CNS Drugs

, Volume 20, Issue 12, pp 969–979 | Cite as

Potential of Levetiracetam in

A Preliminary Review
Leading Article

Abstract

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.

Keywords

Bipolar Disorder Olanzapine Mood Disorder Levetiracetam Partial Seizure 

Notes

Acknowledgements

The authors would like to thank the Stanley Foundation for funding the first placebo-controlled clinical trial of levetiracetam in bipolar depression, which is being conducted at the Department of Psychiatry, Yale School of Medicine through the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center, New Haven, Connecticut, USA.

Dr Bhagwagar is the primary investigator on a double-blind, placebo-controlled trial of levetiracetam as an adjunctive therapy in bipolar depression, funded by the Stanley Medical Research Institute (SMRI 05T-681). This study has been running since October 2005.

Dr Bhagwagar is on the speakers panel for AstraZeneca and Bristol Myers Squibb and has served on advisory boards for Janssen Cilag in the US, as well as Eli Lilly, GlaxoSmithKline and Bristol Myers Squibb in the UK. Dr Muralidharan has no conflicts of interest that are directly relevant to the contents of this review.

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

References

  1. 1.
    Husum H, Bolwig TG, Sanchez C, et al. Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties. Epilepsy Behav 2004; 5(2): 204–15PubMedCrossRefGoogle Scholar
  2. 2.
    Niespodziany I, Klitgaard H, Margineanu DG. Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices. Neuroreport 2003; 14(9): 1273–6PubMedCrossRefGoogle Scholar
  3. 3.
    Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998; 284(2): 474–9PubMedGoogle Scholar
  4. 4.
    Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol 1998; 353(2–3): 191–206PubMedCrossRefGoogle Scholar
  5. 5.
    Anand A, Shekhar A. Brain imaging studies in mood and anxiety disorders: special emphasis on the amygdala. Ann N Y Acad Sci 2003; 985(1): 370–88PubMedCrossRefGoogle Scholar
  6. 6.
    Blumberg HP, Kaufman J, Martin A, et al. Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60(12): 1201–8PubMedCrossRefGoogle Scholar
  7. 7.
    Strakowski SM, Delbello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 2005; 10(1): 105–16PubMedCrossRefGoogle Scholar
  8. 8.
    Campbell S, Marriott M, Nahmias C, et al. Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 2004; 161(4): 598–607PubMedCrossRefGoogle Scholar
  9. 9.
    Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004; 161(11): 1957–66PubMedCrossRefGoogle Scholar
  10. 10.
    Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48(8): 830–43PubMedCrossRefGoogle Scholar
  11. 11.
    Rigo JM, Hans G, Nguyen L, et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 2002; 136(5): 659–72PubMedCrossRefGoogle Scholar
  12. 12.
    Loscher W, Honack D, Bloms-Funke P. The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. Brain Res 1996; 735(2): 208–16PubMedCrossRefGoogle Scholar
  13. 13.
    Poulain P, Margineanu DG. Levetiracetam opposes the action of GABAA antagonists in hypothalamic neurones. Neurophar-macology 2002; 42(3): 346–52Google Scholar
  14. 14.
    Brambilla P, Perez J, Barale F, et al. GABAergic dysfunction in mood disorders. Mol Psychiatry 2003; 8(8): 721–37PubMedCrossRefGoogle Scholar
  15. 15.
    Sanacora G, Mason GF, Krystal JH. Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 2000; 14(1): 23–45PubMedCrossRefGoogle Scholar
  16. 16.
    Shiah I-S, Yatham LN. GABA function in mood disorders: an update and critical review. Life Sci 1998; 63(15): 1289–303PubMedCrossRefGoogle Scholar
  17. 17.
    Petty F. GABA and mood disorders: a brief review and hypothesis. J Affect Disord 1995; 34(4): 275–81PubMedCrossRefGoogle Scholar
  18. 18.
    Benes FM, Berretta S. GABAergic interneurons; implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25(1): 1–27PubMedCrossRefGoogle Scholar
  19. 19.
    Torrey EF, Barci BM, Webster MJ, et al. Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. Biol Psychiatry 2005; 57(3): 252–60PubMedCrossRefGoogle Scholar
  20. 20.
    Motohashi N. GABA receptor alterations after chronic lithium administration: comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16(4): 571–9PubMedCrossRefGoogle Scholar
  21. 21.
    Vargas C, Tannhauser M, Barros HM. Dissimilar effects of lithium and valproic acid on GABA and glutamine concentrations in rat cerebrospinal fluid. Gen Pharmacol 1998; 30(4): 601–4PubMedCrossRefGoogle Scholar
  22. 22.
    Berrettini WH, Rubinow DR, Nurnberger Jr JI, et al. CSF substance P immuno-reactivity in affective disorders. Biol Psychiatry 1985; 20(9): 965–70PubMedCrossRefGoogle Scholar
  23. 23.
    Larsson OM, Gram L, Schousboe I, et al. Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes. Neuropharmacology 1986; 25(6): 617–25PubMedCrossRefGoogle Scholar
  24. 24.
    Shiah IS, Yatham LN, Baker GB. Divalproex sodium increases plasma GABA levels in healthy volunteers. Int Clin Psychopharmacol 2000; 15(4): 221–5PubMedCrossRefGoogle Scholar
  25. 25.
    Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42Suppl. 4: 24–7PubMedCrossRefGoogle Scholar
  26. 26.
    Coupez R, Straetemans R, Sehgal G, et al. Levetiracetam: relative bioavailability and bioequivalence of a 10% oral solution (750mg) and 750mg tablets. J Clin Pharmacol 2003; 43(12): 1370–6PubMedCrossRefGoogle Scholar
  27. 27.
    Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85(2): 77–85PubMedCrossRefGoogle Scholar
  28. 28.
    Nicolas JM, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Dispos 1999; 27(2): 250–4PubMedGoogle Scholar
  29. 29.
    Klitgaard H. Levetiracetam: The preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001; 42Suppl. 4: 13–8PubMedGoogle Scholar
  30. 30.
    Zona C, Niespodziany I, Marchetti C, et al. Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Scizure 2001; 10(4): 279–86CrossRefGoogle Scholar
  31. 31.
    Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 2002; 43(1): 9–18PubMedCrossRefGoogle Scholar
  32. 32.
    Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 2001; 306(1-2): 5–8PubMedCrossRefGoogle Scholar
  33. 33.
    Roberts GM, Majoie H, Leenen LA, et al. Ketter’s hypothesis of the mood effects of antiepileptic drugs coupled to the mechanism of action of topiramate and levetiracetam. Epilepsy Behav 2005; 6(3): 366–72PubMedCrossRefGoogle Scholar
  34. 34.
    Birnstiel S, Wulfert E, Beck SG. Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission. Naunyn Schmiedebergs Arch Pharmacol 1997; 356(5): 611–8PubMedCrossRefGoogle Scholar
  35. 35.
    Margineanu DG, Wulfert E. Inhibition by levetiracetam of a non GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus. Br J Pharmacol 1997; 122: 1146–50PubMedCrossRefGoogle Scholar
  36. 36.
    Noyer M, Gillard M, Matagne A. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995; 286: 137–46PubMedCrossRefGoogle Scholar
  37. 37.
    Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004; 101(26): 9861–6PubMedCrossRefGoogle Scholar
  38. 38.
    Lamberty Y, Margineanu DG, Klitgaard H. Absence of negative impact of levetiracetam on cognitive function and memory in normal and amygdala-kindled rats. Epilepsy Behav 2000; 1(5): 333–42PubMedCrossRefGoogle Scholar
  39. 39.
    Barrueto Jr F, Williams K, Howland MA, et al. A case of levetiracetam (Keppra) poisoning with clinical and toxicokinetic data. J Toxicol Clin Toxicol 2002; 40(7): 881–4PubMedCrossRefGoogle Scholar
  40. 40.
    Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000; 41(10): 1276–83PubMedCrossRefGoogle Scholar
  41. 41.
    Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam 2000mg daily and 4000mg daily, without titration in patients with refractory epilepsy. Scizure 2000; 9(2): 80–7CrossRefGoogle Scholar
  42. 42.
    Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55(2): 236–42PubMedCrossRefGoogle Scholar
  43. 43.
    Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41(9): 1179–86PubMedCrossRefGoogle Scholar
  44. 44.
    Physician’s Desk Reference. Montvale (NJ): Medical Economics Co, Inc; 2004Google Scholar
  45. 45.
    Harden C. Safety profile of levetiracetam. Epilepsia 2001; 42 Suppl. 4: 36–9PubMedGoogle Scholar
  46. 46.
    French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 2001; 47(1-2): 77–90PubMedCrossRefGoogle Scholar
  47. 47.
    Mula M, Trimble M, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003; 61(5): 704–6PubMedCrossRefGoogle Scholar
  48. 48.
    Vigevano F. Levetiracetam in pediatrics. J Child Neurol 2005; 20(2): 87–93PubMedCrossRefGoogle Scholar
  49. 49.
    Speechio LM, Gambardella A, Giallonardo AT, et al. Open label, long-term, pragmatic study on levetiracetam in the treatment of juvenile myoclonic epilepsy. Epilepsy Res 2006; 71: 32–9CrossRefGoogle Scholar
  50. 50.
    Glauser TA, Ayala R, Elterman RD, et al. Double-blind, placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006; 66: 1654–60PubMedCrossRefGoogle Scholar
  51. 51.
    Bergey G. Initial treatment of epilepsy: special issues in treating the elderly. Neurology 2004; 63: S40–8PubMedCrossRefGoogle Scholar
  52. 52.
    Cramer J, Leppik I, De Rue K, et al. Tolerability of levetiracetam in elderly patients with CNS disorders. Epilepsy Res 2003; 56: 135–45PubMedCrossRefGoogle Scholar
  53. 53.
    Alsaadi T, Koopmans S, Apperson M, et al. Levetiracetam monotherapy for elderly patients with epilepsy. Scizure 2004; 13(1): 58–60CrossRefGoogle Scholar
  54. 54.
    Ferrendelli J. Use of levetiracetam in a population of patients aged 65 and older: a subset analysis of the KEEPER trial. Epilepsy Behav 2003; 4: 702–9PubMedCrossRefGoogle Scholar
  55. 55.
    Gibson G. Efficacy of levetiracetam in developmentally disabled patients: a review of the literature and six case reports. Epilepsy Behav 2002; 3: 280–4PubMedCrossRefGoogle Scholar
  56. 56.
    Kaplan L. The effect of levetiracetam on behavior and seizures in mentally retarded adults with refractory epilepsy [abstract]. Epilepsia 2001; 42: 152Google Scholar
  57. 57.
    O’Rourke MH, Sharma D, Besag F. Add-on levetiracetam in adult mental retardation with intractable seizures [abstract]. Epilepsia 2001; 42: 155Google Scholar
  58. 58.
    Brodtkorb E, Klees TM, Nakken KO, et al. Levetiracetam in adult patients with and without learning disability: focus on behavioral adverse effects. Epilepsy Behav 2004; 5: 231–5PubMedCrossRefGoogle Scholar
  59. 59.
    Huber B, Bommel W, Hauser I, et al. Efficacy and tolerability of levetiracetam in patients with therapy-resistant epilepsy and learning disabilities. Scizure 2004; 13: 168–75CrossRefGoogle Scholar
  60. 60.
    Zesiewicz T, Sullivan K, Maldonado J, et al. Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2005; 20(9): 280–4CrossRefGoogle Scholar
  61. 61.
    Frucht S, Louis E, Chuang C, et al. A pilot tolerability and efficacy study of levetiracetam in patients with chronic myoclonus. Neurology 2001; 57(6): 1112–4PubMedCrossRefGoogle Scholar
  62. 62.
    Chatterjee A, Louis E, Frucht S. Levetiracetam in the treatment of paroxysmal kinesiogenic choreoathetosis. Mov Disord 2002; 17(3): 614–5PubMedCrossRefGoogle Scholar
  63. 63.
    Enggaard T, Klitgaard N, Sindrup S. Specific effect of levetiracetam in experimental human pain models. Eur J Pain 2006; 10(3): 193–8PubMedCrossRefGoogle Scholar
  64. 64.
    Janzsky J, Pannek H, Janzsky I, et al. Failed surgery for temporal lobe epilepsy: predictors for a long-term seizure-free course. Epilepsy Res 2005; 64: 35–44CrossRefGoogle Scholar
  65. 65.
    Miller G. Efficacy and safety of levetiracetam in pediatric migraine. Epilepsy Res 2005; 64: 35–44CrossRefGoogle Scholar
  66. 66.
    Ciesielski A-S, Samson S, Steinhoff BJ. Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study. Epilepsy Behav. In pressGoogle Scholar
  67. 67.
    Post RM, Putnam F, Contel NR, et al. Electroconvulsive seizures inhibit amygdala kindling: implications for mechanisms of action in affective illness. Epilepsia 1984; 25(2): 234–9PubMedCrossRefGoogle Scholar
  68. 68.
    Husum H, Mikkelsen JD, Hogg S, et al. Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram. Neuropharmacology 2000; 39(8): 1463–73PubMedCrossRefGoogle Scholar
  69. 69.
    Lamberty Y, Margineanu DG, Klitgaard H. Effect of the new antiepileptic drug levetiracetam in an animal model of mania. Epilepsy Behav 2001; 2(5): 454–9PubMedCrossRefGoogle Scholar
  70. 70.
    Lamberty Y, Gower A, Klitgaard H. The new antiepileptic drug levetiracetam normalizes chlordiazepoxide withdrawal-induced anxiety in mice. Eur J Pharmacol 2003; 439: 101–6CrossRefGoogle Scholar
  71. 71.
    Gower A, Falter U, Lamberty Y. Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat. Eur J Pharmacol 2003; 481: 67–74PubMedCrossRefGoogle Scholar
  72. 72.
    Lamberty Y, Falter U, Gower A, et al. Anxiolytic profile of the antiepileptic drug levetiracetam in the Vogel conflict test in the rat. Eur J Pharmacol 2003; 469: 97–102PubMedCrossRefGoogle Scholar
  73. 73.
    Goldberg JF, Burdick KE. Levetiracetam for acute mania. Am J Psychiatry 2002; 159(1): 148PubMedCrossRefGoogle Scholar
  74. 74.
    Soria CA, Remedi C. Levetiracetam as mood stabilizer in the treatment of pharmacogenic hypomania in bipolar disorder II in elderly patients. Int J Neuropsychopharmacol 2002; 5 Suppl.1:S57Google Scholar
  75. 75.
    Braunig P, Kruger S. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol 2003; 17(2): 239–41PubMedCrossRefGoogle Scholar
  76. 76.
    Grunze H, Langosch J, Born C, et al. Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design. J Clin Psychiatry 2003; 64(7): 781–4PubMedCrossRefGoogle Scholar
  77. 77.
    Kaufman KR. Monotherapy treatment of bipolar disorder with levetiracetam. Epilepsy Behav 2004; 5(6): 1017–20PubMedCrossRefGoogle Scholar
  78. 78.
    Bersani G. Levetiracetam in bipolar spectrum disorders: first evidence of efficacy in an open, add-on study. Hum Psychopharmacol 2004; 19(5): 355–6PubMedCrossRefGoogle Scholar
  79. 79.
    Post RM, Altshuler LL, Frye MA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005; 66(3): 370–4PubMedCrossRefGoogle Scholar
  80. 80.
    Stoner SC, Lea J, Wolf AL, et al. Levetiracetam for mood stabilization and maintenance of seizure control following multiple treatment failures. Ann Pharmacother 2005; 39(11): 1928–31PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of PsychiatryYale UniversityNew HavenUSA

Personalised recommendations