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CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 89 NUMBER 1 | JANUARY 2011 89
articles
nature publishing group
In the 1990s, there were case reports involving abnormal bleeding
aer the use of selective serotonin reuptake inhibitors (SSRIs);
1–6
subsequent observational studies provided evidence of the risk
of abnormal bleeding in patients on antidepressant therapy.
Several studies have suggested that the use of SSRIs, in particu-
lar, is associated with (gastrointestinal) bleeding,
7–16
although
the magnitude of the risk estimate diered between studies.7–16
Mechanistically, serotonin (5-hydroxytryptamine, 5-HT) seems
to play a role in this adverse eect. Peripheral 5-HT is stored
in platelets and released during a thrombotic event, stimulating
platelet aggregation.
17,18
Because mature platelets are not capa-
ble of synthesizing 5-HT, they are dependent on the reuptake of
5-HT from plasma. Drugs with inhibitory eects on the sero-
tonin reuptake transporter (5-HTT) could aect the platelet sero-
tonin content or its release from dense granules, thereby aecting
primary hemostasis.
19,20
at is, serotonergic medication would
not cause bleeding as such but could inuence the duration of
bleeding and/or volume of blood loss in conditions involving
underlying diseases or concomitant use of drugs that are known
to cause bleeding, such as nonsteroidal anti-inammatory drugs
(NSAIDs). Previous work by our group showed an association
between serotonergic antidepressant drugs and the need for peri-
operative blood transfusion in orthopedic surgery, whereas non-
serotonergic antidepressant drugs showed no such association.
21
Also, Meijer et al. showed an association between the degree of
serotonin reuptake inhibition and the risk of bleeding in a cohort
of new users of antidepressants.10
Both the function of 5-HTT in platelet serotonin transport
and the role of the 5-HT
2A
receptor, which is the only serotoner-
gic receptor identied on the platelet membrane, are well charac-
terized.
22
e 5-HT
2A
receptor mediates 5-HT-induced platelet
aggregation.23 By interacting with 5-HTT and the 5-HT2A recep-
tor, drugs with serotonergic properties play a major role in regu-
lating extracellular 5-HT concentration. Although many studies
have focused on the association between the use of serotonergic
antidepressants and the risk of bleeding events, little is known
with respect to the use of other serotonergic drugs. Besides anti-
depressants, drugs with other therapeutic indications, such as
antipsychotics and antimigraine drugs, act as antagonists or ago-
nists on the 5-HTT and the 5-HT receptors.
17,24
Randomized
clinical trials involving the atypical antipsychotics risperidone
and olanzapine (both with high anity for the 5-HT
2A
receptor)
in elderly patients with dementia revealed an increased incidence
of cerebrovascular adverse events, including cerebral hemor-
rhage.
25,26
Furthermore, there are some case reports describing
a possible association between abnormal bleeding and the use
of serotonergic drugs other than antidepressants.27,28 In addi-
tion, observational studies in elderly users of antipsychotics
users have assessed the risk of cerebrovascular events, including
intracranial hemorrhage.29,30
1Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht,
The Netherlands; 2Altrecht Medical Health, Den Dolder, The Netherlands; 3Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht,
The Netherlands. Correspondence: BM Verdel (b.m.verdel@uu.nl)
Received 16 July 2010; accepted 1 September 2010; advance online publication 24 November 2010. doi:10.1038/clpt.2010.240
Use of Serotonergic Drugs and the Risk
of Bleeding
BM Verdel1, PC Souverein1, SD Meenks1, ER Heerdink1,2,3, HGM Leufkens1 and TCG Egberts1,3
We assessed several classes of serotonergic drugs in order to evaluate whether they constitute a risk factor for
hospitalization for bleeding (gastrointestinal, intracranial, or in the female genital tract). A case–control study was
conducted using data from the PHARMO record linkage system (RLS). The study population comprised 28,289 cases and
50,786 matched controls. Current use of antidepressant drugs was associated with all three types of bleeding, whereas
antipsychotic drugs were associated with an increased risk of gastrointestinal and intracranial bleeding. Current use
of ergoline derivatives increased the risk of female genital tract bleeding. The risks of gastrointestinal and intracranial
bleeding were higher in new users of antidepressant and antipsychotic drugs as compared with those who were already
receiving these drugs. No clear association was found between the degree of affinity for the serotonin (5-HT) transporter
or the 5-HT2A receptor and the risk of any of the three types of bleeding. The association between antipsychotic drugs and
gastrointestinal bleeding may warrant further research, in view of the fact that this association was rather unexpected.
90 VOLUME 89 NUMBER 1 | JANUARY 2011 | www.nature.com/cpt
articles
Table 1 Characteristics of cases and control patients
Female genital tract bleeding Gastrointestinal bleeding Intracranial bleeding
Cases
(n = 13,399),
n (%)
Controls
(n = 25,683),
n (%)
OR
(95% CI)
Cases
(n = 9,239),
n (%)
Controls
(n = 15,605),
n (%)
OR
(95% CI)
Cases
(n =5,651),
n (%)
Controls
(n = 9,498),
n (%)
OR
(95% CI)
Age (years)
18–39 2,932 (21.9) 5,748 (22.4) NA 782 (8.5) 1,514 (9.7) NA 242 (4.3) 473 (5.0) NA
40–59 7,991 (59.6) 15,100 (58.8) NA 2,115 (22.9) 3,867 (24.8) NA 1,403 (24.8) 2,572 (27.1) NA
60–79 2,120 (15.8) 4,126 (16.1) NA 4,135 (44.8) 6,806 (43.6) NA 2,781 (49.2) 4,594 (48.4) NA
≥80 356 (2.7) 709 (2.8) NA 2,207 (23.9) 3,418 (21.9) NA 1,225 (21.7) 1,859 (19.6) NA
Gender (female) 13,399
(100.0)
25,683
(100.0)
NA 4,362 (47.2) 7,421 (47.6) NA 2,978 (52.7) 5,063 (53.3) NA
Hospital admissions (ever) before index date
Angina
pectoris
75 (0.6) 106 (0.4) 1.40
(1.04–1.88)
314 (3.4) 276 (1.8) 1.92
(1.62–2.28)
127 (2.2) 193 (2.0) 1.06
(0.84–1.33)
Cancer 419 (3.1) 1,237 (4.8) 0.63
(0.56–0.71)
920 (10.0) 667 (4.3) 2.42
(2.17–2.69)
343 (6.1) 415 (4.4) 1.38
(1.19–1.61)
Cardiac
dysrhythmia
117 (0.9) 165 (0.6) 1.40
(1.10–1.79)
472 (5.1) 418 (2.7) 1.94
(1.68–2.23)
289 (5.1) 246 (2.6) 2.01
(1.68–2.40)
Cataract 273 (2.0) 472 (1.8) 1.17
(1.00–1.38)
943 (10.2) 1,268 (8.1) 1.24
(1.13–1.37)
578 (10.2) 720 (7.6) 1.34
(1.18–1.51)
Heart failure 47 (0.4) 129 (0.5) 0.69
(0.49–0.98)
411 (4.4) 242 (1.6) 2.78
(2.35–3.28)
144 (2.5) 127 (1.3) 1.80
(1.41–2.31)
Myocardial
infarction
60 (0.4) 101 (0.4) 1.13
(0.82–1.56)
322 (3.5) 296 (1.9) 1.81
(1.54–2.13)
131 (2.3) 169 (1.8) 1.31
(1.03–1.66)
Peptic ulcer 6 (0.0) 19 (0.1) 0.59
(0.24–1.49)
154 (1.7) 24 (0.2) 11.06
(7.12–17.17)
20 (0.4) 14 (0.1) 2.31
(1.16–4.61)
Stroke 25 (0.2) 66 (0.3) 0.72
(0.45–1.14)
125 (1.4) 98 (0.6) 2.05
(1.56–2.68)
148 (2.6) 65 (0.7) 3.59
(2.67–4.82)
Comedication within 6 months before index date
NSAIDs 4,340 (32.4) 4,365 (17.0) 2.36
(2.25–2.49)
2,454 (26.6) 2,686 (17.2) 1.76
(1.65–1.87)
1,201 (21.3) 1,712 (18.0) 1.24
(1.14–1.35)
Acetylsalicylic
acid, low dose
391 (2.9) 555 (2.2) 1.42
(1.24–1.63)
1,427 (15.4) 1,663 (10.7) 1.49
(1.37–1.61)
771 (13.6) 982 (10.3) 1.32
(1.19–1.47)
Platelet
aggregation
inhibitors
692 (5.2) 1,084 (4.2) 1.29
(1.16–1.43)
2,539 (27.5) 2,959 (19.0) 1.59
(1.49-.1.70)
1,438 (25.4) 1,788 (18.8) 1.43
(1.31–1.56)
Diuretics 1,141 (8.5) 1,682 (6.5) 1.40
(1.28–1.52)
2,421 (26.2) 2,570 (16.5) 1.81
(1.69–1.94)
1,055 (18.7) 1,594 (16.8) 1.07
(0.98–1.18)
Proton pump
inhibitors
1,268 (9.5) 1,720 (6.7) 1.49
(1.38–1.61)
2,227 (24.1) 1,797 (11.5) 2.47
(2.30–2.66)
729 (12.9) 1,094 (11.5) 1.12
(1.01–1.24)
Oral
antidiabetic
drugs
589 (4.4) 863 (3.4) 1.37
(1.23–1.53)
1,141 (12.3) 1,373 (8.8) 1.40
(1.29–1.53)
513 (9.1) 860 (9.1) 0.98
(0.87–1.10)
Statins 778 (5.8) 955 (3.7) 1.69
(1.53–1.87)
1,615 (17.5) 2,136 (13.7) 1.34
(1.24–1.44)
880 (15.6) 1,328 (14.0) 1.13
(1.02–1.24)
Vitamin K
antagonists
282 (2.1) 406 (1.6) 1.37
(1.17–1.61)
1,465 (15.9) 989 (6.3) 2.77
(2.53–3.04)
950 (16.8) 591 (6.2) 3.14
(2.79–3.53)
Oral
glucocorticoids
972 (7.3) 1,480 (5.8) 1.28
(1.18–1.40)
1,208 (13.1) 1,209 (7.7) 1.76
(1.61–1.92)
524 (9.3) 817 (8.6) 1.09
(0.97–1.23)
Iron
preparations
1,516 (11.3) 517 (2.0) 6.07
(5.47–6.74)
698 (7.6) 303 (1.9) 4.06
(3.52–4.68)
169 (3.0) 157 (1.7) 1.78
(1.42–2.23)
Paracetamol 504 (3.8) 939 (3.7) 1.02
(0.91–1.15)
1,111 (12.0) 893 (5.7) 2.28
(2.07–2.51)
462 (8.2) 535 (5.6) 1.46
(1.28–1.67)
CI, confidence interval; NA, not applicable; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 89 NUMBER 1 | JANUARY 2011 91
articles
Therefore, the objective of this study was to assess the
association between the use of antidepressants, antipsychotics,
and ergoline derivatives (partial agonists for the 5-HT
2A
recep-
tor) and the risk of gastrointestinal, intracranial, and female
genital tract bleeding. e classication of serotonergic drugs
was made in the traditional therapeutics-based manner as well
as according to the degree of anity for the 5-HTT and 5-HT
2A
receptor.
RESULTS
e study population consisted of 28,289 patients with hospital
admissions for gastrointestinal, intracranial, or female genital
tract bleeding during the study period and 50,786 matched
controls. e characteristics of cases and controls are shown
in Table 1. Female genital tract bleeding was the most frequent
type of bleeding (n = 13,399, 47.4%), followed by gastrointestinal
(n = 9,239, 32.7%) and intracranial bleeding (n = 5,651, 20.0%).
Frequently prescribed drugs among patients with gastrointes-
tinal and intracranial bleeding and their matched controls were
NSAIDs, platelet aggregation inhibitors, diuretics, and statins.
Patients hospitalized for bleeding in the female genital tract dif-
fered from patients with gastrointestinal and intracranial bleed-
ing with respect to age (81% were younger than 60 years of age)
and had fewer prior hospital admissions for other causes and less
comedication (except use of NSAIDs and iron preparations).
Aer adjustment for confounders, current use of serotonergic
medication was associated with increased risks of hospitaliza-
tion for bleeding in the female genital tract (odds ratio (OR)
2.08; 95% condence interval (CI) 1.89–2.28), gastrointestinal
bleeding (OR 1.49; 95% CI 1.35–1.65), and intracranial bleeding
(OR 1.42; 95% CI 1.16–1.49). Current use of two or more sero-
tonergic drugs increased the risk of gastrointestinal and female
genital tract bleeding ~2.5-fold as compared with nonuse of the
drugs (data not shown). e association between current use of
a serotonergic drug, classied according to drug classes, and the
risks of gastrointestinal, intracranial, and female genital tract
bleeding are shown in Tab l e 2 . Current use of antidepressants
was associated with increased risks of all three bleeding types,
whereas current use of an antipsychotic drug was associated with
increased occurrence of gastrointestinal or intracranial bleed-
ing. In addition, current use of ergoline derivatives, although
not associated with gastrointestinal bleeding (OR 1.80, 95% CI
0.94–3.45) or intracranial bleeding (OR 0.93, 95% CI 0.47–1.85),
did increase the risk of female genital tract bleeding (OR 2.29,
95% CI 1.28–4.08). No dierences were found between the dif-
ferent antidepressant and antipsychotic drug classes with regard
to the occurrence of bleeding.
e risks of gastrointestinal and intracranial bleeding were
higher in new users of antidepressants and antipsychotics as
compared with those who were already receiving these drugs.
e use of antidepressant drugs was not associated with female
genital tract bleeding in new users; this is in contrast to the nd-
ing in patients already receiving the drugs (Ta bl e 3 ). Ta bl e 4
shows the association between the degree of anity of the drug
for the 5-HTT and 5-HT
2A
receptor and bleeding (female geni-
tal tract, gastrointestinal, and intracranial). No association was
found between the degree of anity for the 5-HTT and 5-HT
2A
receptor and bleeding at any of the three sites. Tab l e 5 shows the
results of stratication according to high or low bleeding risk
proles. e risks of gastrointestinal and female genital tract
bleeding were increased to a statistically signicant extent in
both low-risk and high-risk patients receiving a serotonergic
drug, as compared with nonusers. e risk estimates for gas-
trointestinal bleeding did not dier between the two risk groups.
Table 2 Association between current use of one serotonergic drug and different bleeding types
Drug class
Female genital tract bleeding Gastrointestinal bleeding Intracranial bleeding
Cases
(n = 13,399),
n (%)
Controls
(n = 25,683),
n (%)
Adjusted ORa
(95% CI)
Cases
(n = 9,239),
n (%)
Controls
(n = 15,605),
n (%)
Adjusted ORb
(95% CI)
Cases
(n =5,651),
n (%)
Controls
(n = 9,498),
n (%)
Adjusted OR
(95% CI)
Antidepressant
drugs
929 (6.9) 703 (2.7) 2.37 (2.12–2.64) 622 (6.7) 701 (4.5) 1.36 (1.20–1.53) 372 (6.6) 429 (4.5) 1.41 (1.21–1.64)
SSRIs 561 (4.2) 427 (1.7) 2.30 (2.01–2.64) 338 (3.7) 386 (2.5) 1.39 (1.19–1.63) 196 (3.5) 223 (2.3) 1.39 (1.13–1.70)
TCAs 190 (1.4) 154 (0.6) 2.12 (1.69–2.66) 174 (1.9) 190 (1.2) 1.29 (1.03–1.61) 108 (1.9) 126 (1.3) 1.35 (1.03–1.78)
Other
antidepressants
178 (1.3) 122 (0.5) 2.50 (1.95–3.20) 110 (1.2) 125 (0.8) 1.25 (0.95–1.65) 68 (1.2) 80 (0.8) 1.46 (1.03–2.05)
Antipsychotic
drugs
72 (0.5) 139 (0.5) 0.89 (0.66–1.21) 171 (1.9) 147 (0.9) 1.79 (1.41–2.27) 90 (1.6) 97 (1.0) 1.44 (1.06–1.95)
Phenothiazines 13 (0.1) 19 (0.1) 1.07 (0.51–2.26) 22 (0.2) 13 (0.1) 2.99 (1.47–6.09) 16 (0.3) 12 (0.1) 1.48 (0.92–2.38)
Butyrophenones 11 (0.1) 60 (0.2) 0.30 (0.15–0.58) 94 (1.0) 74 (0.5) 1.79 (1.29–2.47) 41 (0.7) 38 (0.4) 1.29 (0.81–2.06)
Other
antipsychotics
48 (0.4) 60 (0.2) 1.48 (0.99–2.22) 55 (0.6) 60 (0.4) 1.49 (1.01–2.19) 33 (0.6) 47 (0.5) 1.26 (0.76–2.09)
Ergoline
derivatives
33 (0.2) 21 (0.1) 2.29 (1.28–4.08) 22 (0.2) 18 (0.1) 1.80 (0.94–3.45) 14 (0.2) 24 (0.3) 0.93 (0.47–1.85)
CI, confidence interval; OR, odds ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
aAdjusted for use of nonsteroidal anti-inflammator y drugs (NSAIDs), proton pump inhibitors, and iron preparations (6 months before index date). bAdjusted for use of NSAIDs,
proton pump inhibitors, and paracetamol (6 months before index date). cAdjusted for use of NSAIDs, platelet aggregation inhibitors, and vitamin K antagonists (6 months before
index date).
92 VOLUME 89 NUMBER 1 | JANUARY 2011 | www.nature.com/cpt
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In the low-risk group, the risk of female genital tract bleeding
was higher in patients receiving a serotonergic drug as com-
pared with nonusers (OR 2.50, 95% CI 2.21–2.83), whereas the
corresponding risk estimate for patients in the high-risk group
was considerably lower (OR 1.58, 95% 1.37–1.83). e risk of
intracranial bleeding was increased in the high-risk group but
not in the low-risk group.
DISCUSSION
In this study, we found that not only the use of serotonergic
antidepressants but also the use of antipsychotic drugs was asso-
ciated with an increased risk of hospital admission for gastroin-
testinal bleeding. Antidepressant drugs were also associated with
increased risks of intracranial and female genital tract bleeding.
Ergoline derivatives were associated only with female genital
Table 4 Association between the affinity for the 5-HTT and 5-HT2A receptor and different bleeding types
Drug classes
Female genital tract bleeding Gastrointestinal bleeding Intracranial bleeding
Cases
(n = 13,399),
n (%)
Controls
(n = 25,683),
n (%)
Adjusted ORa
(95% CI)
Cases
(n = 9,239),
n (%)
Controls
(n = 15,605),
n (%)
Adjusted ORb
(95% CI)
Cases
(n = 5,651),
n (%)
Controls
(n = 9,498),
n (%)
Adjusted ORc
(95% CI)
Antidepressants
5-HTT affinity
High 619 (4.6) 461 (1.8) 2.43 (2.12–2.77) 360 (3.9) 429 (2.7) 1.37 (1.17–1.59) 217 (3.8) 247 (2.6) 1.45 (1.19–1.76)
Medium 240 (1.8) 176 (0.7) 2.39 (1.94–2.94) 200 (2.2) 199 (1.3) 1.45 (1.17–1.78) 110 (1.9) 135 (1.4) 1.27 (0.97–1.66)
Low 64 (0.5) 61 (0.2) 1.91 (1.31–2.79) 56 (0.6) 69 (0.4) 1.19 (0.82–1.73) 42 (0.7) 45 (0.5) 1.63 (1.04–2.54)
Antipsychotics
5-HT2A receptor affinity
High 20 (0.1) 43 (0.2) 0.87 (0.50–1.51) 70 (0.8) 55 (0.4) 2.01 (1.38–2.93) 26 (0.5) 38 (0.4) 1.20 (0.71–2.02)
Medium 28 (0.2) 61 (0.2) 0.89 (0.55–1.42) 79 (0.9) 65 (0.4) 1.88 (1.32–2.67) 48 (0.8) 32 (0.3) 2.16 (1.35–3.46)
Low 0 (0.0) 2 (0.0) NE 2 (0.0) 0 (0.0) NE 0 (0.0) 1 (0.0) NE
Ergoline derivatives
5-HT2A receptor affinity
High 28 (0.2) 13 (0.1) 3.49 (1.72–7.07) 5 (0.1) 6 (0.0) 1.38 (0.40–4.73) 6 (0.1) 8 (0.0) 1.44 (0.48–4.30)
Medium 5 (0.0) 8 (0.0) 0.98 (0.31–3.11) 17 (0.2) 12 (0.1) 2.06 (0.95–4.46) 8 (0.1) 16 (0.2) 0.74 (0.30–1.78)
5-HT, serotonin; 5-HTT, serotonin reuptake transporter; CI, confidence interval; NE, not estimable; OR, odds ratio.
aAdjusted for use of nonsteroidal anti-inflammator y drugs (NSAIDs), proton pump inhibitors, and iron preparations (6 months before index date). bAdjusted for use of NSAIDs,
proton pump inhibitors, and paracetamol (6 months before index date). cAdjusted for use of NSAIDs, platelet aggregation inhibitors, and vitamin K antagonists (6 months before
index date).
Table 3 Association between serotonergic drugs and bleeding for prevalent and new users
Drug classes
Female genital tract bleeding Gastrointestinal bleeding Intracranial bleeding
Cases
(n = 13,399),
n (%)
Controls
(n = 25,683),
n (%)
Adjusted ORa
(95% CI)
Cases
(n = 9,239),
n (%)
Controls
(n = 15,605),
n (%)
Adjusted ORb
(95% CI)
Cases
(n = 5,651),
n (%)
Controls
(n = 9,498),
n (%)
Adjusted ORc
(95% CI)
Antidepressants
Prevalent
users
909 (6.8) 671 (2.6) 2.43 (2.18–2.72) 587 (6.4) 685 (4.4) 1.34 (1.19–1.51) 359 (6.4) 421 (4.4) 1.40 (1.20–1.63)
New users 20 (0.1) 32 (0.1) 1.20 (0.67–2.18) 35 (0.4) 16 (0.1) 3.06 (1.63–5.74) 13 (0.2) 8 (0.1) 2.30 (0.90–5.88)
Antipsychotics
Prevalent
users
70 (0.5) 113 (0.4) 1.14 (0.83–1.57) 143 (1.5) 137 (0.9) 1.67 (1.30–2.15) 71 (1.3) 93 (1.0) 1.24 (0.89–1.72)
New users 2 (0.0) 26 (0.1) 0.14 (0.03–0.61) 28 (0.3) 10 (0.1) 4.22 (1.98–9.00) 19 (0.3) 4 (0.0) 6.43 (2.09–19.76)
Ergoline derivatives
Prevalent
users
28 (0.2) 18 (0.1) 2.30 (1.23–4.28) 22 (0.2) 17 (0.1) 1.94 (1.00–3.75) 10 (0.2) 24 (0.3) 0.70 (0.33–1.51)
New users 5 (0.0) 3 (0.0) 3.83 (0.80–18.42) 0 (0.0) 1 (0.0) NE 4 (0.1) 0 (0.0) NE
CI, confidence interval; NE, not estimable; OR, odds ratio.
aAdjusted for use of nonsteroidal anti-inflammator y drugs (NSAIDs), proton pump inhibitors, and iron preparations (6 months before index date). bAdjusted for use of NSAIDs,
proton pump inhibitors, and paracetamol (6 months before index date). cAdjusted for use of NSAIDs, platelet aggregation inhibitors, and vitamin K antagonists (6 months before
index date).
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 89 NUMBER 1 | JANUARY 2011 93
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tract bleeding. Aer stratication according to high and low
bleeding-risk proles, the association between current use of a
serotonergic drug and female genital tract bleeding was higher
to a statistically signicant extent among patients with a low
bleeding risk, as compared with nonusers of such drugs.
We performed stratied analyses on bleeding types, given
their dierent etiologies. Gastrointestinal and intracranial bleed-
ing are oen caused by trauma (e.g., vascular rupture and peptic
ulcers and erosions) in contrast to female genital tract bleeding,
which usually results from hormone-related or structural gyne-
cologic disorders. We assessed the association between current
use of antidepressants, antipsychotics, and ergoline derivatives
and gastrointestinal, intracranial, and female genital tract bleed-
ing. Although previous observational studies did not nd an
association between the use of SSRIs and risk of hemorrhagic
stroke,11,31,32 we found a statistically signicant increase in the
risk of intracranial bleeding associated with the use of SSRIs
(OR 1.39; 95% CI 1.19–1.63). Antipsychotic drugs were associ-
ated with the risk of gastrointestinal bleeding (OR 1.79, 95% CI
1.41–2.27) and intracranial bleeding (OR 1.44; 95% CI 1.06–
1.95). It is not clear whether the observed association between
antipsychotics with anity for the 5-HT2A receptor (but not
for the 5-HTT receptor) and the risk of gastrointestinal and
intracranial bleeding is a result of decreased platelet aggrega-
tion. Serotonin and the 5-HTT and the 5-HT
2A
receptor play
a role in platelet aggregation. Drugs with anity for the trans-
porter or this receptor could consequently aect hemostasis.
Antagonists of the 5-HTT and/or 5-HT
2A
receptor (e.g., SSRIs
and antipsychotics) can increase bleeding time by inhibiting
the uptake and storage of platelet serotonin, whereas agonists
of the 5-HT
2A
receptor should stimulate platelet aggregation.
erefore, it is interesting to observe that ergoline derivatives,
a group with (partial) agonistic eect on the 5-HT
2A
receptor,
increased the risk of female genital tract bleeding. Ergotamine
preparations constituted 50% of all the ergoline derivatives
dispensed. Ergotamine is used in the treatment of migraine.
e occurrence of migraine is related to the female menstrual
cycle, probable triggered by a fall in estrogen levels. e asso-
ciation between current use of ergoline derivatives and female
genital tract bleeding is therefore not surprising. No associa-
tion was found between the use of ergoline derivatives and gas-
trointestinal or intracranial bleeding. In theory, antagonists of
the 5-HT
2A
receptor, such as ketanserin, should be associated
with bleeding complications. However, the number of patients
using 5-HT2A receptor antagonists was too low to be able to
evaluate such an association. In new users, the dissimilarity in
results between gastrointestinal and intracranial bleeding on
the one hand and female genital tract bleedings on the other is
obvious. No association was observed in new users between the
use of antidepressant or antipsychotic drugs and female genital
tract bleeding. e association between serotonergic drugs and
increased bleeding risk is probably not a consequence of a toxic
reaction to the drug itself but the result of decreased platelet
aggregation. is eect has been demonstrated for SSRIs admin-
istered to patients with depression, as compared with healthy
controls.
33
Paroxetine decreases serotonin storage in the plate-
lets and lowers platelet function by >80% aer 14–21 days.
34
e
dierence in results between prevalent users and new users can
be explained by the fact that the relative shortage of serotonin
induced by starting the use of a serotonergic drug may correct
itself aer a few weeks, resulting in a new balance.
e strength of this study is that we used a large population-
based database, thereby enabling us to evaluate several types of
bleeding. All drug prescriptions lled are routinely recorded,
and information bias of drug exposure is therefore unlikely.
Our study had several potential limitations. In the PHARMO
record linkage system (RLS) database, no information on smok-
ing status, alcohol intake, or use of over-the-counter medicines
is recorded. ese factors are considered important confound-
ers of the association between drug use and the risk of bleed-
ing. Because we used hospital admission data, only bleeding
events leading to hospitalization were included in our analyses.
e possibility that serotonergic drug use may increase the risk
of mild bleeding events cannot be excluded. We included only
antidepressants, antipsychotics, and ergoline derivatives in our
analyses, but the possibility cannot be ruled out that patients
used other medications, such as tramadol or ketanserin, which
have anity for the 5-HTT and 5-HT2A receptor. However, it
seems unlikely that there would have been dierential use of
these drugs between cases and controls. Another limitation is
that confounding by indication may not be excluded. Other
risk factors, such as depression, were not taken into account. In
patients with depression, abnormalities in pathways involved in
platelet activation have been shown to be present.
In summary, current use of antidepressants and antipsychotic
drugs may increase the risk of gastrointestinal and intracranial
bleeding. New users of a serotonergic drug have an increased
risk of gastrointestinal and intracranial bleeding, in contrast to
prevalent users. e association between antipsychotic drugs
and gastrointestinal bleeding may warrant further research
because this association was rather unexpected. e risk of gas-
trointestinal, intracranial, and female genital tract bleeding may
Table 5 Association between current use of serotonergic drugs
and bleeding, stratified according to risk profile
Female genital
tract bleeding Gastrointestinal Intracranial
Adjusted ORa
(95% CI)
Adjusted ORb
(95% CI)
OR
(95% CI)
Low-risk profile
No use 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
Current use 2.50 (2.21–2.83) 1.45 (1.24–1.70) 1.20 (0.99–1.45)
High-risk profile
No use 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
Current use 1.58 (1.37–1.83) 1.44 (1.26–1.65) 1.63 (1.38–1.92)
High-risk profile: use of nonsteroidal anti-inflammatory drugs, vitamin K antagonists,
heparin, platelet aggregation inhibitors, direct and other thrombin inhibitors,
antifibrinolytics, and vitamin K and other hemostatics (6 months before index date).
CI, confidence interval; OR, odds ratio.
aAdjusted for use of proton pump inhibitors and iron preparations (6 months before
index date). bAdjusted for use of proton pump inhibitors and paracetamol (6 months
before index date).
94 VOLUME 89 NUMBER 1 | JANUARY 2011 | www.nature.com/cpt
articles
not be associated with the degree of anity of the drug for the
5-HTT and 5-HT2A receptor.
METHODS
Setting. Data for this study were obtained from the PHARMO RLS
(http://www.pharmo.nl). The PHARMO RLS includes the demo-
graphic details and complete medication history of more than 2 million
community-dwelling residents of more than 25 population-defined
areas in the Netherlands from 1985 onward, and it is further linked to
hospital admission records as well as to several other health registries
that include pathology, clinical laboratory findings, and general prac-
titioner data. Because almost all patients in the Netherlands are regis-
tered with a single community pharmacy, independent of prescriber,
pharmacy records are essentially complete with regard to prescription
drugs.35
For this study, drug dispensing data and hospitalization data were
used. e computerized drug dispensing histories contain information
concerning the dispensed drug, dispensing date, prescriber, amount
dispensed, prescribed dosage regimen, and estimated duration of use.
e duration of use of each dispensed drug is estimated by dividing
the number of dispensed units by the prescribed number of units to be
used per day. Drugs are coded according to the Anatomical erapeutic
Chemical classication.
36
e Ho spital Admiss ion Reg ister enc ompass es
all hospital admissions in the Netherlands and includes detailed infor-
mation concerning the primary and secondary discharge diagnoses,
diagnostic, surgical and treatment procedures, type and frequency of
consultations with medical specialists, and dates of hospital admission
and discharge. All diagnoses are coded according to the International
Classication of Diseases, 9th edition (ICD-9-CM).
Study population. A case–control study was conducted within the
PHARMO RLS. Cases were dened as patients 18 years of age or older
with a rst hospital admission for gastrointestinal, intracranial, or female
genital tract bleeding (for ICD-9 codes see Appendix 1) in the period
January 1998 to December 2007. e date of hospital admission was the
index date. For each case, up to two control patients without a history of
abnormal bleeding during the study period were matched for gender, year
of birth, geographical area, index date, and duration of exposure history
prior to the index date per the PHARMO RLS data. Both cases and con-
trols were eligible for inclusion if a minimum of 365 days of history was
available for them in the PHARMO RLS prior to the index date.
Exposure: definition and assessment.
For e ach case and e ach control, all
prescriptions for antidepressants, antipsychotics, and ergoline derivatives
(Appendix 2) before the index date were identied.
37,38
Serotonergic
drugs were classied according to their pharmacotherapeutic group
and also categorized on the basis of their anity for the 5-HTT and the
5-HT
2A
receptors (high: K
i
<10 nmol/l; medium: K
i
10–1,000 nmol/l;
and low: K
i
>1,000 nmol/l; or no data). K
i
data were obtained from the
Psychoactive Drug Screening Program funded by the National Institute
of Mental Health (http://pdsp.med.unc.edu). is program provides
screening of psychoactive compounds for pharmacological and func-
tional activity at cloned human or rodent CNS receptors, channels, and
transporters. e database contains more than 47,000 K
i
values, and new
information accrues to it on a regular basis. e K
i
values were taken
from experiments with human receptor cell lines. If there was more
than one K
i
value for a specic serotonergic drug–receptor interaction,
an average value was calculated. If no Ki value from a human recep-
tor cell line was available, a K
i
for a drug–animal receptor interaction
was used.
Exposure to serotonergic drugs was classied according to the timing
of use in relation to the index date. Current users of a serotonergic drug
were dened as patients with a prescription for the drug within 90 days
before the index date. Recent users were those with the latest prescription
between 91 and 180 days before the index date. Past users were those with
prescription dates between 181 and 365 days prior to the index date, and
distant past users were those with prescription dates >365 days before the
index date. Exposure to serotonergic drugs was categorized as “no use”
if there was no recorded use of serotonergic medication from the rst
entry in the PHARMO RLS until the index date. Among current users,
we assessed whether patients were new users of serotonergic medication,
dened as not having a prescription in a 6-month time window before
the dispensing date of the previous prescription.
Appendix 1 Outcomes
Diagnosis ICD-9 code
Subarachnoid hemorrhage 430
Intracerebral hemorrhage 431
Nontraumatic extradural hemorrhage 432.0
Subdural hemorrhage 432.1
Unspecified intracranial hemorrhage 432.9
Other and unspecified capillary diseases 448.9
Gastric ulcer, acute with hemorrhage 531.00
Gastric ulcer, acute with hemorrhage and perforation 531.2
Gastric ulcer, chronic or unspecified with hemorrhage 531.4
Gastric ulcer, chronic or unspecified with hemorrhage and
perforation
531.6
Duodenal ulcer, acute with hemorrhage 532.0
Duodenal ulcer, acute with hemorrhage and perforation 532.2
Duodenal ulcer, chronic or unspecified with hemorrhage 532.4
Duodenal ulcer, chronic or unspecified with hemorrhage
and perforation
532.6
Peptic ulcer, acute with hemorrhage 533.0
Peptic ulcer, acute with hemorrhage and perforation 533.2
Peptic ulcer, chronic or unspecified with hemorrhage 533.4
Peptic ulcer, chronic or unspecified with hemorrhage and
perforation
533.6
Gastrojejunal ulcer, acute with hemorrhage 534.0
Gastrojejunal ulcer, acute with hemorrhage and perforation 534.2
Gastrojejunal ulcer, chronic with hemorrhage 534.4
Gastrojejunal ulcer, chronic with hemorrhage and
perforation
534.6
Gastritis and duodenitis, with hemorrhage 535.01
Hemoperitoneum (nontraumatic) 568.81
Hemorrhage of rectum and anus 569.3
Gastrointestinal hemorrhage 578.0
Blood in stool 578.1
Hemorrhage of gastrointestinal tract unspecified 578.9
Excessive or frequent menstruation 626.2
Puberty bleeding 626.3
Ovulation bleeding 626.5
Metrorrhagia 626.6
Postcoital bleeding 626.7
Other uterine hemorrhage 626.8
Unspecified uterine hemorrhage 626.9
Premenopausal menorrhagia 627.0
Postmenopausal bleeding 627.1
ICD-9, International Classification of Diseases, 9th revision.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 89 NUMBER 1 | JANUARY 2011 95
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Data analysis.
e strength of the association between use of serotonergic
drugs and the occurrence of gastrointestinal, intracranial, and female
genital tract bleeding was estimated using conditional logistic regression
and was expressed as crude and adjusted ORs with 95% CIs. Potential
confounders were prescription drugs associated with bleeding and drugs
used in the treatment of medical conditions associated with bleeding,
such as NSAIDs, oral glucocorticoids, proton pump inhibitors, and plate-
let aggregation inhibitors. Use of concomitant drugs was recorded within
a 6-month period prior to the index date, as were hospitalizations (ever)
for several comorbidities. For each bleeding type, a separate model was
tted. Covariates were included in the regression model if they induced
a change of 5% change or more in the crude matched OR for current use
of serotonergic drugs. We stratied our analyses for patients with a low
or high bleeding-risk prole (the latter being dened as use of NSAIDs,
vitamin K antagonists, heparin, platelet aggregation inhibitors, direct
and other thrombin inhibitors, antibrinolytics, or vitamin K and other
hemostatics in a 6-month time window before the index date). All statis-
tical analyses were performed using SPPS for Windows (version 16.0.1;
SPSS, Chicago, IL).
CONFLICT OF INTEREST
The Division of Pharmacoepidemiology and Pharmacotherapy, of which
authors B.M.V., P.C.S., E.R.H., H.G.M.L., and T.C.G.E. are employees, has
received unrestricted funding for pharmacoepidemiological research
from GlaxoSmithKline, Novo Nordisk, the privately and publicly funded
Top Institute Pharma (http://www.tipharma.nl, includes co-funding from
Appendix 2 Serotonergic study drugs and their affinity
constants for the 5-HTT and the 5-HT2A receptor
Drug class Drug
Affinity
for 5-HTT
(in nmol/l)
Affinity
for 5-HT2A
(in nmol/l)
Ergoline derivativesa
Lisuride — 2.15
Cabergoline — 6.17
Dihydroergotamine — 39 (Rat)
Ergotamine — 0.81
Methysergide >10,000 21.21
Bromocriptine — 107.2
Pergolide — 38.1
Antipsychotic drugs
Phenothiazines Chlorpromazine 1,296 42.4
Levomepromazine — —
Fluphenazine 5,950 29.4
Perphenazine — 5.6
Prochlorperazine — 15
Perazine — —
Periciazine — —
Thioridazine 1,259 17.9
Pipotiazine — —
Butyrophenones Haloperidol >1,000 96.7
Pipamperone >1,000 6.3
Bromperidol — 26 (Rat)
Benperidol — 2.5 (Rat)
Droperidol — 3.5 (Rat)
Other antipsychotics Sertindole >1,000 0.43
Flupentixol — 87.5
Chlorprothixene — 0.43
Zuclopenthixol — —
Pimozide — 13.7
Penfluridol — 104.5 (Rat)
Clozapine >1,000 7.9
Olanzapine >1,000 5.2
Quetiapine >1,000 344
Tetrabenazine — —
Sulpiride — 10,000 (Rat)
Tiapride — —
Lithium — —
Risperidone >1,000 1.21
Aripiprazole >1,000 21.9
Antidepressants
TCAs Desipramine 95.4 105 (Rat)
Imipramine 8.37 77.8 (Rat)
Clomipramine 0.21 35.5
Opipramol — —
Trimipramine 149 —
Drug class Drug
Affinity
for 5-HTT
(in nmol/l)
Affinity
for 5-HT2A
(in nmol/l)
Amitriptyline 27.6 23
Nortriptyline 207 5.0 (Rat)
Doxepin 68 26.0 (Rat)
Dosulepin — —
Maprotiline 5,800 51 (Rat)
SSRIs Fluoxetine 5.42 196.7
Citalopram 6.09 >10,000
Paroxetine 0.26 >10,000
Sertraline 1.11 >1,000
(Rat)
Fluvoxamine 5.55 >10,000
(Rat)
Escitalopram 1.80 —
Other antidepressants Phenelzine >10,000 —
Tranylcypromine 39,000 >10,000
Moclobemide — —
Mianserin 4,000 19.4
Trazodone 367 35.8
Nefazodone 403 8.55 (Rat)
Mirtazapine >10,000 69
Venlafaxine 68.7 >1,000
(Rat)
Duloxetine 1.73 504 (Rat)
5-HT, serotonin; 5-HTT, serotonin reuptake transporter; SSRI, selective serotonin
reuptake inhibitor; TCA, tricyclic antidepressant.
aPartial agonist for the 5-HT2A receptor.
From http://pdsp.med.unc.edu.
Appendix 2 Continued
96 VOLUME 89 NUMBER 1 | JANUARY 2011 | www.nature.com/cpt
articles
universities, government, and industry), the Dutch Medicines Evaluation
Board, and the Dutch Ministry of Health. S.D.M. declared no conflict
of interest.
© 2010 American Society for Clinical Pharmacology and Therapeutics
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