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Epilepsy Comorbidities: How Can Animal Models Help?

  • Carl E. Stafstrom
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 813)

Abstract

An epilepsy comorbidity is a condition or disorder that occurs at a frequency greater than chance in a person with epilepsy. Examples of common epilepsy comorbidities are depression, anxiety, and intellectual disability. Epilepsy comorbidities can be quite disabling, sometimes affecting a patient’s quality of life to a greater extent than seizures. Animal models offer the opportunity to explore shared pathophysiological mechanisms, therapeutic options, and consequences of both the epilepsy syndrome and a given comorbidity. In this chapter, depression is used as an example of how animal models can inform translational questions about epilepsy comorbidities.

Keywords

Epilepsy Comorbidity Depression Animal models 

References

  1. 1.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, ArlingtonGoogle Scholar
  2. 2.
    Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang F, Phadke A, Mission J, Agarwal RK, Englot DJ, Motelow J, Nerseyan H, Waxman SG, Levin AR (2008) Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49:400–409PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Brooks-Kayal AR, Bath KG, Berg AT, Galanopoulou AS, Holmes GL, Jensen FE, Kanner AM, O’Brien TJ, Whittemore VH, Winawer MR, Patel M, Scharfman HE (2013) Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54(Suppl 4):44–60PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34:865–877PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    England MJ, Liverman CT, Schultz AM, Strawbridge LM (2012) Epilepsy across the spectrum: promoting health and understanding. Institute of Medicine (US) Committee on the Public Health Dimensions of the Epilepsies. National Academies Press, Washington, DCGoogle Scholar
  6. 6.
    Epps SA, Kahn AB, Holmes PV, Boss-Williams KA, Weiss JM, Weinshenker D (2013) Antidepressant and anticonvulsant effects of exercise in a rat model of epilepsy and depression comorbidity. Epilepsy Behav 29:47–52PubMedCrossRefGoogle Scholar
  7. 7.
    Epps SA, Tabb KD, Lin SJ, Kahn AB, Javors MA, Boss-Williams KA, Weiss JM, Weinshenker D (2012) Seizure susceptibility and epileptogenesis in a rat model of epilepsy and depression co-morbidity. Neuropsychopharmacology 37:2756–2763PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Epps SA, Weinshenker D (2013) Rhythm and blues: animal models of epilepsy and depression comorbidity. Biochem Pharmacol 85:135–146PubMedCrossRefGoogle Scholar
  9. 9.
    Ettinger AB, Weisbrot DM, Nolan EE, Gadow KD, Vitale SA, Andriola MR, Lenn NJ, Novak GP, Hermann BP (1998) Symptoms of depression and anxiety in pediatric epilepsy patients. Epilepsia 39:595–599PubMedCrossRefGoogle Scholar
  10. 10.
    Gaitatzis AS, Sisodiya SM, Sander JW (2012) The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 53:1282–1293PubMedCrossRefGoogle Scholar
  11. 11.
    Gilliam F, Hecimovic H, Sheline Y (2003) Psychiatric comorbidity, health, and function in epilepsy. Epilepsy Behav 4(Suppl 4):S26–S30PubMedCrossRefGoogle Scholar
  12. 12.
    Gilliam FG, Maton BM, Martin RC, Sawrie SM, Faught RE, Hugg JW, Viikinsalo M, Kuzniecky RI (2007) Hippocampal 1H-MRSI correlates with severity of depression symptoms in temporal lobe epilepsy. Neurology 68:364–368PubMedCrossRefGoogle Scholar
  13. 13.
    Hamid H, Liu H, Cong X, Devinsky O, Berg AT, Vickery BG et al (2011) Long-term association between seizure outcome and depression after resective epilepsy surgery. Neurology 77:1972–1976PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hamiwka LD, Wirrell EC (2009) Comorbidities in pediatric epilepsy: beyond “just” treating the seizures. J Child Neurol 24:734–742PubMedCrossRefGoogle Scholar
  15. 15.
    Hesdorffer DC, Hauser WA, Olafsson E, Ludvigsson P, Kjartansson O (2006) Depression and suicide attempt as risk factors for incident unprovoked seizures. Ann Neurol 59:35–41PubMedCrossRefGoogle Scholar
  16. 16.
    Igelström KM (2012) Preclinical antiepileptic actions of selective serotonin reuptake inhibitors – implications for clinical trial design. Epilepsia 53:596–605PubMedCrossRefGoogle Scholar
  17. 17.
    Jobe PC (2003) Common pathogenic mechanisms between depression and epilepsy: an experimental perspective. Epilepsy Behav 4(Suppl 3):S14–S24PubMedCrossRefGoogle Scholar
  18. 18.
    Jones NC, O’Brien TJ (2013) Stress, epilepsy, and psychiatric comorbidity: how can animal models inform the clinic? Epilepsy Behav 26:363–369PubMedCrossRefGoogle Scholar
  19. 19.
    Jones NC, Salzberg MR, Kumar G, Couper A, Morris MJ, O’Brien TJ (2008) Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation. Exp Neurol 209:254–260PubMedCrossRefGoogle Scholar
  20. 20.
    Kanner AM (2006) Depression and epilepsy: a new perspective on two closely related disorders. Epilepsy Curr 6:141–146PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Kanner AM (2012) Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol 11:1093–1102PubMedCrossRefGoogle Scholar
  22. 22.
    Kanner AM (2013) The treatment of depressive disorders in epilepsy: what all neurologists should know. Epilepsia 54(Suppl 1):3–12PubMedCrossRefGoogle Scholar
  23. 23.
    Kelley MS, Jacobs MP, Lowenstein DH (2009) The NINDS epilepsy research benchmarks. Epilepsia 50:579–582PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Koh SR, Magid R, Chung H, Stine CD, Wilson DN (2007) Depressive behavior and selective downregulation of serotonin receptor expression after early-life seizures: reversal by environmental enrichment. Epilepsy Behav 10:26–31PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Kondziella D, Alvestad S, Vaaler A, Sonnewald U (2007) Which clinical and experimental data link temporal lobe epilepsy with depression? J Neurochem 103:2136–2152PubMedCrossRefGoogle Scholar
  26. 26.
    Lin JJ, Mula M, Hermann BP (2012) Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 380:1180–1192PubMedCrossRefGoogle Scholar
  27. 27.
    Lutz P-E (2013) Multiple serotonergic paths to antidepressant efficacy. J Neurophysiol 109:2245–2249PubMedCrossRefGoogle Scholar
  28. 28.
    Machado-Vieira R, Salvadore G, Diaz Granados N, Ibrahim L, Latov D, Wheeler-Castillo C, Baumann J, Henter ID, Zarate CA Jr (2010) New therapeutic targets for mood disorders. ScientificWorldJournal 10:713–726PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Mazarati A, Siddarth P, Baldwin RA, Shin D, Caplan R, Sankar R (2008) Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 131(Pt 8):2071–2083PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Mazarati AM, Pineda E, Shin D, Tio D, Taylor AN, Sankar R (2010) Comorbidity between epilepsy and depression: role of hippocampal interleukin-1beta. Neurobiol Dis 37:461–467PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Mazarati AM, Shin D, Kwon YS, Bragin A, Pineda E, Tio D, Taylor AN, Sankar R (2009) Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy. Neurobiol Dis 34:457–461PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    McCaughey SA (2008) The taste of sugars. Neurosci Biobehav Rev 32:1024–1043PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Möhler H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62:42–53PubMedCrossRefGoogle Scholar
  34. 34.
    Mula M (2013) Treatment of anxiety disorders in epilepsy: an evidence-based approach. Epilepsia 54(Suppl 1):13–18PubMedCrossRefGoogle Scholar
  35. 35.
    Piedad J, Rickards H, Besag FM, Cavanna AE (2012) Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations. CNS Drugs 26:319–335PubMedCrossRefGoogle Scholar
  36. 36.
    Pineda E, Shin D, Sankar R, Mazarati AM (2010) Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms. Epilepsia 51(Suppl 3):110–114PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Russ SA, Larson K, Halfon N (2012) A national profile of childhood epilepsy and seizure disorder. Pediatrics 129:256–264PubMedCrossRefGoogle Scholar
  38. 38.
    Russo E, Citraro R, Donato G, Camastra C, Iuliano R, Cuzzocrea S, Constanti A, De Sarro G (2013) mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology 69:25–36PubMedCrossRefGoogle Scholar
  39. 39.
    Salamone JD, Correa M (2012) The mysterious motivational functions of mesolimbic dopamine. Neuron 76:470–485PubMedCrossRefGoogle Scholar
  40. 40.
    Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62:63–77PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Sarkisova K, van Luijtelaar G (2011) The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog Neuro-psychopharmacol Biol Psychiatry 35:854–876CrossRefGoogle Scholar
  42. 42.
    Sarkisova KY, Kulikov MA, Midzianovskaia IS, Folomkina AA (2008) Dopamine-dependent nature of depression-like behavior in WAG/Rij rats with genetic absence epilepsy. Neurosci Behav Physiol 38:119–128PubMedCrossRefGoogle Scholar
  43. 43.
    Sarkisova KY, Kuznetsova GD, Kulikov MA, van Luijtelaar G (2010) Spike-wave discharges are necessary for the expression of behavioral depression-like symptoms. Epilepsia 51:146–160PubMedCrossRefGoogle Scholar
  44. 44.
    Sarkisova KY, Midzianovskaia IS, Kulikov MA (2003) Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res 144:211–226PubMedCrossRefGoogle Scholar
  45. 45.
    Stafstrom CE (2006) Behavioral and cognitive testing procedures in animal models of epilepsy. In: Pitkänen A, Schwartzkroin PA, Moshé SL (eds) Models of seizures and epilepsy. Elsevier Academic Press, Amsterdam, pp 613–628Google Scholar
  46. 46.
    Tabb K, Boss-Williams KA, Weiss JM, Weinshenker D (2007) Rats bred for susceptibility to depression-like phenotypes have higher kainic acid-induced seizure mortality than their depression-resistant counterparts. Epilepsy Res 74:140–146PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S (2007) Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 48:2336–2344PubMedGoogle Scholar
  48. 48.
    van Luijtelaar G, Mishra AM, Edelbroek P, Coman D, Frankenmolen N, Schaapsmeerders P, Covolato G, Danielson N, Niermann H, Janeczko K, Kiemeneij A, Burinov J, Bashyal C, Coquillette M, Lüttjohann A, Hyder F, Blumenfeld H, van Rijn CM (2013) Anti-epileptogenesis: electrophysiology, diffusion tensor imaging and behavior in a genetic absence model. Neurobiol Dis 60:126–138PubMedCrossRefGoogle Scholar
  49. 49.
    Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuro-pharmacology 69:16–24Google Scholar
  50. 50.
    West CH, Weiss JM (1998) Effects of antidepressant drugs on rats bred for low activity in the swim test. Pharmacol Biochem Behav 61:67–79PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Departments of Neurology and PediatricsUniversity of WisconsinMadisonUSA

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