Memantine for Fragile X–Associated Tremor/Ataxia Syndrome

Abstract

Objective Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial. Method A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity. Results Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007). Conclusion This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.

Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder

“…Primary outcome measures include the California Verbal Learning Test. Secondary end points are other cognitive measures, such as the Behavioral Dyscontrol Scale (BDS-2), CANTAB battery, COWAT, ERP measures, and a tremor/balance measure, the CATSYS, used in previous treatment studies of FXTAS [117]. It is hoped that this treatment will stabilize the progression of FXTAS and improve memory and executive function deficits in addition to anxiety that these carriers have.…”

Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome

“…As in our previous studies, the MMSE was not emphasized, because it mostly measures cortical functions, whereas FXTAS dementia combines cortical and subcortical features. 6,18,29,69 While MMSE scores may be lower in a subgroup of participants with FXTAS and prominent recall deficits, this may not be true of others. Future research can utilize other instruments, better suited for detecting executive dysfunction and subcortical cognitive deficits.…”

“…The percentage of benzodiazepine users (13%) is consistent with previous treatment studies in FXTAS. 68,69 This could be because clinical practice guidelines strongly suggest avoiding benzodiazepines in patients with FXTAS, especially those with dementia, due to deleterious cognitive effects and high risk of falls. 48,70 …”

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice

“…This hypothesis can be easily tested in the expanded CGG KI mice using mGluR antagonists while performing PPI of the acoustic startle, and will bring important mechanistic knowledge. Nevertheless, in a controlled trial administration of memantine - an NMDA receptor uncompetitive antagonist - did not return benefic results for FXTAS patients (64). An explanation for these results could be the proxies used to assess recovery, such as intention tremor (using CATSYS) and executive function (using behavioral dyscontrol scale), when mGluR could be more related to sensorimotor gating.…”