166 Copyright © 2012 Korean Neuropsychiatric Association
Adjunctive Memantine Therapy for Cognitive Impairment
in Chronic Schizophrenia: A Placebo-Controlled Pilot Study
Jung Goo Lee1, Sae Woom Lee2, Bong Ju Lee3, Sung Woo Park4,
Gyung Mee Kim3 and Young Hoon Kim5
1Department of Psychiatry, Haeundae Paik Hospital, College of Medicine and Paik Institute for Clinical Research, Inje University, Busan, Korea
2Department of Psychiatry, Jamyung Hospital, Busan, Korea
3Department of Psychiatry, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Korea
4Department of Neuroscience Research, Paik Institute for Clinical Research, Inje University, Busan, Korea
5Department of Psychiatry, Haeundae Paik Hospital, School of Medicine and Paik Institute for Clinical Research,
FIRST Research Group, Inje University, Busan, Korea
ObjectiveaaTo investigate the effects of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on cognitive impairments
in patients with chronic schizophrenia.
MethodsaaA 12-week, placebo-controlled trial was conducted to determine the effectiveness of memantine as an adjunctive treatment
with conventional antipsychotic medications in 26 patients with chronic schizophrenia. The subjects were evaluated with the Korean
version of the Mini-Mental State Examination (K-MMSE), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating
Scale for Depression (HAM-D), and a standard neuropsychological screening test.
ResultsaaMemantine treatment was not associated with significantly improved cognitive test scores compared with the placebo control
treatment. An improvement in the scores on the PANSS negative subscale was noted with memantine, but it was not significant.
ConclusionaaAdjunctive memantine treatment did not improve cognitive functioning or affect psychopathology in patients with
chronic schizophrenia in the present study. Memantine, however, was tolerated well and did not exacerbate positive symptoms in pa-
tients with chronic schizophrenia.
Psychiatry Investig 2012;9:166-173
Key Wordsaa Memantine, Cognition, Antipsychotic drugs, Schizophrenia, Tolerability.
Received: March 24, 2011 Revised: December 25, 2011
Accepted: February 24, 2012 Available online: May 22, 2012
Correspondence: Young Hoon Kim, MD, PhD
Department of Psychiatry, Haeundae Paik Hospital, School of Medicine and
Paik Institute for Clinical Research, FIRST Research Group, Inje University,
1435 Jwa-dong, Haeundae-gu, Busan 612-862, Korea
Tel: +82-51-797-3303, Fax: +82-51-894-6709, E-mail: email@example.com
cc This is an Open Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (http://creativecommons.org/licenses/by-
nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduc-
tion in any medium, provided the original work is properly cited.
Print ISSN 1738-3684 / On-line ISSN 1976-3026
Cognitive impairment represents a core feature of schizo-
phrenia in the majority of patients with the disorder.1,2 Cogni-
tive deficits appear during the initial episode of the illness3
and may appear even in those who are not taking antipsy-
chotic medications,4,5 suggesting that these deficits do not re-
flect the deteriorative effects of treatment. Cognitive impair-
ment is associated with poor functional outcome and long-
term prognosis.6 Because cognitive impairment is among the
strongest predictors of functional outcome in patients with
schizophrenia,6,7 the improvement of cognitive functioning
has been identified as an important goal of treatment.8,9
Despite the known beneficial effects of conventional anti-
psychotics on positive symptoms, some studies have shown
that these drugs might have negative effects on cognitive fun-
ctioning,10,11 although other, more systematic analyses have
suggested that such drugs provide a modest benefit.12 Howev-
er, evidence also exists that atypical antipsychotic drugs might
benefit cognitive functioning. Atypical antipsychotic drugs
have been associated with greater improvement in cognitive
functioning than conventional antipsychotic medications,13-15
although these benefits were relatively slight and have not been
consistently shown. Thus, although atypical antipsychotic
drugs may offer some benefits to cognitive functioning in
schizophrenia,17 significant deficits still persist in this domain
and alternative therapies for enhancing cognitive functioning
online © ML Comm
JG Lee et al.
Several novel strategies to treat cognitive impairment in
schizophrenia have been explored. Extensive psychopharma-
cological research has focused on dopamine receptors in the
prefrontal cortex, nicotinic and muscarinic acetylcholine re-
ceptors, the glutamatergic excitatory synapse, various sero-
tonin receptors, and the γ-aminobutyric acid (GABA) sys-
tem.18 Previously, Lee and colleagues19 conducted a placebo-
controlled trial of galantamine, a combined acetylcholine-
sterase inhibitor and allosteric potentiator of the nicotinic
receptor, to examine the effects of the drug on the cognitive
functioning of individuals with chronic schizophrenia. This
trial showed no significant effects on cognitive functioning.
Glutamate is the primary excitatory neurotransmitter for
approximately 60% of neurons20 and also plays a principal
role in modulating long-term potentiation. Moreover, gluta-
mate is considered to be a key cellular mechanism in learning
and memory.21 Glutamate dysregulation may be involved in
the neuropathology of schizophrenia,22 as evidenced by stud-
ies using N-methyl-D-aspartate (NMDA) receptor antago-
nists, phencyclidine (PCP) and ketamine. PCP and ketamine
produce the wide range of schizophrenic symptoms, includ-
ing psychotic symptoms, negative symptoms, and cognitive
impairment.23,24 NMDA hypofunctioning results in decreased
stimulation of central GABAergic neurons.25 This ultimately
may lead to the excessive release of glutamate into the synapse
and consequently causes significant neuronal cell death.26
Thus, NMDA-mediated neuronal cell death is believed to play
a role in the pathology of schizophrenia. Therefore, drugs that
block excessive NMDA receptor-induced glutamate activity
may attenuate this excitotoxic process.27
Memantine is currently approved for the treatment of mod-
erate to severe Alzheimer’s disease. It is a moderate affinity,
noncompetitive, voltage-dependent NMDA receptor antago-
nist with rapid kinetics.26 These pharmacological features
might allow memantine to modulate the pathological NMDA
receptor activity thought to occur in Alzheimer’s disease,
while permitting normal physiological activation of the re-
ceptor required for learning and memory.29,30 Memantine is
clinically well tolerated and lacks the psychotomimetic effects
seen with other NMDA receptor antagonists such as ketamine
and PCP.28,31 Because memantine treatment successfully slows
neurodegeneration in dementia,32 it may also have a positive
impact on the symptoms of schizophrenia.33 Krivoy and col-
leagues34 reported that menantine, in combination with con-
ventional antipsychotic treatment, improved the negative sym-
ptoms of schizophrenia. Moreover, de Luceana and colleague35
reported that memantine in combination with clozapine ther-
apy was associated with improvement in negative and positive
symptoms. Lieberman and colleagues,36 however, reported
that memantine was not efficacious as an adjunctive therapy.
In this randomized, double blind, placebo-controlled study,
the potential effects of adjunctive memantine treatment on
cognitive functioning in chronic schizophrenia was investi-
gated. In addition, patient psychopathology was evaluated,
and the adverse effects of memantine were assessed.
Subjects aged between 18 and 50 years were recruited from
seven in-patient units in hospitals located in Busan and Ma-
san, South Korea. The hospitals included Jamyung, Semy-
oung, Dongnae, Daenam, Busan Municipal, Hyungju, and
Dongsuh. Informed consent was obtained from each patient,
and the Institutional Review Board at Busan Paik Hospital
approved the protocol for the present study (Trial Number:
07-27). All patients were diagnosed with schizophrenia ac-
cording to the standard structured clinical interview for
DSM-IV Axis I disorders (SCID-I)37 and had been stabilized
using conventional antipsychotic medications for a minimum
of three months prior to this study. The level of cognitive im-
pairment required for participation was defined as a total per-
formance score between 18 and 24 on the Korean version of
the Mini-Mental Status Examination.38,39 Subjects with a his-
tory of substance abuse or dependence, head trauma, severe
neurological disorders, depression, or other medical problems
were excluded. Although patients who were undergoing treat-
ment with medications that affected cognitive performance
were also excluded, patients receiving antiparkinsonian anti-
cholinergic or benzodiazepine-based drugs were included if
the dosing regimen did not change over the 12-week study
period. Smokers were also included in this study.
Twenty-six subjects were enrolled in the 12-week, double
blind trial. Simple randomization based on a random-num-
bers table was used to assign subjects to either the placebo or
the memantine group. Central randomization was also used
to avoid the center effect. An investigator who was unaware of
randomization assignments was assigned to each site to guar-
antee the integrity of the double-blind study design. After the
baseline evaluation, subjects were randomly selected to re-
ceive memantine treatment or a placebo, in addition to a fixed
daily dose of conventional antipsychotic medication (chlor-
promazine-equivalent dose: 1145 mg/day).40 Subjects in the
memantine group received an initial dose of five mg/day,
which was increased weekly in five mg increments until
reaching a maximum dose of 20 mg/day. This maximum dose
was chosen according to the effective dose established for pa-
tients with dementia.41 Primary (neuropsychological tests),
168 Psychiatry Investig 2012;9:166-173
Memantine for Cognitive Impairment in Schizophrenia
and secondary outcome (psychiatric symptoms) variables
were assessed at baseline, week 6, and week 12. The checklist
for adverse events was completed at weeks 6 and 12.
The Positive and Negative Symptom Scale42 and the 17-
item Hamilton Rating Scale for Depression43 were used to as-
sess the severity of psychiatric symptoms and depressed
mood. The Clinical Global Impression Severity and Improve-
ment scales (CGI-S and CGI-I) were also administered to all
subjects. Adverse events in response to memantine treatment
were assessed using an adverse events checklist, which in-
cluded the adverse events mostly commonly observed in pa-
tients with dementia.44 A battery of neuropsychological tests
was administered to evaluate changes in several domains of
cognitive functioning. The K-MMSE, the Hopkins Verbal
Learning Test (HVLT), the Rey Complex Figure Test (RCFT),
the Digit Span Forward and Backward Test, the Digit Symbol
Substitution Test (DSST), the Stroop test, the Trail Making
Test (Part A), the Verbal Fluency Test (VFT), and the Boston
Naming Test were used to assess attention, auditory and visu-
al memory, and executive functioning. The HVLT was also
used to examine immediate memory span, new learning, sus-
ceptibility to interference, and delayed recall. The VFT was
used to examine verbal productivity and intactness of the lex-
Baseline comparisons between the two groups were per-
formed using the Mann-Whitney U test for continuous vari-
ables and Fisher’s exact test for categorical variables. The effi-
cacy of memantine and placebo were analyzed with repeated
measures analysis of variance (ANOVA) using group (me-
mantine versus placebo) as the between-subjects factor and
time (baseline, week 6, and week 12) as the within-subjects
factor. A p value of ≤0.05 was considered statistically signifi-
Twenty-nine subjects met the eligibility criteria at baseline.
However, three subjects withdrew their consent after random
assignment. The remaining 26 subjects were randomly as-
signed to memantine (n=15) or placebo (n=11) treatment
groups and completed the 12-week trial.
Table 1 presents demographic and baseline data for the
study population. No significant differences in demographic
or clinical variables were observed between the treatment
groups at baseline. The following mean scores±standard de-
viation (SD) were recorded for the memantine versus placebo
groups, respectively: PANSS: 74.5±14.9, 74.7±14.2; HAM-D:
1.4±2.0, 2.2±1.8; and K-MMSE: 22.0±1.6, 21.6±1.6. All sub-
jects also received conventional antipsychotic drugs, and the
mean chlorpromazine-equivalent dose did not differ between
treatment groups. Fourteen patients (53.8%) received a com-
bination of two antipsychotic drugs.
Table 1. Demographic and baseline clinical data
Duration of illness (months)
Daily chlorpromazine equivalent dose (mg)
Duration of medication (months)
Clinical rating scale scores
Gender (% male)
Use of anticholinergic drugs (% subjects)
Smokers (% subjects)
Data were analyzed using the Mann–Whitney U-test for continuous variables and Fisher’s exact test for categorical variables. SD: standard
deviation, PANSS: Positive and Negative Syndrome Scale, HAM-D: Hamilton Rating Scale for Depression, K-MMSE: Korean version of the
Mini-Mental State Examination, CGI-S: Clinical Global Impression Ratings-Severity
JG Lee et al.
Effect of adjunctive memantine therapy
on psychiatric symptoms
Psychiatric symptoms at baseline and week 12 did not
change in response to memantine treatment. Mean PANSS
scores did not differ between the memantine and placebo
groups (Table 2). None of the subjects displayed a favorable
response to memantine treatment in terms of their CGI-S or
CGI-I scores (i.e., an improvement of ≥2 points).
Effect of adjunctive memantine therapy
on K-MMSE scores
The mean K-MMSE score increased from 22.0±1.6 at base-
Table 2. Effects of memantine compared with placebo on psychiatric assessment scores over the 12-week study period
Baseline Week 12 Week 12
General psychopathology subscale
Data were analyzed using repeated measures analysis of variance (ANOVA). p-value was calculated from time by group interaction. SD: stan-
dard deviation, PANSS: Positive and Negative Syndrome Scale, HAM-D: Hamilton Rating Scale for Depression, CGI-S: Clinical Global Im-
Table 3. Effects of memantine compared with placebo on measures of cognitive functioning over the 12-week study period
Immediate recall 13.0±5.5
Delayed recall 4.1±2.7
Immediate recall 17.4±4.5
Delayed recall 2.5±2.0
Color 48.2±20.6 66.5±48.5
Trail making part A‡
Boston Naming Test†
Data were analyzed using repeated-measures analysis of variance (ANOVA). p-value was calculated from time by group interaction. *Scores,
†Numbsers, ‡Seconds. K-MMSE: Korean Mini Mental State Examination, SD: standard deviation, HVLT: Hopkin’s Verbal Learning Test,
RCFT: Rey Complex Figure Test, DSST: Digit Symbol Substitution Test
170 Psychiatry Investig 2012;9:166-173
Memantine for Cognitive Impairment in Schizophrenia
line to 24.3±2.8 at week 12 in the memantine group and from
21.6±1.6 at baseline to 22.7±3.2 at week 12 in the placebo
group. However, these increases were not significantly differ-
ent at the end of study period (p=0.41).
Effects of adjunctive memantine therapy
on impaired cognitive functioning
Table 3 summarizes the results of the tests of cognitive
functioning for both groups. No statistically significant differ-
ence was observed between groups in regard to any cognitive
measure, although several tests indicated slight improvements
after memantine treatment. In addition, the mean scores for
immediate and delayed recall on the HVLT increased in the
memantine group compared to the placebo group, but overall
scores did not differ between groups at the end of the study
period. The mean value obtained on the Stroop test was larger
in the memantine group, but differences between groups did
not reach statistical significance. The mean score on the Trail
Making Test decreased in the memantine group compared to
the placebo group, but the overall scores of the groups did not
differ at the end of the study period. Improved scores on the
Boston Naming Test were observed in the memantine group,
but the between-group difference was not significant. The
treatment groups did not differ in regard to any other out-
come measures, including the RCFT, the Digit Span Forward
and Backward Test, and the VFT.
Adverse events as a result of adjunctive
Memantine was well tolerated and the incidence of adverse
events was similar between groups. In total, 47% of the me-
mantine group and 55% of the placebo group experienced
adverse events. The most common adverse events were dizzi-
ness, diarrhea, and constipation, but these symptoms were
transient and mild to moderate in intensity. No subject dem-
onstrated serious adverse effects during the study (Table 4).
The present study investigated the effects of adjunctive me-
mantine therapy in combination with conventional antipsy-
chotic medication in patients with chronic schizophrenia. The
cognitive functioning profiles of subjects in the present study
were very similar to the profiles of subjects with dementia re-
ported in previous studies.45,46 No statistically significant dif-
ferences were observed in the memantine group compared
with the placebo group. Therefore, these results do not sup-
port the hypothesis that adjunctive memantine therapy im-
proves cognitive functioning. Similarly, adjunctive meman-
tine therapy was not associated with improvements in the
psychopathology of schizophrenia. Krivoy and colleagues34
reported that memantine did not improve cognitive function-
ing during a 6-week open-label study. Lieberman and col-
leagues also reported that memantine adjunctive therapy
failed to affect cognitive symptoms.36 In this 8-week random-
ized, placebo-controlled study, memantine was used in com-
bination with antipsychotic medication. Memantine did not
have an effect on the Brief Assessment of Cognition in Sc-
hizophrenia (BACS) or the PANSS negative score. However,
de Luceana and colleagues35 reported significantly increased
MMSE scores after 12 weeks of adjunctive memantine treat-
ment in combination with clozapine therapy. Krivoy and col-
leagues34 reported a 21% decrease in the PANSS negative sub-
scale scores. Significant improvement on the negative sub-
scales of the Brief Psychiatry Rating Scale (BPRS) was reported
by de Luceana and colleagues.35 Silver and colleagues47
showed that amantadine, an antiviral agent with indirect do-
paminergic agonist and NMDA antagonist action, was asso-
ciated with improved visuomotor coordination compared to
a placebo treatment. However, amantadine did not show ben-
eficial effects on cognitive functioning. Gama and colleagues48
reported that adjunctive memantine therapy improved scores
on the Brief Psychiatric Rating Scale (BPRS) among patients
with schizophrenia. However, the observed decrease in
PANSS scores was not significantly different between groups
in the present study, Despite the absence of data regarding the
effects of memantine on patients with schizophrenia, me-
mantine, unlike other NMDA receptor antagonists, did not
induce psychosis. These observations indicate that meman-
tine may represent a safer alternative for patients with schizo-
Previous studies have suggested that the glutamatergic sys-
tem is involved in the pathophysiology and treatment of de-
pression.49 For this reason, patients with depression were ex-
cluded from the present study. During the study period, no
significant differences related to depression were observed.
Although a recent study reported that memantine adjunc-
tive therapy was associated with adverse treatment effects,36
fewer adverse events were reported with memantine therapy
in patients with chronic schizophrenia in the present study
compared with patients with Alzheimer’s dementia (AD).
Reisberg and colleagues41 reported adverse events in 84% of
Table 4. Adverse effects of memantine and placebo
JG Lee et al.
memantine-treated AD patients and 87% of placebo-group
patients. Agitation and urinary tract infections were the most
common adverse events.
Tariot and colleagues50 reported that 78% of AD patients
receiving memantine and 72% of those receiving placebo ex-
perienced adverse events. At least 5% of the memantine
group, double the proportion found in the placebo group, ex-
perienced confusion and headaches. However, in the current
study, no differences in adverse events were observed between
the memantine and placebo groups. This discrepancy be-
tween schizophrenia and AD in the occurrence of adverse
events might derive from differences in the physiological
characteristics or ages of subjects.
This study has several limitations. First, most subjects were
undergoing treatment with anticholinergic drugs during the
study period. A large body of evidence from human and non-
human animal studies has established that the cholinergic
neurotransmitter system is important for attention, memory,
and learning.51,52 Anticholinergic drugs impair cognitive and
information processing both in normal populations53 and in
individuals with schizophrenia.54 Moreover, several lines of
evidence indicate that NMDA antagonists interact with cho-
linergic systems,55-57 although the interaction between cholin-
ergic and glutamatergic systems is complex and poorly un-
derstood. Second, the majority of subjects in this study were
chronic and institutionalized patients and might have been
unresponsive to memantine treatment for this reason. More-
over, the relatively high doses of antipsychotic drugs may have
resulted in memantine insensitivity. Third, subjects in this
study were allowed to smoke. It is known that cigarette smok-
ing may enhance cognitive functioning in smokers with schi-
zophrenia.58 Furthermore, the study duration may have been
insufficient. Although this study cannot exclude the possibili-
ty of a task-learning effect, memantine therapy tended to
show a stronger positive effect on cognitive functioning as
time passed. Memantine treatment has been shown to signif-
icantly improve cognitive functioning for up to 28 weeks41
among those with Alzheimer’s dementia. Other studies on the
effects of memantine on cognitive functioning report im-
provement for 24 weeks.59,60 Therefore, we can hypothesize
that the 12-week duration of this study might be too short to
warrant any conclusions. Finally, the small sample size may
have masked significant effects. Although this study can be
regarded as pilot study for a large-scale trial, the implications
of the results might be restricted, and further study with a
larger sample is needed.
Cognitive impairment represents a cardinal feature of schi-
zophrenia and a strong predictor of poor vocational and so-
cial outcomes. The level of cognitive impairment is a better
predictor of functional outcome than is the severity of posi-
tive or negative symptoms. Therefore, an urgent need exists to
develop therapies that target cognitive deficits. Our findings
indicate that adjunctive memantine therapy does not have
beneficial effects on cognitive functioning or psychopatholo-
gy among patients with schizophrenia. However, future stud-
ies that address the limitations described above are required
to examine more deeply the effects of memantine on cogni-
tive impairment in schizophrenia.
This work was supported by Grant from Inje University, 2010.
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