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Effects of Selective Serotonin Reuptake Inhibitors on Platelet Function

Mechanisms, Clinical Outcomes and Implications for Use in Elderly Patients

Abstract

Among the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are often preferred to other classes of antidepressants in the treatment of depression in the elderly because of their better safety profile. Most of the known effects of SSRIs, either beneficial or adverse, are linked to their inhibitory action on the serotonin reuptake transporter (5-HTT). This reuptake mechanism is present not only in neurons but also in other cells such as platelets.

Serotoninergic mechanisms seem to play an important role in haemostasis, and their importance in this regard has long been underestimated. Abnormal activation may lead to a pro-thrombotic state, as may occur in patients with major depressive disorder, whilst downregulation, as occurs in patients treated with SSRIs, may have two clinical consequences, both of particular interest in the elderly. On the one hand, there may be an increased risk of bleeding; on the other hand, a reduction in thrombotic risk may be possible. Polymorphism in the promoter region of the gene that transcribes the 5-HTT has been shown to have a relevant impact on its function and, in turn, on the beneficial and adverse effects of SSRIs.

Bleeding has been a concern since the introduction of SSRIs, with multiple case reports published and communicated to the pharmacovigilance systems. The first epidemiological study was published in 1999 and since then, 34 epidemiological studies from different areas, most of them including elderly patients in their study populations, have been published with a variety of results. Broadly, the epidemiological evidence supports a moderately increased risk of bleeding associated with the use of SSRIs, which may be critically dependent on patient susceptibility and the presence of risk factors.

The impairment of primary haemostasis induced by SSRIs may result, as a beneficial counterpart, in a reduction in the thrombotic risk. A small number of clinical trials and an increasing number of epidemiological studies that include elderly patients have been conducted to clarify whether SSRIs reduce the risk of primary and secondary ischaemic disorders. However, the results have been inconclusive with some studies suggesting a preventive effect and others no effect or even an increased risk. Behind such contradictory results may be the role of depression itself as a cardiovascular risk factor and, therefore, a major confounding factor. How to disentangle its effect from that of the antidepressants is the methodological challenge to be overcome in future studies.

In this complex scenario, the elderly seem to be at a crossroads, because they are the group in which both the risks and the benefits can be the greatest. Studies performed to date have provided us with some clues that can help orient clinicians in taking the most appropriate course of action. For instance, as the gastrointestinal bleeding risk appears to increase with age, prudent advice in patients with a previous history of upper-gastrointestinal bleeding or peptic ulcer, and in those who take NSAIDs, oral anticoagulants, antiplatelet drugs or corticosteroids, would be to suggest addition of an acid-suppressing agent to the drug regimen in those elderly patients in whom SSRIs are indicated.

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References

  1. 1.

    Lynnes JM, Caine ED, King DA, et al. Psychiatric disorders in older primary care patients. J Gen Intern Med 1999; 14: 249–54

    Article  Google Scholar 

  2. 2.

    Hybels CF, Blazer DG. Epidemiology of late-life mental disorders. Clin Geriatr Med 2003; 19: 663–96

    PubMed  Article  Google Scholar 

  3. 3.

    Unutzer J. Late-life depression. N Engl J Med 2006; 357: 2269–76

    Article  Google Scholar 

  4. 4.

    Unutzer J, Katon W, Callahan CM, et al. Depression treatment in a sample of 1,801 depressed older adults in primary care. J Am Geriatr Soc 2003; 51: 505–14

    PubMed  Article  Google Scholar 

  5. 5.

    Stone MB, Jones ML. Clinical review: relationship between antidepressant drugs and suicidality in adults [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf [Accessed 2011 Feb 10]

  6. 6.

    Draper B, Berman K. Tolerability of selective serotonin reuptake inhibitors: issues relevant to the elderly. Drugs Aging 2008; 25: 501–19

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Cheeta S, Schifano F, Oyfeso A, et al. Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998–2000. Br J Psychiatry 2004; 184: 41–7

    PubMed  Article  Google Scholar 

  8. 8.

    Harman JS, Edlund MJ, Fortney JC. Trends in antidepressant utilization from 2001 to 2004. Psychiatr Serv 2009; 60: 611–6

    PubMed  Article  Google Scholar 

  9. 9.

    Newman SC, Schopflocher D. Trends in antidepressant prescriptions among the elderly in Alberta during 1997 to 2004. Can J Psychiatry 2008; 53: 704–7

    PubMed  Google Scholar 

  10. 10.

    Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009; 60: 355–66

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Lingjarde O. Blood platelets as a model system for studying serotonergic dysfunction and effects of antidepressants. Pharmacol Toxicol 1990; 66Suppl. 3: 61–8

    Article  Google Scholar 

  12. 12.

    Lesch KP, Wolozin BL, Murphy DL, et al. Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 1993; 60: 2319–22

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Serebruany VL, O’Connor CM, Krishnan RR, et al. Hypothesis: antiplatelet effects of selective serotonin reuptake inhibitors cause clinical benefits on cardiovascular disease and increase risks of bleeding. J Cardiovasc Pharmacol Ther 2005; 10: 163–4

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Skop BP, Brown TM. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996; 37: 12–6

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Gerretsen P, Pollock BG. Pharmacogenetics and the serotonin transporter in late-life depression. Expert Opin Drug Metab Toxicol 2008; 4: 1465–78

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Luddington NS, Madadapu A, Husk M, et al. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. J Clin Psychiatry 2009; 11:93–102

    Google Scholar 

  17. 17.

    Lotrich FE, Pollock BG, Kirshner M, et al. Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients. J Psychiatry Neurosci 2008; 33: 123–30

    PubMed  Google Scholar 

  18. 18.

    Galan AM, Lopez-Vilchez I, Diaz-Ricart M, et al. Serotonergic mechanisms enhance platelet-mediated thrombogenicity. Thromb Haemost 2009; 102: 511–9

    PubMed  CAS  Google Scholar 

  19. 19.

    Malinin AI, Ong S, Makarov LM, et al. Platelet inhibition beyond conventional antiplatelet agents: expanding role of angiotensin receptor blockers, statins and selective serotonin reuptake inhibitors. Int J Clin Pract 2006; 60: 993–1002

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Maurer-Spurej E. Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection. Cell Mol Life Sci 2005; 62: 159–70

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Markovitz JH, Shuster JL, Chitwood WS, et al. Platelet activation in depression and effects of sertraline treatment: an open-label study. Am J Psychiatry 2000; 157: 1006–8

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Musselman DL, Marzec UM, Manatunga A, et al. Platelet reactivity in depressed patients treated with paroxetine: preliminary findings. Arch Gen Psychiatry 2000; 57: 875–82

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Shimbo D, Child J, Davidson K, et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol 2002; 89: 331–3

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Whyte EM, Pollock BG, Wagner WR, et al. Influence of serotonin-transporter-linked promoter region polymorphism on platelet activation in geriatric depression. Am J Psychiatry 2001; 158: 2074–6

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Dale GL. Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 2005; 3: 2185–92

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Prodan CI, Joseph PM, Vincent AS, et al. Coated-platelet levels are influenced by smoking, aspirin and selective serotonin reuptake inhibitors. J Thromb Haemost 2007; 5: 2149–51

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Wagner A, Montero D, Martensson B, et al. Effects of fluoxetine treatment of platelet 3H-imipramine binding, 5-HT uptake and 5-HT content in major depressive disorder. J Affect Dis 1990; 20: 101–13

    Article  Google Scholar 

  28. 28.

    Hergovich N, Aigner M, Eichler HG, et al. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000; 68: 435–42

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Javors MA, Houston JP, Tekell JL, et al. Reduction of platelet serotonin content in depressed patients treated with either paroxetine or desipramine. Int J Neuropsychopharmacol 2000; 3: 229–35

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Martensson B, Wagner A, Beck O, et al. Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3H-imipramine binding and serotonin uptake and concentration in major depressive disorder. Acta Psychiatr Scand 1991; 83: 125–33

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Pigott TA, L’Hereux F, Rubenstein CS, et al. A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder. J Clin Psychopharmacol 1992; 12: 156–62

    PubMed  CAS  Google Scholar 

  32. 32.

    Mück-Seler D, Jakovjevic M, Deanovic Z. Effect of anti-depressant treatment on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive patients. J Affect Dis 1991; 23: 157–64

    PubMed  Article  Google Scholar 

  33. 33.

    Narayan M, Anderson G, Cellar J, et al. Serotonin transporter-blocking properties of nefazodone assessed by measurement of platelet serotonin. J Clin Psychopharmacol 1998; 18: 67–71

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Tatsumi M, Groshan K, Blakely RD, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997; 340: 249–58

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: a pilot study. J Clin Psychiatry 1995; 56: 14–6

    PubMed  CAS  Google Scholar 

  36. 36.

    Alderman CP, Moritz CK, Ben-Tovim DL. Abnormal platelet aggregation associated with fluoxetine therapy. Ann Pharmacother 1992; 26: 1517–9

    PubMed  CAS  Google Scholar 

  37. 37.

    Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007; 9: 47–59

    PubMed  Google Scholar 

  38. 38.

    Abdelmalik N, Ruhé HG, Barwari K, et al. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost 2008; 6: 2168–74

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Ruhe HG, Booij J, Weert HC, et al. Evidence why dose-escalation of paroxetine in major depressive disorder is not effective: a 6-week, randomized-controlled trial with assessment of serotonin transporter occupancy. Neuro-psychopharmacology 2009; 34: 999–1010

    CAS  Article  Google Scholar 

  40. 40.

    Hougardy DM, Egberts TC, van der Graaf F, et al. Serotonin transporter polymorphism and bleeding time during SSRI therapy. Br J Clin Pharmacol 2008; 65: 761–6

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Humphries JE, Wheby MS, VandenBerg SR. Fluoxetine and the bleeding time. Arch Pathol Lab Med 1990; 114: 727–8

    PubMed  CAS  Google Scholar 

  42. 42.

    Yaryura-Tobias JA, Kirschen H, Ninan P, et al. Fluoxetine and bleeding in obsessive-compulsive disorder [letter]. Am J Psychiatry 1991; 148:949

    PubMed  CAS  Google Scholar 

  43. 43.

    Ottervanger JP, Stricker BHCH, Huls J, et al. Bleeding attributed to the intake of paroxetine. Am J Psychiatry 1994; 151:781–2

    PubMed  CAS  Google Scholar 

  44. 44.

    Leung M, Shore R. Fluvoxamine-associated bleeding. Can J Psychiatry 1996; 41: 604–5

    PubMed  CAS  Google Scholar 

  45. 45.

    Calhoun JW, Calhoun DD. Prolonged bleeding time in a patient treated with sertraline [letter]. Am J Psychiatry 1996; 153: 443

    PubMed  CAS  Google Scholar 

  46. 46.

    Khon S, Labbate LA. Venlafaxine and ecchymosis [letter]. Can J Psychiatry 1997; 42: 91

    Google Scholar 

  47. 47.

    Balhara Y, Sagar R, Varghese ST. Bleeding gums: duloxetine may be the cause. J Postgrad Med 2007; 53: 44–5

    PubMed  Article  Google Scholar 

  48. 48.

    De Abajo FJ, Montero D, García Rodríguez LA, et al. Antidepressants and risk of upper gastrointestinal bleeding. Pharmacol Toxicol 2006; 98: 304–10

    Google Scholar 

  49. 49.

    De Abajo FJ, García Rodríguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999; 319: 1106–9

    PubMed  Article  Google Scholar 

  50. 50.

    Dunn NR, Pearce GL, Shakir SAW. SSRIs are not more likely than other drugs to cause such bleeding. BMJ 2000; 320: 1405–6

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Van Walraven C, Mamdami MM, Wells PS, et al. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323: 1–6

    Article  Google Scholar 

  52. 52.

    Dalton SO, Johansen C, Mellemkjaer L, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 165: 59–64

    Article  Google Scholar 

  53. 53.

    Tata LJ, Fortun PJ, Hubbard RB, et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther 2005; 22: 175–81

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Wessinger S, Kaplan M, Choi L, et al. Increased use of selective serotonin reuptake inhibitors in patients admitted with acute gastrointestinal hemorrhage: a multi-centre retrospective analysis. Aliment Pharmacol Ther 2006; 23: 937–44

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Opatrny L, Delaney JA, Suissa S. Gastrointestinal bleed risk with the use of selective serotonin receptor antagonists: a new look. Abstracts of the 23rd ICPE. Pharmacoepidemiol Drug Saf 2007; 16: S1–274

    Google Scholar 

  56. 56.

    Helin-Salmivaara A, Huttunen T, Grönroos JM, et al. Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population. Eur J Clin Pharmacol 2007; 63: 403–8

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Lewis JD, Strom BL, Localio AR, et al. Moderate to high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf 2008; 17: 328–35

    PubMed  Article  Google Scholar 

  58. 58.

    Vidal X, Ibañez L, Vendrell L, et al., on behalf of the Spanish-Italian Collaborative Group for the Epidemiology of Gastrointestinal Bleeding. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf 2008; 31: 159–68

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    De Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65: 795–803

    PubMed  Article  Google Scholar 

  60. 60.

    Barbui C, Andretta M, De Vitis G, et al. Antidepressant drug prescription and risk of abnormal bleeding: a case-control study. J Clin Psychopharmacol 2009; 29: 33–8

    PubMed  Article  Google Scholar 

  61. 61.

    Targownik LE, Bolton JM, Metge CJ, et al. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol 2009; 104: 1475–82

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Dall M, Schaffalitzky de Muckadell OB, Lassen AT, et al. An association between selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2009; 7: 1314–21

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Verdel BM, Souverein PC, Meenks SD, et al. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther 2011; 89: 89–96

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Tanaka A, Takahira Y, Izumi N, et al. Aggravation by selective serotonin re-uptake inhibitors (SSRIs) of antral lesions induced by indomethacin in rats: effects of anti-secretory and mucosal protective drugs [abstract]. Gastroenterology 2005: M2063

    Google Scholar 

  65. 65.

    Yamaguchi T, Hidaka N, Suemaru K, et al. The coadministration of paroxetine and low-dose aspirin synergistically enhances gastric ulcerogenic risk in rats. Biol Pharm Bull 2008; 31: 1371–5

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Yamamoto T, Abe K, Hattori K, et al. High prevalence of gastroduodenal mucosa injury in patients taking selective serotonin reuptake inhibitors [letter]. Digestive Endoscopy 2010; 22: 77

    PubMed  Article  Google Scholar 

  67. 67.

    Dall M, Schaffalitzky de Muckadell OB, Lassen AT, et al. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers: a population-based case-control study. Aliment Pharmacol Ther 2010; 32: 1383–91

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Gutthann SP, García Rodríguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997; 8: 18–24

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Hernández-Díaz S, García Rodríguez LA. Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol 2002; 55: 157–63

    PubMed  Article  Google Scholar 

  70. 70.

    Movig KLL, Janssen MWHE, Malefijt JW, et al. Relationship of serotoninergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003; 163: 2354–8

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Andreasen JJ, Riis A, Hjortdal VE, et al. Effect of selective serotonin reuptake inhibitors on requirements for allogeneic red blood transfusion following coronary artery bypass surgery. Am J Cardiovasc Drugs 2006; 6: 243–50

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Salkeld E, Ferris LE, Juurlink DN. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J Clin Psychopharmacol 2008; 28: 230–4

    PubMed  Article  Google Scholar 

  73. 73.

    Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol 2009; 103: 1391–5

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Xiong GL, Jiang W, Clare RM, et al. Safety of selective serotonin reuptake inhibitor use prior to coronary artery bypass grafting. Clin Cardiol 2010; 33: E94–8

    PubMed  Article  Google Scholar 

  75. 75.

    Gärtner R, Cronin-Fenton D, Hundborg HH, et al. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study. BMC Surg 2010; 10: 3

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Van Haelst IM, Egberts TC, Doodeman HJ, et al. Use of serotonergic antidepressants and bleeding risk in orthopedic patients. Anesthesiology 2010; 112: 631–6

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Ware JA, Coller BS. Platelet morphology, biochemistry, and function. In: Beutler E, Lichtman MA, Coller BS, et al., editors. William’s hematology. 5th ed. New York: McGraw-Hill, 1995: 1161–93

    Google Scholar 

  78. 78.

    De Abajo FJ, Jick H, Derby L, et al. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol 2000; 50: 43–7

    PubMed  Article  Google Scholar 

  79. 79.

    Bak S, Tsiropoulos I, Kjaersgaad JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002; 33: 1465–73

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Kharofa J, Sekar P, Haverbusch M, et al. Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke. Stroke 2007; 38: 3049–51

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    Chen Y, Guo JJ, Patel NC. Hemorrhagic stroke associated with antidepressant use in patients with depression: does degree of serotonin reuptake inhibition matter? Pharmacoepidemiol Drug Saf 2009; 18: 196–202

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Smoller JW, Allison M, Cochrane BB, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women’s Health Initiative study. Arch Intern Med 2009; 169: 2128–39

    PubMed  Article  Google Scholar 

  83. 83.

    Kurdyak PA, Juurlink DN, Kopp A, et al. Antidepressants, warfarin, and the risk of hemorrhage. J Clin Psychopharmacol 2005 Dec; 25(6): 561–4

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Schalekamp T, Klungel OH, Souverein PC, et al. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168: 180–5

    PubMed  Article  Google Scholar 

  85. 85.

    Wallerstedt SM, Gleerup H, Sundström A, et al. Risk of clinically relevant bleeding in warfarin-treated patients: influence of SSRI treatment. Pharmacoepidemiol Drug Saf 2009; 18:412–6

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Hauta-Aho M, Tirkkonen T, Vahlberg T, et al. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann Med 2009; 41: 619–28

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Layton D, Clark DWJ, Pearce GL, et al. Is there an association between selective serotonin reuptake inhibitors and risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England. Eur J Clin Pharmacol 2001; 57: 167–76

    PubMed  CAS  Article  Google Scholar 

  88. 88.

    Meijer WE, Heerdink ER, Nolen WA, et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164: 2367–70

    PubMed  Article  Google Scholar 

  89. 89.

    Ziegelstein RC, Meuchel J, Kim TJ, et al. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med 2007; 120: 525–30

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Dentali F, Douketis JD, Lim W, et al. Combined aspirin: oral anticoagulant therapy compared with oral anti-coagulant therapy alone among patients at risk for cardiovascular disease — a meta-analysis of randomized trials. Arch Intern Med 2007; 167: 117–24

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Delaney JA, Opatrny L, Brophy JM, et al. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007; 177: 347–51

    PubMed  Article  Google Scholar 

  92. 92.

    Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med 2003; 65: 201–10

    PubMed  Article  Google Scholar 

  93. 93.

    Glassman AH. Depression and cardiovascular comorbidity. Dialogues Clin Neurosci 2007; 9: 9–17

    PubMed  Google Scholar 

  94. 94.

    Salaycik KJ, Kelly-Hayes M, Beiser A, et al. Depressive symptoms and risk of stroke: the Framingham Study. Stroke 2007; 38: 16–21

    PubMed  Article  Google Scholar 

  95. 95.

    O’Donnell MJ, Xavier D, Liu L, et al., INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010; 376: 112–23

    PubMed  Article  Google Scholar 

  96. 96.

    Bonnet F, Irving K, Terra JL, et al. Anxiety and depression are associated with unhealthy lifestyle in patients at risk of cardiovascular disease. Atherosclerosis 2005; 178: 339–44

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Bruce EC, Musselman DL. Depression, alterations in platelet function, and ischemic heart disease. Psychosom Med 2005; 67Suppl. 1: S34–6

    PubMed  Article  Google Scholar 

  98. 98.

    Brown AD, Barton DA, Lambert GW. Cardiovascular abnormalities in patients with major depressive disorder autonomic mechanisms and implications for treatment. CNS Drugs 2009; 23: 583–602

    PubMed  Article  Google Scholar 

  99. 99.

    Vaccarino V, Johnson BD, Sheps DS, et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol 2007; 50: 2044–50

    PubMed  Article  Google Scholar 

  100. 100.

    Leo R, Di Lorenzo G, Tesauro M, et al. Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy. J Clin Psychiatry 2006; 67: 1760–6

    PubMed  CAS  Article  Google Scholar 

  101. 101.

    Lekakis J, Ikonomidis I, Papoutsi Z, et al. Selective serotonin re-uptake inhibitors decrease the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion molecules. Int J Cardiol 2010; 139: 150–8

    PubMed  Article  Google Scholar 

  102. 102.

    Sher Y, Lolak S, Maldonado JR. The impact of depression in heart disease. Curr Psychiatry Rep 2010; 12: 255–64

    PubMed  Article  Google Scholar 

  103. 103.

    MacDonald TM, McMahon AD, Reid IC, et al. Antide-pressant drug use in primary care: a record linkage study in Tayside, Scotland. BMJ 1996; 313: 860–1

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Cohen HW, Gibson G, Alderman MH. Excess risk of myocardial infarction in patients treated with antide-pressant medications: association with use of tricyclic agents. Am J Med 2000; 108: 2–8

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104: 1894–8

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Meier CR, Schlienger RG, Jick H. Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction. Br J Clin Pharmacol 2001; 52: 179–84

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Hippisley-Cox J, Pringle M, Hammersley V, et al. Antide-pressants as risk factor for ischaemic heart disease: case-control study in primary care. BMJ 2001; 323: 666–9

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108: 32–6

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Schlienger RG, Fischer LM, Jick H, et al. Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction. Drug Saf 2004; 27: 1157–65

    PubMed  Article  Google Scholar 

  110. 110.

    Monster TB, Johnsen SP, Olsen ML, et al. Antidepressants and risk of first-time hospitalization for myocardial infarction: a population-based case-control study. Am J Med 2004 Nov 15; 117(10): 732–7

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Tata LJ, West J, Smith C, et al. General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction. Heart 2005; 91: 465–71

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Barbui C, Percudani M, Fortino I, et al. Past use of selective serotonin reuptake inhibitors and the risk of cerebrovascular events in the elderly. Int Clin Psychopharmacol 2005; 20: 169–71

    PubMed  Article  Google Scholar 

  113. 113.

    Chen Y, Guo JJ, Li H, et al. Risk of cerebrovascular events associated with antidepressant use in patients with depression: a population-based, nested case-control study. Ann Pharmacother 2008; 42: 177–84

    PubMed  Article  Google Scholar 

  114. 114.

    Trifiro G, Dieleman J, Sen EF, et al. Risk of ischemic stroke associated with antidepressant drug use in elderly persons. J Clin Psychopharmacol 2010; 30: 252–8

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Tiihonen J, Lonnqvist J, Wahlbeck K, et al. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry 2006; 63: 1358–67

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003; 54: 227–40

    PubMed  Article  Google Scholar 

  117. 117.

    Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med 1988; 50: 627–33

    PubMed  CAS  Google Scholar 

  118. 118.

    Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004; 66: 802–13

    PubMed  Article  Google Scholar 

  119. 119.

    van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004; 66: 814–22

    PubMed  Article  Google Scholar 

  120. 120.

    Lesperance F, Frasure-Smith N, Talajic M, et al. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002; 105: 1049–53

    PubMed  Article  Google Scholar 

  121. 121.

    Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001; 88: 337–41

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    De Jonge P, Honig A, van Melle JP, et al., MIND-IT Investigators. Nonresponse to treatment for depression following myocardial infarction: association with subsequent cardiac events. Am J Psychiatry 2007; 164: 1371–8

    PubMed  Article  Google Scholar 

  123. 123.

    Whooley MA. Depression and cardiovascular disease: healing the broken-hearted. JAMA 2006; 295: 2874–81

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Whooley MA, de Jonge P, Vittinghoff E, et al. Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 2008; 300: 2379–88

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Huffman JC, Celano CM, Januzzi JL. The relationship between depression, anxiety, and cardiovascular outcomes in patients with acute coronary syndromes. Neuropsychiatr Dis Treat 2010; 6: 123–36

    PubMed  Article  Google Scholar 

  126. 126.

    Brondy B. Common genetic factors for depression and cardiovascular disease. Dialogues Clin Neurosci 2007; 9: 19–28

    Google Scholar 

  127. 127.

    Robinson RG. Poststroke depression: prevalence, diagnosis, treatment, and disease progression. Biol Psychiatry 2003; 54: 376–87

    PubMed  Article  Google Scholar 

  128. 128.

    Ohira T, Iso H, Satoh S, et al. Prospective study of depressive symptoms and risk of stroke among Japanese. Stroke 2001; 32: 903–8

    PubMed  CAS  Article  Google Scholar 

  129. 129.

    Lyketsos CG, Treisman GJ, Lipsey JR, et al. Does stroke cause depression? J Neuropsychiatry Clin Neurosci 1998; 10: 103–7

    PubMed  CAS  Google Scholar 

  130. 130.

    Carney RM, Freeland KE. Depression and coronary heart disease: more pieces of the puzzle. Am J Psychiatry 2007; 164: 1307–9

    PubMed  Article  Google Scholar 

  131. 131.

    Carney RM, Freeland KE. Does treating depression improve survival after acute coronary syndrome? Br J Psychiatry 2007; 190: 467–8

    PubMed  Article  Google Scholar 

  132. 132.

    Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288: 701–9

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289: 3106–16

    PubMed  Article  Google Scholar 

  134. 134.

    Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62: 792–8

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    van Melle JP, de Jonge P, Honig A, et al. Effects of anti-depressant treatment following myocardial infarction. Br J Psychiatry 2007; 190: 460–6

    PubMed  Article  Google Scholar 

  136. 136.

    Lesperance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297: 367–79

    PubMed  CAS  Article  Google Scholar 

  137. 137.

    Hansen BH, Hanash JA, Rasmussen A, et al. Rationale, design and methodology of a double-blind, randomized, placebo-controlled study of escitalopram in prevention of Depression in Acute Coronary Syndrome (DECARD). Trials 2009; 10: 20

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    Rasmussen A, Lunde M, Poulsen DL, et al. A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics 2003; 44: 216–21

    PubMed  CAS  Article  Google Scholar 

  139. 139.

    Robinson RG, Jorge RE, Moser DJ, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA 2008; 299: 2391–400

    PubMed  CAS  Article  Google Scholar 

  140. 140.

    Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs 2009; 23: 427–52

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Swenson JR, Doucette S, Fergusson D. Adverse cardiovascular events in antidepressant trials involving high-risk patients: a systematic review of randomized trials. Can J Psychiatry 2006; 51: 923–9

    PubMed  Google Scholar 

  142. 142.

    Mazza M, Lotrionte M, Biondi-Zoccai G, et al. Selective serotonin reuptake inhibitors provide significant lower rehospitalization rates in patients recovering from acute coronary syndromes: evidence from a meta-analysis. J Psychopharmacol 2010; 24: 1785–92

    PubMed  CAS  Article  Google Scholar 

  143. 143.

    Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003; 108: 939–44

    PubMed  CAS  Article  Google Scholar 

  144. 144.

    Krantz DS, Whittaker KS, Francis JL, et al. Psychotropic medication use and risk of adverse cardiovascular events in women with suspected coronary artery disease: outcomes from the Women’s Ischemia Syndrome Evaluation (WISE) study. Heart 2009; 95: 1901–6

    PubMed  CAS  Article  Google Scholar 

  145. 145.

    Massó González EL, Patrignani P, Tacconelli S, et al. Variability among nonsteroidal anti-inflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010; 62: 1592–601

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Lichtman JH, Bigger JT, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening referral, and treatment. A Science Advisory From the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: Endorsed by the American Psychiatric Association. Circulation 2008; 118: 1768–75

    PubMed  Article  Google Scholar 

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Acknowledgements

The author wishes to thank Guillermo de Abajo for the elaboration of the image depicted in figure 1. The present work was supported by research grants from Fondo de Investigaciones Sanitarias (PI040083 and PI071064). The author has declared no conflicts of interest.

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de Abajo, F.J. Effects of Selective Serotonin Reuptake Inhibitors on Platelet Function. Drugs Aging 28, 345–367 (2011). https://doi.org/10.2165/11589340-000000000-00000

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Keywords

  • Gastrointestinal Bleeding
  • Major Depressive Disorder
  • Platelet Function
  • Escitalopram
  • Oral Anticoagulant