title: Association between haemorrhages and treatment with selective and non-selective serotonergic antidepressants: Possible implications of quantitative signal detection.
abstract: Inhibition of serotonin uptake in platelets seems to be the crucial mechanism underlying SSRI-associated haemorrhages. This effect is also present in antidepressants featuring non-selective serotonin reuptake inhibition (non-SSRI). Impact of selectivity of serotonin reuptake and/or affinity to the serotonin reuptake transporter on the bleeding risk have not yet been studied sufficiently. We retrieved country- and SSRI-/non-SSRI-specific data from the Uppsala Monitoring Centre and used a case/non-case approach to calculate substance-specific reporting odds ratios (ROR) to evaluate the statistical association of treatment with SSRI/non-SSRI and haemorrhages. Country-specific analysis revealed no clear trends towards an increased risk of bleeding related to particular agents of group SSRI/non-SSRI (sporadically ROR>1 for citalopram, duloxetine, escitalopram, fluvoxamine, paroxetine, sertraline, St. John's wort). There was a clear trend in the total dataset towards a "reduced protective effect" (suggested by ROR<1) on the development of haemorrhages with agents featuring comparatively high affinity to the 5-HTT and/or selective serotonin reuptake inhibition (as with escitalopram, citalopram, duloxetine or venlafaxine) in comparison to agents with lower affinity or non-selective serotonin reuptake inhibition (as with mirtazapine or doxepin). Comparison of group-specific aggregated data (SSRI vs. non-SSRI) revealed significant differences regarding the "protective effect" on the development of haemorrhages between groups SSRI vs. non-SSRI in favour of non-SSRI in nearly all countries as well as in the total dataset. Our findings provide preliminary evidence that agents with increased affinity to the 5-HTT and/or selective serotonin reuptake inhibition may be associated with an increased risk of bleeding.
authors.affiliation: University of Ulm, Department of Psychiatry and Psychotherapy III, Leimgrubenweg 12-14, 89075 Ulm, Germany. Electronic address: maximilian.gahr@uni-ulm.de.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Gahr
authors.affiliation: University of Ulm, Department of Psychiatry and Psychotherapy III, Leimgrubenweg 12-14, 89075 Ulm, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Zeiss
authors.affiliation: University of Ulm, Department of Psychosomatic Medicine and Psychotherapy, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lang
authors.affiliation: University of Ulm, Department of Psychiatry and Psychotherapy III, Leimgrubenweg 12-14, 89075 Ulm, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Connemann
authors.affiliation: University Medical Center of Mainz, Department of Psychiatry and Psychotherapy, Untere Zahlbacherstr. 8, 55131 Mainz, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.affiliation: University of Ulm, Institute of Epidemiology and Medical Biometry, Medical Faculty, Schwabstr. 13, 89075 Ulm, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Muche
authors.affiliation: University of Ulm, Department of Psychiatry and Psychotherapy III, Leimgrubenweg 12-14, 89075 Ulm, Germany.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Freudenmann
authors.affiliation: University of Ulm, Department of Psychiatry and Psychotherapy III, Leimgrubenweg 12-14, 89075 Ulm, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Schönfeldt-Lecuona
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D057225:Data Mining; D003866:Depressive Disorder / Q000188:drug therapy*; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D016017:Odds Ratio; D065840:Protective Factors; D012307:Risk Factors; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Depression; Haemorrhages; Pharmacovigilance; Reporting odds ratio; Signal detection