Objective: This proof-of-concept clinical trial will test the efficacy and safety of lamotrigine compared to placebo in patients with dementia with Lewy bodies (DLB).

Background: DLB is the second-most common form of degenerative dementia after Alzheimer’s disease (AD). DLB is characterized by cognitive declines and fluctuation, while also causing movement difficulties and Parkinson’s disease (PD)-like motor impairment. While neuronal hypoexcitability is characteristic of late-stage dementia, several functional imaging studies have found hyperexcitability in the early stages of AD, which appears to promote further pathology and cognitive declines¹. Reducing hyperexcitability may slow the course of dementia, but this theory has not been tested in clinical trials. DLB is an appropriate disease to test the hypothesis because DLB patients have abnormal EEG findings and increased incidence of epilepsy², and hyperexcitability is observed in the PD brains. This study will examine the effect of the anti-epileptic drug lamotrigine (Lamictal) in subjects with DLB.

Method: This double-blind study will enroll 60 subjects aged 60 and older from Severance Hospital in Seoul, Korea, who are diagnosed with DLB based on clinical manifestations with imaging biomarkers. Subjects will be randomized 1:1 to receive standard of care (rivastigmine) plus either oral lamotrigine or matching placebo for 20 weeks. From Weeks 0-2, the dose of lamotrigine will be 25 mg once daily. If the drug is found to be safe, the dose will be increased to 25 mg twice daily (BID) for Weeks 2–4 and 50 mg BID for Weeks 4–20. The primary efficacy endpoint is change from baseline in Clinical Dementia Rating (CDR)-Sum of Boxes at Week 20; secondary endpoints are Mini Mental State Examination, CDR, Caregiver Administered-Neuropsychiatric Inventory, Mayo Fluctuation Scale, Timed Up and Go, Unified Parkinson’s Rating Scale, quantitative EEG, regional uptake of 18F-Fluorodeoxyglucose PET, plasma phosphorylated Tau, GFAP, and Aβ42/40 ratio. Safety and tolerability will be assessed.

Results: The study is estimated to be completed in early 2025. The trial information will be added to clinical trial databases and results will be published.

Conclusion: This Phase 2a trial is designed to determine if lamotrigine protects DLB patients from functional decline and cognitive fluctuation and reduces hyperexcitability.

References: 1. Dias Anastacio et al. 2022. Translational Psychiatry 12:257
2. Beagle et al. 2017. J. Alzheimers Dis. 60:211

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