Phase 2a Trial to Test Effects of Antiseizure Medication Lamotrigine in Dementia With Lewy Bodies

Author(s):

Key Takeaways

The study evaluates lamotrigine's efficacy in DLB, focusing on functional decline, cognitive fluctuation, and hyperexcitability reduction.
Conducted in Seoul, Korea, the trial involves 60 patients aged 60 and older, comparing lamotrigine with rivastigmine over 20 weeks.
Primary endpoint is the change in Clinical Dementia Rating-Sum of Boxes, with secondary endpoints including cognitive and neuropsychiatric assessments.
Safety and tolerability are assessed, with dosage adjustments based on initial safety evaluations.
Lamotrigine's potential links to DLB are explored, considering its effects on seizure risk and neurodegeneration.

The trial, a 20-week study assessing lamotrigine in DLB, will use change in Clinical Dementia Rating-Sum of Boxes as the primary efficacy end point, with several other notable secondary outcomes.

David Greeley, MD, FAAN

At the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania, investigators presented an outline of a new phase 2a study evaluating the therapeutic potential of lamotrigine (Lamictal), an FDA-approved antiseizure medication, in patients with dementia with Lewy bodies (DLB). The study, which will enroll 60 patients aged 60 years and older from a hospital in Seoul, Korea, is estimated to be completed in early 2025.¹

In the study, eligible participants will be randomly assigned 1:1 to either standard of care (rivastigmine) plus either oral lamotrigine or matching placebo for a 20-week treatment period. The trial will use change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) as the primary end point, with additional secondary end points that included Mini Mental State Examination, CDR, Caregiver Administered-Neuropsychiatric Inventory, Mayo Fluctuation Scale, and Timed up and Go test, among others.

Study authors, which included David Greeley, MD, FAAN, an associate professor of neurology at the University of Washington School of Medicine, and colleagues, primarily will test whether lamotrigine can protect patients with DLB from functional decline and cognitive fluctuation, as well as reduce hyperexcitability. The study has several other secondary end points, including Unified Parkinson’s Rating Scale, quantitative EEG, regional uptake of 18F-Fluorodeoxyglucose PET, plasma phosphorylated tau, glial fibrillary acidic protein, and amyloid-ß (Aß)42/40 ratio.

As expected, safety and tolerability will also be evaluated. During weeks 0-2 of the study, participants will receive a daily dose of 25 mg of lamotrigine. If deemed safe, the dosage will be increased to 25 mg twice daily (BID) for weeks 2-4, and further adjusted to 50 mg BID for weeks 4-20.

Lamotrigine, FDA-approved in 1994, is indicated as a first-line treatment for primary generalized tonic-clonic seizures and Lennox-Gastaut syndrome. While epilepsy and DLB are distinct neurological conditions, several research efforts have highlighted the potential links between them. DLB, like other forms of dementia, is associated with a higher risk of seizures. This may stem from the underlying neurodegenerative processes, which disrupt normal brain activity.

In DLB, the hallmark is the abnormal accumulation of alpha-synuclein in the brain, forming Lewy bodies. This disrupts neural networks and could potentially lower the seizure threshold. In addition, damage to the limbic system and cortical regions in DLB overlaps with areas involved in seizure generation, such as the hippocampus. In addition, patients with epilepsy, especially late-onset epilepsy, have been shown to have a higher risk of developing neurodegenerative diseases, including DLB. The thought is that recurrent seizures and interictal discharges may contribute to neurodegeneration, exacerbating cognitive symptoms.

A previously conducted, 16-week, preliminary open-label trial published in 2014 highlighted the therapeutic potential of lamotrigine when used concomitantly with psychotropic drugs in patients with Alzheimer disease who have behavioral and psychological symptoms of dementia (BPSD). The study featured 40 inpatients, with BPSD assessed through the Neuropsychiatric Inventory (NPI) and cognitive function assessed with the Mini-Mental State Examination. The changes in the dosages of concomitant psychotropic drugs were also assessed.²

Published in Psychogeriatrics, results showed significantly lower mean changes in baseline NPI scores and the 2 NPI subscales (anxiety and irritability), but no significant differences when compared with the control group. The mean decrease from baseline on the NPI agitation subscale; however, was significantly greater in the lamotrigine group than in the control group (P <.05). Furthermore, the study also showed that the mean decrease from baseline in the diazepam-equivalent dose was significantly greater in the lamotrigine therapy group than in the control group (P <.05).

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REFERENCES
1. Xi T, Kang S, Kim F, et al. A Randomized, Double-blind, Phase 2a Clinical Trial to Study the Efficacy and Safety of Lamotrigine for Treatment of Patients with Dementia with Lewy Bodies. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 643
2. Suzuki H, Gen K. Clinical efficacy of lamotrigine and changes in the dosages of concomitantly used psychotropic drugs in Alzheimer's disease with behavioral and psychological symptoms of dementia: a preliminary open-label trial. Psychogeriatrics. 2015;15(1):32-7. doi:10.1111/psyg.12085