Skip to main content
SpringerLink
Log in

Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case–Control Analysis Using the Clinical Practice Research Datalink

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship.

Objective

The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders.

Methods

We conducted a retrospective follow-up study with a nested case–control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), ‘other antidepressants’, no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with seizures and matched controls in a nested case–control analysis.

Results

Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67–14.21) in SSRI users, 15.44 (95 % CI 8.99–21.89) in SNRI users, 8.33 (95 % CI 4.68–11.98) in TCA users, 9.33 (95 % CI 6.19–12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49–5.62) in past users of antidepressants. In the case–control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48–2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20–3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63–1.53), compared with non-users.

Conclusion

Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. World Health Organization (WHO). Disease burden. Regional estimates for 2000–2011. 2013. http://www.who.int/healthinfo/global_burden_disease/estimates_regional/en/index1.html. Accessed 18 Mar 2014.

  2. Smith DJ, Nicholl BI, Cullen B, Martin D, Ul-Haq Z, Evans J, et al. Prevalence and characteristics of probable major depression and bipolar disorder within UK biobank: cross-sectional study of 172,751 participants. PLoS One. 2013;8:e75362.

    Article  PubMed  PubMed Central  Google Scholar 

  3. National Institute for Health and Care Excellence (NICE). Depression in adults: recognition and management. NICE guidance CG90. 2009. http://guidance.nice.org.uk/CG90/NICEGuidance/pdf/English. Accessed 24 Mar 2014.

  4. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H-J. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14:334–85.

    Article  PubMed  Google Scholar 

  5. Judge BS, Rentmeester LL. Antidepressant overdose-induced seizures. Psychiatr Clin North Am. 2013;36:245–60.

    Article  PubMed  Google Scholar 

  6. Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf. 2002;25:91–110.

    Article  CAS  PubMed  Google Scholar 

  7. Reichert C, Reichert P, Monnet-Tschudi F, Kupferschmidt H, Ceschi A, Rauber-Lüthy C. Seizures after single-agent overdose with pharmaceutical drugs: analysis of cases reported to a poison center. Clin Toxicol (Phila). 2014;52:629–34.

    Article  CAS  PubMed  Google Scholar 

  8. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62:345–54.

    Article  PubMed  Google Scholar 

  9. Block F, Dafotakis M. Drug-induced seizures [in German]. Fortschr Neurol Psychiatr. 2013;81:28–34.

    CAS  PubMed  Google Scholar 

  10. Steinert T, Baier H, Fröscher W, Jandl M. Epileptic seizures during treatment with antidepressants and neuroleptics [in German]. Fortschr Neurol Psychiatr. 2011;79:138–43.

    Article  CAS  PubMed  Google Scholar 

  11. Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract. 2005;59:1435–40.

    Article  CAS  PubMed  Google Scholar 

  12. Köster M, Grohmann R, Engel RR, Nitsche MA, Rüther E, Degner D. Seizures during antidepressant treatment in psychiatric inpatients—results from the transnational pharmacovigilance project “Arzneimittelsicherheit in der Psychiatrie” (AMSP) 1993–2008. Psychopharmacology (Berl). 2013;230:191–201.

    Article  PubMed  Google Scholar 

  13. Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gartlehner G, Thieda P, Hansen RA, Gaynes BN, Deveaugh-Geiss A, Krebs EE, et al. Comparative risk for harms of second-generation antidepressants: a systematic review and meta-analysis. Drug Saf. 2008;31:851–65.

    Article  CAS  PubMed  Google Scholar 

  15. The Clinical Practice Research Datalink (CPRD). 2014. http://www.cprd.com. Accessed 9 Apr 2014.

  16. Williams T, van Staa T, Puri S, Eaton S. Recent advances in the utility and use of the General Practice Research Database as an example of a UK Primary Care Data resource. Ther Adv Drug Saf. 2012;3:89–99.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Khan NF, Harrison SE, Rose PW. Validity of diagnostic coding within the General Practice Research Database: a systematic review. Br J Gen Pract. 2010;60:e128–36.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol. 2010;69:4–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Reed C, Hong J, Novick D, Lenox-Smith A, Happich M. Health care costs before and after diagnosis of depression in patients with unexplained pain: a retrospective cohort study using the United Kingdom General Practice Research Database. Clinicoecon. Outcomes Res. 2013;5:37–47.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146:891–5.

    PubMed  PubMed Central  Google Scholar 

  21. Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case–control study. BMJ. 2005;330:389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf. 2004;27:203–13.

    Article  CAS  PubMed  Google Scholar 

  23. Jick SS, Jick H, Knauss TA, Dean AD. Antidepressants and convulsions. J Clin Psychopharmacol. 1992;12:241–5.

    Article  CAS  PubMed  Google Scholar 

  24. Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer’s disease or vascular dementia: a population-based nested case–control analysis. Epilepsia. 2013;54:700–7.

    Article  CAS  PubMed  Google Scholar 

  25. Martinez C, Sullivan T, Hauser WA. Prevalence of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res. 2009;87:137–43.

    Article  PubMed  Google Scholar 

  26. Gasse C, Derby L, Vasilakis-Scaramozza C, Jick H. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy. 2000;20:629–34.

    Article  CAS  PubMed  Google Scholar 

  27. Camilo O, Goldstein LB. Seizures and epilepsy after ischemic stroke. Stroke. 2004;35:1769–75.

    Article  PubMed  Google Scholar 

  28. World Health Organization WHO. ATC/DDD Index 2014. 2014. http://www.whocc.no/atc_ddd_index/. Accessed 31 Mar 2014.

  29. Schulz KF, Grimes DA. Case–control studies: research in reverse. Lancet. 2002;359:431–4.

    Article  PubMed  Google Scholar 

  30. Wilden JA, Cohen-Gadol AA. Evaluation of first nonfebrile seizures. Am Fam Physician. 2012;86:334–40.

    PubMed  Google Scholar 

  31. Hesdorffer DC, Hauser WA, Olafsson E, Ludvigsson P, Kjartansson O. Depression and suicide attempt as risk factors for incident unprovoked seizures. Ann Neurol. 2006;59:35–41.

    Article  PubMed  Google Scholar 

  32. Saragoussi D, Chollet J, Bineau S, Chalem Y, Milea D. Antidepressant switching patterns in the treatment of major depressive disorder: a General Practice Research Database (GPRD) study. Int J Clin Pract. 2012;66:1079–87.

    Article  CAS  PubMed  Google Scholar 

  33. Olafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 2005;4:627–34.

    Article  PubMed  Google Scholar 

  34. Kotsopoulos IAW, van Merode T, Kessels FGH, de Krom MCTFM, Knottnerus JA. Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia. 2002;43:1402–9.

    Article  PubMed  Google Scholar 

  35. Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk factor for seizures in older adults. Ann Neurol. 2000;47:246–9.

    Article  CAS  PubMed  Google Scholar 

  36. Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol. 2012;72:184–91.

    Article  PubMed  Google Scholar 

  37. Kanner AM. Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol. 2012;11:1093–102.

    Article  CAS  PubMed  Google Scholar 

  38. Furukawa TA, McGuire H, Barbui C. Low dosage tricyclic antidepressants for depression. Cochrane Database Syst Rev. 2003;(3):CD003197. doi:10.1002/14651858.CD003197

  39. Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ. 2014;348:g254.

    Article  PubMed  Google Scholar 

  40. Cardamone L, Salzberg MR, O’Brien TJ, Jones NC. Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder? Br J Pharmacol. 2013;168:1531–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Salzberg M. Neurobiological links between epilepsy and mood disorders. Neurol Asia. 2011;16(Suppl 1):37–40.

    Google Scholar 

Download references

Acknowledgments

We thank Pascal Egger (Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland) for the programming and technical support.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, Basel Pharmacoepidemiology Unit, University of Basel, Basel, Switzerland

    Marlene Bloechliger, Christoph R. Meier & Michael Bodmer

  2. National Poisons Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland

    Alessandro Ceschi & Hugo Kupferschmidt

  3. Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, Ente Ospedaliero Cantonale Lugano, Lugano, Switzerland

    Alessandro Ceschi

  4. Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland

    Stephan Rüegg

  5. Division of Clinical Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

    Stephan Kraehenbuehl

  6. Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, MA, USA

    Susan S. Jick & Christoph R. Meier

  7. Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, 4031, Basel, Switzerland

    Christoph R. Meier

  8. Medical Department, Zuger Kantonsspital, Zug, Switzerland

    Michael Bodmer

Authors
  1. Marlene Bloechliger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Ceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Rüegg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo Kupferschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephan Kraehenbuehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan S. Jick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph R. Meier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Bodmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph R. Meier.

Ethics declarations

Funding

No sources of funding were used to assist in the preparation of this study.

Conflict of interest

Marlene Bloechliger, Alessandro Ceschi, Stephan Rueegg, Hugo Kupferschmidt, Stephan Kraehenbuehl, Susan S. Jick, Christoph R. Meier, and Michael Bodmer have no conflicts of interest that are directly related to the content of this study.

Authors’ contributions

Study conception and design: Marlene Bloechliger, Alessandro Ceschi, Stephan Rueegg, Hugo Kupferschmidt, Stephan Kraehenbuehl, Susan S. Jick, Christoph R. Meier, and Michael Bodmer. Acquisition of data, guarantors for the study: Susan S. Jick and Christoph R. Meier. Analysis and interpretation of data: Marlene Bloechliger, Christoph R. Meier, Michael Bodmer. Drafting the manuscript: Marlene Bloechliger. Editing the manuscript: Alessandro Ceschi, Stephan Rueegg, Hugo Kupferschmidt, Stephan Kraehenbuehl, Susan S. Jick, Christoph R. Meier, and Michael Bodmer.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 385 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bloechliger, M., Ceschi, A., Rüegg, S. et al. Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case–Control Analysis Using the Clinical Practice Research Datalink. Drug Saf 39, 307–321 (2016). https://doi.org/10.1007/s40264-015-0363-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-015-0363-z

Keywords

Search

Navigation