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Medicines Q&As
Q&A 163.3
What is the risk of gastrointestinal bleeding associated with
selective serotonin reuptake inhibitors (SSRIs)?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 2nd March 2015
Background
An association between selective serotonin reuptake inhibitor (SSRI) use and upper gastrointestinal
(GI) bleeding was reported in 1999 following analysis of data from a UK general practice research
database (1). Further evidence supporting this association has emerged since (2-5), but recent
publications have found SSRI use to result in a more modest increase in the risk of upper GI bleeding
than originally reported (6-8) and some have found no association at all (9,10). In several studies in
which an increased risk has been noted with SSRIs alone, the risk has been found to be elevated
further by the concomitant use of SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) (6-8).
Two main mechanisms have been proposed for SSRI-associated upper GI bleeding. Firstly, serotonin
plays an important role in the haemostatic response to injury by promoting platelet aggregation
(1,11,12). Serotonin is not synthesised in platelets but is taken up into platelets from the bloodstream.
At therapeutic doses SSRIs block this reuptake of serotonin leading to a depletion of serotonin and,
ultimately, an increased risk of bleeding. Secondly, SSRIs have been shown to directly increase
gastric acidity which could increase the risk of ulcer development, and therefore, bleeding (5). Due to
reports of bleeding, including GI bleeding, manufacturers advise caution in patients with a history of
bleeding disorders and in those taking SSRIs concomitantly with antiplatelets and other drugs that
might increase the risk of bleeding (13-18).
Answer
In a systematic review and meta-analysis designed to provide a more precise estimate of the risk of
upper GI bleeding with SSRIs, with or without concomitant NSAID use (6), results were analysed from
15 case-control studies (393 268 participants) and four cohort studies. An increased risk of upper GI
bleeding with SSRIs was found in both analyses (case-control studies: odds ratio [OR] 1.66; 95%
confidence interval [CI]:1.44-1.92; cohort studies: OR 1.68; 95% CI: 1.13-2.50). Using data from 10
case-control studies (223 336 participants), the risk was found to be increased further in patients
taking both SSRIs and NSAIDs (OR 4.25; 95% CI: 2.82-6.42) (6).
Although comprehensive, the above meta-analysis by Anglin et al (6) did not investigate the effects of
acid suppressing agents in patients receiving SSRIs. A case-control study by de Abajo et al (2008)
(19), which was included in the meta-analysis, sought to identify subgroups of patients at an
increased risk of bleeds with SRIs (serotonin reuptake inhibitors; including SSRIs and venlafaxine, a
serotonin and noradrenaline reuptake inhibitor (SNRI)), and to determine whether acid suppressing
agents were effective in minimising this risk. The study drew data from a UK general practice
database and matched 1321 patients with upper GI tract bleeding who had been referred to a hospital
or consultant with 10,000 control subjects. Odds ratios were adjusted for age, sex, calendar year,
smoking status, alcohol intake, antecedents of GI disorder and concomitant use of NSAIDs, systemic
corticosteroids, warfarin, low-dose aspirin and other antiplatelet drugs (19).
Again, an increased risk of upper GI bleeding was found with SSRIs (adjusted OR 1.6; 95% CI: 1.22.1) compared with non-use of antidepressants. The risk of upper GI bleeding was elevated further in
patients receiving concomitant NSAIDs (OR 4.8; 95% CI: 2.8-8.3) or corticosteroids (OR 4.0; 95% CI:
1.3-12.3) (19).
It was noted that acid suppressing agents protected against upper GI bleeding in patients receiving
either SRIs or both SRIs and NSAIDs. The odds ratio of upper GI bleeding associated with SRIs was
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lower in those taking acid-suppressing agents (OR 1.4; 95% CI: 0.8-2.3) than in those not taking an
acid suppressant (OR 2.0; 95% CI: 1.5-2.8). The benefit was even greater in those on an SRI and
NSAID: OR 9.1; 95% CI: 4.8-17.3 in non-users of acid suppressors versus OR 1.1; 95% CI: 0.3-3.4 in
current users of acid suppressors. In context, this would mean that for every 2000 patients receiving
an SRI only, or every 250 patients receiving an SRI with an NSAID, without GI protection, one patient
would have an upper GI bleed. With GI protection, 5000 or more patients would need to be treated
with an SRI or SRI with an NSAID in order for one case to be attributed to these drugs (19). Another
study found that concomitant therapy with a proton-pump inhibitor (PPI) significantly reduced the odds
of SSRI-related upper GI bleeding: OR 0.39; 95% CI: 0.16-0.94 with a PPI and OR 1.43; 95% CI:
1.09-1.89 without a PPI (20). Before these studies, gastro-protective agents such as H2 receptor
antagonists, PPIs or misoprostol had not been shown to reduce the risk of GI bleeds associated with
SSRIs alone (3,21) or in combination with NSAIDs (21).
It has been suggested that recent initiation of SSRIs increases the risk of upper GI bleeding. In a
case-control study (22), the highest adjusted OR for serious upper GI bleeding was found to be in
patients who had started using SSRIs within the last 0-30 days. This finding is supported by another
study, which reported that mortality was increased in the 30 days following hospital admission for
peptic ulcer bleeding in patients who had started SSRIs within 60 days of admission (particularly
those over 80 years). In this study, long-term exposure to SSRIs (i.e. current use of SSRIs with first
prescription prior to 60 days before admission with GI bleeding), either alone, or with NSAIDs did not
increase 30-day mortality after peptic ulcer bleeding (23).
In order to look specifically at short-term (7-28 day) SSRI use and upper GI bleeding, Wang et al
(2014) (24) used records from the Taiwan National Health Insurance Database (1998-2009) for 5,377
psychiatric inpatients who had experienced an upper GI bleed. To reduce the impact of confounding
factors, a case-crossover design was used for this study, enabling each patient to act as their own
control. The risk of upper GI bleeding after exposure to a specific drug was estimated by calculating
the ratio of patients who were exposed to that drug during the 14 days immediately before the bleed,
to patients who were exposed only during the preceding 14 days, i.e. days 15-28 before the bleed.
This was repeated for the 7-day and 28-day windows before the bleed. SSRIs were associated with
an increased risk of upper GI bleeding in all three windows, in male, but not female patients (males:
adjusted OR 2.43; 95% CI:1.75-3.38; females: adjusted OR 1.01; 95% CI: 0.63-1.61), and for SSRIs
with high and intermediate, but not low, affinity of the serotonin transporter (high affinity: adjusted OR
1.75; 95% CI: 1.31-2.34; intermediate affinity: adjusted OR 1.74; 95% CI: 1.23-2.45; low affinity:
adjusted OR 1.27; 95% CI: 0.94-1.72) (24).
Another study, in which the medical records of 36,389 patients with major depressive disorder were
examined, found the adjusted relative risk for GI bleeds to be modestly higher in patients receiving
antidepressants with a higher affinity for the serotonin transporter (relative risk for high versus lowmoderate affinity antidepressants = 1.17 (95% CI 1.02-1.34). Patients in this study received
monotherapy with an SSRI, SNRI or other new-generation antidepressant (25).
The degree to which different antidepressants inhibit serotonin reuptake and patient age were factors
of interest in one observational study in 317,824 elderly patients which looked at upper GI bleeding
rates. The antidepressants these patients were taking were split into 3 groups, low (e.g. nortriptyline,
doxepin, trazodone), intermediate (e.g. imipramine, amitriptyline, fluvoxamine, venlafaxine) and high
(paroxetine, sertraline, fluoxetine, clomipramine) inhibition of serotonin reuptake (26). Absolute
differences between these antidepressant groups were greatest (and statistically significant) for
patients aged 80 and over (bleeding rates for high versus low inhibition: 14.7 per 1000 person years
versus 10.6 per 1000 person years; number needed to harm [NNH] =244), and those with previous
upper GI bleeding (bleeding rates for high versus low inhibition: 40.3 per 1000 person years versus
28.6 per 1000 person years; NNH=85) (26).
Current NICE guidance on depression states that SSRIs are associated with an increased risk of
bleeding, especially in older people or in people taking other drugs that have the potential to damage
the gastrointestinal mucosa or interfere with clotting. NICE recommends considering prescribing a
gastroprotective drug in older people who are taking non-steroidal anti-inflammatory drugs (NSAIDs)
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or aspirin (27). For patients who are taking multiple drugs that could cause bleeding, it has been
recommended that informed medical advice is sought before starting regular use of non-prescription
drugs, such as ibuprofen (28).
Summary
The results from most, but not all observational studies suggest that there is an association between
the use of SSRIs and upper GI bleeds. Several studies have found the use of SSRIs with
concomitant NSAIDs to increase the risk of upper GI bleeding further. Being over the age of 80 or
having a previous history of GI bleeding may also add to the risk of upper GI bleeding with SSRIs.
There is also evidence that the risk is higher in patients who have just started taking SSRIs, in those
taking SSRIs with a high/intermediate affinity for the serotonin receptor, and in male patients. If an
SSRI is required in a patient at high risk of an upper GI bleed then the use of a gastro-protective
agent could be considered. Studies have shown the use of acid suppressing drugs, e.g. PPIs, to be
protective against upper GI bleeds in patients receiving single-therapy SSRI or combined NSAID and
SSRI treatment. Current NICE guidance on depression recommends considering a gastroprotective
drug in older people on SSRIs who are also taking NSAIDs or aspirin. Another source recommends
that patients taking multiple drugs that could cause bleeding seek informed medical advice before
starting regular use of non-prescription drugs such as ibuprofen.
Limitations
Studies that have looked at the risk of GI bleeds in SSRI users have differed widely with respect to
the confounding factors taken into account. Many are retrospective studies (selection bias not always
accounted for) with heterogeneous populations.
References
1. de Abajo FJ, Garcia Rodriguez LA, Montero D. Association between selective serotonin
reuptake inhibitors and upper gastrointestinal bleeding: population based case-control
study. Br Med J 1999;319:1106-9.
2. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction
between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs.
Aliment Pharmacol Ther 2008;27:31-40.
3. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake inhibitors and risk of upper GI
bleeding: confusion or confounding? Am J Med 2006;119:719-27.
4. de Abajo FJ, Montero D, Garcia Rodriguez LA et al. Antidepressants and risk of upper
gastrointestinal bleeding. Basic Clin Pharmacol Toxicol 2006;98:304-10.
5. Andrade C, Sandarsh S, Chethan KB et al. Serotonin reuptake inhibitor antidepressants
and abnormal bleeding: A review for clinicians and a reconsideration of mechanisms. J
Clin Psychiat 2010;71(12):1565-75.
6. Anglin R, Yuan Y, Moayyedi P et al. Risk of upper gastrointestinal bleeding with selective
serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory
use: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:811-819.
7. Wang Y-P, Chen Y-T, Tsai C-F, et al. Short-term use of serotonin reuptake inhibitors and
risk of upper gastrointestinal bleeding. Am J Psychiat 2014;171:54-61.
8. Oka Y, Okamoto K, Kawashita N et al. Meta-analysis of the risk of upper gastrointestinal
hemorrhage with combination therapy of selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs. Biol Pharm Bull 2014;37(6):947-53.
9. Hreinsson JP, Kalaitzakis E, Gudmundsson S et al. Upper gastrointestinal bleeding:
incidence, etiology and outcomes in a population-based setting. Scand J Gastroenterol
2013;48:439-47.
10. Carvajal A, Ortega S, Del Olmo L et al. Selective serotonin reuptake inhibitors and
gastrointestinal bleeding: a case-control study. PLoS ONE 2011;6(5): e19819.
doi:10.1371/journal.pone.0019819.
Available through NICE Evidence Search at www.evidence.nhs.uk
Medicines Q&As
11. van Walraven C, Mamdani MM, Wells PS et al. Inhibition of serotonin reuptake by
antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective
cohort study. Br Med J 2001;323:1-6.
12. Dalton SO, Johansen C, Mellemkjoer L et al. Use of selective serotonin reuptake
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associated with selective serotonin reuptake inhibitors and venlafaxine therapy. Arch Gen
Psych 2008;65:795-803.
20. 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.
21. Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding. Br Med J 2005;331:529-30.
22. Dall M, Schaffalitzky de Muckadell OB, Touborg Lassen A et al. An association between
selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding.
Clin Gastroenterol Hepatol 2009;7:1314-21.
23. Gasse C, Christensen S, Riis A et al. Preadmission use of SSRIs alone or in combination
with NSAIDs and 30-day mortality after peptic ulcer bleeding. Scand J Gastroenterol
2009;44:1288-95.
24. Wang Y-P, Chen Y-T, Tsai C-F, et al. Short-term use of serotonin reuptake inhibitors and
risk of upper gastrointestinal bleeding. Am J Psychiat 2014;171:54-61
25. Castro VM, Gallagher PJ, Clements CC et al. Incident user cohort study of risk of
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antidepressants. BMJ Open 2012;2:e000544.doi:10.1136/bmjopen-2011-000544.
26. van Walraven C, Mamdani MM, Wells PS et al. Inhibition of serotonin reuptake by
antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective
cohort study. Br Med J 2001;323:655-8.
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90). London: National Institute for Health and Care Excellence . Accessed via
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Medicines Q&As
Quality Assurance
Prepared by
Alex Bailey, Welsh Medicines Information Centre
Date Prepared
2nd March 2015
Checked by
Gail Woodland, Welsh Medicines Information Centre
Date of check
Search strategy
 Embase (exp Serotonin Uptake Inhibitor/ae, to [Adverse Drug Reaction, Drug Toxicity] AND
exp Gastrointestinal Hemorrhage/) limited to human and english language
 Medline (exp Serotonin Uptake Inhibitors/ae, to [Adverse Effects, Toxicity] AND exp
Gastrointestinal Hemorrhage/) limited to human
 IDIS Drug(s): ("antidepressants-ssris 28160700" and Descriptors: "side ef digestive 78" AND
All fields: “bleeding” )
 Micromedex (Searched under individual SSRI names in DrugDex and Martindale, also
checked Drug Consults)
 EMC (Searched under individual SSRI names)
 In-house database/ resources (SSRI and bleed*)
 Stockley’s (online) ssris, ssris warfarin
 NeLM (for previous version)/NHS Evidence (ssri* AND bleed*; selective serotonin reuptake,
ssri, gastrointestinal bleed*) (2008-12)
 Pharmline (for previous version) “serotonin reuptake inhibitors” AND “haemorrhagegastrointestinal”
 Meyler’s Side Effects of Drugs (15th ed) selective serotonin re-uptake inhibitors
Available through NICE Evidence Search at www.evidence.nhs.uk