Elsevier

The Lancet Neurology

Volume 8, Issue 7, July 2009, Pages 613-618
The Lancet Neurology

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Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial

https://doi.org/10.1016/S1474-4422(09)70146-2Get rights and content

Summary

Background

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB.

Methods

We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005–08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516.

Findings

72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0·7, 95% CI 0·04–1·39; p=0·03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12·4, 95% CI 6·0–30·9; p=0·004), there were no significant differences between the groups in secondary outcome measures.

Interpretation

Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings.

Funding

The Western Norway Regional Health Authority; H Lundbeck A/S.

Introduction

25 milion people worldwide have dementia, including 700 000 in the UK. Dementia with Lewy bodies (DLB) and dementia associated with Parkinson's disease (PDD) have similar clinical and neuropathological symptoms and account for 15–20% of the global incidence of dementia.1 The complex courses of DLB and PDD include motor, cognitive, attentional, and psychiatric symptoms, and make these forms of dementia particularly challenging in terms of quality of life for patients and carers, admission to nursing homes, and health-related costs.1 Modest clinical benefits are seen in cognition, function, and neuropsychiatric symptoms with rivastigmine,2, 3 but not all patients respond to or can tolerate cholinesterase inhibitors. Better single or combination therapies are, therefore, urgently needed.

Memantine is an N-methyl D-aspartate (NMDA) receptor antagonist that affects glutamatergic neuronal transmission and prevents the toxic effects of raised concentrations of the excitatory neurotransmitter glutamate.4 Memantine has proven efficacy as a treatment for Alzheimer's disease.5 Altered glutamatergic markers have been identified in patients with DLB,6 providing a rationale for therapy with memantine for these individuals. However, preliminary evidence based on case reports has been highly variable and implicates not only the potential for memantine to improve cognitive and motor symptoms in patients with DLB,7 but also the possibility of adverse events, including worsening in cognition8 and psychosis.9 Controlled trials are clearly needed to establish whether memantine has a potential role in the treatment of DLB and PDD; therefore, we did a placebo-controlled study to test the hypothesis that memantine is more effective than placebo for treating the symptoms of patients with PDD or DLB.

Section snippets

Patients

Patients with mild or moderate PDD or DLB (ie, a mini-mental state examination [MMSE]10 score of 12 points or higher) were recruited at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005–08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and subsequently developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition

Results

75 patients were randomly assigned, and 72 (40 with PDD and 32 with DLB) started study medication (figure 1). Of these, 34 were assigned to memantine and 38 to placebo. 16 withdrew before the end of the study owing to adverse events, although five of these attended the 12-week visit, and 56 completed 24 weeks. There were no significant differences in any of the demographic or clinical variables or treatment characteristics between the treatment groups for the randomised (table 1) or LOCF

Discussion

The main finding of this study is that the patients who received memantine improved more than the patients who received placebo. A moderate-to-substantial improvement was reported by eight (27%) patients in the memantine group; no patients in the placebo group reported more than a slight improvement. The difference in CGIC scores between the groups was 0·7, and the effect size was 0·52, which is usually thought to be a medium-sized effect.22 This difference compares favourably with the results

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