Memantine was observed to be safe but there was little evidence to support efficacy for enhancing cognitive effects among adolescents and young adults with Down syndrome. These findings, from a randomized, double-blind, placebo-controlled phase two trial, were published in The Lancet Neurology.
Down syndrome typically results from trisomy 21 and patients with Down syndrome are particularly susceptible to neurodevelopmental and neurodegenerative disorders. By 40 years of age, Alzheimer disease (AD) neuropathology is universal and dementia onsets at about 55 years of age. Memantine was approved for the treatment of AD and preliminary animal models suggested it may be efficacious in Down syndrome.
The objective of the current study was to assess whether memantine would improve episodic memory in adolescents and young adults with Down syndrome.
Patients (N=160) with Down syndrome aged 15-32 years were recruited at two sites in Brazil and the United States between 2015 and 2020. Stratified by age and gender, participants were randomized to receive memantine (n=81) or placebo (n=79). Dosing followed the standard AD titration, starting at a dose of 5 mg once daily and escalating to 10 mg twice daily. Participants were monitored for cognitive changes by neuropsychological assessments at baseline and after 16 weeks of therapy.
The participants in the intervention and control cohorts were 53% and 54% girls or women, aged mean 20.4 (standard deviation [SD], 4.7) and 20.3 (SD, 4.2) years, and 37% and 28% had severe intellectual disability, respectively.
Change from baseline in California Verbal Learning Test-second edition short form (CVLT-II-sf) total free recall scores did not differ between cohorts (0.34; 95% CI, -0.98 to 1.67; P =.61). Similarly, no significant group differences were observed for change from baseline in the 13 other neuropsychological assessments (all P ³.050).
In a post-hoc analysis using only patient data for individuals with plasma memantine >0.4 mmol/L and the matched placebo individual, a significant difference was observed for CVLT-II-sf total free recall scores (effect estimate, 3.04; 95% CI, 1.55-4.54; P <.0001), favoring memantine treatment. No significant group differences were observed for the other neuropsychological assessments.
No significant differences for adverse events were overserved. The most common events were signs and symptoms of upper respiratory viral infection (11% vs 15%), transient dizziness (10% vs 8%), anxiety (7% vs 5%), and mood changes to irritability (3% vs 6%) among the intervention cohort and the cohort with control individuals, respectively.
This study was limited by not reaching its sample size goal of 200 participants, but recruitment was terminated early due to the COVID-19 pandemic.
This study found little evidence to support the use of memantine among individuals with Down syndrome. However, the post-hoc analysis suggested that higher doses of memantine may be more effective at enhancing cognitive effects. A small-scale pharmacokinetic and tolerability study is needed as no evidence is currently available to support the use of high doses of memantine among individuals with Down syndrome.
Costa ACS, Brandão AC, Boada R, et al. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. Published online January 1, 2022. doi:10.1016/S1474-4422(21)00369-0