Background: Lamotrigine, a drug that is used in epilepsy and pain, is neuroprotective in animal models of MS, i.e. it prevents damage from inflammation. A clinical trial of this drug in SPMS was unfortunately negative. This study evaluated the effect of lamotrigine on a MRI measure called the magnetisation transfer ratio or MTR; MTR is a structural marker and a measure of intact brain tissue. The better the MTR the less damage. Pathology studies have shown that it correlates very well with myelination.
Epub ahead of print: Hayton et al. Longitudinal changes in magnetisation transfer ratio in secondary progressive multiple sclerosis: data from a randomised placebo controlled trial of lamotrigine. J Neurol. 2011 Sep 9.
Objective: This study assessed the impact of lamotrigine on MTR in a group of SPMS’ers.
Methods: 117 SPMS’ers were recruited into a double-blind, parallel-group trial. Subjects were randomly assigned to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years.
Results: Significant differences between the treated and placebo arms were seen in the normal appearing grey matter and lesion peak height. Unfortunately, in both cases there was a greater reduction in MTR in the treated MS’ers.
Conclusion: These data did not show that lamotrigine was neuroprotective.
“This study confirms the clinical results; using a relatively sensitive MRI-based measure of tissue integrity lamotrigine was not neuroprotective.”
“The results of the lamotrigine trial were very disappointing; here is a trial in progressive MS, which was backed by scientific discovery from our animal models, that failed. Are the animal models at fault?”
“Why did this trial go wrong? Firstly, lamotrigine was tried as a monotherapy. I believe it needs to be added on top of existing DMTs that suppress inflammation. SPMS is still inflammatory and unless we address the inflammatory component of MS neuroprotective therapies are unlikely to work. The exception being that some drugs may have dual modes of action, i.e. anti-inflammatory and neuroprotective properties. Secondly, MS’ers with progressive MS tolerate lamotrigine and similar drugs very poorly due to side-effects. In this study most patients could not tolerate the drug at the target dose. Thirdly, lamotrigine is not that neuroprotective. Several other basic studies have suggested you need even higher doses than the target dose in this study.”
“Please don’t despair; we have learnt a lot from this trial and going forward we will hopefully be able to design better studies.”
“Another take home message from this study is that we, the MS research community, are trying to treat progressive MS; it is just proving a lot harder than we expected.”
Extra reading: lamotrigine