Memantine-induced myoclonus and delirium exacerbated by trimethoprim

To report a case of myoclonus and delirium seen in a patient taking a combination of memantine and trimethoprim.

A 78-year-old woman was admitted to the medical center in October 2007 with rapid deterioration of Alzheimer's dementia and progressive myoclonus. In 2003, donepezil 5 mg/day had been initiated and her disease slowly progressed. In 2006, memantine 10 mg twice daily was added. Myoclonic activity and delirium were noted in 2007 when a urinary tract infection (UTI) was treated with double-strength trimethoprim/sulfamethoxazole (TMP/SMX 160 mg/800 mg). After discontinuation of TMP/SMX, the patient's condition returned to baseline level. Several weeks later, trimethoprim 100 mg daily was added for UTI prophylaxis. Within weeks, spontaneous generalized myoclonic activity resumed to the extent that the patient was unable to walk. She became increasingly delirious. A week before admission, levodopa/carbidopa 250 mg/100 mg was added for presumptive restless legs syndrome and the patient became extremely delirious and combative, requiring hospitalization. Because of the striking similarity of dose-related toxicities reported with amantadine, a slightly different aminoadamantane, memantine was withheld. Trimethoprim was discontinued due to a likely interaction with memantine. Donepezil and famotidine were withheld due to questions of therapeutic necessity. After 3 days, the myoclonus had completely resolved and the patient was no longer agitated or combative during the remainder of her hospitalization. She was cooperative and ambulatory and was discharged.

Memantine is cleared primarily through the kidneys and should be renally dosed. Drugs that interfere with elimination-that is, other drugs utilizing the organic cation transporter-2 in the tubule, such as trimethoprim, metformin, or imipramine-may lead to drug accumulation. Our patient, who had impaired renal function, developed severe myoclonus and delirium after trimethoprim was added to therapy with memantine. As there were no reports of myoclonus and delirium with this drug combination and because of the structural, pharmacologic, and pharmacokinetic similarities between the aminoadamantanes memantine and amantadine, we researched similar dual adverse effects reported with amantadine. Amantadine has led to the same adverse effects noted in our patient, not only in patients with renal impairment, but also in one patient when trimethoprim was added to a stable dose of amantadine.

This is the first reported case of a drug interaction between memantine and trimethoprim, which resulted in clinically significant myoclonus and delirium. Clinicians should be aware of this potential interaction, since there have been reports of this adverse effect with the use of amantadine. Because memantine chemically and pharmacologically resembles amantadine, it is quite possible that their toxicities are similar.