Memantine Exacerbates Corrected QT Interval Prolongation in Alzheimer's Disease: A Case Report from an Unintentional Rechallenge

To the Editor: Psychotropic medications, such as antipsychotics and antidepressants, often cause corrected QT interval (QTc) prolongation on electrocardiogram, a risk factor for torsades de pointes and sudden cardiac death.1, 2 Antidementia drugs are associated with few adverse cardiovascular events and can be safely used in elderly individuals with Alzheimer's disease,3 although some case reports have indicated that antidementia drugs can also cause heart rhythm disorder, including QTc prolongation and torsades de pointes.4-6 Memantine, an N-methyl-D-aspartate glutamate receptor antagonist, is used to treat moderate to severe Alzheimer's disease and alleviate behavioral and psychological symptoms of dementia (BPSDs).7 A case in which unintentional rechallenge with memantine caused QTc prolongation is presented. A 70-year-old man with Alzheimer's disease was admitted to the hospital for treatment of diabetes mellitus. He also had complete right bundle branch block (CRBBB) but no history of severe heart disease. During hospitalization, he displayed delirium and insomnia, and the physician administered haloperidol (1.5 mg/d) and lorazepam (3 mg/d), but the delirium persisted. He was then transferred to Hakomatsu Hospital. Laboratory data showed no electrolyte abnormality (sodium, 145 mmol/L; potassium, 4.8 mmol/L; chlorine, 109 mmol/L). Electrocardiography (ECG) performed on the day of admission showed a CRBBB pattern and a QTc of 450 ms. Oxypertine (20 mg/d), an antipsychotic drug often used for the treatment of delirium in Japan, was administered, and the delirium and insomnia gradually subsided. After treatment of delirium and insomnia, his Mini-Mental State Examination score was 11. Ten days after admission, 5 mg/d memantine was added and gradually increased to 20 mg/d over 1 month. Fifty-four days after the admission, ECG demonstrated QTc prolongation (504 ms), and administration of oxypertine, haloperidol, and memantine were discontinued. Five days after discontinuation, the QTc had decreased to 474 ms. Seven days after discontinuation, the man exhibited excitement and irritability, and haloperidol and memantine were restarted, resulting in improvement of these symptoms, but ECG demonstrated QTc prolongation again (504 ms), and memantine only was discontinued. QTc decreased to 484 ms in 3 days and returned to basal level (450 ms) by 3 weeks after discontinuation of memantine. The man continued to receive haloperidol (1.5 mg/d), which did not affect his QTc. No electrolyte abnormalities, renal dysfunction, or liver dysfunction were observed. In this case, slight prolongation of QTc was observed before administration of memantine that was not sufficient for a diagnosis of QTc prolongation. Memantine was added for the treatment of Alzheimer's disease, and QTc was prolonged to a level that fulfilled the criteria for QTc prolongation. When QTc prolongation was first observed in this man, the cause was assumed to be oxypertine; although haloperidol can prolong QTc,8 it was not regarded as the main cause of QTc prolongation because he had already been receiving it when he was transferred to the hospital. When memantine was restarted for the treatment of BPSDs, it was confirmed that memantine caused QTc prolongation. A case was recently reported in which QTc was prolonged from 438 to 504 ms after the administration of memantine for Alzheimer's disease.9 This person had cardiac enlargement, pulmonary congestion, renal dysfunction, and a history of acute myocardial infarction. In contrast, although the individual described herein had CRBBB and slight prolongation of QTc, he had no history of severe heart disease. There are many factors that can exacerbate drug-induced QT prolongation, for example, female sex, older age, electrolyte abnormalities, heart disease, renal disease, and diabetes mellitus.1 In the case presented previously,6 the individual had many of these risk factors, including female sex, older age, heart failure, myocardial infarction, and renal dysfunction. The man described herein was an elderly person and had slight prolongation of QTc and diabetes mellitus as risk factors for QTc prolongation. Therefore, when memantine is administered to elderly adults with multiple risk factors for QTc prolongation, regardless of severity, ECG should be performed routinely during the administration of memantine. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Dr. Monji received an honorarium from Diichi-Sankyo pharmaceuticals. Author Contributions: Kajitani drafted the manuscript and takes responsibility for this case report. Kajitani, Yanagimoto: study concept, design, bibliographic search. Monji, Maruyama: data analysis and interpretation. Sponsor's Role: None.