"My moon landing" - this is how Lundbeck celebrates the blob of marmalade in the middle of a slice of toast of a patient with ALZHEIMER's disease in an advertisement for EBIXA (memantine) (1). However, enthusiasm is in fact out of place. In the studies published so far, the data on the benefit of memantine (AXURA, EBIXA) are by no means impressive. The European licensing of the amantadine-related "NMDA* receptor antagonist" five years ago is based mainly on a single 28-week study with 252 patients, which showed a positive outcome in only one of the two primary end points (2). This and a small study that was too short with only twelve weeks (3) and included more patients with vascular dementia than with ALZHEIMER's disease (a-t 2002; 33: 91) were not sufficient for American licensing approval (4). Licensing was granted in the USA only after submission of a further 24-week study with 404 patients, in which memantine was taken in addition to donepezil (ARICEPT) for at least six months and compared with placebo (5) (a-t 2004; 35: 18). However, the American licensing authority assesses the effect in all three studies as "small" (6).

These three published studies with a total of 726 patients with ALZHEIMER's disease in the licensed indication (moderate to severe ALZHEIMER's disease**) (7,8) are in contrast to three unpublished negative studies, which can be found in the company's own study register and include a total of 873 patients (9,10):

	A six-month American phase III study of 350 ambulant patients (MEM-MD-01) has been concluded already in 2003. Neither the primary activities of daily life (ADCS-ADL19***, modified) nor cognitive functions, which are tested with a scale specially designed for severe impairment (SIB***), turn out better with memantine 20 mg daily than with placebo (9).
	In another six-month American study of 265 residents of old people's and nursing homes (MEM-MD-22) no significant differences were found between memantine 20 mg daily and placebo (9) in any of the tested scales.
	In a third 16-week study (no. 10116) of 258 patients, the primary cognitive functions (SIB) tested in the memantine group did also not differ from those in the placebo group (10).

Although only one of the three unpublished negative studies (MEM-MD-01) is included in the analysis of the British National Institute for Clinical Excellence (NICE), this comes to the conclusion for memantine that "the absolute magnitude of the differences of all outcomes is modest" and that the evidence is insufficient to confirm clinically relevant efficacy in the licensed indication (11).

The NICE does not usually receive unpublished data either. As in Germany, these are also regarded in Great Britain as one of the manufacturer's protected company secrets. However, the Institute can find out the number of study participants in relevant studies from the British medicines authority. Therefore, it can estimate the proportion of unpublished data. For most psychiatric agents it became clear that "less than half and possibly on average only a third of clinical studies are published" (12). The benefit and harm of a medicine can be reliably assessed only when all the data are accessible. Tim KENDALL, director of the national centre for mental health in Great Britain and closely involved in drawing up the NICE guidelines, describes the consequences: if this ideal situation were to be reached some day, it might be that not many treatments would remain (12).

	The data on the efficacy of memantine (AXURA, EBIXA) in moderate to severe ALZHEIMER's disease on the basis of the published studies are sparse. The measured effects are classified as "small".
	None of the studies in which no benefit can be demonstrated has been published. The three negative studies involve more that half of all patients from studies in the licensed therapeutic indication.
	Suppression of negative data is widespread with psychiatric drugs: not even half, but rather only a third on average of clinical studies are published. A serious assessment on the basis of the published data is not possible.

(R = randomised study)

1

Lundbeck: advertisement for EBIXA, Der Nervenarzt [The Neurologist] March 2007; 78

2

REISBERG, B. et al.: N. Engl. J. Med. 2003; 348: 1333-41

3

WINBLAD, B., PORITIS, N.: Int. J. Geriatr. Psychiatry 1999; 14: 135-46

4

Scrip 2002; No. 2785: 26

5

TARIOT, P.N. et al.: JAMA 2004; 291: 317-24

6

FDA/CDER: Medical Review Memantine, status Jan. 2003; http://www.fda.gov/cder/foi/nda/2003/21-487_Namenda.htm

7

EMEA: Scientific discussion of AXURA on 15th Nov. 2005

8

Scrip 2005; No. 3076: 18

9

Forest Laboratories: http://www.forestclinicaltrials.com

10

Lundbeck Clinical Trial registry: http://www.lundbecktrials.com

11

NICE technology appraisal guidance 111, Nov. 2006

12

KENDALL, T., McGOEY, L.: Biosocieties 2007; 2: 129-40

NMDA: N-methyl-D-aspartate receptor, belonging to the group of glutamate receptors.

In 2005 the indication was extended in Europe from "moderately severe to severe" (FOLSTEIN Mini Mental Test [MMSE] < 15 points) to "moderate to severe" (MMSE < 20), while the extension sought for mild ALZHEIMER's disease was rejected, as in the USA (7,8).

ADCS-ADL19 = Alzheimer's Disease Cooperative Study-Activities of Daily Living: scale for recording activities of daily life. Modified form with 19 items and a maximum of 54 points. Higher score corresponds to better function. SIB = Severe Impairment Battery; tests cognitive functions, suitable especially at MMSE scores < 15. Maximum score is 100 points.