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- For patients at high risk of abnormal bleeding, consider prescribing an antidepressant with low serotonin reuptake inhibition, which may lower risk.
- For patients taking high–serotonin reuptake inhibition antidepressants, recommend avoidance or minimal use of nonsteroidal anti-inflammatory drugs and aspirin.
Patients taking selective serotonin reuptake inhibitors (SSRIs) seem to be at higher risk of bleeding episodes than those taking non-SSRI antidepressants. But risk also varies within the SSRI category.
What the literature tells us
We identified 7 retrospective studies, 1 pilot study, and several case reports that discuss the relationship between SSRIs and bleeding. We also identified 2 additional papers that addressed the issue from epidemiologic and pharmacologic perspectives. While many case reports also document this relationship, our focus is on studies with larger samples.
Degree of reuptake inhibition matters
The most recent study1,2 examined SSRI use and the risk of abnormal bleeding associated with the degree of serotonin reuptake inhibition (SRI). Antidepressants were divided into 3 groups: high SRI (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil]), intermediate SRI (venlafaxine [Effexor], amitriptyline [Limbitrol], fluvoxamine [Luvox]), and low SRI (mirtazapine [Remron], bupropion [Wellbutrin], nortriptyline [Aventyl, Pamelor]). The high-SRI group showed the greatest risk of hospitalization due to abnormal bleeding (odds ratio [OR]=2.6 compared with the low-SRI group), followed by the intermediate-SRI group (OR=1.9 compared with the low-SRI group).
Similarly, another study3 found a 3.7-fold increased risk of blood transfusion among elderly users of SSRIs (paroxetine, fluoxetine, clomipramine [Anafranil]) who underwent orthopedic surgery.
A third study4 showed patients taking high-SRI antidepressants (paroxetine, fluoxetine, sertraline, and clomipramine) had a higher risk of developing upper gastrointestinal (GI) bleeding compared with those taking low-SRI antidepressants (bupropion, nortriptyline, desipramine [Norpramin, Pertofrane]). This risk was even higher among patients with a history of GI bleeding.
NSAIDs, aspirin aggravate bleeding potential
A population-based case-control study5 also found an increased incidence of upper GI bleeding with SSRIs, though this effect was not found to be modified by age, sex, dose, or treatment duration. The effect however, was enhanced by the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), with a relative risk (RR) of 15.6 (95% CI, 6.6–36.6), as well as with aspirin but to a lesser degree (RR=7.2; 95% CI, 3.1–17.1).
A large (N=26,005) cohort study6 of all users of antidepressants in a Danish county found that the risk of upper GI bleeding was higher with SSRIs compared with non-SSRIs and other antidepressants. Concomitant use of aspirin and NSAIDs further increased the risk by 12.2 and 5.2 times, respectively.
Risk of bleeding not dependent on duration of therapy
A large observational cohort study7 found rates of abnormal bleeding 1 month after initiating SSRI therapy (fluoxetine, fluvoxamine, sertraline, paroxetine) did not differ significantly from 2 to 6 months into treatment. Nonetheless a combined SSRI cohort was found to be at greater risk for a hemorrhagic event compared with a baseline cohort.
The remaining 2 retrospective studies found no evidence of increased intracranial hemorrhage in patients taking SSRIs.8,9
In terms of clotting and bleeding parameters, a pilot study (n=10) did not show any significant differences before and after a trial of fluoxetine.10 One case report,11 however, has suggested that antidepressants may influence these parameters as was seen by a prolonged bleeding time.
The retrospective studies examined the degree that SRI increased the risk of abnormal bleeding, and considered confounding factors such as body mass index, NSAID use, smoking status, sex, and age. However, these were not randomized controlled trials and most participants were women.
Serotonin promotes platelet aggregation, and it is thought that SSRIs limit uptake of blood serotonin by platelets.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1,3,4,6 SSRIs also appear to modify the formation of platelet plugs, as well as the responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.12
Take-home messages
SSRI use increases risk of bleeds, admission for abnormal bleeding, and perioperative transfusion. Moreover, the higher the degree of SRI, the higher the risk of bleeding.
Concomitant use of NSAIDs or aspirin further increases this risk.
Antidepressants with low SRI, such as bupropion and mirtazapine, may be associated with a lower risk of abnormal bleeding, although data are insufficient to make a definitive conclusion. Further research is needed to determine if these antidepressants may be more appropriate for patients at high risk of abnormal bleeding.
More research is also needed to clarify conflicting results to date on whether antidepressants cause abnormalities in bleeding or clotting profiles.
CORRESPONDENCE
Shree Bhalerao BA, BSc, Pgd, MD, FRCPC, St. Michael’s Hospital, Medical Psychiatry Service, 30 Bond St. Cardinal Carter Wing Rm 17046, Toronto, ON M5B 1W8 Canada. E-mail: [email protected].
1. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004;164:2367-2370
2. Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997;340:249-258
3. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003;163:2354-2358
4. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001;323:655-658
5. de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106-1109
6. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003;163:59-64
7. Layton D, Clark DW, Pearce GL, Shakir SA. 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;57:167-176
8. de Abajo FJ, Jick H, Derby L, Jick S, Schmitz S. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol 2000;50:43-47
9. Bak S, Tsiropoulos I, Kjaersgaard JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002;33:1465-1473
10. Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: a pilot study. J Clin Psychiatry 1995;56:14-16
11. Calhoun JW, Calhoun DD. Prolonged bleeding time in a patient treated with sertraline. Am J Psychiatry 1996;153:443.-
12. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000;68:435-442
- For patients at high risk of abnormal bleeding, consider prescribing an antidepressant with low serotonin reuptake inhibition, which may lower risk.
- For patients taking high–serotonin reuptake inhibition antidepressants, recommend avoidance or minimal use of nonsteroidal anti-inflammatory drugs and aspirin.
Patients taking selective serotonin reuptake inhibitors (SSRIs) seem to be at higher risk of bleeding episodes than those taking non-SSRI antidepressants. But risk also varies within the SSRI category.
What the literature tells us
We identified 7 retrospective studies, 1 pilot study, and several case reports that discuss the relationship between SSRIs and bleeding. We also identified 2 additional papers that addressed the issue from epidemiologic and pharmacologic perspectives. While many case reports also document this relationship, our focus is on studies with larger samples.
Degree of reuptake inhibition matters
The most recent study1,2 examined SSRI use and the risk of abnormal bleeding associated with the degree of serotonin reuptake inhibition (SRI). Antidepressants were divided into 3 groups: high SRI (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil]), intermediate SRI (venlafaxine [Effexor], amitriptyline [Limbitrol], fluvoxamine [Luvox]), and low SRI (mirtazapine [Remron], bupropion [Wellbutrin], nortriptyline [Aventyl, Pamelor]). The high-SRI group showed the greatest risk of hospitalization due to abnormal bleeding (odds ratio [OR]=2.6 compared with the low-SRI group), followed by the intermediate-SRI group (OR=1.9 compared with the low-SRI group).
Similarly, another study3 found a 3.7-fold increased risk of blood transfusion among elderly users of SSRIs (paroxetine, fluoxetine, clomipramine [Anafranil]) who underwent orthopedic surgery.
A third study4 showed patients taking high-SRI antidepressants (paroxetine, fluoxetine, sertraline, and clomipramine) had a higher risk of developing upper gastrointestinal (GI) bleeding compared with those taking low-SRI antidepressants (bupropion, nortriptyline, desipramine [Norpramin, Pertofrane]). This risk was even higher among patients with a history of GI bleeding.
NSAIDs, aspirin aggravate bleeding potential
A population-based case-control study5 also found an increased incidence of upper GI bleeding with SSRIs, though this effect was not found to be modified by age, sex, dose, or treatment duration. The effect however, was enhanced by the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), with a relative risk (RR) of 15.6 (95% CI, 6.6–36.6), as well as with aspirin but to a lesser degree (RR=7.2; 95% CI, 3.1–17.1).
A large (N=26,005) cohort study6 of all users of antidepressants in a Danish county found that the risk of upper GI bleeding was higher with SSRIs compared with non-SSRIs and other antidepressants. Concomitant use of aspirin and NSAIDs further increased the risk by 12.2 and 5.2 times, respectively.
Risk of bleeding not dependent on duration of therapy
A large observational cohort study7 found rates of abnormal bleeding 1 month after initiating SSRI therapy (fluoxetine, fluvoxamine, sertraline, paroxetine) did not differ significantly from 2 to 6 months into treatment. Nonetheless a combined SSRI cohort was found to be at greater risk for a hemorrhagic event compared with a baseline cohort.
The remaining 2 retrospective studies found no evidence of increased intracranial hemorrhage in patients taking SSRIs.8,9
In terms of clotting and bleeding parameters, a pilot study (n=10) did not show any significant differences before and after a trial of fluoxetine.10 One case report,11 however, has suggested that antidepressants may influence these parameters as was seen by a prolonged bleeding time.
The retrospective studies examined the degree that SRI increased the risk of abnormal bleeding, and considered confounding factors such as body mass index, NSAID use, smoking status, sex, and age. However, these were not randomized controlled trials and most participants were women.
Serotonin promotes platelet aggregation, and it is thought that SSRIs limit uptake of blood serotonin by platelets.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1,3,4,6 SSRIs also appear to modify the formation of platelet plugs, as well as the responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.12
Take-home messages
SSRI use increases risk of bleeds, admission for abnormal bleeding, and perioperative transfusion. Moreover, the higher the degree of SRI, the higher the risk of bleeding.
Concomitant use of NSAIDs or aspirin further increases this risk.
Antidepressants with low SRI, such as bupropion and mirtazapine, may be associated with a lower risk of abnormal bleeding, although data are insufficient to make a definitive conclusion. Further research is needed to determine if these antidepressants may be more appropriate for patients at high risk of abnormal bleeding.
More research is also needed to clarify conflicting results to date on whether antidepressants cause abnormalities in bleeding or clotting profiles.
CORRESPONDENCE
Shree Bhalerao BA, BSc, Pgd, MD, FRCPC, St. Michael’s Hospital, Medical Psychiatry Service, 30 Bond St. Cardinal Carter Wing Rm 17046, Toronto, ON M5B 1W8 Canada. E-mail: [email protected].
- For patients at high risk of abnormal bleeding, consider prescribing an antidepressant with low serotonin reuptake inhibition, which may lower risk.
- For patients taking high–serotonin reuptake inhibition antidepressants, recommend avoidance or minimal use of nonsteroidal anti-inflammatory drugs and aspirin.
Patients taking selective serotonin reuptake inhibitors (SSRIs) seem to be at higher risk of bleeding episodes than those taking non-SSRI antidepressants. But risk also varies within the SSRI category.
What the literature tells us
We identified 7 retrospective studies, 1 pilot study, and several case reports that discuss the relationship between SSRIs and bleeding. We also identified 2 additional papers that addressed the issue from epidemiologic and pharmacologic perspectives. While many case reports also document this relationship, our focus is on studies with larger samples.
Degree of reuptake inhibition matters
The most recent study1,2 examined SSRI use and the risk of abnormal bleeding associated with the degree of serotonin reuptake inhibition (SRI). Antidepressants were divided into 3 groups: high SRI (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil]), intermediate SRI (venlafaxine [Effexor], amitriptyline [Limbitrol], fluvoxamine [Luvox]), and low SRI (mirtazapine [Remron], bupropion [Wellbutrin], nortriptyline [Aventyl, Pamelor]). The high-SRI group showed the greatest risk of hospitalization due to abnormal bleeding (odds ratio [OR]=2.6 compared with the low-SRI group), followed by the intermediate-SRI group (OR=1.9 compared with the low-SRI group).
Similarly, another study3 found a 3.7-fold increased risk of blood transfusion among elderly users of SSRIs (paroxetine, fluoxetine, clomipramine [Anafranil]) who underwent orthopedic surgery.
A third study4 showed patients taking high-SRI antidepressants (paroxetine, fluoxetine, sertraline, and clomipramine) had a higher risk of developing upper gastrointestinal (GI) bleeding compared with those taking low-SRI antidepressants (bupropion, nortriptyline, desipramine [Norpramin, Pertofrane]). This risk was even higher among patients with a history of GI bleeding.
NSAIDs, aspirin aggravate bleeding potential
A population-based case-control study5 also found an increased incidence of upper GI bleeding with SSRIs, though this effect was not found to be modified by age, sex, dose, or treatment duration. The effect however, was enhanced by the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), with a relative risk (RR) of 15.6 (95% CI, 6.6–36.6), as well as with aspirin but to a lesser degree (RR=7.2; 95% CI, 3.1–17.1).
A large (N=26,005) cohort study6 of all users of antidepressants in a Danish county found that the risk of upper GI bleeding was higher with SSRIs compared with non-SSRIs and other antidepressants. Concomitant use of aspirin and NSAIDs further increased the risk by 12.2 and 5.2 times, respectively.
Risk of bleeding not dependent on duration of therapy
A large observational cohort study7 found rates of abnormal bleeding 1 month after initiating SSRI therapy (fluoxetine, fluvoxamine, sertraline, paroxetine) did not differ significantly from 2 to 6 months into treatment. Nonetheless a combined SSRI cohort was found to be at greater risk for a hemorrhagic event compared with a baseline cohort.
The remaining 2 retrospective studies found no evidence of increased intracranial hemorrhage in patients taking SSRIs.8,9
In terms of clotting and bleeding parameters, a pilot study (n=10) did not show any significant differences before and after a trial of fluoxetine.10 One case report,11 however, has suggested that antidepressants may influence these parameters as was seen by a prolonged bleeding time.
The retrospective studies examined the degree that SRI increased the risk of abnormal bleeding, and considered confounding factors such as body mass index, NSAID use, smoking status, sex, and age. However, these were not randomized controlled trials and most participants were women.
Serotonin promotes platelet aggregation, and it is thought that SSRIs limit uptake of blood serotonin by platelets.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1 The decreased amount of serotonin in platelets may increase the risk of abnormal bleeding.1,3,4,6 SSRIs also appear to modify the formation of platelet plugs, as well as the responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.12
Take-home messages
SSRI use increases risk of bleeds, admission for abnormal bleeding, and perioperative transfusion. Moreover, the higher the degree of SRI, the higher the risk of bleeding.
Concomitant use of NSAIDs or aspirin further increases this risk.
Antidepressants with low SRI, such as bupropion and mirtazapine, may be associated with a lower risk of abnormal bleeding, although data are insufficient to make a definitive conclusion. Further research is needed to determine if these antidepressants may be more appropriate for patients at high risk of abnormal bleeding.
More research is also needed to clarify conflicting results to date on whether antidepressants cause abnormalities in bleeding or clotting profiles.
CORRESPONDENCE
Shree Bhalerao BA, BSc, Pgd, MD, FRCPC, St. Michael’s Hospital, Medical Psychiatry Service, 30 Bond St. Cardinal Carter Wing Rm 17046, Toronto, ON M5B 1W8 Canada. E-mail: [email protected].
1. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004;164:2367-2370
2. Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997;340:249-258
3. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003;163:2354-2358
4. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001;323:655-658
5. de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106-1109
6. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003;163:59-64
7. Layton D, Clark DW, Pearce GL, Shakir SA. 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;57:167-176
8. de Abajo FJ, Jick H, Derby L, Jick S, Schmitz S. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol 2000;50:43-47
9. Bak S, Tsiropoulos I, Kjaersgaard JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002;33:1465-1473
10. Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: a pilot study. J Clin Psychiatry 1995;56:14-16
11. Calhoun JW, Calhoun DD. Prolonged bleeding time in a patient treated with sertraline. Am J Psychiatry 1996;153:443.-
12. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000;68:435-442
1. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004;164:2367-2370
2. Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997;340:249-258
3. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003;163:2354-2358
4. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001;323:655-658
5. de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106-1109
6. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003;163:59-64
7. Layton D, Clark DW, Pearce GL, Shakir SA. 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;57:167-176
8. de Abajo FJ, Jick H, Derby L, Jick S, Schmitz S. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol 2000;50:43-47
9. Bak S, Tsiropoulos I, Kjaersgaard JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002;33:1465-1473
10. Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: a pilot study. J Clin Psychiatry 1995;56:14-16
11. Calhoun JW, Calhoun DD. Prolonged bleeding time in a patient treated with sertraline. Am J Psychiatry 1996;153:443.-
12. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000;68:435-442