Authors Accepted Manuscript

Effects of memantine added to risperidone on the

symptoms of schizophrenia: A randomized doubleblind, placebo-controlled clinical trial
Robabeh
Mazinani,
Mohammadreza Khodaei

Somayeh

Nejati,
www.elsevier.com/locate/psychres

PII:
DOI:
Reference:

S0165-1781(16)30358-4
http://dx.doi.org/10.1016/j.psychres.2016.09.028
PSY9962

To appear in: Psychiatry Research

Received date: 27 February 2016
Accepted date: 20 September 2016
Cite this article as: Robabeh Mazinani, Somayeh Nejati and Mohammadreza
Khodaei, Effects of memantine added to risperidone on the symptoms of
schizophrenia: A randomized double-blind, placebo-controlled clinical trial,
Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.09.028
This is a PDF file of an unedited manuscript that has been accepted for
publication. As a service to our customers we are providing this early version of
the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting galley proof before it is published in its final citable form.
Please note that during the production process errors may be discovered which
could affect the content, and all legal disclaimers that apply to the journal pertain.

Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized

double-blind, placebo-controlled clinical trial

Robabeh Mazinania,*, Somayeh Nejatia,b,*, Mohammadreza Khodaeia

a

Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran,

Iran
b

Substance Abuse and Dependence Research Center, University of Social Welfare and
Rehabilitation Sciences, Tehran, Iran
robabeh_mazinani@yahoo.com
so.nejati@uswr.ac.ir
*

Corresponding authors: Department of Psychiatry, University of Social Welfare and

Rehabilitation Sciences, Tehran, Iran

Abstract
The glutamate hypothesis of schizophrenia has changed attitudes in the development of
new medications. This study aimed to evaluate the effects of 20 mg of memantine per day (as
a NMDA receptor antagonist) added to risperidone among male patients with schizophrenia.
In a randomized placebo-controlled, double-blind clinical trial, 46 adult male patients with
schizophrenia were evaluated in both intervention and control groups at weeks 0, 6 and 12.
The positive and negative symptoms scale and the mini mental status examination were used
to assess positive, negative and cognitive symptoms and general psychopathology. The mean
age of the patients was 44.8 for the intervention group and 45.3 for the control group, and the
mean times since diagnosis were 23.5 and 25.7 years in the intervention and the control
group, respectively. Positive and general psychopathologic symptoms showed no significant
differences between the two groups at baseline or after treatment; while negative symptoms
improved significantly in the intervention group at week 12. Cognitive function was also
significantly improved in the intervention group at weeks 6 and 12. Memantine is supported
as an effective adjunct treatment to improve negative and cognitive symptoms in patients
with schizophrenia.

Keywords: Memantine, Positive and negative symptoms, Cognitive function

1. Introduction

Schizophrenia is the most severe and debilitating of the functional psychiatric disorders. The
life-time prevalence of schizophrenia is almost 1%, and these patients occupy 50% of
hospital beds in psychiatric hospitals (Sadock, 2007). Current antipsychotic drugs mainly
affect positive

symptoms but tend to be less effective in ameliorating negative symptoms

(Sharma and Harvey, 2000). Negative symptoms persist over the course of illness and may
become resistant to drug treatment (Lavoie et al., 2008). Neurocognitive deficits are also a
core component of

schizophrenia that may precede the onset of positive symptoms; the

negative effects of cognitive impairment on social function, problem-solving skills, and

ability to find stable employment tend not to be dramatically affected by available
medications (Sadock, 2007). Hence, many studies have focused on finding new treatments
for the alleviation of negative symptoms (e.g., Andreasen, 1982; Sharma and Harvey, 2000).
A number of brain regions have been reported to be involved in schizophrenia, such as the
pre-frontal cortex, hippocampus and thalamus; also of note is that a range of chemical
neurotransmitter interactions have been hypothesized to affect the pathogenesis of the disease
(Sadock, 2007). The glutamate hypothesis of schizophrenia for example, suggests that the
function of N-methyl-d-aspartate (NMDA) receptors is compromised in this disorder. NMDA
receptors play a major role in the formation of complex behaviors as well as in neural
pathways (Silver et al., 2005; Beneyto and Meador-Woodruff, 2008). In this hypothesis,
hyper-stimulation of NMDA receptors with glutamate is thought to lead to high intracellular
concentrations of

calcium, nitric oxide and catalytic enzymes that specifically increase

protease activity, leading to neuronal damage and cell death (Lavoie et al., 2008). The
glutamate hypothesis has stimulated efforts to develop new treatment regimens targeting
NMDA receptors (Schaefer et al., 2007). Amantadine and memantine, two approved
treatment options for Alzheimers disease that are non-selective NMDA receptor antagonists,
have been considered as potential medications for schizophrenia. Although some evidence

suggest promising effects, controversies surround the effects of these medications in the
treatment of schizophrenia (Egerton et al., 2005; Silver et al., 2005; Schaefer et al., 2007;
Beneyto and Meador-Woodruff, 2008; De Lucena et al., 2009; Lieberman et al., 2009; Lee et
al., 2012; Kishi and Iwata, 2013; Rezaei et al., 2013).
Memantine, as a non-selective NMDA receptor antagonist, has had few side effects, and a
meta- analysis of eight studies shows the positive effects of memantine on cognitive
functions and negative symptoms among patients with schizophrenia (Kishi and Iwata, 2013).
The current study aimed to evaluate the effects of memantine added to risperidone in the
treatment of

schizophrenia among male patients residing in an academic hospital in Iran.

2. Methods and Materials

2.1. Study design
This study was designed as a randomized, placebo-controlled, parallel-group, double-blind
trial. Recruitment of the patients was carried out from September to December 2014. The
intervention began in December 2014; patients allocated to intervention received low-dose
memantine and risperidone for 3 to 4 weeks, after which increased dosages were initiated and
continued for 12 weeks. The study was completed in 9 months (September 2014 to April
2015).
2.2. Participants
All patients diagnosed with schizophrenia in the age range of 18 to 55 years were recruited
from different wards of an academic hospital. We conducted semi-structured psychiatric
interviews for DSM-IV Axis I disorders to confirm diagnoses. From 238 patients with
confirmed diagnoses, 112 were eligible to enter the trial. Inclusion criteria for this study were

as follows: patients had been diagnosed at least for 2 years, had not used a long-term
antipsychotic drug for the last 1 month, were not in an acute phase, and had consented to
participate. Exclusion criteria were as follows: patients were excluded if they had received
electroconvulsive therapy in the last 2 weeks, had other Axis I diagnoses, had a history of
using illicit drugs in the past 6 months, had other neurologic or organic disorders (e.g., renal,
hepatic disease), needed to receive other drug regimens, or reported clinically significant
adverse effects. All patients were males.
2.3. Intervention
After initiation of daily risperidone (4 to 6 mg) for 3 to 4 weeks, patients according to random
number table and based on number of medical records were allocated to receive either a
tablet of memantine or a placebo table with the same shape. Patients in the intervention group
received memantine at an initial dose of 5 mg/daily (2 tablets per day); dose increments
continued for 4 weeks until reaching an effective dosage of 20 mg/daily for another 12
weeks. Patients in the control group received a placebo capsules twice daily. Nurses
providing medication in this study and participating patients were both unaware of the
content of the capsules and the sequence of allocation.

2.4. Outcomes
The primary outcome measures were changes in negative and positive symptoms, general
psychopathology, and cognitive symptoms. A well-trained psychologist without knowledge
of treatment assignment (memantine vs. placebo) completed the Positive and Negative
Syndrome Scale (PANSS) and the Mini-Mental Status Examination (MMSE). These
parameters were measured at baseline, 6 weeks, and 12 weeks after initiation of treatment.

The secondary

outcome measures included all analyses that checked for correlations

between response to treatment and patient age or time since first diagnosis.

2.5. Sample size calculation and random allocation

For the purpose of sample size calculation, utilizing Cohens table and the standard
formulations with a power of 80% (=20%) and confidence level of 95% (=0.05), the
number of patients in each group was calculated to be 18. With an expected attrition rate of
20%, appropriate sample size was estimated to be 23.
For random allocation, specific envelopes containing letters A (control) and B (intervention)
were distributed among all participants who completed the initial assessment and provided
written consent for participation.
2.6. Statistical analysis
Means and percentages were used to report continuous and categorical variables,
respectively. Paired t-tests were used for analysis of scores of different scales at different
time points in the study. A general linear model repeated measures model was employed to
evaluate the interaction of time treatment for PANSS and MMSE scores between the two
groups, with the study groups (memantine vs. placebo) as the between-subject variable and
study measurements as the within-subject factor (time). If Mauchlys test of sphericity was
non-significant, Greenhouse-Geisser correction for degrees of freedom was performed.
Pearson and Spearman correlation

coefficients were calculated to check for potential

correlation between response to treatment and general patient characteristics. Level of

significance was defined as <0.05. The Statistical Package for the Social Sciences (IBM Inc.)
version 16.0 was used for all analyses.

2.7. Ethical considerations

The protocol was approved by the Ethics Committee of the University of Social Welfare and
Rehabilitation Sciences, and all steps were in line with the declaration of Helsinki. Either the
patient or his legal guardian would provide written consent after explanation of the main
objectives of the study. They clearly understood their right to withdraw at any time in the
course of the study. All patients were re-assured regarding the confidentiality of their medical
records utilized for the purposes of the present study. The study has been registered on the
Iranian Registry of Clinical Trials under number 24817.
3. Results
In total, 112 patients with a primary diagnosis of schizophrenia were recruited, of whom 66
declined participation in the trial. From the remaining 46 patients, only 36 completed the
study course and were included in final analysis. The participant flow is illustrated in Fig. 1.

Assessed for eligibility (n= 112)

Excluded (n= 66)

Not meeting inclusion criteria (n= 0)
Declined to participate (n= 66)
Randomized (n=46)

Allocated to intervention (n= 23)

Received allocated intervention (n=19)
Did not receive allocated intervention
(Declined further participation) (n= 4)

Lost to follow-up (give reasons) (n=1)

Discontinued intervention (due to adverse drug
reactions) (n= 1)

Allocated to control (n= 23)

Received allocated intervention (n= 20)
Did not receive allocated intervention
(Declined further participation) (n=3)

Lost to follow-up (give reasons) (n=2)

Discontinued intervention (non-compliance)
(n= 2)

Analysed (n=18)
Excluded from analysis (n=0)

Analysed (n=18)
Excluded from analysis (n= 0)

Fig. 1. Flow diagram of trial participants

3.1. General characteristics and baseline scores

General and demographic characteristics of participants, as well as their PANSS and MMSE
scores at baseline, are shown in Table 1. History of schizophrenia in first degree relatives was
present in 10 participants in the intervention group and 12 participants in the control group.
The two groups were matched based on their age and duration of treatment (p=0.8 and p=0.3,
respectively).

Table 1. General characteristics of all participants at baseline

Intervention group
(n=23)

Control group
(n=23)

Mean (SD1)

Mean (SD)

Age (years)

44.8 (6.6)

45.3 (6.2)

p>0.5

Age at onset of illness

(years)

21.3 (6.8)

19.6 (2.8)

p>0.5

Duration since 1st diagnosis (years)

23.5 (8.3)

25.7 (5.4)

p>0.5

Variable

Standard deviation

Table 2. PANSS and MSSE scores of all participants after 12 weeks

Intervention group
(n=23)

Control group
(n=23)

Mean (SD)

Mean (SD)

Positive symptoms score

12.7 (4.8)

15.5 (6.3)

p>0.05

Negative symptoms score

15.1 (4.8)

20.6 (5.2)

p<0.05

General psychopathology score

37.1 (7.4)

36.8 (8.7)

p>0.05

MMSE score

28.2 (1.6)

24.9 (3.0)

p<0.05

Variable

3.2. Inter-group comparisons

Based on PANSS scores, the intervention group had significantly improved with reference to
negative symptoms by 12 weeks after the initiation of memantine; while no changes in
positive symptoms were reported. MMSE scores also showed significant changes after week
12 in the intervention group (Table 3).
Table 3. Comparison of intervention and control groups regarding PANSS and MMSE scores
at baseline, week 6 and week 12
Scores

Item scale

Intervention group
Mean (SD)

Control group
Mean (SD)

Time (weeks)

Time (weeks)

12

P-value2

12

12

Positive symptoms

14.4
(5.4)

13.4
(5.2)

12.7
(4.8)

16.1
(6.2)

15.9
(6.3)

15.5
(6.3)

0.3

0.1

0.09

Negative symptoms

19.4
(5.4)

17.4
(5.1)

15.1
(4.8)

18.9
(5.3)

19.5
(5.3)

20.6
(5.2)

0.7

0.2

0.003

Level of significance: p < 0.05

General
psychopathology

40.6
(8.7)

38.6
(7.9)

37.1
(7.4)

38.0
(8.3)

37.5
(8.3)

36.8
(8.7)

0.3

0.6

MMSE

26.3
(2.8)

28.0
(2.0)

28.2
(1.6)

25.2
(2.7)

25.0
(2.9)

24.9
(3.0)

0.2

0.001 <0.001

0.9

3.3. Repeated measures analyses

Muchlys test of sphericity indicated that the assumption of sphericity had been violated [

(2)= 10.984, p-value=0.004], and therefore a Greenhouse-Geisser correction test was used to
compare difference in positive symptoms. Repeated measures analysis of variance (ANOVA)
testing for positive symptoms indicated a significant effect of the timetreatment interaction
in the intervention group [ (1.336)=20.150, p=0.001] (Fig.2). Corresponding analyses for
2

negative symptoms [ (df:2)=84.667, p<0.001], general psychopathology [ (2)=57.185,

2

p<0.001], and MMSE scores [ (1.082)=40.478, p=0.001] indicated a significant effect for
2

the timetreatment interaction in the intervention group. Changes in different sub-scale

scores are illustrated in the intervention group compared with the control group (Fig. 2).

a. mean scores for

general
psychopathology

b. mean scores for

cognitive symptoms
(MMSE)

41.3
40.
38.8
37.5
36.3
35.
33.8

30.
28.8
27.5
26.3
25.
23.8
22.5
Week 0

Week 6

Memantine

Week 12

Control

Week 0

Week 6

Memantine

Week 12

Control

c. mean scores for

positive symptoms

d. mean scores for

negative symptoms

17.

26.3

12.8

21.
15.8

8.5

10.5

4.3

5.3

0.

0.
Week 0

Week 6

Memantine

Week 12

Control

Week 0

Week 6

Memantine

Week 12

Control

Fig. 2 Timetreatment interactions for a) general psychopathology, b) cognitive symptoms,

c) positive symptoms, and d) negative symptoms in the intervention and control groups

3.4. Correlation analyses

We found no significant correlation (Pearsons correlation) between age, time since initial
diagnosis, and family history with any of the subscale scores at week 12 (Table 3).

Table 3. Correlations between age, time since initial diagnosis, family history, negative
symptoms score, and MMSE score
Demographic variable

Pearson correlation (2-tailed significance)

Negative symptom score

MMSE score

Age (years)

0.116 (0.647)

0.131 (0.606)

Duration since 1st diagnosis

0.208 (0.407)

-0.52 (0.837)

Family history

0.464 (0.052)

-0.075 (0.768)

4. Discussion

The present study indicates that memantine (20 mg/twice daily) added to risperidone (4 to 6
mg/daily) can improve negative symptoms as well as cognitive function among patients
diagnosed with schizophrenia. The current findings confirm previous studies that
demonstrated the effectiveness of NMDA receptor antagonists in relationship to negative

symptom and MMSE scores (Schaefer et al., 2007; De Lucena et al., 2009). The limited
effects of new generation anti-psychotics on negative symptoms of schizophrenia that
adversely influence the quality of life of patients can be enhanced by adjunctive treatment
with drugs like memantine.
There is evidence that NMDA receptor antagonists have beneficial effects on positive as well
as negative symptoms (De Lucena et al., 2009; Koola et al., 2014); however, our findings
showed no statistically significant improvements in positive symptoms or general
psychopathology in the intervention group compared with the control group.
Impaired cognition is another debilitating component of schizophrenia. Our results illustrate
that memantine added to risperidone is associated with improved cognition. Nevertheless,
previous investigations have been inconsistent in this regard (Lee et al., 2012; Koola et al.,
2014).
therapy,

However, most recent studies have suggested the promise of combination drug
including with drugs other than memantine. Acetylcholine esterase inhibitors,

for example, may have synergistic effects on symptoms not generally improved by antipsychotics (Koola et al., 2014; Geerts et al., 2015).
Some evidence also suggest that the synergistic effects may enable clinicians to prescribe
lower dosages of antipsychotics and hence may lead to reduced levels of side effects (John et
al., 2014; Shim and Nadeem, 2014). We also suggest that widely used measurement scales
such as the MMSE can help in timely and precise evaluation of patients cognitive level.
Utilization of more comprehensive tools that require expert personnel can impose barriers in
clinical trials and negatively impact interpretation of findings.
Participants in this study constituted a homogeneous sample of hospitalized male patients
who had been diagnosed for at least 2 years. The homogeneity of the studied sample and
close supervision of medication use in a hospital setting are among the main strengths of the

study. The longer treatment period compared with previous studies also provides a more
comprehensive background for further analysis of findings. Different symptom sub-scales
(including the ones measured by the PANSS), cognition and correlations between sub-scales
and general characteristics were also collected and analyzed to address the limitations of
previous studies that had inconsistent results. The high rates of attrition after the initial
session for patient selection may be seen as a limiting factor concerning the generalizability
of our findings, but the final sample size was consistent with initial power calculations.

The promising effects of memantine on negative symptoms and cognitive function in

schizophrenia can lead to a paradigm shift in development of treatment guidelines. The
observed effects in our study can add to the existing evidence on the benefits of this drug
category (NMDA receptor antagonists). Although, demographic characteristics did not prove
to have been correlated with drug effects, longer-term observations of patients receiving
memantine can

provide valuable confirmatory information about the efficacy and potential

adverse effects of adjunctive memantine administration in schizophrenia.

Conflict of interest
None.

Acknowledgement
The authors thank the personnel of the Razi Hospital for their kind cooperation and support.
The RCT was financially supported by the University of Social Welfare and Rehabilitation
Sciences.

References
Andreasen, N.C., 1982. Negative symptoms in schizophrenia: definition and reliability. Arch. Gen.
Psychiatry 39 (7), 784-788.

Beneyto, M., Meador-Woodruff, J.H., 2008. Lamina-specific abnormalities of NMDA receptorassociated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar
disorder. Neuropsychopharmacology 33 (9), 2175-2186.
De Lucena, D., Fernandes, B.S., Berk, M., Dodd, S., Medeiros, D.W., Pedrini, M., et al., 2009.
Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a doubleblind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J. Clin.
Psychiatry 70 (10), 1478-1423.
Egerton, A., Reid, L., McKerchar, C.E., Morris, B.J., Pratt, J.A., 2005. Impairment in perceptual
attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in
schizophrenia. Psychopharmacology 179 (1), 77-84.
Geerts, H., Roberts, P., Spiros, A., 2015. Assessing the synergy between cholinomimetics and
memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human
patient trial using quantitative systems pharmacology. Front. Pharmacol..6, 198.
John, J., Lukose, A., Manjunath, S., 2014. Off-label use of memantine as adjunctive treatment in
schizophrenia: a retrospective case series study. Pharmacopsychiatry 47 (6), 202-209.
Kishi, T., Iwata, N., 2013. NMDA receptor antagonists interventions in schizophrenia: meta-analysis
of randomized, placebo-controlled trials. J. Psychiatr. Res. 47 (9), 1143-1149.
Koola, M.M., Buchanan, R.W., Pillai, A., Aitchison, K.J., Weinberger, D.R., Aaronson, S.T., et al.,
2014. Potential role of the combination of galantamine and memantine to improve cognition in
schizophrenia. Schizophr. Res. 157 (1), 84-89.
Lavoie, S., Murray, M.M., Deppen, P., Knyazeva, M.G., Berk, M., Boulat, O., et al., 2008.
Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.
Neuropsychopharmacology 33 (9), 2187-2199.
Lee, J. G., Lee, S.W., Lee, B.J., Park, S.W., Kim, G.M., Kim, Y.H., 2012. Adjunctive memantine
therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study.
Psychiatry Investig. 9 (2), 166-173.
Lieberman, J.A., Papadakis, K., Csernansky, J., Litman, R., Volavka, J., Jia, X.D., et al., 2009. A
randomized, placebo-controlled study of memantine as adjunctive treatment in patients with
schizophrenia. Neuropsychopharmacology 34 (5), 1322-1329.
Rezaei, F., Mohammad-Karimi, M., Seddighi, S., Modabbernia, A., Ashrafi, M., Salehi, B., et al.,
2013. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable
schizophrenia: randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 33 (3),
336-342.
Sadock, B., 2007. Kaplan & Sadocks Synopsis of Psychiatry, 10th ed. Lipincott Willoams &
Wilkins, Philadelphia.
Schaefer, M., Leopold, K., Hinzpeter, A., Heinz , A., Krebs, M., 2007. Memantine-associated reversal
of clozapine-induced weight gain. Pharmacopsychiatry 40 (4), 149-151.
Sharma, T., Harvey, P.D., 2000. Cognitive enhancement as a treatment strategy in schizophrenia, in:
Sharma, T., Harvey, P.D. (Eds.), Cognition in Schizophrenia. Impairments, Importance, and
Treatment Strategies. Oxford University Press, Oxford, pp. 286-302.
Shim, S.S., Nadeem, R., 2014. Are NMDA receptor antagonists beneficial in the treatment of
schizophrenia? J. Psychiatr. Res. 51, 19-20.
Silver, H., Goodman, C., Knoll, G., Isakov, V., Modai, I., 2005. Schizophrenia patients with a history
of severe violence differ from nonviolent schizophrenia patients in perception of emotions but not
cognitive function. J. Clin. Psychiatry 66 (3), 300-308.

Highlights

Antipsychotics have been helpful in improving negative symptoms of schizophrenia

Understanding the role of neurotransmitters in the pathogenesis of schizophrenia has led to

the development of new drugs

Memantine can significantly improve negative and cognitive symptoms among patients with
schizophrenia

Adjunct treatment with NMDA receptor antagonists can be considered as a useful addition
to standard care in the future