A retrospective review of memantine use and COVID-19-associated mortality from a national database.

To the Editor,

We read with interest the papers by Brenner and Cimolai regarding the therapeutic potential of memantine for coronavirus disease 2019 (COVID‐19). Memantine, an adamantane derivative and an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that reduces glutamate toxicity by decreasing the prolonged Ca2+ influx in neurons, is used for treating Alzheimer's disease.

Angiotensin‐converting enzyme 2 (ACE2), a cell surface receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is widely distributed in multiple organs, including the nose, lungs, kidneys, liver, blood vessels, immune system, and brain. Memantine may be a candidate drug for COVID‐19 treatment as it interferes with NMDA activity and inhibits excess glutamate release in the medulla, which is a potential neurotoxic effect resulting from ACE2 depletion and which contributes to the development of acute respiratory distress syndrome via activating the sympathetic nervous system, thereby leading to increased blood pressure, systemic vasoconstriction, and pulmonary capillary leakage. , Memantine also directly inhibits viral replication through potential interaction with viral E protein and lysosomal function.

A recent study reported that 22 patients with the neurologic disorder who were diagnosed with polymerase chain reaction‐confirmed SARS‐CoV‐2 infection and treated with memantine or related adamantanes did not develop clinical symptoms of COVID‐19. Brenner introduced this study and commented that memantine and related adamantanes might exert an antiviral effect on COVID‐19. However, 80% of patients with COVID‐19 experience only mild or no symptoms at all, and only 15% have severe infection requiring oxygen. Moreover, the abovementioned study had a small sample size, which affects the reliability of the results.

Thus, we evaluated the national COVID‐19 claim database of South Korea and identified 5726 patients with confirmed COVID‐19, of whom 140 had died. The relationship between treatment with memantine and COVID‐19‐associated mortality was investigated.

Our observations revealed no statistically significant relationship between COVID‐19‐associated mortality and ongoing treatment with memantine after adjustment for clinically relevant potential confounders of age, sex, and/or comorbidities. This result was consistently observed both in the overall analysis of all patients with COVID‐19 and in the subgroup analysis that was limited to patients with dementia (Figure 1).

Figure 1

Likelihood of mortality in patients with confirmed coronavirus disease 2019 according to treatment with memantine. Univariate and multivariable logistic regressions were used to estimate odds ratio and 95% confidence intervals (CIs). Univariate logistic regression did not adjust any confounder. Multivariable logistic regression model 1 adjusted for age and sex. Multivariable logistic regression model 2 adjusted for age, sex, and comorbidities (hypertension, heart failure, chronic kidney disease, chronic lung disease, diabetes mellitus, dyslipidemia, cancer, stroke, Parkinson's disease, epilepsy, and dementia) at admission. The analysis variables for this study were presented in Supporting Information Table

Our results should be interpreted with caution given the disadvantage associated with retrospective analyses and reliability of data. However, memantine is typically prescribed to older patients, who are at higher risk of COVID‐19, and, therefore, ideal candidates for retrospective investigations aimed at determining whether memantine has therapeutic effects on COVID‐19.

In conclusion, our analysis revealed no association between memantine treatment and mortality in patients with COVID‐19. However, we must explore all feasible options for preventing and treating COVID‐19 due to the current lack of licensed vaccines or therapeutics for the disease. A low‐risk and cost‐effective strategy could be trial repurposing of medications that are inexpensive and readily available. Future studies should analyze whether memantine can shorten the clinical course and/or improve patient outcomes according to disease severity as well as overall mortality of COVID‐19.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

Supporting information

Click here for additional data file.