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Abstract

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are nowadays the most widely used antidepressants in the world, mainly because they have a better adverse reaction profile and a higher safety margin in overdoses, when compared to other antidepressants. These drugs recently have been the target of important debates concerning safety issues, among them the possibility that they may increase the risk of bleeding. Over the 1990s, an increasing number of individual cases of bleeding disorders were reported in the literature and to the pharmacovigilance programmes which prompted several epidemiological and pharmacological studies. In this review we have examined all available data. The whole evidence supports the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding. Such disorders may have different degrees of severity and may be located anywhere in the body. The epidemiological evidence is, however, more robust for upper gastrointestinal bleeding. It has been estimated that upper gastrointestinal bleeding may occur at a frequency ranging from 1 in 100 to 1 in 1,000 patient-years of exposure to high-affinity drugs (the SSRIs), with the very old patients being in the highest part of the range. The increased risk may be of particular relevance when the SSRIs are associated with NSAIDs as well as low-dose aspirin.

Selective serotonin reuptake inhibitors (SSRIs) are nowadays the most widely used antidepressants in the world. In 2004 the consumption in Spain through the National Health System was estimated to be 33.4 defined daily doses per 1,000 inhabitants per day, accounting for 76% of the overall use of antidepressants. These figures mean that at any day over the year, 3–4 out of 100 inhabitants are being treated with these drugs. The reason why the SSRIs have been so successful in comparison to other antidepressants is mostly attributed to a better adverse reaction profile and a higher safety margin in overdoses (Cheeta et al. 2004). Recently, however, these drugs have been the target of important debates concerning safety issues, in particular the suicide risk both in adults and adolescents (Gunnell & Ashby, 2004; Martínez et al. 2005) and the withdrawal syndrome (Jureidini et al. 2004; Sanz et al. 2005).

In the last few years, the possibility that the SSRIs may induce bleeding disorders has become a new safety concern. In 1990, Humphries et al. reported a case of a 44-year-old postmenopausal woman who was referred for evaluation of petechiae and prolongation of bleeding time (>15 min.). Platelets count and coagulation tests were normal and the only antecedent of interest was the use of 20 mg/day fluoxetine for the past 2 years. Fluoxetine was discontinued for 2 weeks, the number of petechiae decreased and the bleeding time became normal (6.5 min.). The re-exposure to the drug resulted in flare-up of the petechiae accompanied again with a prolonged bleeding time (>15 min.). As far as we know, this is the first published case of a bleeding disorder associated with an SSRI. Over the 90's, several other cases have been published associated with fluoxetine (Yaryura-Tobias et al. 1991) paroxetine (Ottervanger et al. 1994), fluvoxamine (Leung & Shore 1996); sertraline (Calhoun & Calhoun 1996); and related drugs such as venlafaxine (Khon & Labbate 1997).

The increasing notification of bleeding reports in association with these drugs through the pharmacovigilance schemes (Montero et al. 1996) prompted us to initiate an epidemiological study in order to test the hypothesis that the use of SSRIs would increase the risk of upper gastrointestinal bleeding, a fairly serious and easy-to-validate outcome. We found a threefold increased risk (de Abajo et al. 1999), which supported with more robust data the association suggested by the individual cases. Since then other epidemiological studies have supported this hypothesis. The aim of this paper has been to review the existing evidence from both pharmacological and epidemiological perspectives and to assess the public health implications of this problem.

Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References

In man, almost all circulating serotonin is transported by platelets in dense granules. Platelets are unable to synthesize serotonin, but they avidly take up the amine from plasma, using the same transporter used by neurones (Lesch et al. 1993). Taking advantage of this property blood platelets have been used since long as a model for studying serotoninergic dysfunction in depressed patients and for assessing the effects of antidepressants on the reuptake mechanism (Lingjærde 1990).

In response to certain stimuli (ADP, epinephrine), serotonin is released from platelet stores interacting with endothelial cells, smooth muscle cells, activating platelets and binding to α-granule proteins. Serotonin is a relatively weak platelet activator, however in the presence of proaggregatory factors such as ADP, epinephrine and collagen, serotonin significantly potentiates aggregation (Skop & Brown 1996). Therefore, any intervention that affects platelet serotonin content or its release from dense granules may theoretically have an impact on haemostasis and thrombosis.

In studies performed in human beings all SSRIs have consistently shown a drastic decrease in platelet serotonin content after several weeks of treatment reaching levels around or below 10% of the pretreatment serotonin levels (Wagner et al. 1990; Mück-Seler et al. 1991; Narayan et al. 1998; Hergovich et al. 2000; Javors et al. 2000) (fig. 1). A similar strong effect has also been shown with clomipramine (Martesson et al. 1990). For the other antidepressants, the effect of treatment on platelet serotonin content have been found vary, ranging from no effect with trazodone (Mück-Seler et al. 1991; Pigott et al. 1992), maprotiline (Mück-Seler et al. 1991), and nefazodone (Narayan et al. 1998), to a moderate decrease with desipramine and amitriptyline (Mück-Seler et al. 1991; Javors et al. 2000), being consistent with their known actions on the serotonin reuptake mechanism (see below). More systematic human studies are, however, needed.

image

Figure 1. Effect of treatment with fluoxetine 40 mg in serotonin platelet content. The figure shows the mean values (±standard deviation) before and after 3 and 6 weeks treatment of 14 patients with depressive disorder. Modified from Wagner et al. (1990).

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Although in the middle of the nineties Alderman et al. (1992) and Berk et al. (1995) failed to find a modification in platelet aggregation or haemostasis in patients treated with SSRIs, the application of most modern techniques to measure platelet function led to the confirmation that SSRIs impair both the platelet secretory response (Markovitz et al. 2000) and the platelet aggregation induced by ADP, collagen and thrombin (Serebruany et al. 2001), and that they cause an inhibition of platelet plug formation as reflected by a significant prolongation of the closure-time measured with a platelet function analyzer (Hergovich et al. 2000). Furthermore, in vitro studies have shown that addition of ADP to normal platelets in the presence of SSRIs causes microaggregation and primary aggregation but no or very little dense granule release which leads to the formation of loose and disaggregating clots (Maurer-Spurej 2005).

The blocking properties on serotonin uptake of antidepressants have been studied with several models, among them brain synaptosomes, in vitro human monoamine transporters, and human platelet serotonin content after treatment with antidepressants. The affinity of the most widely used antidepressants for human serotonin, and norepinephrine transporters is shown in table 1 (Tatsumi et al. 1997). Regarding selectivity, some differences were found: in addition to clomipramine, several other tertiary amine tricyclics including amitriptyline and imipramine, were more selective for serotonin re-uptake inhibition than for norepinephrine uptake inhibition, whereas all secondary amine tricyclic antidepressants were selective for norepinephrine over serotonin, as also expected from in vitro animal studies. Drugs known as SSRIs (citalopram, fluoxetine, flovoxamine, paroxetine, and sertraline) showed the greatest selectivity for serotonin transporters (table 1).

Table 1.  Equilibrium dissociation constants (KD's) of antidepressants and selectivity for the human serotonin transporter over norepinephrine transporter (from Tatsumi et al. 1997).
 KD mean±S.E.M. (nM)
AntidepressantSerotonin transporterNorepinephrine transporterSelectivity factor
Amitryptiline4.3±0.135±2 8.1
Amoxapine58±2 16±0.3 0.28
Citalopram1.16±0.014070±80  3500
Clomipramine0.28±0.0138±1 130
Desipramine17.6±0.7 0.83±0.050.047
Dothiepin8.6±0.446±1 5.3
Doxepin68±1 29.5±0.8  0.43
Fluoxetine0.81±0.02240±10 300
Fluvoxamine2.2±0.21300±30  580
Imipramine1.4±0.0337±2 27
Lofepramine70±4 5.4±0.40.077
Maprotiline5800±200 11.1±0.3 0.0019
Mianserin4000±300 71±0.20.018
Nefazodone200±20 360±40 1.8
Nomifensine1010±30  15.6±0.4 0.015
Nortryptiline18±1 4.37±0.070.24
Paroxetine0.13±0.0140±2 300
Sertraline0.29±0.01420±20 1400
Trazodone160±20 8500±300 53
Venlafaxine8.9±0.31060±40  120

Pharmacovigilance of bleeding disorders

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References

In addition to the bleeding disorders reported in the literature in association with the SSRIs, an increasing number of cases have also been reported to the national pharmacovigilance schemes worldwide. In order to have a broad view we performed a search in VIGIBASE, the WHO database of the International Drug Monitoring Program (Uppsala Monitoring Centre 2005). The main results are shown in table 2. Most of the reported cases were mild disorders like bruising, epistaxis, petechiae, prolonged bleeding time and genito-urinary bleeding but an important number of serious cases of gastrointestinal bleeding and cerebral haemorrhage, some with fatal outcome, have been reported as well. The drugs most frequently involved were fluoxetine, paroxetine and sertraline.

Table 2.  Reports of bleeding disorders associated with antidepressants registered in VIGIBASE§. The search was performed on 6th July, 2005.
DrugsYear of first reportTotal no. of bleeding reportsUpper gastrointestinal bleeding reportsCerebral bleeding reports
  • §

     VIGIBASE is the database of the WHO Programme for International Drug Monitoring. It contains summaries of case reports of suspected adverse drug reactions that are heterogenous in regard to source, documentation, quality and causality likelihood.

  • * 

    * One case presented with both upper gastrointestinal bleeding and cerebral bleeding.

SSRIs
 Citalopram1992343 7324
 Escitalopram20035612 2
 Fluoxetine19881.883205*49*
 Fluvoxamine1988160 22 4
 Paroxetine1993962 117 36
 Sertraline1992922 105 25
 Venlafaxine1994521 6725
Non-selective serotonin reuptake inhibitors
 Amitriptyline1969166 33 8
 Dosulepine (dothiepin)197334 4 2
 Imipramine196974 5 –
Other antidepressants
 Desipramine198332 3 2
 Nortriptyline196846 3 5
 Maprotiline197939 3 4
 Trazodone19819910 2
 Nefazodone1995106 12 5
 Mianserine198252 7 2

The epidemiological evidence

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References

The first epidemiological study.

The hypothesis that the use of SSRIs would increase the risk of bleeding received the first epidemiological support in 1999, when our group published a nested case-control study reporting a three times increased risk of upper gastrointestinal bleeding (de Abajo et al. 1999). For this study we used data from the UK-based General Practice Research Database (GPRD), a widely-known data source for pharmacoepidemiological research (García-Rodríguez & Pérez-Guthann 1998). Among the 1,651 cases confirmed as upper gastrointestinal bleeding, 52 (3.1%) were exposed to SSRIs during the 30-day time window before the index date (the date of the upper gastrointestinal bleeding diagnosis), while among the sample of 10,000 controls (a density-based random sample of the source population) we found 95 patients (1.0%) exposed to these drugs. This yielded an odds ratio of 3.0 (95% confidence interval (CI), 2.1–4.4), after adjustment for sex, age, past history of upper gastrointestinal disorder (including dyspepsia, peptic ulcer, and peptic ulcer complications), smoking, and use of NSAIDs, low-dose aspirin, anticoagulants and steroids (table 3). The exposure to drugs, including antidepressants, was assessed according to the computerised records of prescriptions which is considered complete at the GPRD. Additional adjustment for use of antiulcer drugs (antacids, omeprazole and H2 blockers) hardly modified the results (OR=2.9; 2.0–4.2). In the study we also gathered information from 248 cases presenting with ulcer perforation. Interestingly, no association was found with SSRIs (OR=1.3; 0.4–3.7).

Table 3.  Risk of upper gastrointestinal bleeding associated with the use of antidepressants (from de Abajo et al. 1999).
 Cases (N=1,651)Controls (N=10,000)Adjusted RR* (95% CI)
  • * 

    Adjusted for sex, age, calendar year, antecedents of upper gastrointestinal disorders, smoking status, and use of NSAIDs, aspirin, anticoagulants and steroids.

  • #

    Selective Serotonin Reuptake Inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, trazodone, clomipramine).

  • §

    Non-selective Serotonin Reuptake Inhibitors (amitriptyline, dothiepin, imipramine, lofepramine, doxepine).

  • $

    $ Others (nortriptyline, protriptyline, desipramine, trimipramine, maprotiline, amoxapine, mianserin).

Non-use1,3278,7601 (reference)
Current use
 SSRI#52953.0 (2.1–4.4)
 NSRI§742411.4 (1.1–1.9)
 Others$4250.8 (0.2–2.4)
 Multiple3141.0 (0.3–3.7)
Past use
 SSRI#271401.2 (0.8–1.9)
 NSRI§1586881.2 (1.0–1.5)
 Others$6371.0 (0.4–2.6)

All the individual SSRIs with proper information showed an increased risk ranging from 2.1 (0.9–5.1) of clomipramine to 4.3 (2.2–8.3) of paroxetine. We also included trazodone in this group, a drug with a rather selective but weak inhibitory action on the serotonin reuptake (table 1). Surprisingly, trazodone presented the highest increased risk (OR=8.6; 2.1–35.1). However, as trazodone only contributed with four cases, its exclusion from the analysis did not materially change the estimates for the SSRIs as a group (OR=2.9; 2.0–4.2). The main action of trazodone may be to block the 5-HT2 receptors, which, interestingly, are supposed to mediate the platelet aggregation effect of serotonin (Skop & Brown 1996).

A less increased risk was also found for some of the antidepressants considered also to have an inhibitory action, though not selective, on serotonin-reuptake mechanism: amitriptyline (OR=1.9; 1.2–2.9), imipramine (OR=2.1; 0.7–6.2) and lofepramine (OR=1.8; 0.8–4.0), while no association was found (OR=0.8; 0.2–2.4) with the group of antidepressants known to have no action on serotonin reuptake mechanism (nortryptiline, trimipramine, amoxapine, maprotiline, and mianserine). This observation was rather consistent with the mechanistic hypothesis linking the risk of bleeding with a depletion of serotonin from platelets. However, a discordant result was obtained: dothiepin, the tricyclic antidepressant most widely used in the UK, showed no increased risk (OR=1.0, 0.6–1.6). We advanced the explanation that in some experimental models dothiepin has shown a considerable selectivity on norepinephrine reuptake (Ishikawa et al. 1986). However, as far as we know, no in vivo studies have been published on the effect of dothiepin on platelet serotonin content at therapeutic doses.

The 52 cases considered as current users of SSRIs arose from a cohort of 69,593 persons who received a total of 435,021 prescriptions for any of these drugs, a total exposure of 35,731 person-years (assuming that one prescription lasts on average 30 days). The crude incidence rate of upper gastrointestinal bleeding for this population was estimated to be 1.2 per 10,000 prescriptions (1.5 per 1,000 person-years), two thirds of which (0.8 per 10,000 prescriptions or 1 per 1,000 person-years) would be attributable to SSRIs.

We also assessed the possible effect of dose and duration, but apparently these factors had no bearing on the risk of upper gastrointestinal bleeding (table 4). The majority of patients were prescribed medium or low doses, especially in the non-selective serotonin reuptake group where only 12% of current-user controls used equivalent amitriptyline doses over 75 mg. The duration of treatment lasts less than three months in over 40% of current-user controls. As shown in pharmacological studies, 20 mg fluoxetine or equivalents are enough in most patients to reduce serotonin content in more than 80% patients (Narayan et al. 1998). Therefore, although the effect must be dose-dependent, it is possible that the effect of most SSRIs is at therapeutic doses already near to maximum leaving little room to observe a dose-effect in an epidemiological study. The same can be said from the duration of treatment, bearing in mind that the effect is already maximum after 4–6 weeks.

Table 4.  Effect of dose and duration of use among current single users of antidepressants as compared to non use.
 Cases (N=1,651)Controls (N=10,000)Adjusted RR* (95% CI)
  • *

     Adjusted for sex, age, calendar year, antecedents of upper gastrointestinal disorders, smoking status, and use of NSAIDs, aspirin, anticoagulants and steroids.

  • +

     Fluoxetine: ≤20 mg; fluvoxamine: ≤100 mg: paroxetine: ≤20 mg; sertraline: ≤50 mg; citalopram: ≤20 mg; clomipramine: ≤75 mg; trazodone: ≤125 mg.

  • $

     Amitriptyline: ≤75 mg; dothiepin: ≤75 mg; imipramine: ≤75 mg; doxepine: ≤75 mg lofepramine: ≤140 mg;

Daily doses
SSRIs
 Low/medium+41723.0 (2.0–4.6)
 High11233.2 (1.5–6.8)
NSRIs
 Low/medium$67211 1.5 (1.1–2.0)
 High 7301.0 (0.4–2.4)
Duration of treatment
SSRIs
 Less than 91 days18402.7 (1.5–4.9)
 91 days or longer34553.3 (2.1–5.2)
NSRIs
 Less than 91 days27100 1.2 (0.7–1.9)
 91 days or longer47142 1.6 (1.1–2.3)

Perhaps the most striking result of our study was that the concurrent use of SSRIs with NSAIDs greatly increased the risk of upper gastrointestinal bleeding (OR=15.6; 6.6–36.6) (table 5), which shows a strong interaction (e.g. the relative risk of the combination is greater than the sum of the independent relative risks). The concomitant use of NSAIDs with non-selective serotonin-reuptake inhibitors gave rise to an OR of 4.6 as compared to non-use (95%CI, 2.8–7.9), which represents additivity of the independent effects. Likewise, a smaller interaction was observed between SSRIs and aspirin, OR=7.2 (95%CI, 3.1–17.1).

Table 5.  Interaction between current use of SSRIs and current use of NSAIDs as compared to non-use of either drug (from de Abajo et al. 1999).
 Cases (N=1,651)Controls (N=10,000)Adjusted RR* (95% CI)
  • *

     Adjusted for sex, age, calendar year, antecedents of upper gastrointestinal disorders, smoking status, and use of aspirin, anticoagulants and steroids.

Non-use111581801
Current use
 NSAIDs only 2956523.7 (3.2–4.4)
 SSRIs only  38 932.6 (1.7–3.8)
 NSAIDs and SSRIs  16  915.6 (6.6–36.6)

Further epidemiological evidence on upper gastrointestinal bleeding.

Up to July 2005, we have obtained information from 5 other published epidemiological studies which provide data concerning the association between the use of SSRIs and upper gastrointestinal bleeding (table 6). All of them showed an increased risk, although in the one performed by Dunn et al. (2000), reported as a Letter to the Editor, the result did not reach statistical significance.

Table 6.  Epidemiological studies which tested the hypothesis of an association between SSRIs use and an increase of upper gastrointestinal bleeding.
StudyDesignPopulationExposed to SSRIsExposed casesRR (IC95%) versus non-useRR (IC95%) versus other antidepressants
  • §

    Patient-months.

  • φ

    Any kind of gastrointestinal haemorrhage.

  • * 

    * Increased risk per one unit of serotonin reuptake inhibition grade (3 groups).

de Abajo et al. (1999)Nested case-controlGeneral 69,593 523.0 (2.1–4.4) 2.2 (1.4–3.5) 
Dunn et al. (2000)Cohort (PEM)General237,609§103φ1.2 (0.9–1.7)
Van Walraven et al. (2001)CohortElderly (>65 y)101,397404 1.1 (1.0–1.2)*
Dalton et al. (2003)CohortGeneral 17,320 553.6 (2.7–4.7)2.0 (1.0–4.6)
Tata et al. (2005)Nested case-controlGeneral3622.4 (2.1–2.7)
Wessinger et al. (2005)Case-controlHospital 711.5 (1.0–2.1)

The study by Van Walraven et al. (2001) was a large cohort study performed in 383,911 elderly patients in Ontario, Canada exposed to antidepressants. They classified the antidepressants in 3 groups according to the dissociation constant (Kd) for the serotonin transporter provided by Tatsumi et al. (1997) (table 1). The only difference from our classification was that fluvoxamine appeared in the intermediate-affinity group and trazodone in the low-affinity group. They built a statistical model in which the natural log of bleeding rates was a linear function of serotonin reuptake inhibition grade (three groups). After adjusting for age, they found a significantly increased risk of 10.7% (95%CI: 4.6–17.2) per one unit of serotonin reuptake inhibition grade. They also found an effect modification by age, the octogenarians presenting the highest risk: 14.7 cases per 1.000 person-years in the high-affinity group versus 10.6 cases per 1,000 person-years in the low-affinity group. This rate difference corresponded to a number needed to treat in one year for having one extra case harmed (NNH) of 244. In a Cox-regression model, adjusting for sex, age, calendar year, diabetes, antecedents of upper gastrointestinal bleeding, and the use of NSAIDs, aspirin, corticoids, anticoagulants and antiulcer drugs, the hazard ratio of upper gastrointestinal bleeding associated with an increase of one unit in the affinity grade was 1.10 (95% CI: 1.02–1.19). This may be translated into a hazard ratio of 1.22 (1.13–1.32) for high affinity as compared to low-affinity. The interaction with NSAIDs was not studied.

Dalton et al. (2003), performed a cohort study linking the prescription and hospital discharge records from the North Jutland County, Denmark. A total of 26,005 patients using an antidepressant over the study period were included (giving a total follow-up of 28,751 for current use and 29,823 for former use). They compared the standardized rates of upper gastrointestinal bleeding obtained per each of the different subcohorts (SSRIs, Non-SSRIs, and others) with the ones from the population not receiving any antidepressant drugs nor any of the drugs thought to cause upper gastrointestinal bleeding. They found a rate ratio (standardized by sex, 5-year age and calendar year) of 3.6 (95%CI: 2.7–4.7) for current users of SSRIs as compared to non-users, with a rate difference of 3.1 per 1,000 person-years (a NNH of 323 per year). Current users of SSRIs and NSAIDs showed an increased risk of 12.2 (95%CI: 7.1–19.5) (excess risk due to interaction=4.9) with a rate difference of 16.3 per 1,000 person-yeras (NNH of 61 per year), giving strong support to the interaction we first described. The increased risk associated with low-dose aspirin plus SSRIs was reported as 5.2 (95%CI: 3.2–8.0). All of the individual agents showed an increased risk, but the results reached statistical significance only for citolopram (relative risk (RR)=4.1; 2.8–5.7), fluoxetine (RR=3.9; 1.2–9.0) and clomipramine (RR=2.3; 1.0–4.3). An increased risk was also found with amitriptiline (RR=2.5; 1.4–4.1).

Tata et al. (2005) performed a nested case-control study using data from a new database called THIN from the UK, similar in a sense to the GPRD database. In the period of 1990–2003 they found 11,261 people with a first diagnostic code of upper gastrointestinal bleeding and randomly selected 53,156 controls from the source population matched by gender, general practice and age with the cases. Unfortunately, it appears that they did not perform an individual case review nor a clinical validation against the paper-based clinical records, which is a standard procedure in pharmacoepidemiology. This may have led to a gross positive misclassification of cases, considering as valid cases patients who present a suggestive episode of bleeding for the general practitioner but is not confirmed later as a true episode (a selection of only those cases referred to a consultant or a hospital may have helped reduce such a potential misclassification). They found a relative risk of upper gastrointestinal bleeding associated with the use of any SSRI of 2.4 (95% CI: 2.1–2.7). The use of any tricyclic antidepressant was also found to be significantly associated with an increased risk (RR=1.9; 1.7–2.1). But in opposition to the data from de Abajo et al. (1999) and Dalton et al. (2003), they were not able to detect any relevant interaction between SSRIs and NSAIDs (the RR of the combination=2.9; 2.3–3.8). Surprisingly, the relative risk associated with NSAIDs alone (RR=2.2, 2.1–2.3) was much lower than the one reported by many other publications (RR around 4) (Hernández-Díaz & García-Rodríguez 2000), perhaps due to the misclassification mentioned before. No data on individual SSRIs were provided.

While preparing the present MiniReview, the study by Wessinger et al. (2005) has only been reported in abstract form. It refers to the preliminary results of a traditional hospital-based case-control study, including 417 cases with “acute gastrointestinal bleeding” and 500 controls. The use of SSRIs was present in 17% of the cases and 12% of the controls, giving an OR of 1.5 (95%CI: 1.02–2.14), very similar to the one found for NSAIDs/COX2 agents (OR=1.4; 95%CI: 0.99–2.06).

Epidemiological studies concerning other bleeding outcomes.

Five epidemiological studies have been published aiming at assessing the risk of bleeding outcome other than upper gastrointestinal bleeding, among the users of SSRIs and other antidepressants (table 7). Three of them, focusing on abnormal bleeding and perioperative blood transfusion, suggested an increased risk, while two others, both in intracranial haemorrhage, did not.

Table 7.  Epidemiological studies performed to assess the association between the use of SSRIs and bleeding disorders other than upper gastrointestinal bleeding.
StudyDesignOutcomeExposedCasesRR (95%CI)
Layton et al. (2001)Cohort (PEM)Abnormal bleeding 50,150486SSRI versus non-psychiatric drugs: 1.38 (0.82–2.34)
Movig et al. (2003)Case-controlPerioperative blood transfusion 59SSRIs versus non-use: 3.7 (1.4–10.2)
Meijer et al. (2004)Nested case-controlAbnormal bleeding 64,647196High versus low affinity: 2.6 (1.4–4.8) High versus intermediate: 1.9 (1.1–3.5)
de Abajo et al. (2000)Nested case-controlIntracranial bleeding247,234 65SSRIs versus non-use: 0.8 (0.3–2.3)
Bak et al. (2002)Nested case-controlIntracranial bleeding659SSRIs versus non-use: 1.0 (0.6–1.6)

Of special interest is the nested case-control study carried out by Meijer et al. (2004), as they managed to show a moderate linear relationship (R2=0.5085) between the affinity of the antidepressant on the serotonin reuptake transporter and the risk of hospitalization for bleeding, reinforcing the mechanistic hypothesis of an impaired platelet aggregation due to a blockade of serotonin reuptake. The odds ratio of being hospitalised for abnormal bleeding was estimated to be 2.6 (95%CI: 1.4–4.8) among the users of high-affinity serotonin antidepressants as compared to users of low-affinity drugs. Users of intermediate-affinity drugs also showed an increased risk (OR=1.9; 95%CI: 1.1–3.5).

Apparently, the lack of association between SSRI use and intracranial haemorrhage observed in two independent studies is not consistent with the hypothesis of an increased bleeding. However, the pathogenic mechanism leading to intracerebral bleeding may well be different from the one leading to gastrointestinal bleeding, and further studies are certainly warranted.

Conclusions and public health implications

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References

The total evidence provided by pharmacological research, clinical reports and epidemiological studies lends support to the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding. Such disorders may have different degrees of severity and may be located anywhere in the body. The epidemiological evidence is, however, more robust for upper gastrointestinal bleeding. It has been estimated that upper gastrointestinal bleeding may occur at a frequency ranging from 1 in 100 to 1 in 1,000 patient-years of exposure to high-affinity drugs (the SSRIs), with the very old patients being in the highest part of the range. The increased risk may be of particular relevance when the SSRIs are associated with NSAIDs, as well as low-dose aspirin. Doctors should be aware of this risk and, in case both antidepressants and NSAIDs are necessary, they should select the NSAID with the lowest gastrointestinal risk profile, at the lowest possible doses. The use of a proton-pump inhibitor should also be considered when the risk of gastrointestinal bleeding is deemed high.

References

  1. Top of page
  2. Abstract
  3. Pharmacology of SSRIs on platelets and the biological plausibility of their association with bleeding
  4. Pharmacovigilance of bleeding disorders
  5. The epidemiological evidence
  6. Conclusions and public health implications
  7. References
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