More Trials Needed to Clarify Benefits of Alzheimer’s Therapy Memantine in MS

Treatment of up to a year with memantine — an approved therapy for Alzheimer’s disease — failed to prevent cognitive decline and disability, and to significantly reduce fatigue and spasticity in adults with multiple sclerosis (MS), a review of published studies shows.

The therapy, sold under the brand name Namenda, works by preventing glutamate — a nerve-signaling molecule previously suggested to contribute to MS — from accessing its receptors in nerve cells. This prevents excessive calcium from entering nerve cells and causing damage.

Further studies evaluating memantine in different MS types and using more sensitive outcome measures are needed to clarify its potential benefits in this patient population, the researchers noted.

The study, “Memantine for Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Trials,” was published in the journal Frontiers in Neurology.

Glutamate is the main nerve-signaling molecule, or neurotransmitter, responsible for excitatory signals in the brain. As excessive glutamate is toxic to cells, its levels are tightly controlled in the brain.

Previous studies have pointed to the possibility that glutamate toxicity may contribute to MS, including specific symptoms such as cognitive impairment, spasticity (muscle stiffness or spasms) and fatigue.

Memantine, a suppressor of glutamate signaling, is an approved treatment for Alzheimer’s disease that was shown to prevent functional disability and cognitive decline in this patient population.

In MS, its off-label use is typically limited to second-line treatment of MS-related vision problems, including repetitive, involuntary eye movements and oscillopsia, which is the sensation that objects are moving back and forth, trembling, or wiggling.

However, several clinical trials have evaluated whether memantine treatment prevents cognitive impairment and reduces spasticity, fatigue, and disability in MS patients.

Researchers in the Philippines set out to assess memantine’s safety and effectiveness in MS patients by systematically reviewing data from randomized, controlled clinical trials published up to May 2020.

From a total of 203 hits, eight studies were accessed for eligibility, and four of them — covering a total of 285 MS patients — were included in the meta-analysis.

All four studies, published from 2010 to 2020, involved a placebo group and a memantine group. Participants randomly assigned to memantine initially were given a lower daily dose (5 or 10 mg), which was progressively increased to 10 mg twice a day (the recommended maintenance dose for Alzheimer’s).

In three studies, treatment was given for 12 weeks (about three months), while a forth study involved a one-year treatment period.

Most participants were women with relapsing-remitting MS, as well as North Americans and Europeans. Patients’ disability, as assessed with the Expanded Disability Status Scale (EDSS), ranged from mild to severe.

Three studies assessed changes in cognitive function through the Paced Auditory Serial Addition Test score, and two evaluated changes in disability with the EDSS. Changes in spasticity were investigated in one study using the Ashworth Spasticity Scale score, and in fatigue in one study using the Modified Fatigue Impact Scale score.

Results showed that memantine treatment did not result in significant reductions in cognitive impairment, spasticity, fatigue, and disability, compared with a placebo.

The researchers hypothesized that the absence of significant benefits may be associated with the timing of administration — with earlier treatment likely resulting in greater effects — and short treatment duration, as memantine benefits in Alzheimer’s patients are rarely evident after only 12 weeks and even one year of treatment may not be enough to see results in MS.

A subgroup of MS patients with early disease and receiving disease-modifying therapies (DMTs) “might benefit from memantine in terms of protection against cognitive deterioration,” the team wrote.

In addition, low sensitivity of outcome measures to subtle changes, and the possibility that additional factors other than glutamate toxicity may contribute to these MS symptoms also may explain the non-significant results, the researchers noted.

Memantine was generally safe among MS patients. It was associated with mild side effects such as dizziness, headache, and fatigue, which was consistent with data reported in other memantine clinical trials in MS, the team noted.

These findings suggested that “there is not enough evidence to support the [effectiveness] of memantine at a dose of 20 mg per day administered for 12–52 weeks among patients with MS in preventing cognitive deterioration, controlling spasticity, reducing fatigue, and improving the degree of functionality compared with placebo,” the researchers wrote.

Future memantine studies considering different MS types, the effects of co-administration of memantine with DMTs, longer treatment duration, and more sensitive outcome measures “are needed to evaluate the potential benefit of memantine among patients with MS,” they concluded.