CNS Drugs

, Volume 22, Issue 1, pp 27–47 | Cite as

Antiepileptic Drugs in Non-Epilepsy Disorders

Relations between Mechanisms of Action and Clinical Efficacy
Review Article


Antiepileptic drugs (AEDs) are used extensively to treat multiple non-epilepsy disorders, both in neurology and psychiatry. This article provides a review of the clinical efficacy of AEDs in non-epilepsy disorders based on recently published preclinical and clinical studies, and attempts to relate this efficacy to the mechanism of action of AEDs and pathophysiological processes associated with the disorders. Some newer indications for AEDs have been established, while others are under investigation. The disorders where AEDs have been demonstrated to be of clinical importance include neurological disorders, such as essential tremor, neuropathic pain and migraine, and psychiatric disorders, including anxiety, schizophrenia and bipolar disorder.

Many of the AEDs have various targets of action in the synapse and have several proposed relevant mechanisms of action in epilepsy and in other disorders. Pathophysiological processes disturb neuronal excitability by modulating ion channels, receptors and intracellular signalling pathways, and these are targets for the pharmacological action of various AEDs. Attention is focused on the glutamatergic and GABAergic synapses.

In psychiatric conditions such as schizophrenia and bipolar disorder, AEDs such as valproate, carbamazepine and lamotrigine appear to have clear roles based on their effect on intracellular pathways. On the other hand, some AEDs, e.g. topiramate, have efficacy for nonpsychiatric disorders including migraine, possibly by enhancing GABAergic and reducing glutamatergic neurotransmission.

AEDs that seem to enhance GABAergic neurotransmission, e.g. tiagabine, valproate, gabapentin and possibly levetiracetam, may have a role in treating neurological disorders such as essential tremor, or anxiety disorders. AEDs with effects on voltage-gated sodium or calcium channels may be advantageous in treating neuropathic pain, e.g. gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine and valproate.

Co-morbid conditions associated with epilepsy, such as mood disorders and migraine, may often respond to treatment with AEDs. Other possible disorders where AEDs may be of clinical importance include cancer, HIV infection, drug and alcohol abuse, and also in neuroprotection.

A future challenge is to evaluate the second-generation AEDs in non-epilepsy disorders and to design clinical trials to study their effects in such disorders in paediatric patients. Differentiation between the main mechanisms of action of the AEDs needs more consideration in drug selection for tailored treatment of the various non-epilepsy disorders.


Migraine Bipolar Disorder Neuropathic Pain Valproate Gabapentin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I am grateful to Dr Svein I. Johannessen for his helpful advice and discussions during the preparation of this manuscript. No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord 2004; 6: 57–75PubMedGoogle Scholar
  2. 2.
    Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 2004; 10: 685–92PubMedCrossRefGoogle Scholar
  3. 3.
    Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 553–64PubMedCrossRefGoogle Scholar
  4. 4.
    Zaremba PD, Bialek M, Blasczcyk B, et al. Non-epilepsy uses of antiepilepsy drugs. Pharmacol Rep 2006; 58: 1–12PubMedCrossRefGoogle Scholar
  5. 5.
    Golden AS, Haut S, Moshé SL. Nonepileptic uses of antiepileptic drugs in children and adolescents. Ped Neurol 2006; 34: 421–32CrossRefGoogle Scholar
  6. 6.
    Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics 2007; 4: 75–83PubMedCrossRefGoogle Scholar
  7. 7.
    Goodnick PJ. Anticonvulsants in the treatment of bipolar mania. Expert Opin Pharmacother 2006; 7: 401–10PubMedCrossRefGoogle Scholar
  8. 8.
    Rogawski MA. Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 2006; 68: 22–8PubMedCrossRefGoogle Scholar
  9. 9.
    Perucca E. An introduction to antiepileptic drugs. Epilepsia 2005; 46 Suppl. 4: 31–7CrossRefGoogle Scholar
  10. 10.
    Stefan H, Lopes da Silva FH, Löscher W, et al. Epileptogenesis and rational therapeutic strategies. Acta Neurol Scand 2006; 113: 139–55PubMedCrossRefGoogle Scholar
  11. 11.
    Ahmad S, Fowler LJ, Whitton PS. Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids. Epilepsy Res 2005; 63: 141–9PubMedCrossRefGoogle Scholar
  12. 12.
    Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 2002; 16: 669–94PubMedCrossRefGoogle Scholar
  13. 13.
    Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (Eilat VII). Epilepsy Res 2004; 61: 1–48PubMedCrossRefGoogle Scholar
  14. 14.
    Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat conference (Eilat VIII). Epilepsy Res 2007; 73: 1–52PubMedCrossRefGoogle Scholar
  15. 15.
    Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry 2003; 64: 21–7PubMedGoogle Scholar
  16. 16.
    Nemeroff CB. The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 2003; 37: 133–46PubMedGoogle Scholar
  17. 17.
    Johannessen CU, Petersen D, Fonnum F, et al. The acute effect of valproate on cerebral energy metabolism in mice. Epilepsy Res 2001; 47: 247–56PubMedCrossRefGoogle Scholar
  18. 18.
    Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 2006; 69: 273–94PubMedCrossRefGoogle Scholar
  19. 19.
    Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential tremor in gamma-aminobutyric acid A receptor alpha 1 subunit knockout mice. J Clin Invest 2005; 115: 584–6CrossRefGoogle Scholar
  20. 20.
    Jankovic J, Noebels JL. Genetic mouse models of essential tremor: are they essential? J Clin Invest 2005; 115: 774–9CrossRefGoogle Scholar
  21. 21.
    Pathwa R, Lyons KE. Essential tremor: differential diagnosis and current therapy. Am J Med 2003; 115: 134–42CrossRefGoogle Scholar
  22. 22.
    Cutrer FM, Moskowitz MA. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 1996; 36: 579–85PubMedCrossRefGoogle Scholar
  23. 23.
    Yee BK, Keist R, von Boehmer L, et al. Schizophrenia-related sensorimotor deficit links alpha-3-containing GABAa receptors to a dopamine hyperfunction. Proc Natl Acad Sci 2005; 22: 102: 17154–9PubMedCrossRefGoogle Scholar
  24. 24.
    Volk DW, Austin MC, Perri JN, et al. Decreased GAD67 mRNA expression in a subset of prefrontal cortical GABA neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000; 57: 237–45PubMedCrossRefGoogle Scholar
  25. 25.
    Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 2006; 26: 363–82CrossRefGoogle Scholar
  26. 26.
    Akbarian S, Kim JJ, Potkin SG, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995; 52: 258–66PubMedCrossRefGoogle Scholar
  27. 27.
    Kaminski RM, Banerjee M, Rogawski MA. Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist. Neuropharmacology 2004; 46: 1097–104PubMedCrossRefGoogle Scholar
  28. 28.
    Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006; 6: 108–13PubMedCrossRefGoogle Scholar
  29. 29.
    Ueda Y, Doi T, Tokumaru J, et al. Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. Mol Brain Res 2003; 116: 1–6PubMedCrossRefGoogle Scholar
  30. 30.
    McQuay H, Caroll D, Jadad AR, et al. Anticonvulsant drugs for management of pain: a systematic review. BMJ 1995; 311: 1047–52PubMedCrossRefGoogle Scholar
  31. 31.
    Coderre TJ, Kumar N, Lefebyre CD, et al. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. J Neurochem 2005; 94: 1131–9PubMedCrossRefGoogle Scholar
  32. 32.
    Yang RH, Xing JL, Duan JH, et al. Effects of gabapentin on spontaneous discharges and subthreshold membrane potential oscillation of type A neurons in injured DRG. Pain 2005; 116: 187–93PubMedCrossRefGoogle Scholar
  33. 33.
    Cheng JK, Chiou LC. Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci 2006; 100: 471–86PubMedCrossRefGoogle Scholar
  34. 34.
    Tanabe M, Sakaue A, Takasu K, et al. Centrally mediated antihyperalgesic and antiallodynic effects of zonisamide following partial nerve injury in the mouse. Nauyn Schmiedebergs Arch Pharmacol 2005; 372: 107–14CrossRefGoogle Scholar
  35. 35.
    Imamura Y, Bennett GJ. Felbamate relieves several abnormal pain sensations in rats with an experimental peripheral neuropathy. J Pharmacol Exp Ther 1995; 275: 177–82PubMedGoogle Scholar
  36. 36.
    Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylases is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 276: 36734–41PubMedCrossRefGoogle Scholar
  37. 37.
    Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 2003; 38: 157–60PubMedCrossRefGoogle Scholar
  38. 38.
    Bachmann RF, Schloesser RJ, Gould TD, et al. Mood stabilizers target cellular plasticity and resilience cascades: implications for the development of novel therapeutics. Mol Neurobiol 2005; 32: 173–202PubMedCrossRefGoogle Scholar
  39. 39.
    Shaltiel G, Shamir A, Shapiro J, et al. Valproate decreases inositol synthesis. Biol Psychiatry 2004; 56: 868–74PubMedCrossRefGoogle Scholar
  40. 40.
    Evins AE, Demopulos C, Yovel I, et al. Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disord 2006; 8: 168–74CrossRefGoogle Scholar
  41. 41.
    Ju S, Greenberg ML. Valproate disrupts regulation of inositol responsive genes and alters regulation of phospholipid biosynthesis. Mol Microbiol 2003; 49: 1595–603PubMedCrossRefGoogle Scholar
  42. 42.
    Williams RSB, Cheng L, Mudge AW, et al. A common mechanism of action for three mood-stabilizing drugs. Nature 2002; 417: 292–6PubMedCrossRefGoogle Scholar
  43. 43.
    Brunello N, Tascedda F. Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders. Int J Neuropsychopharmacol 2003; 6: 181–9PubMedCrossRefGoogle Scholar
  44. 44.
    Lieb K, Treffurth Y, Hamke M, et al. Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor. J Neurochem 2003; 86: 69–76PubMedCrossRefGoogle Scholar
  45. 45.
    Chetcuti A, Adams LJ, Mitchell PB, et al. Altered gene expression in mice treated with the mood stabilizer sodium valproate. Int J Neuropsychopharmacol 2005; 28: 1–10Google Scholar
  46. 46.
    Xie X, Hagan RM. Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998; 38: 119–30PubMedCrossRefGoogle Scholar
  47. 47.
    Sechi GP, Traccis S, Durelli L, et al. Carbamazepine versus diphenylhydantoin in the treatment of myotonia. Eur Neurol 1983; 22: 113–8PubMedCrossRefGoogle Scholar
  48. 48.
    Rodrigues JP, Edwards DJ, Walters SE, et al. Gabapentin can improve postural stability and quality of life in primary orthostatic tremor. Mov Disord 2005; 20: 865–70PubMedCrossRefGoogle Scholar
  49. 49.
    Keck PE, Strawn JR, McElroy LR. Pharmacologic treatment considerations in co-occurring bipolar and anxiety disorders. J Clin Psychiatry 2005; 67: 8–15Google Scholar
  50. 50.
    Zesiewicz TA, Elbe R, Louis ED, et al. Practice parameter: therapies for essential tremor. Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2005; 64: 2008–20Google Scholar
  51. 51.
    Eisenberg E, Shifrin A, Krivoy N. Lamotrigine for neuropathic pain. Expert Rev Neurother 2005; 5: 729–35PubMedCrossRefGoogle Scholar
  52. 52.
    Lampl C, Katsarava Z, Diener HC, et al. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry 2005; 76: 1730–2PubMedCrossRefGoogle Scholar
  53. 53.
    Premkumar TS, Pick J. Lamotrigine for schizophrenia. Cochrane Database Syst Rev 2006; (4): CD005962PubMedGoogle Scholar
  54. 54.
    Nierneberg IA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatr 2006; 163: 210–6CrossRefGoogle Scholar
  55. 55.
    Ondo WG, Jimenez JE, Vuong KD, et al. An open-label pilot study of levetiracetam for essential tremor. Clin Neuropharmacol 2004; 27: 274–7PubMedCrossRefGoogle Scholar
  56. 56.
    Handforth A, Martin FC. Pilot efficacy and tolerability: a randomized, placebo-controlled trial of levetiracetam for essential tremor. Mov Disord 2004; 19: 1215–21PubMedCrossRefGoogle Scholar
  57. 57.
    Bushara KO, Malik T, Exconde RE. The effect of levetiracetam on essential tremor. Neurology 2005; 64: 1078–80PubMedCrossRefGoogle Scholar
  58. 58.
    Striano P, Coppola A, Vacca G, et al. Levetiracetam for cerebellar tremor in multiple sclerosis: an open-label pilot tolerability and efficacy study. Neurology 2006; 253: 762–6CrossRefGoogle Scholar
  59. 59.
    Drake ME, Greathouse NI, Armentbright AD, et al. Levetiracetam for preventive treatment of migraine [abstract]. Cephalalgia 2001;21: 373Google Scholar
  60. 60.
    Krusz JC. Levetiracetam as prophylaxis for resistant headaches [abstract]. Cephalalgia 2001; 21: 373Google Scholar
  61. 61.
    Magenta P, Arghetti S, Di Palma F, et al. Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies. Neurol Sci 2005; 26: 218–26PubMedCrossRefGoogle Scholar
  62. 62.
    Raja M, Azzoni A. Oxcarbazepine vs. valproate in the treatment of mood and schizoaffective disorders. Int J Neuropsychopharmacol 2003; 6: 409–14Google Scholar
  63. 63.
    MacCleane GJ. Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blind, placebo-controlled, crossover study. Anesth Analg 1999; 89: 985–8Google Scholar
  64. 64.
    Mishory A, Yaroslavsky Y, Bersudsky Y, et al. Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 2000; 157: 463–5PubMedCrossRefGoogle Scholar
  65. 65.
    Applebaum J, Levine J, Belmaker RH. Intravenous fosphenytoin in acute mania. J Clin Psychiatry 2003; 64: 408–9PubMedCrossRefGoogle Scholar
  66. 66.
    Pollack MH, Roy-Byrne PP, Van Ameringen M, et al. The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin Psychiatry 2005; 66: 1401–8PubMedCrossRefGoogle Scholar
  67. 67.
    Van Ameringen M, Mancini C, Pipe B, et al. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65: 1674–8PubMedCrossRefGoogle Scholar
  68. 68.
    White HS. Molecular pharmacology of topiramate: managing seizures and preventing migraine. Headache 2005; 45: S48–56PubMedCrossRefGoogle Scholar
  69. 69.
    Connor GS. A double-blind placebo-controlled trial of topiramate treatment for essential tremor. Neurology 2002; 59: 132–4PubMedCrossRefGoogle Scholar
  70. 70.
    Sechi G, Agnetti V, Sulas FM, et al. Effects of topiramate in patients with cerebellar tremor. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1023–7PubMedCrossRefGoogle Scholar
  71. 71.
    Mclntyre RS, Riccardelli R, Binder C, et al. Open-label adjunctive topiramate in the treatment of unstable bipolar disorder. Can J Psychiatry 2005; 50: 415–22Google Scholar
  72. 72.
    Bartolini M, Silvestrini M, Taffi R, et al. Efficacy of topiramate and valproate in chronic migraine. Clin Neuropharmacol 2005; 28: 277–9PubMedCrossRefGoogle Scholar
  73. 73.
    Silberstein SD, Walter N, Schmitt J, et al. Topiramate in migraine prevention. Arch Neurol 2004; 61: 490–5PubMedCrossRefGoogle Scholar
  74. 74.
    Tiihonen J, Halonen P, Wahlbeck K, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66:1012–5PubMedCrossRefGoogle Scholar
  75. 75.
    Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev 2003; 9: 199–216PubMedCrossRefGoogle Scholar
  76. 76.
    Kochar DK, Rawat N, Agrawal RP, et al. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. QJM 2004; 97: 33–8PubMedCrossRefGoogle Scholar
  77. 77.
    Winterer G, Hermann WM. Valproate and the symptomatic treatment of schizophrenia spectrum patients. Pharmacopsychiatry 2000; 33: 182–8PubMedCrossRefGoogle Scholar
  78. 78.
    Keck PE, McElroy SL, Tugrul KC, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 1993; 54: 305–30PubMedGoogle Scholar
  79. 79.
    Hirschfeld RMA, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry 2003; 64: 841–6PubMedCrossRefGoogle Scholar
  80. 80.
    Swann AC. Valproic acid: clinical efficacy and use in psychiatric disorders. In: Levy RH, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2002: 828–36Google Scholar
  81. 81.
    Morita S, Miwa H, Kondo T. Effect of zonisamide on essential tremor: a pilot crossover study in comparison with arotinolol. Parkinsonism Relat Disord 2005; 11: 101–3PubMedCrossRefGoogle Scholar
  82. 82.
    Sabra AF, Hallett M. Action tremor with altering activity in antagonist muscles. Neurology 1984; 34: 151–6PubMedCrossRefGoogle Scholar
  83. 83.
    Yoshida S, Okada M, Zhu G, et al. Effects of zonisamide on neurotransmitter exocytosis asociated with ryanodine receptors. Epilepsy Res 2005; 67: 153–62PubMedCrossRefGoogle Scholar
  84. 84.
    Lynch B, Lamberg N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci 2004; 101: 9861–6PubMedCrossRefGoogle Scholar
  85. 85.
    Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat conference (Eilat VII). Epilepsy Res 2002; 51: 31–71PubMedCrossRefGoogle Scholar
  86. 86.
    Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanisms of action of pregabalin: the calcium channel α2-δ (alpha-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 2007; 73: 137–50PubMedCrossRefGoogle Scholar
  87. 87.
    Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005; 118: 289–305PubMedCrossRefGoogle Scholar
  88. 88.
    Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav 2004; 5: 627–35PubMedCrossRefGoogle Scholar
  89. 89.
    Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002; 5: 767–74PubMedGoogle Scholar
  90. 90.
    Shannon HE, Eberle EL, Peters SC. Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neuropharmacol 2005; 48: 1012–20CrossRefGoogle Scholar
  91. 91.
    Brill J, Lee M, Zhao S, et al. Chronic valproic acid treatment triggers increased neuropeptide Y expression and signalling in rat nucleus reticularis thalami. J Neurosci 2006; 26: 6813–22PubMedCrossRefGoogle Scholar
  92. 92.
    Winkler I, Blotnik S, Shimshoni J, et al. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain. Br J Pharmacol 2005; 146: 198–208PubMedCrossRefGoogle Scholar
  93. 93.
    Winkler I, Sobol E, Yagen B, et al. Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain. Neuropharmacol 2005; 49: 1110–20CrossRefGoogle Scholar
  94. 94.
    Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs 2006; 15: 637–47PubMedCrossRefGoogle Scholar
  95. 95.
    Corbo J. The role of anticonvulsants in preventive migraine therapy. Curr Pain Headache 2003; 7: 63–6CrossRefGoogle Scholar
  96. 96.
    Erdemolu AK, Ozbakir S. Valproic acid in prophylaxis of refractory migraine. Acta Neurol Scand 2000; 102: 354–8Google Scholar
  97. 97.
    Landy S. Migraine throughout the life cycle: treatment through the ages. Neurology 2004; 62: S2–8PubMedCrossRefGoogle Scholar
  98. 98.
    Czapinski P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 2005; 5: 3–14PubMedCrossRefGoogle Scholar
  99. 99.
    Schechter PJ. Clinical pharmacology of vigabatrin. Br J Clin Pharmacol 1989; 27: 19–22SCrossRefGoogle Scholar
  100. 100.
    Preece NE, Jackson GD, Houseman JA, et al. Nuclear magnetic resonance detection of increased GABA in vigabatrin-treated rats in vivo. Epilepsia 1994; 35: 431–6PubMedCrossRefGoogle Scholar
  101. 101.
    Czuczwar SJ, Patsalos PN. The new generation of GABA enhancers: potential in the treatment of epilepsy. CNS Drugs 2001; 15: 339–50PubMedCrossRefGoogle Scholar
  102. 102.
    Kälviäinen R, Nousiainen I. Visual field defects with vigabatrin: epidemiology and therapeutic implications. CNS Drugs 2001; 15: 217–30PubMedCrossRefGoogle Scholar
  103. 103.
    Sills GJ, Patsalos PN, Butler E, et al. Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina. Neurology 2001; 57: 196–200PubMedCrossRefGoogle Scholar
  104. 104.
    Krauss GL, Johnson MA, Sheth S, et al. A controlled study comparing visual function in patients treated with vigabatrin and tiagabine. J Neurosurg Psychiatry 2003; 74: 339–43CrossRefGoogle Scholar
  105. 105.
    Johannessen CU. Mechanisms of action of valproate: a commentatory. Neurochem Int 2000; 37: 103–10PubMedCrossRefGoogle Scholar
  106. 106.
    Johannessen CU, Johannessen SI. An update on valproate: clinical implications of recent studies for its mechanisms of action (SIIC 2004) [online]. Available from URL: [Accessed 2007 Sep 17]
  107. 107.
    Rudolph U, Möhler H. GABA-based therapeutic approaches: GABAa receptor subtype functions. Current Opin Pharmacol 2006; 6: 18–23CrossRefGoogle Scholar
  108. 108.
    Bennett S, Gronier B. Modulation of striatal dopamine release in vitro by agonists of the glycine B site of NMDA receptors: interaction with antipsychotics. Eur J Pharmacol 2005; 527: 52–9PubMedCrossRefGoogle Scholar
  109. 109.
    Hosak L, Libiger J. Antiepileptic drugs in schizophrenia: a review. Eur Psychiatry 2002; 17: 371–8PubMedCrossRefGoogle Scholar
  110. 110.
    Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20: 6969–78PubMedCrossRefGoogle Scholar
  111. 111.
    Anmann B, Grunze H. Neurochemical underpinnings in bipolar disorder and epilepsy. Epilepsia 2005; 46Suppl. 4: 26–30CrossRefGoogle Scholar
  112. 112.
    Greene JG. Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease. J Physiol 2006; 575: 411–6PubMedCrossRefGoogle Scholar
  113. 113.
    Manji HK, Duman RS. Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 2001; 35: 5–49PubMedGoogle Scholar
  114. 114.
    Rogawski M. Astrocytes get in the act in epilepsy. Nat Med 2005; 11: 919–20PubMedCrossRefGoogle Scholar
  115. 115.
    Guo-Feng T, Hooman A, Takano T, et al. An astrocytic basis of epilepsy. Nat Med 2005; 11: 973–81Google Scholar
  116. 116.
    Harwood AJ, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol 2003; 66: 179–89PubMedCrossRefGoogle Scholar
  117. 117.
    Cordeiro ML, Gundersen CB, Umbach JA. Convergent effects of lithium and valproate on the expression of proteins associated with large dense core vesicles in NGF-differentiated PC12 Cells. Neuropsychopharmacol 2004; 29: 39–44CrossRefGoogle Scholar
  118. 118.
    Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull 2003; 37: 17–24PubMedGoogle Scholar
  119. 119.
    Arban R, Maraia G, Brackenborough K, et al. Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania. Behav Brain Res 2005; 158: 123–32PubMedCrossRefGoogle Scholar
  120. 120.
    Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharmacol 2003; 23: 484–95PubMedCrossRefGoogle Scholar
  121. 121.
    Muzina DJ, Elhaj O, Gajwani P, et al. Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta Psychiatr Scand 2005; 111: 21–8CrossRefGoogle Scholar
  122. 122.
    Selai C, Bannister D, Trimble M. Antiepileptic drugs and the regulation of mood and quality of life (QOL): the evidence from epilepsy. Epilepsia 2005; 46 Suppl. 4: 50–7CrossRefGoogle Scholar
  123. 123.
    Berudsky Y. Phenytoin: an anti-bipolar anticonvulsant? Int J Neuropsychopharmacol 2006; 9: 627–8CrossRefGoogle Scholar
  124. 124.
    Gajwani P, Forsthoff A, Muzina D, et al. Antiepileptic drugs in mood-disordered patients. Epilepsia 2005; 46Suppl. 4: 38–44PubMedCrossRefGoogle Scholar
  125. 125.
    Silberstein SD. Shared mechanisms and comorbidities in neurologic and psychiatric disorders. Headache 2001; 41: S11–7PubMedCrossRefGoogle Scholar
  126. 126.
    Prueter C, Norra C. Mood disorders and their treatment in patients with epilepsy. J Neuropsychiatry Clin Neurosci 2005; 17: 20–8PubMedCrossRefGoogle Scholar
  127. 127.
    Ettinger AB, Reed ML, Goldberg JL, et al. Prevalence of bipolar symptoms in epilepsy vs other chronic health disorders. Neurology 2005; 65: 535–40PubMedCrossRefGoogle Scholar
  128. 128.
    Schmitz B. Depression and mania in patients with epilepsy. Epilepsia 2005; 46 Suppl. 4: 45–9CrossRefGoogle Scholar
  129. 129.
    Kanner AM. Depression in epilepsy: a neurobiological perspective. Epilepsy Curr 2005; 5: 21–7PubMedCrossRefGoogle Scholar
  130. 130.
    Ettinger AB, Kustra RP, Hammer AE. Effect of lamotrigine on depressive symptoms in adult patients with epilepsy. Epilepsy Behav 2007; 10: 148–54PubMedCrossRefGoogle Scholar
  131. 131.
    Jobe PC. Shared mechanisms of antidepressant and antiepileptic treatments: drugs and devices. Clin EEG Neurosci 2004; 35: 25–37PubMedGoogle Scholar
  132. 132.
    Jobe PC. Affective disorder and epilepsy comorbidity: implications for development of treatments, preventions and diagnostic approaches. Clin EEG Neurosci 2004; 35: 53–68PubMedGoogle Scholar
  133. 133.
    Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology 1994; 44: 2105–10PubMedCrossRefGoogle Scholar
  134. 134.
    Bigal ME, Lipton RB, Cohen J, et al. Epilepsy and migraine. Epilepsy Behav 2003; 4: S13–24PubMedCrossRefGoogle Scholar
  135. 135.
    Sechi G, Cocco GA, D’Onofrio M, et al. Disfluent speech in patients with partial epilepsy: beneficial effect of levetiracetam. Epilepsy Behav 2006; 9: 521–3PubMedCrossRefGoogle Scholar
  136. 136.
    Applebaum J, Gayduk J, Agam G, et al. Valnoctamide as a valproate substitute with low teragenic potential: double-blind controlled clinical trial. Bipolar Disord 2005; 7: 27–117CrossRefGoogle Scholar
  137. 137.
    Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull 2003; 37: 5–16PubMedGoogle Scholar
  138. 138.
    Yeow WS, Ziauddin MF, Maxhimer JB, et al. Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01. Br J Cancer 2006; 22: 1436–45CrossRefGoogle Scholar
  139. 139.
    Eyal S, Yagen B, Shimshoni J, et al. Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active constitutional isomers and derivatives. Biochem Pharmacol 2005; 69: 1501–8PubMedCrossRefGoogle Scholar
  140. 140.
    Eyal S, Lamb J, Smith-Yockman M, et al. The antiepileptic and chemotherapeutic agent valproic acid induces P-glycoprotein in human tumor cell lines and in rat liver. Br J Pharmacol 2006; 149: 250–60PubMedCrossRefGoogle Scholar
  141. 141.
    Peixoto MF, Abilio VC, Silva RH, et al. Effects of valproic acid on an animal model of tardive dyskinesia. Behav Brain Res 2003; 142: 229–33PubMedCrossRefGoogle Scholar
  142. 142.
    Myrick H, Malcolm R, Anton R. The use of antiepileptics in the treatment of addictive disorders. Prim Psychiatry 2003; 10: 59–63Google Scholar
  143. 143.
    Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomized controlled trial. Lancet 2003; 361: 1677–85PubMedCrossRefGoogle Scholar
  144. 144.
    Vocci FJ, Elkashef A. Pharmacotherapy and other treatments for cocaine abuse and dependence. Curr Opin Psychiatry 2005; 18: 265–70PubMedCrossRefGoogle Scholar
  145. 145.
    Brodie JD, Figuerosa E, Laska EM, et al. Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of metham-phetamine and/or cocaine addiction. Synapse 2005; 55: 122–5PubMedCrossRefGoogle Scholar
  146. 146.
    Brown ES, Perantie DC, Dhanani N, et al. Lamotrigine for bipolar disorder and comorbid cocaine dependence: a replication and extension study. J Affect Disord 2006; 93: 219–22PubMedCrossRefGoogle Scholar
  147. 147.
    Hoopes SP, Reimherr FW, Hedges DW, et al. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial (Pt 1): improvement in binge and purge measures. J Clin Psych 2003; 64: 1335–41CrossRefGoogle Scholar
  148. 148.
    Nickel C, Tritt K, Muehlbacher M, et al. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int Eat Disord 2005; 38: 295–300CrossRefGoogle Scholar
  149. 149.
    Lomia M, Tchelidze T, Pruidze M. Bronchial asthma as neurogenic paroxysmal inflammatory disease: a randomized trial with carbamazepine. Respir Med 2006; 100: 1988–96PubMedCrossRefGoogle Scholar
  150. 150.
    Costa C, Martella G, Picconi B, et al. Multiple mechanisms underlying the neuroprotective effects of antiepileptic drugs against in vitro ischemia. Stroke 2006; 37: 1319–26PubMedCrossRefGoogle Scholar
  151. 151.
    Wallis RA, Panizzon KL, Niquet J, et al. Neuroprotective effects of the anticonvulsant, fluorofelbamate [abstract]. Epilepsia 2000; 41: 162–3CrossRefGoogle Scholar
  152. 152.
    Dou H, Birusingh K, Faraci J, et al. Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J Neurosci 2003; 23: 9162–70PubMedGoogle Scholar
  153. 153.
    De Paulis T. ONO-2506. Curr Opin Invest Drug 2003; 4: 863–7Google Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Department of Pharmacy, Faculty of Health SciencesOslo University CollegeOsloNorway

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