SSRI and Abnormal Bleeding Risk

VOL 2 #5

Avni Pardasani MD

Selective serotonin reuptake inhibitors (SSRI) medications are used in a wide range of psychiatric disorders, including depression, generalized anxiety disorder, obsessive-compulsive disorder, premenstrual dysphoric disorder, and other conditions (1). Common side effects of SSRI medications are nausea, lack of energy, fatigue, decreased libido and sweating.

GI BLEEDING

Studies have documented an increased risk of upper GI bleeding as an adverse side effect of SSRI medication. There is also an increased risk of upper GI bleeding with concomitant NSAID and SSRI use.

Abnormal bleeding can have life-threatening implications so that it is important to recognize the potential risks of SSRIs and the potential drug interactions with other medications that affect that risk.

MECHANISMS

There are several theories of how SSRIs may affect bleeding. Normally, platelets release serotonin in response to vascular injury which triggers vasoconstriction and platelet aggregation. SSRIs inhibit the entry of serotonin from blood into platelets, decreasing intraplatelet serotonin stores, and decreasing the efficiency of platelet-mediated homeostasis (2). SSRIs have also been shown to increase gastric acidity, which increases the risk for ulcers and therefore upper GI bleeding (3).

Another possible mechanism is that SSRIs potently inhibit P450 enzymes (CYP, 1A2, 2D6, 3A4, etc.) that may inhibit the metabolism and raise blood levels of other drugs (antiplatelet agents, NSAIDs) that are metabolized by these enzymes (4). This may cause an increased bleeding risk when these drugs are used in conjunction with SSRIs.

UTERINE BLEEDING

Research is limited regarding dysfunctional uterine bleeding and SSRI usage. There may be implications for abnormal uterine bleeding, menstruation, pregnancy, and labour. There have been case reports regarding vaginal bleeding as an adverse side effect from SSRI agents. There have been two previous case reports documenting abnormal vaginal bleeding as a side effect from sertraline in postmenopausal women (5). There has also been a case report regarding a woman developing vaginal bleeding after starting venlafaxine, which stopped after discontinuation of the drug (6). In a sub-group analysis of a case-control study regarding the risk of abnormal bleeding associated with antidepressant agents, Meijer et. al. found increased risk of abnormal uterine bleeding in women taking antidepressants with intermediate to high inhibition of serotonin reuptake (7).

The small number of these reports may indicate that the potential risk of bleeding is rare. In more recent literature, Uguz et. al. conducted a cross-sectional study  of 1432 women that found that the prevalence of menstruation disorders was significantly higher in the antidepressant group ( 24.6%) compared to the control group (14.5%) (8). This finding may imply that the effect of antidepressant medications on abnormal uterine bleeding and it’s effect on menstruation may be larger than initially thought.

PMDD

SSRI agents, such as sertraline, fluoxetine, and citalopram, are firstline pharmacotherapy treatment for premenstrual dysphoric disorder. In a Cochrane review analyzing the efficacy and side effect profile of SSRI in premenstrual syndrome, dysfunctional uterine bleeding was not listed as an adverse event (9).

PREGNANCY

Recent Canadian and American studies have suggested that approximately 5% of women are taking antidepressant medications at some point during their pregnancy (10). It is important to establish whether taking SSRIs increase the risk of abnormal bleeding in pregnancy and delivery. There have been conflicting results from studies examining this area. Studies have been under powered. By contrast Hanley et. al. published a population-based cohort study in 2015 which included 225,973 women with 322,224 pregnancies in British Columbia.  They found no significant association between SSRI use in pregnancy and increased risk of postpartum hemorrhage (11).

PERIOPERATIVE BLEEDING

There is an increased risk of perioperative bleeding associated with SSRIs as well as increased requirements for transfusion. Although the evidence at this point is not of high quality Roose and Rutherford conclude that SSRI use increases the risk of

bleeding complications during and immediately after surgery. They could not

estimate the risk for a given patient having a given procedure due to limited data (12).

CONCLUSIONS

Antidepressant prescribers need to be aware of potential bleeding associated with SSRIs and discuss these with patients. It may be necessary to alert general physicians, surgeons, anesthesiologists and obstetricians to these risks.

Reference List

1 . Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010;71(12):1565-1575. http://www.psychiatrist.com/jcp/article/Pages/2010/v71n12/v71n1201.aspx

2. Serebruany VL. Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? Am J Med. 2006;119(2):113–116.

3. Abdel Salam OM. Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats. Pharmacol Res. 2004;50(3):309–316.

4. Zullino DF, Khazaal Y. Increased risk of gastrointestinal adverse effects under SSRI/NSAID combination may be due to pharmacokinetic interactions. Br J Clin Pharmacol. 2005;59(1):118–119, author reply 119.

5. Smith M, Robinson D. Sertraline and vaginal bleeding—a possible association. J Am Geriatr Soc. 2002;50(1):200–201.

6. Linnebur SA, Saseen JJ, Pace WD. Venlafaxine-associated vaginal bleeding. Pharmacotherapy. 2002;22(5):652–655.

7. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition. Arch Intern Med. 2004 Nov 22;164(21):2367-70.

8. Uguz, Faruk et al. Antidepressants and menstruation disorders in women: a cross-sectional study in three centers. General Hospital Psychiatry. 2012 Sep-Oct;34(5):529-33.

9. Brown J, O Brien PM, Marjoribanks J, Wyatt K. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2009 Apr 15;(2).

10. Smolina K, Hanley GE, Mintzes B, Oberlander TF, Morgan S. Trends and Determinants of Prescription Drug Use during Pregnancy and Postpartum in British Columbia, 2002–2011: A Population-Based Cohort Study. PLoS One 2015;10:e0128312.

11. Hanley GE, Mintzes B. Patterns of psychotropic medicine use in pregnancy in the United States from 2006 to 2011 among women with private insurance. BMC Pregnancy Childbirth 2014;14:242.

12. Roose SP, Rutherford BR. Selective Serotonin Reuptake Inhibitors and Operative Bleeding Risk: A Review of the Literature. J Clin Psychopharmacol. 2016 Dec;36(6):704-709.