Background

Levetiracetam is an atypical anti-convulsant medication and 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 anti-convulsives. Levetiracetam 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. Its side effects include sleepiness, headache, lack of energy, and others.

This compound'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).

In recent years, Alzheimer’s research has characterized Aβ-induced hyperactivation, aberrant network activity, and nonconvulsive seizure phenotypes in the J20, APP23, APP/PS1, and in certain strains of Tg2576 transgenic mouse models of AD amyloidosis (Sep 2007 news; Lalonde et al., 2005; Minkeviciene et al., 2009; Shi et al., 2013). In J20 mice, levetiracetam was reported to quiet epileptiform activity in circuits of the medial temporal lobe network, as well as reverse hyperactivity in behavioral assays and deficits in spatial learning assays (Aug 2012 news). Low doses of the drug reportedly reduce hippocampal hyperactivation and improved memory performance in an aging rat model (Koh et al., 2010). In APP knock-in mice, chronic administration of levetiracetam was reported to reduce levels of Aβ42, the β-carboxyl-terminal fragment bur not full-length APP, reduce plaque burden, and to restore levels of presymptomatic endocytic proteins (Rao and Savas, 2021).

In humans, observational research has linked hippocampal hyperactivity and nonconvulsive seizures to cognitive decline in the early stages of Alzheimer's disease, such as amnestic mild cognitive impairment (aMCI, Dec 2011 news; July 2013 news; Vossel et al., 2016). Further studies reported that seizures or subclinical epileptiform brain activity in people with AD coincide with faster loss of cognitive capabilities and more severe disease (Horvath et al., 2021; Voglein et al., 2020).

A proprietary, low-dose formulation of levetiracetam, AGB101, is in a Phase 3 trial evaluating its ability to improve cognition and slow disease progression in people with MCI and AD.

Findings

A one-year study of levetiracetam at 500-2,000 mg daily in Alzheimer's patients who had seizures reported improved attention, verbal fluency, and good tolerability for its use in controlling seizures in AD (Cumbo and Ligori, 2010). It is unclear whether these benefits derived from reduced seizures or global cognitive benefits.

Levetiracetam doses of 1,000 mg/day are routinely used in older people with epilepsy. Several studies have examined lower doses to see if they can normalize brain activity and improve cognition in people with mild cognitive impairment or AD. In one single-center, placebo-controlled Phase 2 trial of low-dose levetiracetam, 17 people with aMCI and 17 age-matched controls who received a two-week course of 250 mg daily 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 (May 2012 news).

In 2010–2012, researchers at Johns Hopkins University Medical School conducted a within-subject crossover, dose-finding Phase 2 study of low-dose levetiracetam in people with amnestic mild cognitive impairment (aMCI) and a clinical dementia rating (CDR) of 0.5 at screening; controls had a CDR of zero. The trial compared 125, 250, and 500 mg of levetiracetam per day against placebo for their effect on neuronal activity in the hippocampus and entorhinal cortex, as well as for performance on a memory task performed while in an MRI scanner. The study enrolled 69 aMCI patients and 24 controls, and analyzed data from 54 patients and 17 controls; 15 participants dropped out; seven moved while inside the scanner. At the two lower doses, levetiracetam was reported to have improved performance on the scanning memory task; the highest dose yielded no further improvement. The low doses were also reported to have reduced abnormal hyperactivity in the hippocampal dentate gyrus and CA3 regions, and to have boosted abnormal hypoactivation in the entorhinal cortex, both measured by fMRI. Full results were published in a peer-reviewed journal (for paper and commentary, see Bakker et al., 2015).

A 2012–2013 study at Beth Israel Deaconess Medical Center, Boston, compared single administration of 2.5 mg/kg and 7.5 mg/kg of levetiracetam to placebo. This trial enrolled 12 patients with mild AD and seizures, and used perfusion MRI to evaluate whether levetiracetam normalized blood flow in the course of controlling seizures. Memory and executive function tests were secondary outcomes. A paper on this study did not report on blood flow; it did report that the higher dose had network effects, specifically changes in coherence of the delta, low-beta, and high-beta bands. Cognition was unchanged (Musaeus et al., 2017). 

In June 2014, a Phase 2a study at the University of California, San Francisco, and the University of Minnesota, Twin Cities, began enrolling 34 people with AD. This 12-week cross-over trial evaluated 125 mg twice-daily levetiracetam for its ability to improve executive function as per the NIH-EXAMINER composite score, reduce the frequency of epileptiform activity, and improve cognitive function and performance on a virtual navigation task. The trial was originally intended only for people with evidence of seizure activity, but that requirement was later dropped to speed recruitment. The study was completed in July 2020, and results are published (Vossel et al., 2021). Levetiracetam treatment did not change the primary outcome, or any secondary measures in the group as a whole. In a subgroup analysis that compared nine participants with epileptiform brain activity to 13 without, the drug improved performance on two secondary outcomes related to executive function and the navigational task in those with clinical or subclinical seizures. Adverse events were mild; no one left the study because of side effects.

An additional Phase 2 study at Beth Israel Deaconess Medical Center began in August 2019, to determine whether levetiracetam normalizes cortical hyperexcitability, brain network function abnormalities, and cognitive dysfunction in 85 people with early AD. Participants must be between 50 and 80 years old, with a positive PET or CSF markers for brain amyloid, and a Clinical Dementia Rating of 0.5–1.0. In a crossover design, patients receive placebo, 250 mg, or 1000 mg levetiracetam daily for four weeks, with a four-week washout between. Primary outcome measures include change in neuropsychological test battery, plus EEG and other measures of cortical excitability and functional connectivity. Healthy controls with CDR=0 will also be evaluated, but receive no treatment. The trial will end in November 2023.

In October 2018, a Phase 2 study at the University of Oxford began enrolling 30 participants with mild to moderate AD and no history of previous seizures to receive levetiracetam 1,000 mg per day for four weeks. Primary outcome is change in accuracy on a computer-based hippocampal-dependent memory test; secondary outcomes include safety, mood, quality of life. Participants will get an EEG before the study to look for patterns that predict who will benefit from the treatment. The protocol for this study, named ILiAD, is published (Sen et al., 2021).

Starting in January 2020, a Phase 2 trial at Walter Reed National Military Medical Center, Bethesda, Maryland, will enroll 65 participants with clinical AD and neuropsychiatric symptoms. Those with detectable epileptiform activity on EEG will receive 500 mg levetiracetam twice a day for one year. The primary outcome is change on the neuropsychiatric inventory; secondary outcomes include change in measures of AD severity, quality of life, and cognitive ability.

Levetiracetam has also 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 (Bezard et al., 2004), numerous small clinical trials were conducted in patients with Parkinson's and levodopa-induced dyskinesia. One pilot trial reported 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 poorly tolerated levetiracetam (see Wolz et al., 2010; Stathis et al., 2011; Wong et al., 2011; Lyons and Pahwa, 2006).

For clinical trials on levetiracetam in MCI/AD, see clinicialtrials.gov.

Clinical Trial Timeline