Background: Antidepressants, in particular selective serotonin reuptake inhibitors, have been associated with antithrombotic and neuroprotective properties and their more widespread use has been suggested in stroke recovery. However, data are sparse on their effects on the clinical outcome, including mortality, associated with early antidepressant treatment after stroke. We aimed to study all-cause 30-day mortality related to early antidepressant treatment in patients with ischemic stroke. Methods: We did a population-based follow-up study identifying patients from the Danish Stroke Registry admitted in the former Aarhus County from 2003 to 2010. During this time, initiation of antidepressant treatment during admission was registered in the Danish Stoke Registry. The registry also holds clinical information including stroke type, stroke severity and quality of in-hospital stroke care. Information on vital status and covariates including comorbidities and co-medication was obtained from the following population-based medical registries: the Danish Civil Registration System, Danish Medicines Agency's Medical Register and The Danish National Patients Registry. Information was linked using the unique civil registration number assigned to all Danish residents. Multivariable logistic regression was used to compute the adjusted odds ratio (OR) of 30-day mortality in patients treated with antidepressants during admission as compared to patients not treated. In addition, we did stratified analyses on sex, age, stroke severity and propensity score-matched analyses as well as multiple imputation. Results: Among 5,070 consecutive first-ever stroke patients without prior antidepressant treatment, 955 (18.8%) started antidepressant treatment during admission with a median time from admission until treatment of 5 days (interquartile range 2-11). The proportion of patients with severe stroke was higher among treated patients as compared to that among non-treated patients. The adjusted OR of 30-day mortality was 0.28 (95% confidence interval (CI) 0.18-0.43) for patients treated during admission as compared to patients not treated during admission. Stratification by stroke severity showed signs of effect modification, stratification by sex and age did not. Included in the propensity score-matched analyses were 1,908 patients matched 1:1. The propensity score-matched adjusted OR of death within 30 days was 0.31 (95% CI 0.19-0.49). Conclusion: Although early antidepressant treatment was more often started in patients with severe stroke, treatment was associated with significantly lower mortality. This result requires replication in randomized trials; however, it indicates that early start of antidepressant treatment after stroke may be safe and a more routine use may be feasible.

Keywords:
Antidepressants, Selective serotonin reuptake inhibitors, Stroke, Mortality
1.
Ayerbe L, Ayis S, Wolfe CD, Rudd AG: Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry 2013;202:14-21.
2.
Bartoli F, Lillia N, Lax A, Crocamo C, Mantero V, Carrà G, Agostoni E, Clerici M: Depression after stroke and risk of mortality: a systematic review and meta-analysis. Stroke Res Treat 2013;2013:862978.
3.
Ahmed A, Simmons Z: Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag 2013;9:483-489.
4.
Hackett ML, Yang M, Anderson CS, Horrocks JA, House A: Pharmaceutical interventions for emotionalism after stroke. Cochrane Database Syst Rev 2010;2:CD003690.
5.
Hackett ML, Anderson CS, House A, Halteh C: Interventions for preventing depression after stroke. Cochrane Database Syst Rev 2008;3:CD003689.
6.
Andersen G, Vestergaard K, Lauritzen L: Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994;25:1099-1104.
7.
Andersen G, Vestergaard K, Riis JO: Citalopram for post-stroke pathological crying. Lancet 1993;342:837-839.
8.
Mortensen JK, Larsson H, Johnsen SP, Andersen G: Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score-matched follow-up study. Stroke 2013;44:420-426.
9.
Jorge RE, Robinson RG, Arndt S, Starkstein S: Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry 2003;160:1823-1829.
10.
Ried LD, Jia H, Feng H, Cameon R, Wang X, Tueth M, Wu SS: Selective serotonin reuptake inhibitor treatment and depression are associated with poststroke mortality. Ann Pharmacother 2011;45:888-897.
11.
Ayerbe L, Ayis S, Crichton SL, Rudd AG, Wolfe CD: Explanatory factors for the increased mortality of stroke patients withdepression. Neurology 2014;83:2007-2012.
12.
Mortensen JK, Larsson H, Johnsen SP, Andersen G: Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score-matched follow-up study. Stroke 2013;44:420-426.
13.
Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, Bejot Y, Deltour S, Jaillard A, Niclot P, Guillon B, Moulin T, Marque P, Pariente J, Arnaud C, Loubinoux I: Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 2011;10:123-130.
14.
Mead GE, Hsieh CF, Lee R, Kutlubaev M, Claxton A, Hankey GJ, Hackett M: Selective serotonin reuptake inhibitors for stroke recovery: a systematic review and meta-analysis. Stroke 2013;44:844-850.
15.
Mortensen JK, Larsson H, Johnsen SP, Andersen G: Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality. Stroke 2014;45:2121-2123.
16.
Mainz J, Krog BR, Bjørnshave B, Bartels P: Nationwide continuous quality improvement using clinical indicators: the Danish National Indicator Project. Int J Qual Health Care 2004;16(suppl 1):i45-i50.
17.
Pedersen CB, Gøtzsche H, Møller JO, Mortensen PB: The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 2006;53:441-449.
18.
Kildemoes HW, Sørensen HT, Hallas J: The Danish National Prescription Registry. Scand J Public Health 2011;39(7 suppl):38-41.
19.
Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH: The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46:263-268.
20.
Langagergaard V, Palnum KH, Mehnert F, Ingeman A, Krogh BR, Bartels P, Johnsen SP: Socioeconomic differences in quality of care and clinical outcome after stroke: a nationwide population-based study. Stroke 2011;42:2896-2902.
21.
Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-383.
22.
Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T: Variable selection for propensity score models. Am J Epidemiol 2006;163:1149-1156.
23.
Austin PC: Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 2011;10:150-161.
24.
Austin PC: Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thorac Cardiovasc Surg 2007;134:1128-1135.
25.
Lim CM, Kim SW, Park JY, Kim C, Yoon SH, Lee JK: Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. J Neurosci Res 2009;87:1037-1045.
26.
Ostergaard L, Jespersen SN, Mouridsen K, Mikkelsen IK, Jonsdottír KÝ, Tietze A, Blicher JU, Aamand R, Hjort N, Iversen NK, Cai C, Hougaard KD, Simonsen CZ, Von Weitzel-Mudersbach P, Modrau B, Nagenthiraja K, Riisgaard Ribe L, Hansen MB, Bekke SL, Dahlman MG, Puig J, Pedraza S, Serena J, Cho TH, Siemonsen S, Thomalla G, Fiehler J, Nighoghossian N, Andersen G: The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model. J Cereb Blood Flow Metab 2013;33:635-648.
27.
Maurer-Spurej E, Pittendreigh C, Solomons K: The influence of selective serotonin reuptake inhibitors on human platelet serotonin. Thromb Haemost 2004;91:119-128.
28.
Hackett ML, Anderson CS: Predictors of depression after stroke: a systematic review of observational studies. Stroke 2005;36:2296-2301.
29.
Mead GE, Dennis M, Lundström E, Murray V, Hackett M, Hankey GJ: Letter by Mead et al regarding article, ‘selective serotonin reuptake inhibitors for stroke: more trials are needed'. Stroke 2013;44:e40-e41.
30.
Kraglund KL, Mortensen JK, Grove EL, Johnsen SP, Andersen G: TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke. Int J Stroke 2015, Epub ahead of print.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.