Selegiline for Alzheimer's disease.
BACKGROUND
Alzheimer's disease is the most common cause of dementia in older people accounting for some 60% of cases with late-onset cognitive deterioration. It is now thought that several neurotransmitter dysfunctions are involved from an early stage in the pathogenesis of Alzheimer's disease-associated cognitive decline. The efficacy of selegiline for symptoms of Alzheimer's disease remains controversial and is reflected by its low rate of prescription and the lack of approval by several regulatory authorities in Europe and elsewhere. Reasons for this uncertainty involve the modest overall effects observed in some trials, the lack of benefit observed in several trials, the use of cross-over designs which harbour methodological problems in a disease like dementia and the difficulty in interpreting results from trials when a variety of measurement scales are used to assess outcomes.


OBJECTIVE
The objective of this review is to assess whether or not selegiline improves the well-being of patients with Alzheimer's disease.


METHODS
The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'selegiline', 'l-deprenyl', "eldepryl" and "monamine oxidase inhibitor-B". MEDLINE, PsycLIT and EMBASE electronic databases were searched with the above terms in addition to using the group strategy (see group details) to limit the searches to randomised controlled trials.


METHODS
All unconfounded, double-blind, randomised controlled trials in which treatment with selegiline was administered for more than a day and compared to placebo in patients with dementia.


METHODS
An individual patient data meta-analysis of selegiline, Wilcock 2002 provides much of the data that are available for this review. Seven studies provided individual patient data and this was pooled with summary statistics from the published papers of the other nine studies. Where possible, intention-to-treat data were used but usually the meta analyses were restricted to completers' data (data on people who completed the study).


RESULTS
There are 17 included trials. There were very few significant treatment effects and these were all in favour of selegiline; cognition at 4-6 weeks and 8-17 weeks, and activities of daily living at 4-6 weeks. There is little evidence of adverse effects caused by selegiline, and few withdrew from trials, apart from the Sano trial. The analyses were conducted on data available. There was no attempt to correct for missing patients because there were so few and withdrawal was probably unconnected with treatment. All trials examined the cognitive effects of selegiline, and in addition 12 trials examined the behavioural and mood effects. The meta-analysis revealed benefits on memory function, shown by improvement in the memory tests from several cognitive tests (the Randt Memory Index from Agnoli 1990 and Agnoli 1992, the BSRT from Sunderland 1992, prose recall from Filip 1991, ADAS-cog from Lawlor 1997, the Wechsler Memory Scale from Loeb 1990 and Mangoni 1991, the Rey -AVL from Piccinin 1990, and the MMSE from Sano 1995, Tariot 1998, Filip 1991, Freedman 1996, Burke 1993 and Riekkinen 1993). The combined memory tests, and overall the combined cognitive tests, analysed using standardised mean differences, showed an improvement due to selegiline compared with placebo at 4-6 weeks (SMD 0.39, 95%CI 0.07 to 0.72, P = 0.02, random effects model ) and 8-17 weeks, ( SMD 0.44, 95%CI 0.04 to 0.84, P = 0.03, random effects model). The meta-analyses of emotional state show no treatment effects. Several studies assessed activities of daily living using several different scales, the GBS-motor function from Agnoli 1990, the NOSIE-daily living from Filip 1991, the BDS-daily living from Loeb 1990 and Mangoni 1991, the DS from Sano 1995 and PIADL from Tariot 1998. The combined tests, analysed using the standardised mean difference, showed an improvement due to selegiline at 4-6 weeks (SMD -0.27, 95% CIs -0.41 to -0.13, P = <.001). The global rating scales, the BDS used by Burke 1993 and Tariot 1998, and the GBS used by Agnoli 1990 and Agnoli 1992, and the GDS used by Freedman 1996 and the CGI by Filip 1991, analysed using standardised mean differences showed no effect of selegiline. A variety of adverse effects were recorded, but very few patients left a trial as a direct result. Four studies reported no side effects. Mangoni 1991 reported poor tolerability for 3 patients out of 68 on treatment and 1 out of 51 on placebo, resulting in dropouts. Small numbers found equally in both groups reported anxiety, agitation, dizziness, nausea and dyspepsia. Piccinin 1990 reported that selegiline was well tolerated with few adverse reactions (dizziness and orthostatic hypotension) and no resulting drop outs. Burke 1993 and Loeb 1990 both reported that selegiline was very well tolerated with no serious side effects. Sano 1995 reported 49 categories of adverse events but found no differences between the 4 arms of the factorial trial. Freedman 1996 reported unequal numbers of dropouts in the trial with 7 subjects withdrawing from the selegiline group and only 1 subject from the placebo group. The meta-analyses of the numbers suffering adverse effects, and of the numbers of withdrawals before the end of the trial show no difference between control and selegiline.


CONCLUSIONS
Despite its initial promise, ie the potential neuroprotective properties, and its role in the treatment of Parkinson's disease sufferers, selegiline for Alzheimer's disease has proved disappointing. Although there is no evidence of a significant adverse event profile, there is also no evidence of a clinically meaningful benefit for Alzheimer's disease sufferers. This is true irrespective of the outcome measure evaluated, ie cognition, emotional state, activities of daily living, and global assessment, whether in the short, or longer term (up to 69 weeks), where this has been assessed. There would seem to be no justification, therefore, to use it in the treatment of people with Alzheimer's disease, nor for any further studies of its efficacy in Alzheimer's disease.
Birks
J
J
Department of Clinical Geratology, University of Oxford, Oxford, UK, OX2 6HE. jacqueline.birks@geratology.ox.ac.uk
Flicker
L
L
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D006801:Humans; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012642:Selegiline / Q000627:therapeutic use*; D017211:Treatment Failure
D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline