Depression is a serious mental health threat proclaimed to be the greatest disease burden in the industrialised world by 2020 (Simon, 2003). In the pharmaceutical combat against depression, selective serotonin reuptake inhibitors (SSRIs) are the current treatment of choice. Indeed, SSRIs are the most prescribed antidepressant medicine (Helms & Eric, 2006). As the name suggests, they increase brain serotonin by blocking its reuptake from the synaptic cleft.

Beside concerns about low efficacy and untoward side effects, there is some evidence linking SSRIs to increased occurrences of internal bleeding (Lee et al., 2012). This new meta-analysis by Hackam and Mrkobrada (2012) reviewed data on the association of SSRIs and brain haemorrhages and tried to come to a more definite conclusion.

Methods

The authors scanned diverse medical databases for controlled epidemiologic studies that estimated bleedings risk ratios of SSRI exposure compared to control conditions. Furthermore, cumulative haemorrhage risk for SSRI and oral anticoagulants vs. anticoagulants alone were calculated.

Data aggregation was limited to prospective and retrospective cohort studies, case-crossover studies and case-control designs.

Four types of hemorrhages were assessed:

1. Any intracranial haemorrhage
2. Haemorrhagic stroke (combination of 3 and 4)
3. Intracerebral haemorrhage alone
4. Subarachnoid hemorrhage alone

In total, 16 studies with 506,441 participants met the inclusion criteria. Covariates and other possible confounders in the primary studies were reported and no publication bias was found.

Results

Fixed effect rate ratios with 95% confidence intervals were reported. As three studies merely contained unadjusted rate ratios, the listed results below will be restricted to these.

Haemorrhages and SSRIs

• Intracranial haemorrhage was associated with SSRI usage (RR 1.48, CI 1.22 – 1.78)
• Haemorrhagic stroke and SSRI usage approached significance (RR 1.17, CI 0.97 – 1.41, p=0.108)
• Strong association between intracerebral haemorrhage and SSRIs (RR 1.68, CI 1.46 – 1.91)
• Subarachnoid haemorrhages were not significantly linked with SSRIs (RR 1.02, CI 0.77 – 1.34)
• Six out of seven studies mentioning length of treatment reported greater risk in short-term than long-term treatment

Haemorrhages and anticoagulant medication

• 5 substudies assessed the link between anticoagulant medication and haemorrhages (3 studies on intracranial haemorrhage, 1 on haemorrhagic stroke and intracerebral haemorrhage, respectively)
• SSRIs in combination with oral anticoagulants were associated with significantly higher risk of haemorrhage than anticoagulants alone (RR 1.56, CI 1.33 – 1.83)

Conclusion

Hackam and Mrkobrada conclude:

SSRI exposure is associated with an increased risk of brain hemorrhage (largely due to intracerebral bleeding). Given an estimated global incidence of 24.6 per 100,000 person-years, 1 additional intracerebral bleeding episode per 10,000 persons treated for 1 year could be expected.

Therefore, practitioners are advised to:

Consider alternate classes of antidepressants in patients with intrinsic risk factors for intracerebral haemorrhage.

Limitations

The reviewed studies show great variation in terms of sample sizes. Because data are pooled, this could lead to over-/underrepresentation and statistical effect skewing. For instance, more than half of all data on intracerebral haemorrhages was provided by one study.

What is more, definition of relevant comorbidities (e.g. hypertension) varied somewhat among primary studies, making comparison difficult. Unfortunately, Hackam and Mrkobrada fail to underline each result with its respective p value. Of course, 5% significance level is implicitly assumed, but p values would have been helpful for a more complete overview.

Also, assessment of primary study quality is lacking. This is especially disadvantageous, as the meta-analysis aggregates observational (i.e. non-randomized and non-blinded) studies without effective placebo control.

Summary

Even though there are some inconsistencies among primary studies, this meta-analysis hints at increased risks of cerebral bleeding under SSRI regimen. Further controlled research is necessary to draw more definite conclusions. Because the incidence of cerebral bleeding is (fortunately) very low in the first place (24.6/100,000), SSRIs might exacerbate risk ratios, while absolute increases remain minimal.

Keeping this and the unparalleled safety profile of SSRIs among antidepressants in mind, changing antidepressants in vulnerable populations should be based on careful individual cost-benefit analyses that share decision-making between doctors and patients.

Links

Hackam DG and Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology, 2012; 79(18), 1862-1865. [Abstract]

Helms RA and Eric T. Textbook of therapeutics: drug and disease management (8^th Edition), 2006. Philadelphia, PA: Lippincott Williams & Wilkins.

Lee YC, Shau WY, Chang CH, Lin MS, and Lai MS. Antidepressant use and the risk of upper gastrointestinal bleeding in psychiatric patients: a nationwide cohort study in Taiwan. Journal of Clinical Psychopharmacology 2012; 32(4), 518-524. [PubMed abstract]

Simon GE. Social and economic burden of mood disorders. Biological Psychiatry 2003; 54(3), 208-215. [PubMed abstract]