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.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
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): 204–15
Niespodziany I, Klitgaard H, Margineanu DG. Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices. Neuroreport 2003; 14(9): 1273–6
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): 474–9
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): 191–206
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): 370–88
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): 1201–8
Strakowski SM, Delbello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 2005; 10(1): 105–16
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): 598–607
Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004; 161(11): 1957–66
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): 830–43
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): 659–72
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): 208–16
Poulain P, Margineanu DG. Levetiracetam opposes the action of GABAA antagonists in hypothalamic neurones. Neurophar-macology 2002; 42(3): 346–52
Brambilla P, Perez J, Barale F, et al. GABAergic dysfunction in mood disorders. Mol Psychiatry 2003; 8(8): 721–37
Sanacora G, Mason GF, Krystal JH. Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 2000; 14(1): 23–45
Shiah I-S, Yatham LN. GABA function in mood disorders: an update and critical review. Life Sci 1998; 63(15): 1289–303
Petty F. GABA and mood disorders: a brief review and hypothesis. J Affect Disord 1995; 34(4): 275–81
Benes FM, Berretta S. GABAergic interneurons; implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25(1): 1–27
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): 252–60
Motohashi N. GABA receptor alterations after chronic lithium administration: comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16(4): 571–9
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): 601–4
Berrettini WH, Rubinow DR, Nurnberger Jr JI, et al. CSF substance P immuno-reactivity in affective disorders. Biol Psychiatry 1985; 20(9): 965–70
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): 617–25
Shiah IS, Yatham LN, Baker GB. Divalproex sodium increases plasma GABA levels in healthy volunteers. Int Clin Psychopharmacol 2000; 15(4): 221–5
Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42Suppl. 4: 24–7
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): 1370–6
Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85(2): 77–85
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): 250–4
Klitgaard H. Levetiracetam: The preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001; 42Suppl. 4: 13–8
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): 279–86
Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 2002; 43(1): 9–18
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): 5–8
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): 366–72
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): 611–8
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: 1146–50
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: 137–46
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): 9861–6
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): 333–42
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): 881–4
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): 1276–83
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): 80–7
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): 236–42
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): 1179–86
Physician’s Desk Reference. Montvale (NJ): Medical Economics Co, Inc; 2004
Harden C. Safety profile of levetiracetam. Epilepsia 2001; 42 Suppl. 4: 36–9
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): 77–90
Mula M, Trimble M, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003; 61(5): 704–6
Vigevano F. Levetiracetam in pediatrics. J Child Neurol 2005; 20(2): 87–93
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: 32–9
Glauser TA, Ayala R, Elterman RD, et al. Double-blind, placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006; 66: 1654–60
Bergey G. Initial treatment of epilepsy: special issues in treating the elderly. Neurology 2004; 63: S40–8
Cramer J, Leppik I, De Rue K, et al. Tolerability of levetiracetam in elderly patients with CNS disorders. Epilepsy Res 2003; 56: 135–45
Alsaadi T, Koopmans S, Apperson M, et al. Levetiracetam monotherapy for elderly patients with epilepsy. Scizure 2004; 13(1): 58–60
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: 702–9
Gibson G. Efficacy of levetiracetam in developmentally disabled patients: a review of the literature and six case reports. Epilepsy Behav 2002; 3: 280–4
Kaplan L. The effect of levetiracetam on behavior and seizures in mentally retarded adults with refractory epilepsy [abstract]. Epilepsia 2001; 42: 152
O’Rourke MH, Sharma D, Besag F. Add-on levetiracetam in adult mental retardation with intractable seizures [abstract]. Epilepsia 2001; 42: 155
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: 231–5
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: 168–75
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): 280–4
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): 1112–4
Chatterjee A, Louis E, Frucht S. Levetiracetam in the treatment of paroxysmal kinesiogenic choreoathetosis. Mov Disord 2002; 17(3): 614–5
Enggaard T, Klitgaard N, Sindrup S. Specific effect of levetiracetam in experimental human pain models. Eur J Pain 2006; 10(3): 193–8
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: 35–44
Miller G. Efficacy and safety of levetiracetam in pediatric migraine. Epilepsy Res 2005; 64: 35–44
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 press
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): 234–9
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): 1463–73
Lamberty Y, Margineanu DG, Klitgaard H. Effect of the new antiepileptic drug levetiracetam in an animal model of mania. Epilepsy Behav 2001; 2(5): 454–9
Lamberty Y, Gower A, Klitgaard H. The new antiepileptic drug levetiracetam normalizes chlordiazepoxide withdrawal-induced anxiety in mice. Eur J Pharmacol 2003; 439: 101–6
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: 67–74
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: 97–102
Goldberg JF, Burdick KE. Levetiracetam for acute mania. Am J Psychiatry 2002; 159(1): 148
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:S57
Braunig P, Kruger S. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol 2003; 17(2): 239–41
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): 781–4
Kaufman KR. Monotherapy treatment of bipolar disorder with levetiracetam. Epilepsy Behav 2004; 5(6): 1017–20
Bersani G. Levetiracetam in bipolar spectrum disorders: first evidence of efficacy in an open, add-on study. Hum Psychopharmacol 2004; 19(5): 355–6
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): 370–4
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): 1928–31
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Muralidharan, A., Bhagwagar, Z. Potential of Levetiracetam in. CNS Drugs 20, 969–979 (2006). https://doi.org/10.2165/00023210-200620120-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-200620120-00002