Neuroleptic Malignant-Like Syndrome as a Potential Etiology for Donepezil Related Rhabdomyolysis

Purpose of Review Donepezil is widely prescribed to slow the progression of Alzheimer’s Disease through its cholinomimetic property as an acetylcholinesterase inhibitor. There is an inverse relationship between acetylcholine and dopamine. Neuroleptic malignant syndrome (NMS), typically associated with dopamine antagonists, could theoretically and inversely be associated with cholinomimetic drugs such as donepezil. This literature review seeks to summarize the body of case reports from the extant literature of temporal associations between donepezil and neuroleptic malignant-like syndromes. Recent Findings While the Canadian government has warned of the associated risk of rhabdomyolysis that “may be the result of complications of NMS”, the US Food and Drug Administration (FDA) package insert for donepezil lists NMS among the category of “adverse events temporally associated... for which there are inadequate data to determine the causal relationship”. This literature review covers 10 cases of donepezil associated neuroleptic malignant-like syndrome and an additional case by the authors of suspected averted donepezil associated rhabdomyolysis, totaling 5 cases with and 6 cases without concurrent antipsychotic prescription. Summary Eight out of 11 cases occurred within 17 days of donepezil either being started or increased. While NMS is also associated with antipsychotic discontinuation, only 5 of 11 cases occurred in the setting of recent discontinuation of antipsychotic medication. The growing literature of donepezil associated neuroleptic malignant-like syndrome supports the possibility of this as the mechanism for donepezil associated rhabdomyolysis.