CNS Drugs

, Volume 16, Issue 5, pp 291–302

Mood Disorders in Patients with Epilepsy

Epidemiology and Management
Therapy In Practice


Patients with epilepsy are at high risk for depression because of an incompletely understood combination of factors that may be both psychosocial and neurological. Interictal depression in patients with epilepsy is an undertreated condition, in part because of concern regarding drug interactions and the risk of exacerbating seizures with antidepressant treatment. Bipolar disorder is not described as occurring with a higher than expected frequency in the population with epilepsy, but high rates of depression and suicide are well recognised, highlighting the need for more emphasis on antidepressive treatment in this group of at-risk patients.

Neurological factors, including site and lateralisation of seizure focus, may be important for the development of depression, with left-sided seizure foci having a higher association with depressive symptoms. Forced normalisation may be a factor in the paradoxical onset of depression in patients with epilepsy whose seizures suddenly become well controlled by anti-seizure treatment. Lowering of folic acid levels by some antiepileptic drugs (AEDs) may also influence the expression of depression in patients with epilepsy.

New AEDs continue to emerge as beneficial treatments themselves for mood disorders, with lamotrigine, gabapentin and, to a lesser extent, topiramate having clinical trials data to support their use in patients with bipolar disease. Similar positive data are available for vagal nerve stimulation. Mood effects of AEDs can be complicated, however, as many of these drugs (e.g. tiagabine) have also been reported to cause depression as an adverse effect. Electroconvulsive therapy in depressed patients with epilepsy requires special consideration.The selective serotonin reuptake inhibitors (SSRIs) and antidepressants that act at multiple receptors (e.g. nefazodone, venlafaxine) are the most appropriate treatments for depressed patients with epilepsy. Among these agents, citalopram has a low risk of interactions with AEDs. Bupropion, clomipramine and maprotiline are associated with a greater risk of seizures compared with other antidepressants and consequently should be used with caution in the treatment of depression in patients with epilepsy.


  1. 1.
    Hermann BP, Seidenberg M, Bell M. Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression. Epilepsia 2000; 41 Suppl. 2: S31–41PubMedCrossRefGoogle Scholar
  2. 2.
    Edeh J, Toone BK, Corney RH. Epilepsy, psychiatric morbidity, and social dysfunction in general practice. Comparison between clinic patients and clinic nonattenders. Neuropsychiatry Neuropsychol Behav Neurol 1990; 3: 180–92Google Scholar
  3. 3.
    Edeh J, Toone B. Relationship between interictal psychopathology and type of epilepsy. Results of a survey in general practice. Br J Psychiatry 1987; 151: 95–101PubMedCrossRefGoogle Scholar
  4. 4.
    Jacoby A, Baker GA, Steen N, et al. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. community study. Epilepsia 1996; 37: 148–61PubMedCrossRefGoogle Scholar
  5. 5.
    Victoroff JI, Benson DF, Engel Jr J, et al. Interictal depression in patients with medically intractable complex partial seizures: electroencephalography and cerebral metabolic correlates [abstract]. Ann Neurol 1990; 28: 221Google Scholar
  6. 6.
    Indaco A, Carrieri PB, Nappi C, et al. Interictal depression in epilepsy. Epilepsy Res 1992; 12: 45–50PubMedCrossRefGoogle Scholar
  7. 7.
    Victoroff JI, Benson DF, Grafton ST, et al. Depression in complex partial seizures. Electroencephalography and cerebral metabolic correlates. Arch Neurol 1994; 51: 155–63PubMedCrossRefGoogle Scholar
  8. 8.
    Robertson MM, Channon S, Baker J. Depressive symptomatology in a general hospital sample of outpatients with temporal lobe epilepsy: a controlled study. Epilepsia 1994; 35: 771–7PubMedCrossRefGoogle Scholar
  9. 9.
    Boyd JH, Weissman MM. Epidemiology. In: Paykel ES, editor. Handbook of affective disorders. New York: The Guilford Press, 1982: 25Google Scholar
  10. 10.
    Blumer D. Postictal depression: significance for the neurobehavioral disorder of epilepsy. J Epilepsy 1992; 5: 214–9CrossRefGoogle Scholar
  11. 11.
    Lambert MV, Robertson MM. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia 1999; 40 Suppl. 10: S21–47PubMedCrossRefGoogle Scholar
  12. 12.
    Lim J, Yagnik P, Schraeder P, et al. Ictal catatonia as a manifestation of nonconvulsive status epilepticus. J Neurol Neurosurg Psychiatry 1986; 49: 833–6PubMedCrossRefGoogle Scholar
  13. 13.
    Betts TA. Neuropsychiatry. In: Laidlaw J, Richens A, Chadwick D, editors. A textbook of epilepsy. 4th ed. Edinburgh: Churchill-Livingston, 1993: 397–458Google Scholar
  14. 14.
    Mendez MF, Doss RC. Ictal and psychiatric aspects of suicide in epileptic patients. Int J Psychiatry Med 1992; 22: 231–7PubMedCrossRefGoogle Scholar
  15. 15.
    Wiegartz P, Seidenberg M, Woodard A, et al. Co-morbid psychiatrie disorder in chronic epilepsy: recognition and etiology of depression. Neurology 1999; 53(5 Suppl. 2): S3–8PubMedGoogle Scholar
  16. 16.
    Reynolds EH. Interictal psychiatric disorders. Adv Neurol 1991; 55: 47–57PubMedGoogle Scholar
  17. 17.
    Robertson MM. Affect and mood in epilepsy: an overview with a focus on depression. Acta Neurol Scand 1992; 86: 127–32CrossRefGoogle Scholar
  18. 18.
    Barraclough B. The suicide rate of epilepsy. Acta Psychiatry Scand 1987; 76: 339–45CrossRefGoogle Scholar
  19. 19.
    Kanner AM, Nieto JC. Depressive disorders in epilepsy. Neurology 1999; 53(5 Suppl. 2): S26–32PubMedGoogle Scholar
  20. 20.
    Manchanda R, Schaefer B, McLachlan RS, et al. Relationship of site of seizure focus to psychiatric morbidity. J Epilepsy 1995; 8: 23–8CrossRefGoogle Scholar
  21. 21.
    Herman BP, Seidenberg M, Haitiner A, et al. Mood state in unilateral temporal lobe epilepsy. Biol Psychiatry 1991; 30: 1205–18CrossRefGoogle Scholar
  22. 22.
    Bromfield EB, Alshuler L, Leiderman DB, et al. Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 1992; 59: 617–23CrossRefGoogle Scholar
  23. 23.
    Robertson M. Mood disorders associated with epilepsy. In: McConnell HW, Snyder PJ, editors. Psychiatric comorbidity in epilepsy. Basic mechanisms, diagnosis, and treatment. Washington, DC: American Psychiatric Press, 1998: 132–67Google Scholar
  24. 24.
    Schmitz EB, Moriarty J, Costa DC, et al. Psychiatric profiles and patterns of cerebral blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion related to the laterality of the epilepsy. J Neurol Neurosurg Psychiatry 1997; 62: 458–63PubMedCrossRefGoogle Scholar
  25. 25.
    Bench CJ, Frackowiak R, Dolan R. Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995; 25: 247–51PubMedCrossRefGoogle Scholar
  26. 26.
    Standage KF, Fenton GW. Psychiatric symptom profiles of patients with epilepsy: a controlled investigation. Psychol Med 1975; 5: 152–60PubMedCrossRefGoogle Scholar
  27. 27.
    Betts TA. A follow-up study of a cohort of patients with epilepsy admitted to psychiatric care in a English city. In: Harris P, Mawdsley C, editors. Epilepsy proceedings of the Hans Berger Centenary symposium. Edinburgh: Churchill Livingston, 1974: 326–38Google Scholar
  28. 28.
    Mendez MF, Doss RC, Taylor JL, et al. Depression in epilepsy: relationship to seizures and anticonvulsant therapy. J Nerv Ment Dis 1993; 181: 444–7PubMedCrossRefGoogle Scholar
  29. 29.
    Landolt H. Some clinical electroencephalographical correlations in epileptic psychoses (twilight states) [abstract]. Electroencephalogr Clin Neurophysiol 1953; 5: 121Google Scholar
  30. 30.
    Landolt H. Serial electroencephalographic investigations during psychotic episodes in epileptic patients and during schizophrenic attacks. In: Lorentz de Haas AM, editor. Lectures on epilepsy. Amsterdam: Elsevier, 1958: 91–133Google Scholar
  31. 31.
    Smith PF, Darlington CL. Neural mechanisms of psychiatric disturbances in patients with epilepsy. In: McConnell HW, Snyder PJ, editors. Psychiatric comorbidity in epilepsy. Basic mechanisms, diagnosis, and treatment. Washington, DC: American Psychiatric Press, 1998: 15–35Google Scholar
  32. 32.
    Trimble M. Non-monoamine oxidase inhibitor antidepressants and epilepsy: a review. Epilepsia 1987; 19: 241–51CrossRefGoogle Scholar
  33. 33.
    Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from electrical stimulation. Exp Neurol 1969; 25: 296–330CrossRefGoogle Scholar
  34. 34.
    Hermann BP, Whitman S. Psychosocial predictors of interictal depression. J Epilepsy 1989; 2: 231–7CrossRefGoogle Scholar
  35. 35.
    Brent D, Crumrine P, Varma R. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987; 80: 909–17PubMedGoogle Scholar
  36. 36.
    Barabas G, Matthews W. Barbiturate anticonvulsants as a cause of severe depression. Pediatrics 1988; 82: 284–5PubMedGoogle Scholar
  37. 37.
    Dodrill CB. Behavioral effects of antiepileptic drugs. In: Smith D, Treiman D, Trimble M, editors. Advances in neurology. Vol. 44. New York: Raven Press, 1991: 213–24Google Scholar
  38. 38.
    Ben-Menachem E, French J. Vigabatrin. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia (PA): Lippincott-Raven Publishers, 1997: 1609–18Google Scholar
  39. 39.
    French J, Pellock J, Ferrendelli J, et al. Results of a multicenter, placebo-controlled, parallel study of vigabatrin (VGB, Sabril) in patients with focal epilepsy whose seizures are difficult to control [abstract]. Neurology 1993; 43 Suppl. 2: A307Google Scholar
  40. 40.
    Penry JK, Wilder BJ, Sachdeo RC, et al. Multicenter dose-response study of vigabatrin in brain and CSF of the rat. Brain Res 1980; 190: 288–92Google Scholar
  41. 41.
    Harden CL, Lazar LM, Pick LH, et al. A beneficial effect on mood in partial epilepsy patients treated with gabapentin. Epilepsia 1999; 40(8): 1129–34PubMedCrossRefGoogle Scholar
  42. 42.
    McElroy SL, Soutullo CA, Keck Jr PE, et al. A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder. Clin Psychiatry 1997; 9(2): 99–103Google Scholar
  43. 43.
    Schaffer CB, Schaffer LC. Gabapentin for the treatment of bipolar disorder [letter]. Am J Psychiatry 1997; 154: 291PubMedGoogle Scholar
  44. 44.
    Sokolski KN, Green C, Maris DE, et al. Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed bipolar symptomatology. Ann Clin Psychiatry 1999; 11(4): 217–22PubMedGoogle Scholar
  45. 45.
    Cabras PL, Hardoy MJ, Hardoy MC, et al. Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study. J Clin Psychiatry 1999; 60(4): 245–8PubMedCrossRefGoogle Scholar
  46. 46.
    Pande AC, Crockatt JG, Janney CA, et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000 Sep; 2 (3 Pt 2): 249–55PubMedCrossRefGoogle Scholar
  47. 47.
    Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999; 60(2): 79–88PubMedCrossRefGoogle Scholar
  48. 48.
    Ichim L, Berk M, Brook S. Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial. Ann Clin Psychiatry 2000; 12(1): 5–10PubMedGoogle Scholar
  49. 49.
    Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 2000; 61(11): 841–50PubMedCrossRefGoogle Scholar
  50. 50.
    Crawford P. An audit of topiramate use in a general neurology clinic. Seizure 1998; 7: 207–11PubMedCrossRefGoogle Scholar
  51. 51.
    Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord 1998; 50(2–3): 245–51PubMedCrossRefGoogle Scholar
  52. 52.
    McElroy SL, Suppes T, Keck Jr PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 2000; 47(12): 1025–33PubMedCrossRefGoogle Scholar
  53. 53.
    Berlant JL. Topiramate in posttraumatic stress disorder: preliminary clinical observations. J Clin Psychiatry 2001; 62 Suppl. 17: 60–3PubMedGoogle Scholar
  54. 54.
    Leppik IE, Gram L, Deaton R, et al. Safety of tiagabine: summary of 53 trials. Epilepsy Res 1999; 33: 235–46PubMedCrossRefGoogle Scholar
  55. 55.
    Dodrill CB, Arnett JL, Shu V, et al. Effects of tiagabine monotherapy on abilities, adjustment, and mood. Epilepsia 1998; 39: 33–42PubMedCrossRefGoogle Scholar
  56. 56.
    Meldrum BS, Chapman AG. Basic mechanisms of Gabitril (tiagabine) and future potential developments. Epilepsia 1999; 40 Suppl. 9: S2–6PubMedCrossRefGoogle Scholar
  57. 57.
    Grunze H, Erfurth A, Marcuse A, et al. Tiagabine appears not to be effective in the treatment of acute mania. J Clin Psychiatry 1999; 60(11): 759–62PubMedCrossRefGoogle Scholar
  58. 58.
    Kaufman KR. Adjunctive tiagabine treatment of psychiatric disorders: three cases. Ann Clin Psychiatry 1998; 10(4): 181–4PubMedGoogle Scholar
  59. 59.
    Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18(4): 707-15Google Scholar
  60. 60.
    Joca SR, Skalisz LL, Beijamini V, et al. The antidepressive-like effect of oxcarbazepine: possible role of dopaminergic neurotransmission. Eur Neuropsychopharmacol 2000; 10(4): 223–8PubMedCrossRefGoogle Scholar
  61. 61.
    Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42(12): 1611–3PubMedCrossRefGoogle Scholar
  62. 62.
    Harden CL, Pulver MC, Ravdin LD, et al. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav 2000; 1: 93–9PubMedCrossRefGoogle Scholar
  63. 63.
    Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000; 47: 276–86PubMedCrossRefGoogle Scholar
  64. 64.
    Edeh J, Toone BK. Antiepileptic therapy, folate deficiency and psychiatric morbidity: a general practice survey. Epilepsia 1985; 26: 434–40PubMedCrossRefGoogle Scholar
  65. 65.
    Froscher W, Maier V, Laage M, et al. Folate deficiency, anticonvulsant drugs, and psychiatric morbidity. Clin Neuropharmacol 1995; 18: 165–82PubMedCrossRefGoogle Scholar
  66. 66.
    Carney MWP, Chary TKN, Laundy M, et al. Red cell folate concentrations in psychiatric patients. J Affect Disord 1990; 19: 207–13PubMedCrossRefGoogle Scholar
  67. 67.
    Torta R, Keller R. Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications. Epilepsia 1999; 40 Suppl. 10: S2–20PubMedCrossRefGoogle Scholar
  68. 68.
    Dell J. Social dimensions of epilepsy: stigma and response. In: Whitman S, Hermann PP, editors. Psychopathology in epilepsy: social perspectives. New York: Oxford University Press, 1986: 185–210Google Scholar
  69. 69.
    Hermann BP, Wyler AR. Depression, locus of control, and the effects of epilepsy surgery. Epilepsia 1989; 30(3): 332–8PubMedCrossRefGoogle Scholar
  70. 70.
    Lefcourt HM. Locus of control. New York: Erlbaum, 1976Google Scholar
  71. 71.
    Katon W, VonKorff M, Lin E, et al. Adequacy and duration of antidepressant treatment in primary care. Med Care 1992; 30: 67–76PubMedCrossRefGoogle Scholar
  72. 72.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
  73. 73.
    Blumer D, Montouris G, Hermann B. Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J Neuropsychiatry Clin Neurosci 1995; 7: 445–56PubMedGoogle Scholar
  74. 74.
    Davidson J. Seizures and bupropion: a review. J Clin Psychiatry 1989; 50: 256–61PubMedGoogle Scholar
  75. 75.
    Dessain EC, Schatzberg AF, Woods BT, et al. Maprotiline treatment in depression: a perspective on seizures. Arch Gen Psychiatry 1986; 43: 86–90PubMedCrossRefGoogle Scholar
  76. 76.
    Jabbari B, Dryan GE, Marsh EE, et al. Incidence of seizures with tricyclic and tetracyclic antidepressants. Arch Neurol 1985; 42: 480–1PubMedCrossRefGoogle Scholar
  77. 77.
    Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepressants: a review. J Clin Psychiatry 1993; 54(8): 289–99PubMedGoogle Scholar
  78. 78.
    DeVeaugh-Geis J, Landau P, Katz R. Preliminary results from a multicenter trial of clomipramine in obsessive-compulsive disorder. Psychopharmacol Bull 1989; 25: 36–40Google Scholar
  79. 79.
    Jick H, Dinan BJ, Hunter JR, et al. Tricyclic antidepressants and convulsions. J Clin Psychopharmacol 1983; 3: 182–5PubMedCrossRefGoogle Scholar
  80. 80.
    Peck AW, Stern WC, Watkinson C. Incidence of seizures during treatment with tricyclic antidepressant drugs and bupropion. J Clin Psychiatry 1983 May; 44 (5 Pt 2): 197–201PubMedGoogle Scholar
  81. 81.
    Physician’s desk reference. Montvale (NJ): Medical Economics, 1999Google Scholar
  82. 82.
    Edwards JG, Inman WHW, Wilton L, et al. Prescription-event monitoring of 10,401 patients treated with fluvoxamine. Br J Psychiatry 1994; 164: 387–95PubMedCrossRefGoogle Scholar
  83. 83.
    Physician’s desk reference. Montvale (NJ): Medical Economics, 2000Google Scholar
  84. 84.
    Dailey JW, Naritoku DK. Antidepressants and seizures: clinical anecdotes overshadow neuroscience. Biochem Pharmacol 1996; 52(9): 1323–9PubMedCrossRefGoogle Scholar
  85. 85.
    Prendiville S, Gale K. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia 1993; 34(2): 381–4PubMedCrossRefGoogle Scholar
  86. 86.
    Leander JD. Fluoxetine, a selective serotonin-uptake inhibitor, enhances the anticonvulsant effects of phenytoin, carbamazepine, and ameltolide (LY201116). Epilepsia 1992; 33(3): 573–6PubMedCrossRefGoogle Scholar
  87. 87.
    Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993; 34(3): 453–68PubMedCrossRefGoogle Scholar
  88. 88.
    The Association of the British Pharmaceutical Industry (ABPI). Compendium of data sheets and summaries of product characteristics. London: Datapharm Publications, 1996Google Scholar
  89. 89.
    Ketter TA, Post RM, Parakh PI, et al. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J Clin Psychiatry 1995; 56(10): 471–5PubMedGoogle Scholar
  90. 90.
    Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol 1996; 19 Suppl. 2: S37–53CrossRefGoogle Scholar
  91. 91.
    Levy RH, Mather GG. Metabolic enzymes and antiepileptic drug interactions. In: French J, Leppik I, Dichter MA, editors. Antiepileptic drug development. Advances in neurology. Vol. 76. Philadelphia (PA): Lippincott-Raven Publishers, 1998: 49–55Google Scholar
  92. 92.
    Shank RP, Gardocki JF, Streeter AJ, et al. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000; 41 Suppl. 1: S3–9PubMedCrossRefGoogle Scholar
  93. 93.
    Kalinowsky LB, Kennedy F. Observations in electroshock therapy applied to the problems of epilepsy. J Nerv Ment Dis 1943; 98: 56–67CrossRefGoogle Scholar
  94. 94.
    Keller CH, Bernstein HJ. ECT as a treatment for neurologic illness. In: Coffey CE, editor. The clinical science of electroconvulsive therapy. Washington, DC: American Psychiatric Press, 1993: 183–210Google Scholar
  95. 95.
    Weiner RD, Coffey CE. Electroconvulsive therapy in the medical and neurologic patient. In: Stoudemeire A, Fogel BS, editors. Psychiatric care of the medical patient. New York: Oxford University Press, 1993: 207–24Google Scholar

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© Adis International Limited 2002

Authors and Affiliations

  1. 1.Comprehensive Epilepsy CenterWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Department of Neurology and PsychiatryWeill Medical College of Cornell UniversityNew YorkUSA

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