed. Montvale, NJ, Medical Economics, 2002, pp 1238-1243
- Gray J, Roth B: Paradoxical trafficking and regulation of 5HT2A receptors by agonists and antagonists. Brain Res Bull 2001; 56:441-451[CrossRef][Medline]
- Pawlak D, Matyszko J, Malyszko JS, Pawlak K, Buczko W, Mysliwiec M: Peripheral serotonergic system in uremia. Thromb Res 1996; 83:189-194[CrossRef][Medline]
- Eknoyan G, Brown CH III: Biochemical abnormalities of platelets in renal failure: evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase. Am J Nephrol 1981; 1:17-21[Medline]
- Matyszko J, Pawlak K, Pawlak D, Buczko W, Mysliwiec M: Importance of serotonergic mechanisms in the thrombotic complications in hemodialyzed patients treated with erythropoietin. Nephron 2000; 84:305-311[CrossRef][Medline]
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