Chemical Name: (S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide
Therapy Type: Small Molecule
Target Type: APP and Amyloid-Related (timeline), Other
Condition(s): Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Discontinued)
Company: GlaxoSmithKline (GSK), Otsuka Pharmaceutical Co., Ltd., UCB S.A.
Approved for: Epilepsy and Partial Seizures in U.S., European Union, plus about 20 other countries
Levetiracetam is a modulator of the synaptic vesicle protein modulator SV2A. It was developed for the treatment of epilepsy but, as a pyrrolidone acetamide, is chemically unrelated to most other anticonvulsive medications. This drug is available as an oral syrup, an intravenous infusion, and immediate- and extended-release tablets. Generic equivalents of these formulations are on the market, as well, and the drug is widely used. Levetiracetam's most frequent side effects are sleepiness, headache, and lack of energy.
Levetiracetam's mechanism of action is not fully understood. It does not act on the GABAergic system and is inactive at classic receptor sites linked to epileptic seizures, such as amino acid-related receptors, adenosine receptors, and ion channels (Sills et al. , 1997). Early on, inhibition of calcium signaling or depolarizing currents were proposed as possible mechanisms of action (Margineanu and Wülfert, 1997).
More recently, SV2A and Levetiracetam have come to be of interest in Alzheimer's research. A human transcriptome study has implicated SV2A in mediating the effect of the ApoE4 risk allele on APP processing, and Levetiracetam in reducing Aβ generation in cells cultured from ApoE4 carriers (see Jul 2013 news story). More broadly, a line of research has sprung up around Aβ-induced hyperactivation, aberrant network activity, and nonconvulsive seizures. These phenotypes are seen in the J20, APP23, APP/PS1, and certain strains of Tg2576 transgenic mouse models of AD (see Sep 2007 news story; Lalonde et al., 2005; Minkeviciene et al., 2009; Shi et al. 2013). In the J20 mice, Levetiracetam was reported to quiet epileptiform activity, reverse hyperactivity in behavioral assays, and deficits in spatial learning assays (see Aug 2012 news story). The drug was reported to reduce hippocampal hyperactivation and improve memory performance in an aging rat model (see Koh et al., 2010).
In humans, observational research is ongoing on the nature and incidence of nonconvulsive seizures and their relationship to cognitive decline in the early stages of Alzheimer's disease, such as amnestic mild cognitive impairment (aMCI) (see Sep 2007 news story).
In a single-center, placebo-controlled Phase 2 trial in 17 people with aMCI and 17 age-matched controls, a two-week course of 50–500 mg of Levetiracetam twice a day reportedly reduced hippocampal activity as measured by fMRI and improved performance on a hippocampal memory task. Other tests in a neuropsychological test battery showed no response (see May 2012 news story).
A one-year study of Levetiracetam in Alzheimer's patients who had seizures reported improved attention, verbal fluency, and good tolerability for its use in controlling seizures in AD (see Cumbo and Ligori, 2010). It is unclear whether these benefits derived from reduced seizures or global cognitive benefits.
An ongoing, single-center clinical study comparing a low and a high dose of Levetiracetam to placebo is enrolling 20 patients with mild AD who have seizures. This trial uses perfusion MRI to evaluate whether Levetiracetam normalizes blood flow in the course of controlling seizures. Memory and executive function tests are primary outcomes. For clinical trials on Levetiracetam, see clinicialtrials.gov.
In addition, Levetiracetam has been tested in patients with Parkinson's disease. Prompted by preclinical data suggesting that Levetiracetam reduces side effects of long-term levodopa therapy in nonhuman primates (Brotchie JM, et al. Neurology. 60 (Suppl. 1): 331, 11 Mar 2003), numerous small clinical trials were conducted in patients with Parkinson's disease who had levodopa treatment-induced dyskinesia. One small pilot trial reported improvements such as longer “on” time without dyskinesia and shorter “off” time with dyskinesia, but subsequent randomized controlled trials produced mixed results. Some studies indicated modest improvement, others did not, and yet others cautioned that PD patients do not tolerate Levetiracetam well (see Wolz et al., 2010; Stathis et al., 2011; Wong et al., 2011; Lyons and Pahwa, 2006).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- Epilepsy Drug Calms the Hippocampus, Aids Memory
- A Genetic Approach to the ApoE4 Puzzle
- Do "Silent" Seizures Cause Network Dysfunction in AD?
- Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
Research Models Citations
- Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Epilepsy Behav. 2010 Apr;17(4):461-6. PubMed.
- Wolz M, Löhle M, Strecker K, Schwanebeck U, Schneider C, Reichmann H, Grählert X, Schwarz J, Storch A. Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. J Neural Transm. 2010 Nov 1;117(11):1279-86. Epub 2010 Aug 29 PubMed.
- Stathis P, Konitsiotis S, Tagaris G, Peterson D. Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2011 Jan 1;26(2):264-70. Epub 2010 Dec 13 PubMed.
- Wong KK, Alty JE, Goy AG, Raghav S, Reutens DC, Kempster PA. A randomized, double-blind, placebo-controlled trial of levetiracetam for dyskinesia in Parkinson's disease. Mov Disord. 2011 Jul 1;26(8):1552-5. Epub 2011 Apr 29 PubMed.
- Lyons KE, Pahwa R. Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol. 2006 May-Jun;29(3) PubMed.
- Sills GJ, Leach JP, Fraser CM, Forrest G, Patsalos PN, Brodie MJ. Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol. 1997 Apr 23;325(1) PubMed.
- Margineanu DG, Wülfert E. Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus. Br J Pharmacol. 1997 Nov 1;122(6):1146-50. PubMed.
- Lalonde R, Dumont M, Staufenbiel M, Strazielle C. Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen. Behav Brain Res. 2005 Feb 10;157(1):91-8. PubMed.
- Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B, Zilberter Y, Harkany T, Pitkänen A, Tanila H. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009 Mar 18;29(11):3453-62. PubMed.
- Shi JQ, Wang BR, Tian YY, Xu J, Gao L, Zhao SL, Jiang T, Xie HG, Zhang YD. Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice. CNS Neurosci Ther. 2013 Nov;19(11):871-81. PubMed.
- Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. PubMed.
- Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer's disease or vascular dementia: A population-based nested case-control analysis. Epilepsia. 2012 Dec 6; PubMed.
- Lippa CF, Rosso A, Hepler M, Jenssen S, Pillai J, Irwin D. Levetiracetam: a practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimers Dis Other Demen. 2010 Mar;25(2):149-54. PubMed.
- Scharfman HE. "Untangling" Alzheimer's disease and epilepsy. Epilepsy Curr. 2012 Sep;12(5):178-83. PubMed.
- Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging. 2003;20(11):791-803. PubMed.
- Devi L, Ohno M. Effects of levetiracetam, an antiepileptic drug, on memory impairments associated with aging and Alzheimer's disease in mice. Neurobiol Learn Mem. 2013 May;102:7-11. PubMed.
- Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced Alzheimer's disease is a risk factor for late-onset seizures. Arch Neurol. 1990 Aug;47(8):847-50. PubMed.
- Belcastro V, Costa C, Galletti F, Pisani F, Calabresi P, Parnetti L. Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur J Neurol. 2007 Oct;14(10):1176-8. PubMed.
- Weiner MF, Womack KB, Martin-Cook K, Svetlik DA, Hynan LS. Levetiracetam for agitated Alzheimer's disease patients. Int Psychogeriatr. 2005 Jun;17(2):327-8. PubMed.
- Zesiewicz TA, Sullivan KL, Maldonado JL, Tatum WO, Hauser RA. Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2005 Sep 1;20(9):1205-9. PubMed.