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Efficacy and safety profile of memantine in patients with cognitive impairment in multiple sclerosis: A randomized, placebo-controlled study

Journal of the Neurological Sciences, April 2016, Pages 69 - 76

Abstract

Memantine, an uncompetitive antagonist of N-methyl-d-aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients.

Aims

The purpose of the “EMERITE” (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS).

Methods

The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18–60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial.

Results

Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p = 0.88). Adjusted mean score difference (memantine minus placebo), was − 0.40 (95% confidence interval: -5.5; + 4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine.

Conclusions

No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected.

Graphical abstract

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Highlights

  • Cognitive impairment is frequently observed in multiple sclerosis (MS).
  • There is currently no drug therapy to improve cognitive impairment.
  • This study suggests that memantine is not effective after 52 weeks but power was decreased due to high discontinuation rate.
  • The safety profile of memantine from this trial was less favorable than that established on the basis of dementia trials.

Keywords: Memantine, Multiple sclerosis, Cognitive disorders, Patient safety, Clinical trial, Randomized, Placebo-controlled, PASAT, Cognitive impairment, Test of Attentional Performance.

1. Introduction

Cognitive impairment is frequently observed in multiple sclerosis (MS) patients and can significantly disrupt day-to-day activities, social relationships, or the ability to work in severe cases [1] and [2]. Currently, no evidence exists for a drug therapy that promotes sustained improvement of cognitive impairment in these patients [3], [4], and [5].

Memantine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has been approved for the treatment of moderate to severe Alzheimer's disease (AD) because this drug has been shown to improve cognitive dysfunction in patients with AD [6] and [7]. However, memantine shows limited clinical effects over the short term for some AD patients and exhibits potentially under-recognized toxicity over the long term [8] and [9].

The rationale for using memantine as a symptomatic therapy for cognitive dysfunction in MS patients reflects the fact that this drug improves the cognitive symptoms of AD, and the glutamatergic system has been implicated in the pathophysiology of MS, as increasing data suggest a potential role for NMDA receptors in both neurodegenerative and inflammatory processes [10], [11], and [12]. Indeed, the pharmacological inhibition of NMDA glutamate receptors via memantine has reduced the severity of experimental autoimmune encephalomyelitis (EAE) in rats and protected retinal ganglion cells from apoptosis in an experimental autoimmune optic neuritis model [13], [14], and [15]. In addition, in vivo evidence of impaired brain glutamate homeostasis, which is associated with lower cognitive performance, has recently been obtained in MS patients [12] and [16]. Consequently, the glutamate system and NMDA receptors have become attractive targets for drug development for MS (including cognitive dysfunction).

Two previous studies using memantine have not demonstrated improved cognitive performance in MS patients. The first study [17] was discontinued after a small number of subjects were enrolled due to adverse reactions. The second study [18] was only conducted for 16 weeks and included all types of MS patients, which limited the chance of observing the potential cognitive effects of memantine due to the heterogeneous population and short-term drug exposure.

We initiated a similar randomized, placebo-controlled study to examine the efficacy and safety of memantine during long-term administration (52 weeks) in moderately impaired, non-demented, relapsing-remitting multiple sclerosis patients (RR-MS). The primary objective of the present study was to show an improvement in working memory and sustained attention, measured using the Paced Auditory Serial Addition Test (PASAT) score. The secondary objectives focused on attentional performance, short term memory, and clinical disability.

2. Design and research plan

The trial was registered at www.clinicaltrials.org (NCT01074619) and was approved by the Regional Ethical Standards Committee on Human Experimentation (France, CPP NOIII 2004-28). The official title was “EMERITE: Effects of MEmantine on cognitive disorders of Relapsing-remITting MultiplE Sclerosis”. All participants provided written informed consent after full explanation of the protocol.

The study was conducted in accordance with the International Conference on Harmonisation (ICH)/WHO Good Clinical Practice Standards.

The full protocol is also available by the link: http://www.chu-caen.fr/gesdoc/docrecherche/ProtocoleSEPamendement14_05122009.pdf.

2.2. Participants

The participants included males and females, 18–60 years of age, with a diagnosis of RR-MS [19] and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The patients were required to have an EDSS score [20] ≤ 5.5, a Dementia Rating score [21] ≥ 130, a PASAT score [22] > 15 but lower than the mean − 1.5 SD of the control value, according to age, gender, and education level, of a healthy French reference cohort [23].

Prior to randomization, the patients were treated for at least three months with one of the following immunomodulator or immunosuppressive treatments:

  • - Interferon β
  • - Glatiramer acetate
  • - Azathioprine
  • - Methotrexate
  • - Mycophenolate mofetil
  • - Natalizumab.

Patients who benefited from mitoxantrone or cyclophosphamide were eligible only if the treatment had ended more than six months prior to randomization.

Women were required to use a medically acceptable method of contraception.

The exclusion criteria consisted of a progressive form of MS or a tumoral form of MS visible on MRI examination, MS relapse in the previous 30 days, intravenous or oral corticoid treatment in the month preceding randomization, any symptomatic or non-medical cognitive therapy or neuropsychological training for cognitive disorders, antidepressant or anxiolytic treatment in the 3 months prior to randomization, a score > 19 on the Montgomery Asberg Depression Rating Scale (MADRS) [24],which was suggestive of significant depressive symptoms, other diagnosed psychiatric conditions, or a known allergy to memantine.

2.3. Study design

The present study was a multicenter (19 centers), 52-week, double-blind, placebo-controlled, parallel group, randomized trial. Eligible patients were assigned to receive a placebo or memantine (twice daily), and the maintenance dose of 20 mg per day was achieved through an upward adjustment of 5 mg per week over the first 3 weeks. Down titration was not permitted during the present study. Memantine (Ebixa®) and the placebo were provided by Lundbeck (Copenhague-Valby Denmark). The data were collected in the Department of Neurology at the French centers of each of the principal investigators. The present study was supported by a grant from the French Ministry of Health (PHRC 2004) and received additional support from Lundbeck, which was not involved in design the protocol, analysis of the data, or drafting of the manuscript.

The study flow chart is shown in Fig. 1. No changes to the methods were made after the commencement of the trial.

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Fig. 1 Flow diagram. *In France, we are not allowed to analyze withdrawals of consent.

2.4. Randomization and masking

Permuted-block randomization (blocks of 6) was used for treatment allocation. A research associate generated the random sequence using the Excel software. Identical drug kits containing the treatment for the full duration of the study were prepared for each patient and numbered according to the randomization list. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial.

2.5. Efficacy

The primary outcome was the PASAT score at week 52, which was used to assess working memory and sustained attention. The scores were adjusted for the baseline PASAT scores (week 0) in the analysis. To avoid potential practice effects, no other measurement of the PASAT scores was obtained between weeks 0 and 52 [25].

We used as secondary outcomes five sub-scores of the set of computerized Tests of Attentional Performance (TAP) by Zimmermann et al. [26], measuring vigilance, alertness, and flexibility (2 sub-scores) and divided attention. This computerized battery, mainly based on reaction time paradigms, is the only one normative attentional battery validated in France. Assessment of divided attention was based on the Reaction Time (RT) and accurate answers ratios to a double task using random presentation of an auditory or visual target stimulus. For vigilance and alertness, RTs were used to evaluate information processing speed. Flexibility was assessed by the number of correct and wrong responses in a task needing the identification of an alternate target using a letter/number simultaneous visual presentation. Thus this battery allows study of different aspects of attention, and direct computer data recording limits any collection bias. The TAP battery has been already used in MS either to evaluate attention [27] or assess the effect of cognitive training [28]. This battery is not part of present consensus recommended tests but at the period where the protocol has been launched, this battery was regularly used in many French centers and has been still used in recent clinical trials. [29] and [30].

The other secondary outcomes (at week 52) included

  • The Digit Span [31] forward and backward scores
  • The EDSS score
  • The annualized relapse rate.

The scores were adjusted according to the baseline scores in the analysis. No changes to the trial outcomes occurred after trial commencement.

3. Statistical analysis

The sample size was based on the assumption of a 4-point difference in the PASAT score between the groups at 1 year. The standard deviation of the score was estimated to be 7.8 on a retrospective series of 109 patients who were followed in our center and met the enrollment criteria of the study; the Pearson correlation coefficient between the PASAT measurements at baseline and at 1 year was estimated as 0.5. For a type I error of 0.05 and a power of 80%, 40 patients per group were required to demonstrate differences using an analysis of covariance (ANCOVA). To account for dropout, 45 patients per group were enrolled.

The baseline characteristics were compared between included and excluded subjects using Chi-square tests and Student's t-tests. The mean scores (PASAT, TAP, Digit span, and EDSS) at 1 year were compared between the two treatment groups using ANCOVA, adjusting for baseline scores after verifying the absence of interactions between the treatment group and baseline scores. No interactions were detected, except for the TAP flexibility scores. In that case, changes from baseline were calculated for each patient, and these changes were compared between the groups using a Mann-Whitney test, considering the asymmetry of the distribution. The annualized relapse rates were also compared using the Mann-Whitney test. All efficacy analyses were performed on the intent-to-treat (ITT) population. Multiple imputation was used to analyze the influence of missing values and dropouts. The level of significance was set at p < 0.05. All analyses were performed using IBM SPSS Software, version 18.0.

3.1. Safety and tolerability

The safety assessment included the recording of adverse events. A physician examined the patients at each visit, including at baseline and at 4, 12, 28, and 52 weeks. The cohort was advised of expected adverse events (headache, dizziness, confusion, hallucinations, agitation, and diarrhea) and instructed to report any other events. The intensities were categorized according to Common Terminology Criteria for Adverse Events version 4.0. We subsequently coded adverse events according to the MedDRA dictionary version 14.0 and compared the adverse event incidence between the memantine and placebo groups.

The frequencies of adverse events in the memantine group were compared with the frequencies in the summary of product characteristics of memantine [32], obtained from clinical trials in patients with mild to severe dementia, which included 1,784 patients treated with memantine and 1,595 patients treated with a placebo.

4. Results

Fifty patients were allocated to the memantine group, and 43 to the placebo group. Seven patients withdrew consent (memantine: n = 2, placebo: n = 5), resulting in 86 patients who were subjected to further analysis (memantine: n = 48, placebo: n = 38). The treatment groups were well matched at baseline (cf. Table 1).

Table 1 Baseline characteristics of the 86 patients.

Characteristic All patients (n = 86) Memantine (n = 48) Placebo (n = 38)
Gender
 Male 29 (33.7%) 14 (29.2%) 15 (39.5%)
 Female 57 (66.3%) 34 (70.8%) 23 (60.5%)
Age
 Mean ± SD 41.5 ± 8.8 39.6 ± 9.1 43.9 ± 7.9
Level of education
 < High school diploma 36 (41.9%) 19 (39.6%) 17 (44.7%)
 High school diploma 26 (30.2%) 14 (29.2%) 12(31.6%)
 > High school diploma 24 (27.9%) 15 (31.2%) 9 (23.7%)
Number of relapses since disease onseta
 1 35 (40.7%) 19 (40.4%) 16 (42.1%)
 2 29 (33.7%) 17 (36.2%) 12 (31.6%)
 3 17 (19.8%) 7 (14.9%) 10 (26.3%)
 4 4 (4.7%) 4 (8.5%) 0 (0%)
Disease durationa
 < 7 years 19 (22.4%) 13 (27.1%) 6 (16.2%)
 ≥ 7 years 66 (77.6%) 35 (72.9%) 31 (83.8%)
EDSS
 Mean ± SD 3.2 ± 1.0 3.1 ± 0.9 3.4 ± 1.0
 Median (Q1; Q3) 3.0 (2.5; 4.0) 3.0 (2.5; 3.5) 3.25 (2.5; 4.0)
PASAT 3 s
 Mean ± SD 33.6 ± 8.6 32.9 ± 8.3 34.5 ± 9.0

a Data missing for 1 patient.

EDSS: Expanded Disability Status Scale; PASAT: Paced Auditory Serial Addition Test.

For the analysis of the primary endpoint, 17 patients with a missing primary outcome were excluded in the memantine group, and 7 patients were excluded in the placebo group, resulting in a total of 31 patients in each group (cf. Fig. 1). The excluded subjects were significantly younger than the non-excluded subjects (mean age = 37.9 years vs. 42.9 years, p = 0.040) and had a significantly better PASAT score at baseline (mean score = 30.0 vs. 35.0, p = 0.014) (Supplementary material, Table 1). However, these differences were not heterogeneous between the treatment groups (interaction test p-value = 0.79 for age and 0.66 for PASAT score at baseline).

4.1. Efficacy

The analysis showed no significant difference between the PASAT scores of the two groups at 1 year (36.7 ± 12.2 for the memantine treatment group vs. 37.4 ± 11.1 for the placebo group (p = 0.88)). Adjusted mean score difference (memantine minus placebo), was − 0.40 (95% confidence interval: -5.5; + 4.7). No significant differences were observed for any secondary outcomes (short term memory and attention scores, EDSS, and relapse rate, cf. Table 2). These findings remained unchanged after multiple imputation of the missing values (Supplementary material, Table 2).

Table 2 Baseline and 1 year (ITT population).

Memantine Placebo Adjusted mean difference (95% CI)b p
na Mean ± SD na Mean ± SD
PASAT
 Baseline 31 34.9 ± 7.6 31 35.2 ± 8.6
 1 year 31 36.7 ± 12.2 31 37.4 ± 11.1 − 0.40 (− 5.48;4.69) 0.88
TAP
 Vigilancec
 Baseline 24 691 ± 187 21 726 ± 217
 1 year 24 704 ± 168 21 651 ± 136 65.3 (− 17.6;148.3) 0.12
 Alertc
 Baseline 23 317 ± 90 23 334 ± 105
 1 year 23 327 ± 85 23 333 ± 121 5.0 (− 46.4;56.4) 0.85
 Divided attentionc
 Baseline 23 756 ± 95 23 743 ± 74
 1 year 23 757 ± 113 23 749 ± 119 − 1.3 (− 60.2;57.6) 0.97
 Positive flexibility
 Baseline 24 40.1 ± 14.0 22 41.7 ± 10.2
 1 year 24 45.6 ± 5.1 22 42.3 ± 9.1 NAd 0.25
 Negative flexibility
 Baseline 24 6.5 ± 13.7 22 4.4 ± 7.0
 1 year 24 1.6 ± 2.8 22 3.7 ± 5.1 NAd 0.46
Digit span
 Forward
 Baseline 31 5.77 ± 1.38 31 5.61 ± 1.02
 1 year 31 5.87 ± 1.31 31 5.84 ± 0.97 − 0.040 (− 0.56;0.47) 0.87
 Backward
 Baseline 31 4.06 ± 1.29 31 3.74 ± 1.00
 1 year 31 4.19 ± 1.35 31 3.90 ± 0.98 0.13 (− 0.40;0.66) 0.63
EDSS
 Baseline 34 3.13 ± 0.98 34 3.37 ± 1.07
 1 year 34 2.99 ± 1.47 34 3.46 ± 0.96 − 0.28 (− 0.72;0.17) 0.22
Annualized relapse rate
 1 year 46 0.47 ± 0.83 36 0.47 ± 1.20 NAd 0.77

a Number of patients without missing data (may vary depending on the outcome).

b Mean score difference at 1 year (Memantine - Placebo) adjusted for baseline score (ANCOVA analysis).

c Mean reaction time (seconds).

d Not possible to compute because ANCOVA assumptions were not met.

PASAT: Paced Auditory Serial Addition Test; TAP: Set of Tests of Attentional Performance; EDSS: Expanded Disability Status Scale.

4.2. Safety and tolerability

In the memantine group, we did not observe any changes in the EDSS score between baseline and at one year (Table 2).

No deaths occurred in the present study. One serious adverse event (epileptic seizures) leading to hospitalization was observed; unblinding of the treatment revealed that the patient was in the placebo group.

However, many non-serious adverse events were observed.

Thirty-six patients (72%) in the memantine group reported adverse events vs. 8 patients (19%) in the placebo group. The proportion of discontinuations due to adverse events, although non-significant, was higher in the memantine group than in the placebo group (eight patients (16.7%) in the memantine group and 2 patients (5.3%) in the placebo group (p = 0.17)).

The adverse events are summarized in Table 3. The most frequent adverse events in the memantine group were dizziness, headache, anxiety symptoms, fatigue, and diarrhea. With the exception of diarrhea, the frequencies of these events were significantly higher in the memantine group than in the placebo group.

Table 3 Summary of adverse events (AEs).a

AE MedDRA v 14.0 Memantine (n = 48) Placebo (n = 38) Absolute difference in proportions (95% CIb) pc
SOC HLT LLT n (%) Time to onset (day) (mean ± SD) CTCAE grade (mean ± SD) n (%) Time to onset (day) (mean ± SD) CTCAE grade (mean ± SD)
Nervous system disorders Neurological signs and symptoms NEC Dizziness 10013573 13 (27.1%) 78 ± 82 1.3 ± 0.5 0 (0.0%) 27.1% (13.4%; 44.2%) 0.0005
Headaches NEC Headache 10019211 13 (27.1%) 67 ± 77 1.3 ± 0.5 3 (7.9%) 176 ± 133 1 ± 0 19.2% (2.8%; 35.9%) 0.023
Asthenic conditions Fatigue 10016256 6 (12.5%) 139 ± 165 1.2 ± 0.4 0 (0.0%) 12.5% (0.8%; 27.9%) 0.032
Psychiatric disorders Anxiety symptoms Agitation 10001497 4 109 ± 130 1 ± 0 0
Nervousness 10029216 1 14 2 ± 0 0
Anxiety 10002855 2 213 ± 23 1 ± 0 0
Total 7 (14.6%) 111 ± 107 1 ± 0.3 0 (0.0%) 14.6% (2.8%; 29.7%) 0.016
Gastrointestinal disorders Diarrhea Diarrhea 10012727 5 (10.4%) 88 ± 120 1.2 ± 0.4 0 (0.0%) 10.4% (− 1.4%; 23.7%) 0.064

a AEs ≥ 2 patients.

b Exact confidence interval computed with the R package “ExactCIdiff”.

c Chi2 or Fisher exact test comparing proportions of AEs.

SOC: system organ class, HLT, high level term, LLT: low level term, CTCAE: Common Terminology Criteria for Adverse Events.

All adverse events were considered of mild or moderate severity.

We conducted complementary analyses to examine the higher rates of nervous system disorders and anxiety symptoms in the memantine group. One hypothesis consisted of a potential confounding effect of interferon therapy associated with neurological and psychiatric side effects. However, the frequency of patients using interferon was not significantly different between the groups (60.4% in the memantine group vs. 52.6% in the placebo group, p = 0.47). Another possibility was a potentiation effect of interferon and memantine. Among the 37 patients who were not treated with interferon (19 in the memantine group and 18 in the placebo group), nervous system disorders or anxiety symptoms were observed in 11 patients (57.9%) in the memantine group vs. 1 patient (5.55%) in the placebo group (Risk Ratio [RR] = 10.4). Among the 49 patients treated with interferon (29 in the memantine group and 20 in the placebo group), nervous system disorders or anxiety symptoms were observed for 15 patients (51.7%) in the memantine group vs. 2 patients (10.0%) in the placebo group (RR = 5.2). The two RRs were not significantly different (p = 0.56, interaction test in a log-binomial regression model).

The frequency of nervous system disorders, dizziness, and headache in the memantine group was significantly higher than expected according to the summary of product characteristics of memantine (Table 4). In addition, we observed a 15% frequency of anxiety symptoms in the memantine group. Anxiety was described, but the frequency was not reported in the summary of product characteristics.

Table 4 Adverse event frequency in memantine group versus in summary of product characteristics of memantine.

Adverse event frequency in memantine group [95% CI] Adverse event frequency in summary of Product Information of memantine
Dizziness 27% [15%–42%] Frequent: 1% to 10%
Headache 27% [15%–42%] Frequent: 1% à 10%
Fatigue 12% [5%–25%] Frequent: 1% to 10%
Anxiety symptoms 15% [6%–28%] Unknown

5. Discussion

These findings are consistent with the negative results of Lovera et al. [18], who conducted a study of 114 MS patients. The present study and that of Lovera et al. both used the standard dose of memantine after the adjustment period and the same main cognitive outcome criterion (PASAT 3 s performance evaluated by the number of correct responses). However, the present study differs from that of Lovera et al. in the duration of treatment and the disease form. First, in the present study, we administered memantine for 52 weeks to ensure that a delayed effect that was not manifested at 16 weeks would be detected. Second, the present study was limited to RR-MS patients to better detect the therapeutic effect of memantine in a less cognitively impaired and homogenous group of patients. Indeed, Lovera et al. included PP- and SP-MS participants with more frequent and severe cognitive alterations [29] and [33] instead of RR-MS participants; these patients have greater axonal injury and cortical demyelination and less brain connectivity than RR-MS patients do. [34] and [35] Moreover, in Lovera study, the percentage of patients with a progressive form of the disease greatly differed between treatment arms (48% for the memantine group vs. 27% for the placebo group). Assuming that people with RRMS are more likely to respond to memantine then the study by Lovera et al. may have missed an effect that occurs only in people with RRMS.

The present study, which included the long-term administration (52 weeks) of memantine in a homogeneous population limited to only individuals with RR-MS, did not show any significant difference compared to the placebo group. However, due to the 95% confidence interval for the mean score difference (− 5.5; + 4.7), we cannot exclude a clinically significant effect (i.e., ≥ 4, as defined in the sample size calculation). The power of the study was compromised because of a large number of missing values and study discontinuations results in a sample size (31 patients in each group compared to a sample size calculation of 40 patients per group) lower than the target. Furthermore, the variability of PASAT scores at one year was also greater than estimated.

The high number of participants with missing outcomes and consent withdrawals was unexpected. Investigators planning future studies evaluating treatments for cognitive impairment of MS patients over one year should adjust the sample size calculation to include study discontinuations, as observed in the present study, and implement procedures to minimize the missing values. The possibility of selection bias cannot be excluded in the present study, as subjects excluded from the analysis were younger and had a better PASAT scores at baseline. This potential bias could limit the generalizability of the results but does not influence the comparability of the two treatment groups, considering the lack of significance of the interaction tests. Furthermore, the analysis based on multiple imputation of missing data was consistent with the primary analysis.

Villoslada et al. [17] conducted a double blind, randomized, placebo-controlled trial with memantine, and this study was halted due to worsening of the main neurological symptoms in most patients (increased muscle weakness, walking difficulties, and fatigue) or the occurrence of additional symptoms (blurred vision, dizziness, and severe headache) in other patients. Fortunately, these adverse events were reversible after discontinuation of the medication. However, Villoslada et al. reported results of memantine administration that were not consistent with the approved labeling, with patients initially receiving 30 mg/d of memantine, despite the necessary 10 mg/week-step dosage adjustment. In addition, the increased neurological deficits reported by Villoslada et al. were more common in patients with progressive forms of MS.

The present study included a homogeneous population of RR-MS patients, and these patients had lower EDSS scores than those in the study by Villoslada et al. The participants in the present study did not show a decline in EDSS scores, while Villoslada et al. observed a decline (the Villoslada et al. study was stopped after only a few participants were enrolled).

Unlike Villoslada et al., in the present study, we strictly followed the recommended methods for the administration and adjustment of the memantine dosage for AD; our strict adherence to the titration likely explains why no major neurological deficits were observed in the present study population.

Indeed, the findings of the present study are consistent with the safety results of Lovera et al. and Villoslada et al., in which memantine was used in patients with MS, and in a double-blind, placebo-controlled study in patients with schizophrenia treated with memantine in combination with atypical antipsychotics [36]. Memantine was not effective and resulted in more adverse events (headache, insomnia, constipation, fatigue, and dizziness).

The safety profile of memantine observed in the present study was less favorable than that observed in trials evaluating memantine as a treatment for dementia [32]. The results of the present study do not favor a potentiation effect of interferon through memantine. Moreover, the toxicity of memantine in AD patients, reported during clinical trials or during post-marketing authorization, showed the same profile as in the present study, but with lower frequencies of neurological and psychiatric adverse events. It is likely that patients with AD underreport adverse reactions due to language impairments; furthermore, clinicians might be more likely to attribute the effects to the disease or to aging [37], [38], and [39]. Moreover, because neurological and psychiatric manifestations are frequent symptoms of MS, these patients might likely develop or experience worsened preexisting symptoms, indicating pseudoexacerbations, consistent with the results of Villoslada et al. As Our study patients were less debilitated than those in previous studies but they still had higher side effects suggesting that even people with MS who are not very disabled should be concerned by memantine side effects.

From a pathophysiological point of view, the biological basis for unexpected or worsened symptoms in MS patients during memantine treatment remains unknown. In different neurological diseases, the stimulation of NMDA receptors might promote compensatory plasticity in surviving neurons, but the sustained activation of these receptors could be neurotoxic [40]. Recently this complex role of NMDA receptors in MS was illustrated by Rossi et al. [41]. These authors studied the impact of specific allelic variants of the NR1 or of the NR2B subunit gene of this glutamate receptor in RR- and PP-MS patients independently. They found that, in RR- and PP-MS patients with the same genotypes, disability progression or neuronal function (indirectly evaluated using composite index and optical coherence tomography parameters respectively) differs according to the allelic variant whereas the same allele preserves cognitive function in both form of the disease. Whatever the limitations of this study these results may suggest that memantine side effects more belong to genetical and pharmacological complex mechanisms that of the disease course.

In summary, the results of the present study suggest that memantine increases the risk of neurological and psychiatric adverse reactions in individuals with cognitive problems due to MS. In the present study, memantine was not effective as a treatment for cognitive impairment. Unfortunately, due to the reduction in power, which reflected the higher than expected discontinuation rate, we cannot completely exclude a beneficial effect. Nevertheless, taken together, the conclusions of the 2 previous randomized studies [17] and [18] and those of the present study strongly suggest that initial treatment with memantine is not useful for treating cognitive disorders, and secondly might promote side effects among the MS population. Accordingly, the improvement of cognitive disorders in MS patients requires new and innovative therapeutic strategies (i.e., remyelination or preventing tissue destruction) that are much more advanced than simple symptomatic drug therapy.

Acknowledgments

The authors would like to thank Pr Bernard LAURENT (St Etienne), Pr Philippe COURATIER (Limoges), Pr Pierre LABAUGE (Montpellier) for their independent expertise and Pr Jean-Louis MONTASTRUC for his helpful comments.

The authors would also like to thank CHU de Caen for institutional sponsorship.

Appendix A. Supplementary data

Download file

Supplementary tables.

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Footnotes

a Department of Biostatistics and Clinical Research, Centre Hospitalier Universitaire de Caen, France

b Department of Neurology, Centre Hospitalier de Poissy, France

c Department of Neurology, Centre Hospitalier Régional et Universitaire de Strasbourg, France

d Department of Neurology, Centre Hospitalier Régional et Universitaire de Lille, France

e Department of Neurology, Centre Hospitalier Universitaire de Nîmes, France

f Department of Neurology, Centre Hospitalier de Fort-de-France, France

g Department of Neurology, Centre Hospitalier Universitaire de Nancy, France

h Department of Neurology, Centre Hospitalier Universitaire de Bordeaux, France

i Department of Neurology, Centre Hospitalier de Cherbourg, France

j Department of Neurology, Centre Hospitalier de Lorient, France

k Department of Neurology, Centre Hospitalier Universitaire de Clermont-Ferrand, France

l Department of Neurology, Centre Hospitalier Universitaire de Toulouse, France

m Department of Neurology, Centre Hospitalier Universitaire de Nice, France

n Department of Neurology, Centre Hospitalier Universitaire de Nantes, France

o Department of Neurology, Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France

p Department of Neurology, Assistance Publique des Hôpitaux de Paris, France

q Department of Neurology, Groupement des Hôpitaux de l'Institut Catholique de Lille, France

r Department of Neurology, Centre Hospitalier Universitaire de Reims, France

s Department of Neurology, Centre Hospitalier Universitaire de Caen, France

t INSERM U 919, GIP Cyceron, Caen, France

Corresponding author at: Cellule de Promotion de la Recherche Clinique, Bureau 03-810, CHU de CAEN, Avenue de la Côte de Nacre, 14033 Caen cedex, France.


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