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Alzheimer’s Disease
Assessment Scale-Cognitive (ADAS-Cog). The 21 patients who were non- Numerous clinical trials with selegiline have been performed with variable
responders entered a three-month open-label study of ALC 2g/day in results and insufficient evidence to justify routine clinical use in AD.
9
A
addition to the AChEI. The proportion of responders increased from 38% 2005 meta-analysis
10
suggested an increase in all-cause mortality with
after treatment with AChIE alone to 50% on combination therapy. This alpha-tocopherol. Together with the results of the Alzheimer’s Disease
study reports a positive response rate after the addition of ALC, but Co-operative Study trial, these findings have led to a marked reduction
further studies have not yet been performed. in the use of these agents, and the combination has not been advocated
by any major consensus statements.
Hormone Replacement Therapy
Substantial epidemiological and experimental evidence suggested that Donepezil and Alpha-tocopherol
estrogen therapy might benefit women with AD. Rigaud et al. examined A retrospective study
11
investigating 40 AD patients who were on
whether hormone replacement therapy (HRT) could show benefit when combination therapy with donepezil ≥5mg daily and vitamin E ≥1,000IU
combined with the cholinesterase inhibitor rivastigmine in menopausal daily for at least one year were compared with historical data of patients
women with mild to moderate AD.
7
One hundred and seventeen patients with no AD treatment obtained from the 1986–1996 Consortium to
treated with rivastigmine were randomized to HRT (estrogen and Establish a Registry for Alzheimer’s Disease (CERAD)
12
database, which
progesterone) versus placebo for 28 weeks. Outcome measures included was created prior to the availability of these treatment options. The
the ADAS-Cog, MMSE, Global Deterioration Scale (GDS), Clinical Global average MMSE of patients on donepezil and vitamin E declined at a
Change-plus (CGC-Plus), Neuropsychiatric Inventory (NPI), and significantly lower rate at the one-, two, and three-year follow-up
Instrumental Activities of Daily Living (IADL). There was no discernable compared with historical data from the CERAD. This study had significant
benefit to combining HRT with rivastigmine. inherent limitations.
Antioxidants Multivitamins
Antioxidant therapy held considerable interest as a potential form of The combination of vitamin B
12
0.5mg and an over-the-counter
therapy for AD. Several studies attempted to examine its benefits in nutritional supplement containing folic acid 1mg and vitamin B
6
5mg
various combinations with other agents. (other vitamins and iron were also included) was tested as an adjunct to
an AChEI in mild to moderate AD in 89 patients over 26 weeks.
13
The aim
Selegiline and Alpha-tocopherol (Vitamin E) was to determine whether oral multivitamin supplementation containing
Selegiline, a monoamine oxidase inhibitor, inhibits oxidative deamination vitamins B
6
and B
12
and folic acid would improve cognitive function and
and therefore may reduce neuronal damage and have other positive reduce serum homocysteine levels in patients with mild to moderate AD.
effects on AD. Alpha-tocopherol (vitamin E) is a lipid-soluble vitamin that Although no statistical significance was found on primary or secondary
interacts with cell membranes, traps free radicals, and is thought to outcome measures, there was a significant decline in the serum
interrupt the sequence of reactions that damages cells. homocysteine concentration in the treatment group.
One of the larger combination studies that has been conducted, the Selective Serotonin Re-uptake Inhibitors
Alzheimer’s Disease Co-operative Study, addressed whether selegiline,
alpha-tocopherol, or a combination of the two could slow the course of Sertraline
clinical decline in AD.
8
AD patients of moderate severity, as measured by Sertraline has been assessed as an adjunct to donepezil in the treatment of
a Clinical Dementia Rating score of 2, from 23 participating sites were behavioral symptoms in outpatients with AD (MMSE between 8 and 23).
14
randomized to one of four groups (selegiline 10mg, alpha-tocopherol AD patients with an NPI total score >5 (minimum severity score 2 in at least
2,000IU, a combination of selegiline and alpha-tocopherol, or placebo) one domain) were treated with donepezil 5–10mg for eight weeks, and
over a two-year period. The primary outcome measure for these 341 then randomized to 12 weeks with sertraline 50–200mg or placebo. The
patients was the time to reach one of four possible end-points: death, primary outcome measures were the 12-item NPI and the Clinical Global
institutionalization, severe dementia defined as a Clinical Dementia Impression Improvement (CGI-I) and Severity (CGI-S) scales. The treatment
Rating score of 3, or loss of the ability to perform at least two of three group consisted of 124 patients, and 120 patients received placebo. There
basic activities of daily living (eating, grooming, and using the toilet). were no statistically significant differences on outcome measures. Post hoc
analysis suggested a ‘modest’ improvement on the CGI-I score in patients
The results of undjusted comparisons of selegiline with placebo, alpha- in the treatment group. Additionally, in a sub-group of patients with
tocopherol with placebo, and combined treatment with placebo were not moderate to severe behavioral and psychological symptoms—as defined by
statistically significant. When the baseline score on the MMSE was included a Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD) three-item
as a co-variate, a significant delay in the primary outcome was found with aggressiveness, affective disturbance, and anxiety/phobias score ≥6—of
seleginile (risk ration 0.57; p=0.012), alpha-tocopherol (risk ratio 0.47; those on sertraline, 60% achieved a positive response compared with 40%
p=0.001), and combination therapy (risk ratio 0.69; p=0.049). There was (p=0.006) of those on placebo. A positive response was defined as a ≥50%
no additive benefit in the combined treatment group. The estimated reduction in a four-item NPI-behavioral subscale. Sertraline was generally
increase in median survival was 230 days for the patients receiving alpha- well tolerated. Diarrhea was significantly more common (p<0.05) in the
tocopherol, 215 days for those receiving selegiline, and 145 days for those donepezil plus sertraline group compared with the donepezil plus placebo
receiving both compared with the patients receiving placebo. There was no group. This study was insufficient to define best practice with respect to
improvement in cognition in any of the groups. the use of this combination strategy.
32 US NEUROLOGY
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