Skip to main content
SpringerLink
Log in

Are Antiepileptic Drugs Used in the Treatment of Migraine Associated with an Increased Risk of Suicidality?

Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Three antiepileptic drugs (AEDs), valproic acid, gabapentin, and topiramate (TPM), are used frequently in the prophylactic treatment of migraines. In December 2008, the US Food and Drug Administration issued a warning suggesting that the use of all AEDs is associated with an increased risk of suicidal ideation and behavior. This warning has been received by the medical community with great skepticism, and the validity of the findings of the meta-analysis that led to its publication has been questioned because of various methodological problems. Yet, migraine by itself is associated with an increased risk of suicidal ideation and behavior as well as with an increased risk of psychiatric disorders that facilitate the development of suicidal behavior. Furthermore, TPM has been associated with psychiatric adverse events that potentially could result in suicidal ideation and behavior. In this article, we review data to determine whether the AEDs used in the prevention of migraine are associated with an increased risk of suicidality.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Jette N, Patten S, Williams J, et al. Comorbidity of migraine and psychiatric disorders--a national population-based study. Headache. 2008;48:501–516. This is an important reference that illustrates the high prevalence of psychiatric comorbidities in the general population of patients who suffer from migraine.

    Article  PubMed  Google Scholar 

  2. Breslau N, Lipton RB, Stewart WF, et al. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology. 2003;60:1308–12.

    PubMed  CAS  Google Scholar 

  3. • Rogawski MA. Common pathophysiologic mechanisms in migraine and epilepsy. Arch Neurol. 2008;65:709–14. This review paper provides a comprehensive review of the pathogenic mechanisms operant in migraine and epilepsy and explain the rationale for the use of antiepileptic drugs in the prophylactic treatment of migraines.

    Article  PubMed  Google Scholar 

  4. Brandes JL, Saper JR, Diamond M, et al. MIGR-002 Study Group. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;25(291):965–73.

    Article  Google Scholar 

  5. Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:19–128.

    Google Scholar 

  6. Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58:1652–9.

    PubMed  CAS  Google Scholar 

  7. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Translational Sciences, Office of Biostatistics (2008). Statistical review and evaluation: Antiepileptic drugs and suicidality. May 21, 2008.

  8. Kessler RD, Borges G, Walters EE. Prevalence of and risk factors for lifetime suicide attempts in the National Comorbidity Survey. Arch Gen Psychiatry. 1999;56:617–26.

    Article  PubMed  CAS  Google Scholar 

  9. Saaman Z, Farmer A, Craddock N, et al. Migraine in recurrent depression: case-control study. Br J Psychiatry. 2009;194:350–4.

    Article  Google Scholar 

  10. Fasmer OB. The prevalence of migraine in patients with bipolar and unipolar affective disorders. Cephalalgia. 2001;21:894–5.

    Article  PubMed  CAS  Google Scholar 

  11. Breslau N, Schultz LR, Stewart WF, et al. Headache types and panic disorder: directionality and specificity. Neurology. 2001;56:350–4.

    PubMed  CAS  Google Scholar 

  12. Breslau N, Lipton RB, Stewart WF, et al. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology. 2003;60:1308–12.

    PubMed  CAS  Google Scholar 

  13. Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatry Res. 1991;37:11–23.

    Article  PubMed  CAS  Google Scholar 

  14. Wang SJ, Juang KD, Fuh JL, et al. Psychiatric comorbidity and suicide risk in adolescents with chronic daily headache. Neurology. 2007;68:1468–73.

    Article  PubMed  Google Scholar 

  15. •• Demarquay G, Lothe A, Royet JP, Costes N, Mick G, Mauguière F, Ryvlin P. Brainstem changes in 5-HT1A receptor availability during migraine attack. Cephalalgia. 2011;31:84–94. This is a state-of-the-art study that demonstrates the pathogenic role of serotonin in migraine.

    Article  PubMed  CAS  Google Scholar 

  16. Ferrari MD. Sumatriptan in the treatment of migraine. Neurology. 1993;43(6 Suppl 3):S43–7.

    PubMed  CAS  Google Scholar 

  17. Sargent PA, Kjaer KH, Bench CJ, et al. Brain serotonin 1A receptor binding measured by positron emission tomography with [11 C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57:174–80.

    Article  PubMed  CAS  Google Scholar 

  18. Drevets WC, Frank E, Price JC, et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry. 1999;46:1375–87.

    Article  PubMed  CAS  Google Scholar 

  19. Neumeister A, Bain E, Nugent AC, et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. 2004;24:589–91.

    Article  PubMed  CAS  Google Scholar 

  20. Asberg M, Bertilsson L, Martensson B. Indolamine metabolites, depression and suicide. Adv Biochem Psychopharmacol. 1984;39:87–97.

    PubMed  CAS  Google Scholar 

  21. Lester D. The concentrations of neurotransmitter metabolites in the cerebrospinal fluid of suicidal individuals: a meta-analysis. Pharmacopsychiatry. 1995;28:45–50.

    Article  PubMed  CAS  Google Scholar 

  22. Oquendo MA, Placidi GP, Malone KM, et al. Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression. Arch Gen Psychiatry. 2003;60:14–22.

    Article  PubMed  Google Scholar 

  23. Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688:121–33.

    Article  PubMed  CAS  Google Scholar 

  24. Arango V, Huang YY, Underwood MD, Mann JJ. Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res. 2003;37(5):375–86.

    Article  PubMed  Google Scholar 

  25. Sareen J, Cox BJ, Afifi TO, et al. Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. Arch Gen Psychiatry. 2005;62:1249–57.

    Article  PubMed  Google Scholar 

  26. Brent DA, Crumrine PK, Varma RR, Allan M, Allman C. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics. 1987;80:909–17.

    PubMed  CAS  Google Scholar 

  27. Trimble RM, Rϋsch N, Betts T, Crawford PM. Psychiatric symptoms after therapy with new antiepileptic drugs: Psychopathological and seizure related variables. Seizure. 2000;9:249–54.

    Article  PubMed  CAS  Google Scholar 

  28. Mula M, Trimble MR, Lhatoo SD, Sander JW. Topiramate and psychiatric adverse events in patients with epilepsy. Epilepsia. 2003;44:659–63.

    Article  PubMed  Google Scholar 

  29. Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy. Epilepsia. 2007;61:704–6.

    Google Scholar 

  30. Mula M, Sander JW. Suicidal ideation in epilepsy and levetiracetam therapy. Epilepsy Behav. 2007;11:130–2.

    Article  PubMed  Google Scholar 

  31. Redden L, Pritchett Y, Robieson W, Kovacs X, Garofalo M, Tracy K, et al. Suicidality and divalproex sodium: analysis of controlled studies in multiple indications. Ann Gen Psychiatry. 2011;18;10:1.

    Article  Google Scholar 

  32. Gibbons RD, Hur K, Brown CH, Mann JJ. Gabapentin and suicide attempts. Pharmacoepidemiol Drug Saf. 2010;19:1241–7.

    Article  PubMed  CAS  Google Scholar 

  33. • Hesdorffer DC and Kanner AM. The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm? Epilepsia. 2009;50:978–86. This article provides a critical assessment of the FDA meta-analysis and points out methodological problems that question the conclusion that all AEDs can increase the risk of suicidality.

    Article  PubMed  Google Scholar 

  34. GlaxoSmithKline (2006) Briefing Document: Paroxetine Adult Suicidality Analysis: Major Depressive Disorder and non-Major Depressive Disorder. Available at: (http://www.gsk.com/media/par_current_analysis.htm) [Accessed April 5, 2006].

  35. Dr. Katz memo and briefing document to PCNS and PD Advisory Committees (2008) Briefing document for the July 10, 2008 Advisory Committees to discuss antiepileptic drugs (AEDs) and suicidality. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA-Katz.pdf.

  36. Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data. Biometrics. 1985;41:55–68.

    Article  PubMed  CAS  Google Scholar 

  37. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2005;64:172–4.

    Google Scholar 

  38. Gibbons RD, Jur K, Brown CH, Mann JJ. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry. 2009;66:1354–60.

    Article  PubMed  CAS  Google Scholar 

  39. Olesen JB, Hansen PR, Erdal J, et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf. 2010;19:518–24.

    PubMed  Google Scholar 

  40. Patorno E, Bohn RL, Wahl PM, Avorn J, Patrick AR, Liu J, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA. 2010;303:1401–9.

    Article  PubMed  CAS  Google Scholar 

  41. VanCott AC, Cramer JA, Copeland LA, Zeber JE, Steinman MA, Dersh JJ, et al. Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VS hospital system. BMC Med. 2010;8:4.

    Article  PubMed  Google Scholar 

  42. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med. 2010;363:542–51.

    Article  PubMed  CAS  Google Scholar 

  43. Hesdorffer DC, Berg AT, Kanner AM. An update on antiepileptic drugs and suicide: are there definitive answers yet? Epilepsy Curr. 2010;10:137–45.

    Article  PubMed  Google Scholar 

  44. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.

    Article  PubMed  CAS  Google Scholar 

  45. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77–100.

    Article  Google Scholar 

  46. Beck AT, Brown G, Epstein N, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893–7.

    Article  PubMed  CAS  Google Scholar 

  47. Sheehan BV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini International Neuropsychiatric Interview (MINI): the development and validation of structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22–33.

    PubMed  Google Scholar 

Download references

Disclosures

Dr. Andreas Kanner has served as a consultant for Pfizer, Lundberg Laboratories, and GlaxoSmithKline; has received grants or has grants pending with Pfizer, GlaxoSmithKline, and Novartis; has received payment for the development of educational presentations for Pfizer and GlaxoSmithKline; and has received travel expense compensation from Pfizer, Lundberg Laboratories, and GlaxoSmithKline.

Author information

Authors and Affiliations

  1. Department of Neurological Sciences, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL, 60612, USA

    Andres M. Kanner

Authors
  1. Andres M. Kanner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andres M. Kanner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kanner, A.M. Are Antiepileptic Drugs Used in the Treatment of Migraine Associated with an Increased Risk of Suicidality?. Curr Pain Headache Rep 15, 164–169 (2011). https://doi.org/10.1007/s11916-011-0199-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-011-0199-x

Keywords

search

Navigation