Donepezil-induced QTc prolongation: A case report

Abstract

Background Several psychoactive medications are known to cause QTc prolongation. Patient factors also increase the risk for QTc prolongation, including bradycardia, female sex, older age, metabolic abnormalities, and polypharmacy. Donepezil, a cholinesterase inhibitor, prolongs the QTc interval through a multimodal mechanism. Patient History A 26-year-old African American female was admitted to the inpatient psychiatric hospital following a suicide attempt that was not an overdose. Past medical history was significant for major depression, traumatic brain injury, seizures, hemiplegia, gastroesophageal reflux disease, and tachycardia. Two baseline electrocardiograms (EKGs) were obtained showing normal QTc intervals. After several weeks, donepezil (5 mg by mouth once daily) was initiated for cognitive rehabilitation and titrated over 3 weeks to a dose of 20 mg. An EKG performed after the last dose change showed a prolonged QTc of 463 ms. Another follow-up EKG performed 9 days later showed further prolongation to 528 ms. Laboratory values were within normal limits during her hospital stay. Donepezil was discontinued completely, leading to normalization of the QTc interval. Discussion QTc prolongation and torsades de pointes have been identified in postmarketing case reports of donepezil. Instances of QTc prolongation have predominantly been documented in the geriatric population, primarily in those with additional risk factors. Additionally, current literature does not support the use of donepezil for neurocognitive rehabilitation in daily doses exceeding 10 mg. A temporal and causal relationship was observed between the initiation and titration of donepezil and development of QTc prolongation.

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

“…Including this initial report, ten cases of QT c prolongation with donepezil were identified, of which five had clearly identified episodes of TdP. 33 , 49 , 52 – 58 Salient features of these cases are summarised in Table 2 . Eight of the ten cases were in women and two in men.…”

“…The mean age of affected individuals was 77.3 ± 5.8 years (mean ± SEM). However, one case was an outlier 58 in the respect that it involved a young woman (26 years) treated with donepezil for cognitive rehabilitation rather than for AD. The mean age of the nine AD patients receiving donepezil was 83 ± 1.4 years.…”

“…This is significant because drug-induced QT prolongation and its associated risk of TdP are known to be exacerbated by the presence of at least one risk factor, 59 – 61 which is the case here. It is also notable that one QT c prolongation case with donepezil occurred in a young adult, 58 indicating that a risk of repolarisation delay with the drug can occur in younger individuals possessing additional risk factors (in this case receipt of quetiapine, expected to be synergistic in predisposing to QT c prolongation 62 ). For most scenarios in which AChEis are likely to be deployed, however, older age is an unmodifiable risk factor.…”

Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias – A narrative review

“…However, not all patients were on multiple medications, nor did all patients have comorbidities. 69,[88][89][90][91][92] Of the four donepezil cases, two cases had minimal comorbidity or polypharmacy relative to other cases, 69,88 perhaps making donepezil more likely to be causally associated with the QT C prolongation and arrhythmia (relative to the other cases). For the Vogel et al case, 92 donepezil was also considered the likely cause of the observed QT C prolongation, in spite of the existing comorbidities and polypharmacy.…”

“…Importantly, the Vogel et al case was the only one we found occurring in a young individual. 92 Findings also worth highlighting include one case having observations of complete atrioventricular block, bradycardia, and ventricular tachyarrhythmia, 69 as well as a case with findings of low heart rate concurrently with premature ventricular contractions 89 (premature ventricular contractions are concerning when in combination with bradycardia 32 ).…”