Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00064
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: June 2008
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Joshua A. Epstein, Pharm.D. candidate

Major depressive disorder (MDD) is charac-
terized as a disabling psychiatric disorder, presenting
with a loss of pleasure and interest in activities that
normally bring satisfaction and enjoyment. MDD is
a common disorder, roughly occurring at least once
in the lifetime of 16.2% of US adults (32.6-35.1 mil-
lion people), and at least once in the past year of
6.6% of US adults (13.1-14.2 million people).1 Stud-
ies show that being female, middle aged, divorced,
low income, or Native American increase the risk of
depression. Approximately 80% of depressed people
are not currently treated and for those that are, anti-
depressants only work for 55-65% of them.2 In a
group of studies evaluated by the FDA, placebos
were approximately 80% as effective as the six lead-
ing antidepressant medications.3
Antidepressants work by attempting to cor-
rect a misbalance of neurotransmitters in the brain.
Low levels of serotonin (5-HT) and norepinephrine
(NE) can cause depressive symptoms and the correc-
tion of these deficiencies has been associated with an
improvement of mood. Serotonin-Norepinephine
Reuptake Inhibitors (SNRI) are a newer class of anti-
depressants that work on both neurotransmitters be-
lieved to play a major role in causing depression.
Desvenlafaxine, by Wyeth Pharmaceuticals,
Inc., is the third drug in the SNRI class and is the
metabolite of venlafaxine. Desvenlafaxine was ap-

proved by the FDA in February of 2008, and is ex-
pected to be distributed in the second quarter of
2008. The only FDA approved indication for des-
venlafaxine is for the treatment of MDD. Desvenla-
faxine is also being investigated as the first non-
hormonal treatment for vasomotor symptoms attrib-
uted to menopause; however, that is not a currently
approved indication.
The objective of this article is to review the
pharmacology, pharmacokinetics, dosing, and toxic-
ity of desvenlafaxine. In addition, a summary of
clinical trials will be discussed.

Pharmacology and Pharmacokinetics
The mechanism of action of desvenlafaxine is
through selective blocking of the reuptake of sero-
tonin and norepinephrine. This increases the levels
of both neurotransmitters in the synapse which is
thought to be beneficial in depressed individuals.
Table 1 outlines the pharmacokinetics of des-
venlafaxine. As a once daily dose, the pharmacoki-
netics are linear and dose proportional from 100 mg-
600 mg per day. High fat meals increase the maxi-
mum concentration (Cmax) by 16% but do not affect
Area under the Curve (AUC). This implies that des-



W PharmaNote


Volume 23, Issue 9 June 2008


Table 1. Pharmacokinetics of desvenlafaxine4
Pharmacokinetic Parameters

t1/2 Tss F Tp PB Vd
Desvenlafaxine 11 h 4-5 d 80% 7.5 h 30% 3.4 L/kg
F= Bioavailaility; PB = Protein binding; tl/2 Half-life; Tp = Time to peak plasma concentrations; Tss = Time to steady state; Vd = Volume of distribution

venlafaxine may be taken with or without food. The
main route of metabolism is through conjugation me-
diated by UDP-glucuronosyltransferase (UGT) iso-
forms, and through a minor pathway of oxidative me-
tabolism using the CYP3A4 enzyme. Approximately
45% is excreted unchanged in the urine and 19% is
excreted as the glucuronide metabolite.4
Maximum concentration and AUC increase
by 32% and 55%, respectively, in patients older then
75 years of age when compared to patients 18 to 45
years of age. Dosing adjustments might be necessary
to avoid adverse effects in this particular population.4
The pharmacokinetic profile of patients with
hepatic insufficiency changes significantly; however,
the clinical significance is minimal. AUC increases
35% in patients with severe hepatic impairment and
clearance is decreased by 36%. The half life (tl/2)
increases by 40% in these same patients.4 Adjusting
the initial dose of desvenlafaxine is not needed, but
careful monitoring of these patients is recommended.
Patients renal function should be assessed
prior to beginning desvenlafaxine. According to the
prescribing information, elimination is significantly
correlated with creatinine clearance (CrC1). The
AUC increases by 42%, 56%, and 116%, in patients
with mild, moderate and end stage renal disease
(ESRD). The tl/2 of desvenlafaxine was increased to
15.5 hours and 22.8 hours for moderate and end stage
renal disease. It is recommended that patients with
significant renal disease be dosed every other day
with desvenlafaxine.4

Clinical Trials
Liebowitz et al. performed a placebo-
controlled, randomized, double-blind trial, using a
dose titration of desvenlafaxine.5 Patients were
treated in an outpatient setting for major depressive
disorder based on DSM-IV criteria. The primary
outcome measure was an improvement in the 17-item
Hamilton Rating Scale for Depression at final
evaluation. Secondary measures evaluated various
other depression measurement tools such as Mont-

gomery-Asberg Depression Rating Scale (MADRS).
The authors concluded there was no significant dif-
ference between desvenlafaxine and placebo based
on the primary endpoint. However, there was a sig-
nificant difference (p=0.047) between desvenlafaxine
vs placebo with the MADRS. The rate of adverse
effects for desvenlafaxine was twice the rate noted
with placebo (Table 2).
In a similar study performed by Wyeth as
part of their phase 3 study program, desvenlafaxine
was used at twice the dose as the Liebowitz study.6
The authors found an adjusted mean change from
baseline in the Hamilton Rating Scale for Depression
(HAM-D) total score which was significantly greater
for both 200 mg (p= 0.002) and 400 mg (p=0.008)
doses of desvenlafaxine vs placebo. This phase 3
clinical trial also recorded adverse effects that oc-
curred in at least ten percent of patients, which was
twice the rate of placebo.6
The most complete study was performed by
Demartinis et al. where a dose titration of desvenla-
faxine was compared to placebo in 461 patients for
eight weeks.' With nearly equivalent participants in
each arm of the study (100 mg/day, 200 mg/day, 400
mg/day, and placebo) there was a significant im-
provement in HAM-D, Clinical Global Impressions-
Improvement Scale (CGI-I) and the Clinical Global
Impressions- Severity Scale (CGI-S) score for nearly
all doses of desvenlafaxine when compared to pla-
cebo. The HAM-D scores for the desvenlafaxine
100 mg/day and 400 mg/day arms were 12.75 and
12.50 respectively, which were both significantly
lower than the HAM-D score for placebo of 15.31 (p
= 0.0038, 0.0023, respectively). The HAM-D scores
for desvenlafaxine 200 mg/day (13.31), was not sig-
nificant (p = 0.0764). The CGI-I scores were signifi-
cantly better then placebo for all groups. The CGI-S
scores were statistically better then placebo for both
the 100 mg/day and 400 mg/day, but not 200 mg/day
(p = 0.017, 0.046, 0.142, respectively). The authors
concluded desvenlafaxine's effectiveness for the
short-term treatment of MDD.7

PharmaNote Volume 23, Issue 9 June 2008

Volume 23, Issue 9 June 2008


Table 2. Clinical Trial Summary Comparing Desvenlafaxine to Placebo

Study Year Design Dse Duration Results

No SS differences for HAM-D
Liebowitz et al.5 2007 R, DB, PC 100-200 mg/day 234 8 weeks scores. SS differences for
MADRS (p = 0.047).

SS difference in HAM-D score
Garland et al.6 2006 R, DB, PC 200-400 mg/day 375 8 weeks between 200 mg and 400 mg
doses vs placebo (p = 0.002,
0.008 respectively)

HAM-D scores were SS lower
for desvenlafaxine vs placebo at
100 mg/day (p = 0.0038), and at
400 mg/day (p = 0.0023), but not
SS at 200 mg/day (p = 0.0764).
CGI-I scores were SS better then
DeMartinis et al. 2007 R, DB, PC 100-400 mg/day 461 8 weeks t-
placebo at all doses. CGI-S
scores were SS better then pla-
cebo at 100 mg/day and 400 mg/
day, but not at 200 mg/day. (p =
0.017, 0.046, 0.142, respec-

CGI-I = Clinical Global Impressions-Improvement Scale; CGI-S = Clinical Global Impressions- Severity Scale DB= Double Blinded; HAM-D = Hamilton Rating
Scale for Depression; MADRS = Montgomery-Asberh Depression Rating Scale; q1 # of participants; PC = Placebo Controlled; SS = Statistically significant

Larger clinical trials that perform head-to-
head studies with other antidepressants need to be
performed before conclusive evidence based medi-
cine can be applied regarding the role of desvenla-
faxine in the long-term treatment of depression.

Dosing and Administration
According to the prescribing information, the
recommended initial and usual dose is 50 mg by
mouth once daily with or without food. The maxi-
mum dose is 400 mg daily. Desvenlafaxine is avail-
able as a 50 mg and 100 mg extended-release tablet.
It is recommended to take the tablets at the same
time everyday and do not crush, chew or divide the
tablets. Gradual dose reduction is appropriate when
using higher then 50 mg daily.

Toxicity and Safety
The most immediate concern when beginning
any antidepressant medication is the potential in-
crease in the rate of suicidal ideation, especially in
adolescents and young adults. This occurs during the
early phases of drug therapy and may subside in

about 6-8 weeks. Patient's beginning treatment with
desvenlafaxine should be monitored closely for
worsening of depressive symptoms including suici-
dal thoughts and unusual changes in behavior.
Other adverse effects that have been reported
in at least 10% of patients using of desvenlafaxine
include abdominal pain, asthenia, anorexia, constipa-
tion, dry mouth, nausea, vomiting, dizziness, insom-
nia, nervousness, somnolence, sweating, tremor, ver-
tigo, and abnormal ejaculation.6 This contrasts to
approximately 5% of patients who reported adverse
effects from the placebo-treated groups with severity
judged as mild-to-moderate. Discontinuation of this
medication should be considered if the side effects
become severe.

Since desvenlafaxine has not yet been distrib-
uted, cost is not available.

Desvenlafaxine has recently been approved
by the FDA for the treatment of major depressive

PharmaNote Volume 23, Issue 9 June 2008

Volume 23, Issue 9 June 2008


disorder, and is scheduled for distribution within 8-
12 weeks. Desvenlafaxine will provide physicians
and patients with another option in the treatment of
depression. The pharmcokinetics and pharmacology
of desvenlafaxine is comparable to other available
SSRI's and SNRI's. Some clinical trials show supe-
riority over placebo while some show non-
inferiority. There are no head-to-head trials compar-
ing desvenlafaxine to other active drugs, and there-
fore conclusions regarding its place in therapy cannot
be made. Many of the clinical trials comparing des-
venlafaxine to placebo, show beneficial effects at
doses between 100 mg and 400 mg daily, yet the rec-
ommended dosage is 50 mg daily. Without pub-
lished efficacy trials of desvenlafaxine 50 mg daily,
the lowest effective dose remains unknown. Des-
venlafaxine has shown promise in the nonhormonal
treatment of vasomotor symptoms attributed to
menopause, but the FDA has not currently approved
desvenlafaxine for that indication.

1. Kessler RC, Berglund P, Demler O, et al. The
epidemiology of major depressive disorder: re-
sults from the National Comorbidity Survey Rep-
lication (NCS-R). JAMA 2003;289:3095-105.
2. Murray B, Fortinberry A. Depression Facts and
Stats. http://www.upliftprogram.com/
depression_stats.html. Viewed on 3/16/08.
3. Boyles S. Are Antidepressants Effective? http://
are-antidepressants-effective.Viewed on 3/16/08.
4. Pristiq[desvenlafaxine]. Prescribing Information
Wyeth Pharmaceuticals, Inc. Philadelphia, PA.
Revised April 2008.
5. Liebowitz MR, Yeung PP, Entsuah R. A random-
ized, double-blind, placebo-controlled trial of
desvenlafaxine succinate in adult outpatients with
major depressive disorder. J Clin Psychiatry
6. Garland C, Media Contact. Desvenlafaxine data
show significant improvement in symptoms of
depression in adults vs. placebo. Summary of
Phase 3 studies by Wyeth Pharmaceuticals. Pub-
lic Release on 5/25/2006.
7. DeMartinis NA, Yeung PP, Entsuah R, Manley
AL. A double-blind, placebo-controlled study of
the efficacy and safety of desvenlafaxine succi-
nate in the treatment of major depressive disor-
der. J Clin Psychiatry 2007;68:677-88.


Michael Martin, Pharm.D. candidate

Alzheimer's disease is the most common
form of dementia and the seventh leading cause of
death in the United States. It is named for German
physician Alois Alzheimer, who first described the
disease in 1906. It is estimated that nearly 5 million
Americans and upwards of 24 million people world-
wide are afflicted with the disease.1 Approximately
10% of people in the United States have Alzheimer's
disease at age 70, but this number increases to 40%
by age 90.2
Alzheimer's disease is characterized by errors
in protein folding in the brain. These proteins,
known as amyloid precursor protein (APP) and tau,
gradually build up and form intracellular tangles and
extracellular plaques that will eventually go on to
cause the death of the neuron. This progressive atro-
phy is particularly prominent in the cortex, an area of
the brain associated with thinking, speech, and mem-
ory. Initial symptoms include short-term memory
loss and confusion, but eventually can progress to
mood swings, anger, long-term memory loss, loss of
language ability, and ultimately fatal loss of bodily
functions. While there is a defined early-onset (prior
to age 65) form of Alzheimer's with known genetic
causes, these account for only 4-5% of all total Alz-
heimer's cases. The remaining 95% of cases are con-
sidered sporadic with no familial inheritance and
have no well-defined cause.
Given that Alzheimer's disease is so debili-
tating, particularly in its later stages, it is not surpris-
ing that the associated direct and indirect costs of the
disease are enormous. It is estimated that the aver-
age yearly cost of care for an institutionalized Alz-
heimer's patient is between $40,000 and $50,000.3
The total cost of caring for patients with Alzheimer's
disease is expected to triple by the year 2040, largely
due to the increasing age of the population and the
number of people that will be living with Alz-
heimer's disease.4

PharmaNote Volume 23, Issue 9 June 2008

Volume 23, Issue 9 June 2008


While there is no cure for Alzheimer's dis-
ease, there are several medications on the market de-
signed to help treat the symptoms of the disease.
This article will review each of these drugs, its
mechanism of action, side effects, cost, and indica-
tions for use.

Patients with Alzheimer's disease have a
gradual decline in memory and their ability to learn,
at least in part due to the death of cholinergic neu-
rons. Postmortem exam of the brains of patients
with Alzheimer's disease show lesions from the fore-
brain leading to the hippocampus, the region of the
brain involved in memory. The deficit in cholinergic
neurotransmission is believed to be related to this
decline. By inhibiting cholinesterases, the enzymes
responsible for the degradation of acetylcholine, lev-
els of acetylcholine in the CNS will increase, even
with a decreased level of cholinergic neurons.
Tacrine was the first cholinesterase inhibitor
approved for the treatment of mild-to-moderate Alz-
heimer's disease in 1993. Tacrine is less selective for
neuronal acetylcholinesterase than other, newer
agents of the same class and thus exhibits more pe-
ripheral cholinergic effects. The most common side
effects of tacrine include nausea, vomiting, diarrhea,
myalgia, and ataxia. Tacrine can significantly ele-
vate liver enzymes, particularly transaminases. A
patient's transaminases must be monitored every
other week from at least week 4 to week 16 after
starting therapy.
There are mixed reports of tacrine's effective-
ness in the treatment of Alzheimer's. One study
found 120 mg and 160 mg doses, but not 80 mg, pro-
duced a significant (p<0.001) improvement in cogni-
tion after 30 weeks of therapy, as measured by the
Alzheimer's Disease Assessment Scale Cognitive
subscale (ADAS-cog), a validated scale to assess
memory, attention, orientation, and language abil-
ity.5'6 The same study, among others, found that
tacrine therapy produced statistically significant im-
provements in global function, as measured by the
Clinician Interview-Based Impression (CIBI)
(p<0.002) and Final Comprehensive Consensus As-
sessment (FCCA) (p<0.001).7 Of patients that with-
drew from the study due to side effects, the most
common reasons were asymptomatic liver transami-
nase elevation (28%) and gastrointestinal (GI) com-
plaints (16%). A separate study found that after nine

months of treatment with tacrine, only 2 of 22 tests
of cognition showed any improvement favoring
treatment: the color form sorting test (p=0.002) and
the similarities test (p=0.04).8 This study also evalu-
ated caregiver burden and found no improvement
after nine months of therapy (p=0.397). This finding
is consistent with the results of other studies.9
Tacrine is available as Cognex 10 mg, 20
mg, 30 mg, and 40 mg capsules. The starting dose is
10 mg four times a day, with subsequent 10 mg titra-
tions every 4 weeks based on patient tolerance.
Based on a 160 mg (40 mg four times a day) dosing
regimen, a one-month supply costs approximately
$300. Although the patent expired in September
2007, there are no generic equivalents at this time,
likely due to low demand relative to other Alz-
heimer's disease therapies.

Donepezil, the second cholinesterase inhibi-
tor for the treatment of mild-to-moderate Alzheimer's
disease, was approved in 1996 under the brand name
Aricept. Unlike tacrine, donepezil has not been as-
sociated with hepatotoxicity, possibly due to its
unique chemical structure. Its long half-life also al-
lows for once-daily dosing. Furthermore, its en-
hanced affinity for neuronal acetylcholinesterase
relative to tacrine gives it a reduced incident of pe-
ripheral adverse reactions. In 2004, a rapidly disinte-
grating tablet was approved under the brand name
Aricept ODT. In 2006, both brands received ap-
proval for the treatment of severe Alzheimer's dis-
An analysis of several clinical trials showed
that donepezil affected both cognition and global
function in Alzheimer's patients.10 A separate analy-
sis showed that these effects varied based on dose
after 24 weeks of therapy (p=0.005).1 A one-year
study comparing donepezil and galantamine showed
no difference in primary outcome, as measured by
the change in Mini-Mental State Exam (MMSE)
score after one year of therapy, based upon treatment
strategy.12,13 Galantamine-treated patients' MMSE
score did not differ significantly from baseline (-0.52
+ 0.39 points), while donepezil-treated patients ex-
perienced a significant deterioration from baseline (-
1.58 0.42 points; p<0.0005). The between-group
difference, however, was not statistically significant
(p=0.1). The secondary outcome of cognition was
measured using the ADAS-cog. While no difference

PharmaNote Volume 23, Issue 9 June 2008

Volume 23, Issue 9 June 2008


based on therapy was shown for the overall popula-
tion, patients with a baseline MMSE score of 12-18
seemed to benefit more with galantamine therapy
over donepezil. Patients treated with galantamine
experienced a 1.61 0.80 point worsening in MMSE
score versus baseline, while patients treated with
donepezil experienced a worsening of 4.08 0.84
points (p<0.05). The reasoning behind this subgroup
of patients' benefit from galantamine over donepezil
is unknown.
The most commonly reported side effects of
donepezil include nausea, vomiting, anorexia, diar-
rhea, fatigue, and muscle cramps. The 5 mg dose is
generally well-tolerated, but the incidence of side
effects increases with the 10 mg dose, particularly
during the upward dose titration phase. Aricept and
Aricept ODT are available as 5 mg and 10 mg tab-
lets. Upward dose titration should not occur until 4-
6 weeks after the start of therapy. Average monthly
cost for both strengths averages $185. Patents on
donepezil will not expire until 2010.

Galantamine is a natural alkaloid originally
from the bulbs of the common snowdrop flower,
Galanthus nivalis. Galantamine tablets and oral so-
lution were approved in 2001 for the treatment of
mild-to-moderate Alzheimer's disease under the
brand name Reminyl. This brand name was later
changed in the US to Razadyne to avoid confusion
with the diabetes drug Amaryl (glimepiride). Gal-
antamine tablets require twice daily dosing, as well
as a slow titration to therapeutic doses to limit GI
side effects. Once-daily Razadyne ER tablets were
approved in 2004 and have similar tolerability and
efficacy compared to twice daily galantamine tab-
Like other cholinesterase inhibitors, most of
the common side effects of galantamine are related
to GI effects. The most frequently reported include
nausea, vomiting, diarrhea, dyspepsia, and abdomi-
nal pain. These symptoms occur most frequently
during the dose-titration phase of therapy and gener-
ally resolve with long-term treatment. One study
reported that women and those with lower BMI at
the start of therapy were more likely to experience
nausea and vomiting.15 Other CNS effects include
dizziness, headache, depression, fatigue, and insom-
Numerous studies have shown a significant


improvement in cognitive function with galantamine
therapy for both those with Alzheimer's disease and
those with mild cognitive impairment, considered a
potential precursor or "transitional state" to Alz-
heimer's disease.14,16 These effects have also been
observed in patients suffering from mixed dementia,
a combination of both Alzheimer's disease and vas-
cular dementia.17 Patients treated with galantamine
24 mg/day showed a significant improvement in
ADAS-cog score at 6 months (-1.1 points; p<0.05).
Galantamine is available as 4, mg, 8 mg, 12,
mg, 16 mg, and 24 mg tablets along with a 4 mg/ml
oral solution. The monthly cost is similar for all
strengths and averages $200. Patents for galantamine
will not expire until December 2008.

Rivastigmine is a structurally distinct choli-
nesterase inhibitor for the treatment of mild-to-
moderate Alzheimer's that was approved in 2000 un-
der the brand name Exelon. Rivastigmine displays
10-fold greater inhibition of neuronal acetylcholi-
nesterase compared to its peripheral effects, which
may help explain its lower incidence of peripheral
cholinergic side effects. Rivastigmine is not metabo-
lized by the cytochrome P450 system and exhibits
low protein binding, giving it a low potential for
drug interactions. Like other cholinesterase inhibi-
tors, it is recommended to wait four weeks between
dose titrations. In July 2007, once-daily transdermal
patches were also approved for Alzheimer's treat-
The most common side effects of rivastig-
mine include nausea, vomiting, fatigue, diarrhea, and
anorexia. To reduce the incidence of side effects, it
is recommended to take rivastigmine twice-daily
with food. However, at dosages greater than 6 mg
daily, the discontinuation rate is still approximately
15%. If a patient ever misses doses for more than
several days, it is recommended that they re-start at
the lowest dose and titrate slowly back up to avoid
side effects. There is evidence to suggest that these
effects are lower when using the transdermal system.
Multiple studies have shown improvement
with rivastigmine therapy based upon the ADAS-cog
scale, but these findings have failed to show im-
provement based on other assessment batteries.18,
In one study, 45% of placebo-treated patients experi-
enced a decline in ADAS-cog score of at least 4
points, generally regarded as the change necessary to

Volume 23, Issue 9 June 2008

show a clinical difference, after one year of ther-
apy.19 Only 18.3% of rivastigmine patients experi-
enced the same decline in ADAS-cog score. Patients
treated with rivastigmine significantly improved
compared to placebo based upon change in MMSE
score (p<0.001). Interestingly, two studies using the
same protocol showed different results: one showed
improvements at all doses18, while the other only
showed improvement for higher (6 mg to 12 mg
daily) doses.20
Rivastigmine is available in 1.5 mg, 3 mg,
4.5 mg, and 6 mg capsules, as well as 4.6 mg and 9.5
mg transdermal patches. The average monthly cost
of therapy is similar for both dosage forms at ap-

proximately $200. While generic equivalents of
rivastigmine were approved by the FDA in late 2007,
the manufacturer successfully defended a patent law-
suit preventing generic equivalents until 2012.

Memantine was the first therapy approved for
moderate-to-severe Alzheimer's disease in 2003 un-
der the brand name Namenda. Memantine is a low-
affinity non-competitive antagonist of N-methyl-D-
aspartic acid (NMDA) receptors, a unique mecha-
nism among Alzheimer's medications. Chronic exci-
tatory activity at NMDA receptors may play a role in
the neuronal death that characterizes Alzheimer's.

Table 1. Summary of Clinical Trials for Approved Alzheimer's Disease Medications

Product Trial Trial Type Population studied Results



Donepezil vs.




Knapp et al. 19945

Passmore et al. 20051

Wilcock et al. 200312

Brodaty et al. 200514

Karaman et al. 200519

Peskind et al. 200621

Randomized controlled

Randomized controlled

Randomized, parallel-
group trial

Randomized, controlled

Randomized, controlled

Randomized, controlled

653 patients at least 50
years old with mild to
moderate Alzheimer's

2376 patients with Alz-
heimer's disease

182 patients with Alz-
heimer's disease

971 patients with Alz-
heimer's disease

44 patients with ad-
vanced moderate Alz-
heimer' s

403 patients with mild
to moderate Alz-
heimer' s

Significant differences
in ADAS-cog at
160mg/day after 30
weeks of study (p <

Significant differences
after 6 weeks that were
maintained through 24
weeks of study (p <

No significant differ-
ence in ADAS-cog
score vs galantamine
after 52 weeks of study

Significant difference in
ADAS-cog score after 6

Significant differences
in Mini-Mental State
Exam score after 12

Significant differences
in ADAS-cog score
after 24 weeks of study
(p = 0.003)

PharmaNote Volume 23, Issue 9 June 2008

Volume 23, Issue 9 June 2008


NMDA receptor activation by glutamate is linked to
an influx of intracellular calcium. Excessive calcium
in neurons has been shown to cause neuronal damage
or cell death. By antagonizing these receptors, it is
believed that memantine can slow further neuronal
damage. However, glutamate itself is also linked
with learning and memory, so appropriate drug ther-
apy ideally should prevent neurotoxicity while also
not disrupting the normal physiological actions of
Memantine is generally well-tolerated. Side
effects include dizziness, confusion, headache, and
drowsiness. Memantine produces significant differ-
ences using numerous assessment scales including
the ADAS-cog (p=0.003) and Severe Impairment
Battery (p=0.002), but results have not been as con-
sistent when using the Mini-Mental State Exam
(p=0.68).21-23 A previous review of clinical trials
showed a nonsignificant but consistent decrease in
rates of aggression in patients treated with donepe-
Memantine is available as both 5 mg and 10
mg tablets, as well as a 10 mg/5 mL oral solution.
The average monthly cost is approximately $185.
The patent for memantine is not set to expire until
April 2010.

New Medications
There are a number of new medications in the
pipeline for the treatment of Alzheimer's disease.
Many of the drugs currently in clinical trials revolve
around altering splicing of APP, either through direct
enzyme inhibition or modulation to reduce the for-
mation of certain variants, or through the use of re-
combinant antibodies to help facilitate their removal
from the brains of effected individuals.25 Bapineuzu-
mab, a monocloncal antibody against Ap, a product
of APP splicing associated with Alzheimer's disease,
is currently in phase III clinical trials. There is also
evidence that existing drugs, including statins26 and
etaneracept27, may be associated with decreased inci-
dence of Alzheimer's disease. These associations
are currently undergoing further study.

There is no available drug for the treatment
of Alzheimer's disease that alters or slows the under-
lying progression of the disease. Current practice
guidelines from the American Psychiatric Associa-
tion28 make no specific recommendations regarding
pharmacotherapy, only saying that all currently

available agents have evidence supporting their use
to treat the cognitive effects of Alzheimer's disease.
However, there is debate as to whether these statisti-
cally significant effects translate into clinically
meaningful improvement. Currently available medi-
cations may offer some symptomatic relief to help
ease the burden on caregivers.

1. Herbert LE, Scherr PA, Bienias JL, et al. Alz-
heimer's disease in the US population: Preva-
lence estimates using the 2000 census. Archives
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