CLINICAL FOCUS

Primary Psychiatry. 2006;13(10):48-55

Glutamate in the Neurobiology and

Treatment of Dementias
Kelly M. Cosman, BS, and Anton P. Porsteinsson, MD

ABSTRACT
FOCUS POINTS
How might the neurotransmitter glutamate be involved in the
• Glutamate is one of the chief neurotransmitters in the brain
pathology of dementia? Glutamate is an essential component in and is necessary for the formation and storage of memories.
physiologic processes, playing a critical role in cognition and the • The role of glutamate in the pathogenesis of dementia and
the use of glutamate antagonists in dementia treatment
formation of memories. Under pathologic conditions, however, have been increasingly prevalent areas of research.
glutamate has been associated with excitotoxicity (neuronal dam- • In pathologic conditions, excessive stimulation by gluta-
mate is associated with excitotoxicity (neuronal injury)
age) and apoptosis (cell death). This excitotoxic effect may be an
and apoptosis (cell death), which may play a role in the
underlying culprit in the pathology of dementia. Numerous research pathogenesis of dementia.
studies have been conducted to evaluate the drug memantine, an • Antagonism of glutamate seems to preserve cognitive func-
tion and global measures in varying degrees of severity of
N-methyl-D-aspartate-receptor antagonist of glutamate, and its Alzheimer’s disease and mild-to-moderate vascular dementia.
effects on patients with dementia. Results have lent support for • The N-methyl-D-aspartate receptor site has been identi-
the use of memantine in the treatment of dementias caused by fied as an ideal target for glutamate antagonism.
• The glutamate antagonist memantine has been shown to be
Alzheimer’s disease and vascular insult. both efficacious and safe in numerous clinical trials.

INTRODUCTION Alzheimer’s disease is by far the best known and most

Dementia is a devastating disorder that possesses the
potential to deprive a person of his or her identity, caus-
ing dramatic changes in personality, memory, and cognitive
abilities.1 The prevalence of dementia in people ≥65 years of
age in North America has been estimated to be between 6%
and 10%, which is approximately double when milder cases
are included.2 Numerous studies demonstrate that both the
prevalence and incidence of dementia increases dramatically
with age,2-5 specifically in people >85 years of age.6
prevalent variant of neurodegenerative dementia, accounting
for approximately 70% of cases.7 It is estimated that approxi-
mately 4.5 million United States residents are afflicted with
Alzheimer’s disease.8 The precise etiology of Alzheimer’s disease
is not completely understood. Studies indicate that it is a com-
plex, heterogenous disorder involving numerous pathophysi-
ologic processes. A cascade of events typically produces the
classic neuropathologic features of neuritic plaques, neurofi-
brillary tangles, and synaptic degeneration; however, genetic

Ms. Cosman is a research assistant in the Program in Neurobehavioral Therapeutics at the University of Rochester School of Medicine and Dentistry in Rochester, New York. Dr. Porsteinsson is director of
the Program in Neurobehavioral Therapeutics and associate professor in the Department of Psychiatry at the University of Rochester School of Medicine and Dentistry.
Disclosure: Ms. Cosman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Porsteinsson is a consultant to Abbott, AstraZeneca, Bristol-Myers Squibb, Eisai,
Forest, Janssen, Novartis, Organon, and Pfizer; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eisai, Janssen, Novartis, Organon, and Pfizer; and receives grant support from Abbott,
AstraZeneca, Bristol-Myers Squibb, Eisai, Elan, Eli Lilly, Forest, Janssen, Merck, Mitsubishi, Myriad Neurosciences, Neurochem, Novartis, Ono Pharma, Pfizer, and sanofi-aventis.
Please direct all correspondence to: Anton P. Porsteinsson, MD, University of Rochester School of Medicine, Monroe Community Hospital, 435 East Henrietta Rd, Rochester, NY 14620; Tel: 585-760-6560; Fax: 585-760-
6572; E-mail: Anton_Porsteinsson@urmc.rochester.edu.

Primary Psychiatry © MBL Communications 48 October 2006

 Glutamate in the Neurobiology and Treatment of Dementias
predisposition and epidemiologic factors contribute to the risk
of developing Alzheimer’s disease as well as to the nature of
its progression.7,9,10 Cholinesterase inhibitors (ChEIs) are the
only medications currently Food and Drug Administration
approved in the US for the treatment of mild-to-moderate
Alzheimer’s disease. ChEIs confer modest cognitive, global,
and functional benefits but do not appear to prevent cell
death in Alzheimer’s disease and thus cannot alter the disease’s
progression.11 However, in addition to cholinergic pathways,
mechanisms of neuronal degeneration and other neurotrans-
mitter pathways may also be involved in the pathogenesis of
Alzheimer’s disease, including the glutamatergic system.12
Although not as widely known in society as Alzheimer’s
disease, vascular dementia is another leading form of demen-
tia, accounting for approximately 10% to 20% of dementia
cases.13 The etiology of dementia related to vascular insult is
diverse and cannot be depicted as one universal mechanism.14
The general course of events includes the blockage of blood
vessels, resulting in damage and death of tissues in the sur-
rounding areas.15 As neurons die at the site of the blockage,
they release excess glutamate and overstimulate neighboring
neurons, potentially expanding the area of damage.16
In addition to its physical effects, there are tremendous eco-
nomic and social consequences of dementia. For example, in
1994, the lifetime cost for care for a patient with Alzheimer’s
disease averages approximately $175,000 in the US.17 As
dementia worsens, patients become increasingly impaired
cognitively and functionally, creating high stress levels for the
patient and caregivers. Advances in medical treatment and tech-
nology are needed to reduce these effects. Research is ongoing
to investigate the role of glutamate in such dementias and to
examine the therapeutic use of glutamate antagonists.
EXCITOTOXICITY IN DEMENTIAS
Glutamate is the principal excitatory neurotransmitter in
the brain. It plays a central role in synaptic transmission in
corticocortical association fibers and the majority of hippo-
campal pathways. Glutamate stimulates a number of post-
synaptic membrane receptors, of which there are two main
classes. The metabotropic class of receptors mediates slower
and longer-lasting cellular effects, using G-protein second
messenger systems. Conversely, ionotropic receptors control
rapid synaptic activity via the regulation of the flow of cations
(serum sodium [Na+], potassium [K+], and serum calcium
[Ca++]) into the cell through ligand-gated ion channels. There
are three types of ionotropic receptors: N-methyl-D-aspartate
(NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propi-
Primary Psychiatry © MBL Communications
onic acid, and kainate receptors, each with complex substruc-
tures. The receptors and respective substructures provide a
variety of potential sources from which to modify glutamater-
gic neurotransmission.12,18,19
Modulation of glutamate activity at the NMDA recep-
tor site has been of particular interest, as there has been an
increasing amount of evidence suggesting that it is a logical
target for cognitive enhancement and possible neuropro-
tection associated with Alzheimer’s disease and vascular
dementia. These receptors are present at high concentra-
tions throughout the brain, especially in the neocortex and
hippocampus. Normal activation of the NMDA receptor is
a required step in memory encoding and storage, a process
which occurs via a mechanism of synaptic plasticity called
long-term potentiation (LTP).19 However, under pathologic
conditions the receptor may become excessively stimulated
by glutamate. In this instance, the excessive activation at
the receptor site leads to an overload of calcium in the cell,
which impairs neuronal homeostasis. Continued impairment
gradually causes excitotoxicity (neuronal damage) and may
eventually lead to cellular apoptosis (programmed mecha-
nisms of cell death).20 Such excitotoxicity has been impli-
cated in neurodegenerative disorders such as Alzheimer’s
disease, Parkinson’s disease, and Huntington’s disease, as well
as cerebral ischemia.12,16,18
Particular to Alzheimer’s disease, the protein β-amyloid
(Aβ), whose level is typically heightened as part of the disease
pathology, is thought to enhance the toxicity of glutamate.
Several preclinical studies have shown that the presence of Aβ
peptide fragment 25–35 adversely affects calcium homeostasis
in the presence of glutamate, consequently exacerbating the
neurotoxic effects of glutamate.21,22 Exposure to glutamate
alone was found to significantly reduce the survival rate of
both mature cerebellar granule cells and human cortical neu-
rons. Furthermore, addition of Aβ25–35 significantly exac-
erbated the neurotoxicity of glutamate; however, this effect
was not demonstrated when the Aβ peptide was a scrambled
sequence of amino acids from the Aβ25–35 peptide.21,22
In addition to the effects that Aβ is thought to have on gluta-
mate toxicity, glutamate and excessive activation of the NMDA
receptor are believed to enhance the production of pathologic
forms of Aβ and another Alzheimer’s disease-related protein, tau.
Excessive stimulation by glutamate reduces the energy levels of
affected neurons, causing neurotoxicity and cell death. Cellular
energy reduction has been associated with the elevation of the
β-site amyloid precursor protein-cleaving enzyme, β-secretase,
which is essential for the rate-limiting step in the formation
of Aβ.23 Thus, reduction of energy levels caused by glutamate
49 October 2006
 K.M. Cosman, A.P. Porsteinsson
neurotoxicity may indirectly increase the production of Aβ.
Studies have also shown that glutamate, as a neurotransmitter,
strengthens tau immunoreactivity, indicating an increase in the
production of phosphorylated tau.24 Additionally, both acute
and chronic toxic activation by NMDA increases tau immuno-
reactivity.25 Hence, it seems that a vicious cycle emerges, where
each pathologic condition tends to exacerbate the other.12,18,26
In the case of vascular dementia, hypoxic-ischaemia has
been associated with increasing extracellular levels of gluta-
mate. The lack of oxygen and glucose resulting from isch-
aemia results in depleted cellular energy levels, which can
activate glutamatergic mechanisms.26 Excessive activation
may lead to overstimulation of the glutamate receptor, pro-
moting excitotoxicity and apotosis.
The glutamatergic system has been identified as a logical
target for both cognitive enhancement and interruption of the
pathophysiologic conditions associated with Alzheimer’s disease
and vascular dementia.27,28 Stimulation of NMDA receptors
by glutamate may improve memory and cognition; however,
excessive stimulation is associated with neuronal injury and
toxicity. In normal circumstances, magnesium (Mg)2+ occupies
the NMDA receptor channel and blocks Ca2+ entry into the
neuron. During physiologic learning and memory processes,
high concentrations of synaptic glutamate are transiently
released; due to its strong voltage dependency, Mg2+ leaves the
NMDA receptor and allows normal Ca2+ influx. However,
under pathologic conditions such as with Alzheimer’s disease
and other neurologic diseases, neurons and glia cells continue
a sustained release of glutamate, prolonging the depolariza-
tion that displaces Mg2+ from the NMDA receptor channel.
Consequently, continuous influx of Ca2+ is allowed into the
neuron, potentially elevating the intraneuronal Ca2+ pool to a
level that will prevent the transmission of a physiologic signal.
Neuronal degeneration may also occur if the Ca2+ concentra-
tion becomes too high or is elevated for too long a duration.
Preclinical data support the NMDA receptor as a prom-
ising target for neuroprotective agents as the high Ca2+
permeability of this receptor likely underlies its neurotoxic
potential. It is possible to counteract glutamate excitotoxicity
by blocking the NMDA receptor with a compound that has a
higher affinity to the receptor than Mg2+. However, if NMDA
receptor activity is completely blocked, normal physiologic
activity of the NMDA receptor (such as learning activity
and LTP) is blocked along with the pathologic activity. High
affinity compounds such as MK801 or phencyclidine impair
learning in animal models and can produce psychotomimetic
effects. Approaches with moderate-affinity NMDA receptor
antagonists have been more fruitful.12,18,26,27
Primary Psychiatry © MBL Communications
MEMANTINE
Mode of Action
Memantine (1–amino-3, 5-dimethyladamantane hydrochlo-
ride) is a moderate-affinity, non-competitive, NMDA receptor
antagonist that exerts voltage-dependent effects with rapid
blocking/unblocking kinetics. Memantine, acting at the NMDA
receptor site, allows normal glutamatergic neurotransmission
under physiologic circumstances while inhibiting excitotoxicity
under conditions of chronic glutamatergic stimulation.28-30
Memantine occupies the same NMDA receptor channel
as Mg2+ but is less voltage dependent and does not leave the
channel so easily with minor depolarization, thus prevent-
ing the sustained influx of Ca2+ during pathologic release of
glutamate. During physiologic glutamate release, memantine
leaves the channel and allows normal influx of Ca2+. A signal
is produced which can be recognized and processed due to
reduced intraneuronal noise.28-30
Memantine reduces acute excitotoxic damage in vitro and in
vivo following administration of glutamate agonists. In models
of global and focal ischemia, it confers protection against Aβ-
induced neurotoxicity and improved cognitive performance in
rats.28-30 This particular mechanism yields support for the use
of memantine in the treatment of vascular dementia.
In addition to its action at the NMDA receptor cite,
memantine also blocks serotonin (5-HT)3 receptors at physi-
ologic concentrations. Antagonism at 5-HT3 has been pos-
tulated to facilitate LTP, have antipsychotic and antinausea
effects, and decrease gastric hypermotility.29,30
Pharmacokinetics
Following oral administration, memantine is completely
absorbed with a Tmax of 4–6 hours and an oral bioavailability
of 100%. Food does not affect its bioavailability. Memantine
shows linear pharmacokinetics over the therapeutic dose range.
It is extensively distributed in tissue and readily crosses the
blood-brain barrier. Memantine is approximately 45% protein
bound. The terminal half-life of memantine is 60–80 hours. It
undergoes little metabolism and is excreted largely unchanged
in the urine. There are no therapeutically active metabolites.
Memantine clearance is reduced with increasing degrees of
renal impairment. The cytochrome P450 system is minimally
involved in the metabolism of memantine. These data indicate
that no pharmacokinetic interactions with drugs metabolized
by these enzymes are to be expected. Medications or conditions
that raise urine pH may decrease the urinary elimination of
memantine, resulting in increased plasma levels.31
50 October 2006
 Glutamate in the Neurobiology and Treatment of Dementias
Data from preclinical trials, pharmacokinetic studies, pivot-
al trials, and postmarketing studies suggest that the combined
use of memantine and a ChEI is safe and well tolerated.32-34
The following sections provide a review of results from several
multicenter, randomized, double-blind, placebo-controlled,
parallel-arm studies which evaluated the use of memantine in
the treatment of dementias.
MEMANTINE IN ADVANCED
ALZHEIMER’S DISEASE
Studies of memantine in the treatment of moderate-to-severe
Alzheimer’s disease have provided the strongest results favoring
its use (Table 1).35-38 One study that evaluated memantine mono-
therapy for the treatment of moderate-to-severe Alzheimer’s
disease found statistically significant differences in measures of
cognition, daily functioning, and global assessment, with the
largest effect seen in the measure of cognition.36 The double-
blind period of this study as well as an open-label extension study
with the same group of participants showed that memantine
was both safe and effective in this group over a 1-year period.
Another study was conducted to assess the efficacy and safety of
memantine when used in combination with a ChEI for the treat-
ment of moderate-to-severe Alzheimer’s disease. Analyses from
this study provided strong and statistically significant results
favoring dual therapy with memantine and ChEI. Furthermore,
treatment with dual therapy resulted in improved cognitive
performance relative to baseline, whereas treatment with ChEI
alone was associated with continued cognitive decline. This
study also supported the safety of memantine therapy in patients
with advanced Alzheimer’s disease.38
MEMANTINE IN EARLY ALZHEIMER’S
DISEASE
Studies of the use of memantine in the treatment of
mild-to-moderate Alzheimer’s disease also show support for
memantine, although results were not as strong as those seen
in studies of moderate-to-severe Alzheimer’s disease (Table
2; A.P. Porsteinsson, unpublished data, July 2006).39,40 One
study of memantine monotherapy demonstrated significant
differences in cognitive and global measures, but not in
measures of daily function.39 Two unpublished trials did not
find benefit of memantine over placebo at endpoint (A.P.
Porsteinsson, unpublished data, July 2006).40 During the
course of the first study,40 the placebo group did not decline as
anticipated and instead improved on the Alzheimer’s Disease
Primary Psychiatry © MBL Communications
Assessment Scale–Cognitive Subscale and the Clinician
Interview Based Impression of Change-Plus Caregiver Input
at certain data points.40 The second unpublished trial evalu-
ated memantine’s use in combination with a ChEI in the
treatment of mild-to-moderate Alzheimer’s disease. Neither
measure used for the efficacy analysis elicited statistically
significant differences using the initially planned analyses.
However, both measures displayed numerical advantages
in favor of the use of memantine. Furthermore, additional
analyses revealed statistically significant findings in support of
memantine when differences due to ChEI type and duration
of treatment were considered (A.P. Porsteinsson, unpublished
data, July 2006). A meta-analysis that included all of these tri-
als shows a statistically significant but very small advantage to
memantine over placebo on cognition (intent-to-treat analy-
sis), which was barely detectable clinically, but no effect on
behavior, activities of daily living, or observed cases analysis of
cognition. Overall, the results that were reported from all of
these studies found memantine treatment to be safe and well
tolerated in the treatment of early Alzheimer’s disease (A.P.
Porsteinsson, unpublished data, July 2006).39,40
MEMANTINE IN MIXED AND
VASCULAR DEMENTIAS
Several studies have also considered the use of memantine in
the treatment of vascular dementia (Table 3).41-44 One study that
included participants with vascular dementia (51%) as well as
moderate-to-severe Alzheimer’s disease (49%) found statistically
significant differences between treatment groups in both a mea-
sure of global assessment and a measure of functional and behav-
ioral disturbances; however, the effect of the second measure was
relatively small.42 Mean scores were not provided for the results
from the global assessment scale; thus, effect sizes could not be
calculated. However, the efficacy results were statistically superior
for memantine over placebo. Two other studies were conducted
to evaluate the use of memantine exclusively in vascular demen-
tia.43,44 Both studies used measures of global assessment and
cognition as their primary efficacy outcomes. The measures of
global assessment did not show statistically significant differences
between treatment groups. However, the measures of cognition
did provide significant differences with small-to-moderate effect
sizes. It was noted that the normal decline in function that is
associated with vascular dementia tends to be slower than that
seen in Alzheimer’s disease, which may make it more difficult to
show a strong treatment effect with this study group. The results
from all three studies demonstrated that memantine use was safe
and well tolerated in the treatment groups.42-44
51 October 2006
 K.M. Cosman, A.P. Porsteinsson

TABLE 1
MEMANTINE IN ADVANCED ALZHEIMER’S DISEASE36-38
Target
Inclusion Concomitant Study Memantine Efficacy Outcomes: Conclusions/
Study Name Criteria Medications Duration Dose Measure (Effect Size)* Safety Outcomes Comments
MRZ960536 Diagnosis of Anticonvulsants, 28 weeks 10 mg BID Primary: No clinically impor- Memantine was shown
probable AD antiparkinso- tant differences in to be safe, well toler-
CIBIC-plus (0.27 LOCF/0.27
nians, hypnot- AEs between the ated, and efficacious
OC)
ics, anxiolytics, treatment groups in the treatment of
MMSE 3–15 neuroleptics, or ADCS-ADLsev (0.32 moderate-to-severe
GDS stage 5 cholinomimetic LOCF/0.53 OC) AD
or 6 agents, and any
FAST ≥stage investigational
medications were Secondary:
6a
excluded SIB (0.49 LOCF/0.48 OC)
MMSE (0.26 LOCF/0.11 OC)
FAST (0.31 LOCF/0.31 OC)
GDS (0.21 LOCF/0.21 OC)
NPI (0.21 LOCF/0.18 OC)
MRZ9605 Completion Same as above 24 weeks 10 mg BID The measures used in No clinically impor- Memantine was shown
open-label of MRZ9605 MRZ9605 were continued for tant differences in to be well tolerated
extension37 placebo-con- the open-label extension AEs between those over a period of 52
trolled study who switched to and weeks
those who remained
After switching to meman- on memantine
tine, patients from the
placebo group experienced
significant benefits in all
measures when their per-
formance was compared to
their rate of decline in the
double-blind phase (P<.05)
MEM-MD- Diagnosis of Concomitant 24 weeks 10 mg BID Primary: Incidence of treat- Treatment with
0238 probable AD medications were ment-emergent AEs, memantine in addition
SIB (5.01 LOCF/4.74 OC)
permitted if dos- EKG abnormalities, to donepezil resulted
ing was stable ADCS-ADL19 (2.78 and potentially in improvements in
MMSE 5–14 LOCF/3.03 OC) clinically significant measures of cogni-
laboratory findings tion, function, clinical
Ongoing treat- or vital sign mea- global status, and
ment with Secondary: surements was simi- behavior relative to
donepezil for 6 CIBIC-plus (3.36 LOCF/3.11 lar between groups baseline
months prior to OC)
enrollment (last 3
months at stable NPI (3.87 LOCF/3.33 OC) Early discontinua- Memantine therapy
dose of 5–10 mg) BGP (4.01 LOCF/4.18 OC) tion was less in the was shown to be
was required memantine group safe when combined
(7%) than in the with donepezil for the
placebo group (12%) treatment of moder-
ate-to-severe AD

*Effect size=(meanmem–meanplac)/(SDpooled), where SDpooled=√[(nmem–1)(sdmem)2+(nplac–1)(sdplac)2)/(nmem+nplac)] and ≥.2=small effect, ≥.5=medium effect, ≥.8=large effect.
AD=Alzheimer’s disease; MMSE=Mini-Mental State Examination; GDS=Global Deterioration Scale; FAST=Functional Assessment Staging instrument; CIBIC-plus=Clinician’s Interview-
Based Impression of Change Plus Caregiver Input; LOCF=last observation carried forward; OC=observed cases; ADCS-ADLsev=Alzheimer’s Disease Cooperative Study Activities of Daily
Living Inventory modified for more severe dementia; SIB=Severe Impairment Battery; NPI=Neuropsychiatric Inventory; AEs=adverse events; ADCS-ADL19=19-item Alzheimer’s Disease
Cooperative Study Activities of Daily Living Inventory; BGP=Behavioral Rating Scale for Geriatric Patients.
Cosman KM, Porsteinsson AP. Primary Psychiatry. Vol 13, No 10. 2006.

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 Glutamate in the Neurobiology and Treatment of Dementias

TABLE 2
MEMANTINE IN EARLY ALZHEIMER’S DISEASE39,40*
Target
Inclusion Concomitant Study Memantine Efficacy Outcomes: Conclusions/
Study Name Criteria Medications Duration Dose Measure (Effect Size)* Safety Outcomes Comments
MEM-MD- Diagnosis of Treatment with 24 weeks 10 mg BID Primary: The only significantly This study sup-
1039 probable AD a ChEI within 30 different AE was ports the safety and
ADAS-cog (0.15 LOCF/0.13
days of screening somnolence (7% efficacy, with small
OC)
and during the memantine vs. 1% effects on global mea-
MMSE 10–22 study period was CIBIC-plus (0.32 LOCF/0.02 placebo, P=.002) sures and behavior,
MADRS <22 not permitted OC) of memantine in the
treatment of mild-to-
No clinically mean- moderate AD
Any previous Secondary: ingful differences
treatment with NPI (0.21 LOCF/0.13 OC) between groups’
memantine was changes in lab test
ADCS-ADL23 (0.01 LOCF/0.0
not permitted values, vitals signs,
OC)
or EKG results
Study Diagnosis of Treatment with 24 weeks 10 mg BID Primary: Safety analysis It was noted that
9967940 probable AD a ChEI within 30 results have not during the course of
CIBIC-plus (0.04 LOCF)
days of screening been reported the study, the placebo
and during the ADAS-cog (0.09 LOCF) group did not decline
MMSE 11–23 study period was as anticipated, and
not permitted Discontinuation due instead improved on
Secondary: to AEs was higher the ADAS-cog and
ADCS-ADL (0.07 LOCF) in the memantine CGIC-plus at certain
group (9%) than the data points
NPI (0.19 LOCF)
placebo group (4%)
Extension of study is
currently ongoing to
evaluate memantine
use over 2.5–3-year
period
MEM-MD-12* Diagnosis of Ongoing treat- 24 weeks 20 mg/day Primary: No statistically Additional analyses
probable AD ment with ChEI given once important differ- revealed statistically
ADAS-cog (0.11 LOCF)
for at least 6 at night ences in AEs and no significant findings in
months prior to CIBIC-plus (0.04 LOCF/0.04 clinically significant support of memantine
MMSE 10–22 enrollment (last OC) differences between when considering dif-
MADRS <22 3 months at the groups’ labora- ferences due to ChEI
stable dose) was tory findings, vital type and duration
Secondary:
required sign measurement, of use
ADCS-ADL23, NPI, MMSE, and and EKG results
RUD: no statistically sig-
nificant differences between
groups
* A.P. Porsteinsson, unpublished data, July 2006.
AD=Alzheimer’s disease; MMSE=Mini-Mental State Examination; MADRS=Montgomery-Asberg Depression Rating Scale; ChEI=cholinesterase inhibitor; ADAS-cog=Alzheimer’s
Disease Assessment Scale-Cognitive Subscale; LOCF=last observation carried forward; OC=observed cases; CIBIC-plus=Clinician’s Interview-Based Impression of Change Plus
Caregiver Input; NPI=Neuropsychiatric Inventory; ADCS-ADL23=23-item Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; RUD=Resource Utilization in
Dementia scale.
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Primary Psychiatry © MBL Communications 53 October 2006

 K.M. Cosman, A.P. Porsteinsson

TABLE 3
MEMANTINE IN MIXED AND VASCULAR DEMENTIA41-44
Target
Inclusion Concomitant Study Memantine Efficacy Outcomes: Safety Conclusions/
Study Name Criteria Medications Duration Dose Measure (effect size)* Outcomes Comments
M-Best DSM-III-R MAOIs, neuro- 12 weeks 10 mg/day Primary: No significant No valid measure of
Study41,42 diagnosis of leptics, tricyclic differences cognitive function was
CGI-C: mean scores were not reported,
dementia antidepres- in safety used for this study
however stratified Wilcoxon test showed
sants, hypnot- measures
significant treatment differences favor-
ics, nootropics, were observed
ing memantine at week 12 (memantine
GDS stages or cerebral between treat- Memantine was found
response=73%, placebo response=45%,
5–7 circulation ment groups to be safe and effica-
P<.001)
stimulating cious on global mea-
MMSE <10
agents were sures in the treatment
not permitted of severe AD and VaD
BGP care dependence sub-score (0.17 ITT)
MMM 30043 Symptomatic Anticonvulsant, 28 weeks 20 mg/day Primary: Frequency Memantine was safe
mild-moder- anti-Parkinson, of AEs was and well tolerated in
CIBIC-plus (0.20 OC)
ate VaD centrally acting similar the treatment of mild-
antihyperten- ADAS-cog (0.48 OC) between treat- to-moderate VaD
sive, hypnotic, ment groups
MMSE 12–20 anxiolytic, (memantine
antipsychotic, Secondary: 76%, placebo Small effects were
and cogni- MMSE (0.33 OC) 74%) seen in most mea-
No diagnosis tion-enhancing sures, with the great-
of AD agents were CGI-C physician (0.24 OC) est effect occurring
not permitted CGI-C caregiver (0.23 OC) No clinically with measures of
significant cognitive function
NOSGER total score (0.04 OC) effects of
GBS total score (0.24 OC) memantine
were found in It was noted that
biochemical natural decline is
markers, vital slower in VaD than in
sign measure- AD, which may reduce
ments, or EKG the emergence of a
results treatment effect

MMM 50044 Diagnosis of Investigational 28 weeks 10 mg/day Primary: Emergence of Memantine was found
probable VaD drugs, psy- AEs was simi- to be well tolerated
ADAS-cog (0.24 LOCF)
chotropic lar between in the treatment of
medications, CGI-C: results were not statistically sig- groups (77% mildto-moderate VaD
HIS ≥4 drugs with psy- nificant and means were not reported memantine,
MMSE 10–22 chiatric side- 75% placebo)
effects and oral A small treatment
anticoagulants Secondary: effect was found only
were not per- NOSGER (0.10 TPP) with the ADAS-cog
mitted
GBS total score (0.06 TPP)
MMSE: minimal changes from baseline,
and no statistically significant differ-
ences between groups at endpoint
DSM-III-R=Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised; GDS=Global Deterioration Scale; MMSE=Mini-Mental State Examination; MAOI=monoamine
oxidase inhibitor; CGI-C=Clinical Global Impression of Change; BGP=Behavioral Rating Scale for Geriatric Patients; ITT=intent-to-treat analysis; AD=Alzheimer’s disease;
VaD=vascular dementia; CIBIC-plus=Clinician’s Interview-Based Impression of Change Plus Caregiver Input; OC=observed cases; ADAS-cog=Alzheimer’s Disease Assessment
Scale-Cognitive Subscale; NOSGER=Nurse’s Observational Scale for Geriatric Patients; GBS=Gottsfries-Brane-Steen scale; AE=adverse event; EKG=electrocardiogram;
HIS=Hachinski ischaemic score; LOCF=last observation carried forward; TPP=treated-per-patient.
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 Glutamate in the Neurobiology and Treatment of Dementias

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