Elsevier

The Lancet Neurology

Volume 12, Issue 2, February 2013, Pages 149-156
The Lancet Neurology

Articles
Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(12)70320-4Get rights and content

Summary

Background

Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD.

Methods

We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974.

Findings

Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI −3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, −0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one).

Interpretation

Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD.

Funding

Forest Research Institute.

Introduction

Frontotemporal lobar degeneration or frontotemporal degeneration (FTD) is a common cause of dementia in individuals who develop symptoms before age 65 years. FTD encompasses three core clinical syndromes—behavioural variant frontotemporal dementia (bvFTD), and two primary progressive aphasias (PPA): semantic dementia and progressive non-fluent aphasia.1 BvFTD is the most common form of the disease and features prominent social and behavioural deficits as well as executive dysfunction. Semantic dementia often begins as aphasia, with progressive semantic knowledge loss, but also often features prominent behavioural abnormalities similar to bvFTD.2 Progressive non-fluent aphasia presents as a motor speech disorder with few other cognitive or behavioural impairments. No medications have been approved by the US Food and Drug Administration (FDA) to treat FTD, and only a handful of randomised, placebo-controlled trials have been done in FTD.3 Despite the absence of efficacy data supporting the use of drugs approved for the treatment of Alzheimer's disease, such drugs are frequently prescribed to patients with FTD off-label in the USA, with 55% of patients in a recent study4 using either an acetylcholinesterase inhibitor or memantine.

Memantine is approved by the European Medicines Agency and the FDA for the treatment of moderate-to-severe Alzheimer's disease and has also shown beneficial effects in clinical trials of vascular dementia, Parkinson's-related dementias, and dementia of mixed causes (reviewed in Kalia and colleagues5). Although the neuropathological changes and underlying neurotransmitter deficits are different in FTD than in Alzheimer's disease, a scientific rationale exists for the use of memantine to treat FTD. First, memantine is believed to act as a non-competitive inhibitor of NMDA receptors, which might be overactivated in various neurodegenerative diseases, including FTD.5 Second, analyses of data from clinical trials of memantine in Alzheimer's disease showed clear benefits on various abnormal behaviours, as assessed by the neuropsychiatric inventory (NPI).6 Since many of these behaviours are prominent features of FTD, memantine might also be predicted to improve these deficits. Third, several open-label treatment studies in bvFTD and semantic dementia have shown symptomatic improvements with memantine treatment.7, 8 In one of these studies,8 we showed that initiation of memantine treatment was associated with a transient improvement in behaviour as measured by the NPI9 in patients with bvFTD and semantic dementia.8 Since the transient improvement in NPI scores might have been attributable to a placebo effect or an effect of memantine treatment, the present study tested the hypothesis that memantine would improve or stabilise behaviour as measured by the NPI and clinical global impression of change (CGIC)10 compared with placebo, after 26 weeks of treatment.

Section snippets

Study design and participants

In this multicentre, randomised, double-blind, placebo-controlled trial, we recruited patients from nine US academic dementia research centres with expertise in the diagnosis of FTD (University of California, San Francisco [UCSF] and Los Angeles [UCLA]; Mayo Clinic, Rochester and Jacksonville; Northwestern University Medical Center; Case Western Reserve Medical Center; University of North Carolina; Johns Hopkins University; and University of Pennsylvania). Study visits occurred between Dec 12,

Results

Of the 100 patients assessed for eligibility, 81 patients (64 with bvFTD and 17 with semantic dementia) were randomly assigned to memantine (39 patients) or placebo (42 patients; figure 1). Five patients (two given memantine, three given placebo) discontinued treatment before the end of the study (figure 1). Despite randomisation, the placebo group contained more men than the memantine group (table 1; p=0·01). There were no other baseline differences in demographic variables, concomitant

Discussion

We noted no benefit of 20 mg daily memantine treatment in FTD on either of the primary outcome measures—the NPI, or the CGIC—after 26 weeks of treatment. There was evidence of worse cognitive performance on tests of naming (BNT) and processing speed (digit symbol) associated with memantine treatment, and a suggestive increase in cognitive adverse events compared with the placebo group. However, the worse neuropsychological performance in the memantine group was not associated with a difference

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