Memantine for Lewy Body Disorders: Systematic Review and Meta-Analysis

Objective

To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders.

Methods

The meta-analysis included randomized controlled trials of memantine for Lewy body disorders in all patients with Lewy body disorders. Motor function, activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Exam, discontinuation rate, and individual side effects were evaluated.

Results

No significant effects of memantine on motor function scores, Mini-Mental State Exam scores, Neuropsychiatric Inventory scores, and activity of daily living scores were found. However, memantine was superior to placebo in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference: −0.26; 95% confidence interval: −0.51 to −0.02; z = 2.08; p = 0.04; two studies; N = 258). Dropout due to all causes, inefficacy, or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo, and confusion were found between the groups.

Conclusion

Our results suggest that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorders. Further, memantine is well tolerated.

Introduction

Lewy body disorders, such as Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB), are neurodegenerative diseases characterized by accumulation of Lewy bodies in brain cells. Major symptoms of Lewy body disorders are parkinsonisms. PD is a common neurodegenerative disease in the elderly population, with a prevalence estimated at 166.8 per 100,000.1, 2 PDD and DLB, which are similar diseases, are the second most common causes of dementia and account for 15%–20% of the global incidence of dementia.³

The U.S. Food and Drug administration approved memantine for the treatment of moderate-to-severe Alzheimer disease in 2003. Memantine is postulated to exert its therapeutic effect through its action as a low-to-moderate affinity noncompetitive (open channel) N-methyl-d-aspartate (NMDA) receptor antagonist, which binds preferentially to the NMDA receptor-operated calcium channels.4, 5 Memantine blocks the effects of pathologically elevated sustained levels of glutamate that may lead to neuronal dysfunction.⁶

Recently, memantine has been used for the treatment of Lewy body disorders. Several studies have reported that abnormalities in glutaminergic neural transmission were associated with the pathophysiology of Lewy body disorders. First, in a postmortem study, the expression of metabotropic glutamate receptors in patients with DLB was decreased in comparison with age-matched control subjects.⁷ Second, an animal model of parkinsonism showed glutamatergic overactivity in their striatums.⁸ Third, in rats with parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, memantine reduced NMDA-dependent glutaminergic hyperactivity and restored akinesia and rigidity.⁹

To our knowledge, seven randomized controlled trials (RCTs) of memantine for Lewy body disorders have been performed to date.10, 11, 12, 13, 14, 15, 16 Regarding global assessment, the findings of different studies have been controversial. One study¹⁰ reported that memantine was superior to placebo in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC),¹⁷ whereas another study¹¹ showed that memantine was not superior to placebo in ADCS-CGIC. Finally, another study¹² showed that memantine was not superior to placebo in the Clinician's Interview-Based Impression of Change Plus Caregiver Input.¹⁸

For cognitive function, two studies4, 13 reported that memantine was superior to placebo in the Mini-Mental State Exam (MMSE),¹⁹ whereas another study¹² showed that memantine was not superior to placebo in the MMSE. Regarding behavioral disturbance, three studies10, 11, 12 reported that memantine was not superior to placebo using the neuropsychiatric inventory (NPI).²⁰ With respect to activities of daily living, one study¹⁰ reported that memantine was superior to placebo in disability assessment for dementia,²¹ whereas two studies11, 15 showed that memantine was not superior to placebo. One study¹¹ found memantine and placebo were similar in Alzheimer's Disease Cooperative Study-Activities of Daily Living, 23 items (ADCS-ADL23),²² whereas another study¹⁵ showed that memantine was not superior to placebo in Unified Parkinson's Disease Rating Scale-Activities of Daily Living (UPDRS-ADL).

On motor function, two studies14, 16 reported that memantine was superior to placebo on the UPDRS-motor. Another study¹³ showed that memantine was superior to usual care in UPDRS-motor, whereas three other studies11, 12, 15 showed that memantine was not superior to placebo on the UPDRS-motor scale. Furthermore, another study¹⁰ showed that memantine was not superior to placebo in the modified UPDRS.

These discrepant results may be due to the small sample sizes of these trials. A meta-analysis produces a weighted summary result (more weight given to larger studies). By combining results from more than one study, a meta-analysis has the advantage of increasing statistical power (which is often inadequate in studies with a small sample size).²³ Moreover, we can combine outcomes with different measurements using standardized mean difference (SMD) analyses.²⁴ To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders.