Off-label drug ineffective in frontotemporal dementia

By Eleanor McDermid, Senior medwireNews Reporter

A randomized, controlled trial has dashed hopes that memantine therapy could benefit patients with frontotemporal dementia (FTD).

"These study findings are obviously disappointing, especially in view of the consistently positive benefits shown in moderate-to-severe Alzheimer's disease and other dementia syndromes," says John Hodges (Neuroscience Research Australia and University of New South Wales, Sydney) in a commentary accompanying the study in The Lancet Neurology.

Memantine has been much used off label for patients with FTD. Indeed, Adam Boxer (University of California, San Francisco, USA) and team were unable to recruit the planned 140 patients partly because many preferred to use memantine off label rather than risk being assigned to receive placebo.

The team eventually recruited 81 patients who had characteristic brain atrophy and behavioral variant FTD according to Neary criteria (n=64) or semantic dementia (n=17). During 26 weeks of treatment, memantine had no significant effect on patients' neuropsychiatric inventory (NPI) scores or their clinical global impression of change (CGIC) scores, relative to placebo.

Specifically, there was a nonsignificant average 2.2-point difference in the change in NPI scores between the 39 patients allocated to take memantine 20 mg/day and the 42 given placebo. The two groups had identical change in CGIC scores.

Although the study failed to recruit the anticipated number of patients, the negative findings are in line with those of a previous randomized trial, which involved 49 patients.

Secondary functional and motor outcomes were unaffected by treatment allocation. However, patients given memantine had significantly faster declines on two of seven cognitive tests - digit symbol and Boston naming - than patients taking placebo.

Hodges says that the message from the only two randomized trials to date is clear: "Memantine should not be prescribed to patients with frontotemporal dementia, and treatment might, in fact, hasten cognitive decline." Although he cautions that the evidence for decline is "rather mixed."

Hodges suggests that drugs such as memantine are unlikely to offer much benefit. "Attempting to improve the symptoms of frontotemporal dementia with drugs that alter the balance of neurotransmitters in such a devastating and rapidly progressive disease seems analogous to re-arranging the deck chairs on the Titanic."

He believes new drugs directly targeting the pathologic process are needed, although this is challenging because of the heterogeneous pathology of FTD. About half of patients have tau inclusion pathology, and trials of tau-modifying drugs are underway, he notes.

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