Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized,...
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Memantine as adjunctive treatment to risperidonein children with autistic disorder: a randomized,double-blind, placebo-controlled trial
Ali Ghaleiha1, Mahtab Asadabadi2, Mohammad-Reza Mohammadi2, Maryam Shahei2,
Mina Tabrizi3, Reza Hajiaghaee4, Elmira Hassanzadeh2 and Shahin Akhondzadeh2
1 Research Center for Behavioral Disorders and Substance Abuse, Hamadan University of Medical Sciences, Hamadan, Iran2 Psychiatric Research Centre, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran3 Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran4 Institute of Medicinal Plants (ACECR), Tehran, Iran
Abstract
Autism is a neurodevelopmental disorder that causes significant impairment in socialization and communi-
cation. It is also associated with ritualistic and stereotypical behaviour. Recent studies propose both hyper-and
hypoglutamatergic ideologies for autism. The objective of this study was to assess the effects of memantine plus
risperidone in the treatment of children with autism. Children with autism were randomly allocated to risper-
idone plus memantine or placebo plus risperidone for a 10-wk, double-blind, placebo-controlled study. The dose
of risperidone was titrated up to 3 mg/d and memantine was titrated to 20 mg/d. Children were assessed at
baseline and after 2, 4, 6, 8 and 10 wk of starting medication protocol. The primary outcome measure was the
irritability subscale of Aberrant Behavior Checklist–Community (ABC-C). Difference between the two treatment
arms was significant as the group that received memantine had greater reduction in ABC-C subscale scores for
irritability, stereotypic behaviour and hyperactivity. Eight side-effects were observed over the trial, out of the 25
side-effects that the checklist included. The difference between the two groups in the frequency of side-effects
was not significant. The present study suggests that memantine may be a potential adjunctive treatment strategy
for autism and it was generally well tolerated. This trial is registered with the Iranian Clinical Trials Registry
(IRCT1138901151556N10 ; www.irct.ir)
Received 10 January 2012 ; Reviewed 3 April 2012 ; Revised 6 July 2012 ; Accepted 10 July 2012
Key words : Autism, glutamate, memantine, NMDA, trial.
Introduction
Autistic disorder is one of a group of neurodevelop-
mental disorders known as pervasive developmental
disorders (PDDs). These disorders are characterized by
three core deficits : impaired communication ; impaired
reciprocal social interaction ; restricted, repetitive and
stereotypic patterns of behaviours or interests. Autism
has also been referred to as autism spectrum disorder
(ASD), because the severity and manifestation of the
symptoms vary widely, ranging from modest social
impairment to severe developmental and behavioural
challenges. ASDs affect approximately one in 88 children
in the United States. ASDs are usually lifelong chronic
disabilities (Mohammadi & Akhondzadeh, 2007).
These core symptoms are frequent targets of medical,
behavioural and educational interventions. Associated
symptoms such as hyperactivity, anxiety, aggression, in-
somnia and gastrointestinal symptoms are also common
in ASDs and are frequent targets of both conventional
treatments and complementary and alternative medicine
therapies (Mohammadi & Akhondzadeh, 2007).
At present, there is no cure for the core symptoms
of autism. However, several groups of medications, in-
cluding atypical antipsychotics, have been used to treat
associated behavioural problems such as aggression and
self-injury (Nazeer, 2011). Pharmacological intervention
may aid in the implementation of behavioural ap-
proaches by reducing interfering symptoms associated,
such as hyperactivity and irritability (McPheeters et al.
2011). Glutamate, the major excitatory neurotransmitter,
is highly concentrated throughout the brain and is crucial
to neuronal plasticity and the maintenance of cognitive
functioning (Carlson, 2012). However, excess glutamate
has been shown to be a potent neurotoxin that leads to
neuronal cell death and is deemed to play a role in the
pathophysiology of some neuropsychiatric disorders
Address for correspondence : Professor S. Akhondzadeh PhD, Psychiatric
Research Center, Roozbeh Psychiatric Hospital, Tehran University of
Medical Sciences, South Kargar Street, Tehran 13337, Iran.
Tel. : 98 21 88281866 Fax : +98 21 55419113
Email : [email protected]
International Journal of Neuropsychopharmacology, Page 1 of 7. f CINP 2012doi:10.1017/S1461145712000880
ARTICLE
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(Carlson, 2012). Recently, a hyperglutamatergic hypoth-
esis of autism was proposed based on evidence of
hyperglutamatergia in the brain of individuals with
autism (Fatemi et al. 2011). This hypothesis is proposed
from several lines of evidence. For example, the levels of
rate-limiting enzymes glutamate acid decarboxylase
65 and 67 were reduced in the brains of autistic subjects
(Fatemi et al. 2002). In addition, increased gliosis has been
found in the brains of autistic subjects, suggesting that
increases in the number of glial cells may contribute to
increases in glutamate availability in the brain (Laurence
& Fatemi, 2005). It has been reported that infantile autism
is a hypoglutamatergic disorder. This hypothesis is based
on two findings: (1) neuroanatomical and neuroimaging
studies indicating aberrations in brain regions that are
rich in glutamate neurons ; (2) similarities between
symptoms produced by N-methyl-D-aspartate (NMDA)
antagonists in healthy subjects and those seen in autism
(Carlsson, 1998).
Memantine (1-amino-3, 5-dimethyladamanantate) is
a medication approved by the FDA for treatment of
moderate to severe Alzheimer’s disease. The drug blocks
the NMDA receptor-associated ion channel similar to
magnesium by binding to or near the magnesium binding
site (Lipton, 2004). Memantine acts as an uncompetitive,
low affinity, open-channel blocker that enters the receptor
channel preferentially when it is excessively open
(Lipton, 2004). Four open label studies were identified
investigating the use of memantine for PDD (Chez et al.
2007; Erickson et al. 2007; Niederhofer, 2007 ; Owley et al.
2006). These studies demonstrated symptomatic – in
particular behavioural – improvement in subjects taking
memantine. Nevertheless, the lack of double-blind design
or control groups is considered as weaknesses of these
studies. We assessed the effects of memantine plus
risperidone in the treatment of autistic disorder. To our
knowledge, this study is the first double-blind and
placebo-controlled clinical trial assessing the adjunctive
role of memantine in the management of autism.
Method
This was a 10-wk, parallel group, placebo-controlled
trial launched at the specialty clinic for autism in the
children’s out-patient clinic of Roozbeh Hospital [Tehran
University of Medical Sciences (TUMS), Iran] during
January 2009–January 2011.
Participants
Children were considered for participation in the project
if they were aged between 4 and 12 yr and met DSM IV-
TR criteria for diagnosis of autism (APA, 2000). Criteria
for the diagnosis of autism as defined by the Diagnostic
and Statistical Manual of the American Psychiatric
Association were assessed for each child in order to
provide documentation of the diagnosis before study
entry. The diagnosis was confirmed by a child
psychiatrist (M. R. Mohammadi) based on behavioural
observation of the child and semi-structured interview
with the parents with six or more DSM-IV-TR criteria
deemed necessary for a diagnosis of autism. The children
had to have an Aberrant Behavior Checklist–Community
(ABC-C) Irritability subscale score of o12 at screening
and baseline (Aman et al. 1985). In addition, diagnosis
was corroborated by the Autism Diagnostic Interview-
Revised, which was administered by an experienced
child psychiatrist (Lord et al. 1994). There were no re-
gional restrictions for participants as they were referred
by paediatricians, family physicians and parents from
different parts of Tehran and different regions of Iran.
The children presented with a chief complaint of severely
disruptive symptoms related to autistic disorder and
most sought medical interventions. The exclusion criteria
were concomitant schizophrenia or psychotic disorders,
having a history of drug or alcohol abuse or tardive
dyskinesia, having received any antipsychotic drug
treatments 6 months prior to enrolment or having
any significant active medical problem. Due to ethical
concerns raised by the Institutional Review Board (IRB),
we did not discontinue the patients’ treatment to make
the patient drug-free prior to entry. Instead, we included
those patients who were drug-free for 6 months prior to
entry due to other reasons (such as discontinuation of
treatment by parents). Severe mental retardation, which
makes the diagnosis of autism inconclusive (based on the
clinical judgement of a child psychiatrist), was also an
exclusion criterion. Potential subjects were excluded if
they had previously received memantine. In addition,
children with active clinical seizures were excluded.
The protocol was approved by the IRB of TUMS (Grant
No: 6964). The trial was performed in accordance with
the Declaration of Helsinki and subsequent revisions
and was approved by the ethics committee at TUMS.
Written informed consents were obtained from the
parents of the children before entering the trial. This trial
is registered with the Iranian Clinical Trials Registry
(IRCT1138901151556N10; www.irct.ir).
Study design
Forty patients were randomly assigned to two groups
of equal size of either memantine (Ebixa ; Lundbeck
A/S, Denmark) plus risperidone (Risperdal ; Janssen
Pharmaceuticals, Belgium) or placebo plus risperidone
for 10 wk. The dose of risperidone (0.5 mg tablets) was
titrated up to 2 mg/d (starting dose of 0.5 mg with sub-
sequent dose increase in 0.5 mg increments in the weekly
dosage for the first 3 wk) for children weighing between
10 and 40 kg and 3 mg/d for children weighing >40 kg.
Participants were started on 5 mg/d memantine (5 mg
caplets) once daily, taken either whole or crushed. This
was titrated up or down in 5-mg increments every week.
These children were gradually titrated up to a maximum
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dose of 15 mg/d for children weighing between 10
and 40 kg and 20 mg/d for children weighing >40 kg.
Placebo was identical in appearance (shape, size, colour
and taste) and was dispensed by the investigational
drug pharmacist. We started both drugs (memantine and
risperidone) simultaneously. Although some patients
had received psychosocial interventions before entry,
they did not receive any psychosocial therapies during
the course of the trial.
Outcome
The primary outcome measure was the irritability sub-
scale of ABC-C (Aman et al. 1985). ABC-C is a 58-item
tool to evaluate the existence and severity of disruptive
behaviours and designated for rating the individuals
with developmental disabilities. It assesses five types
of behavioural abnormalities, three of which address
the core deficits of autism (lethargy/social withdrawal,
stereotypic behaviour and inappropriate speech) and
the remaining two appraise the associated disturbances
(irritability, hyperactivity/non-compliance). The ABC-C
rating scale has been used in several studies in Iranian
populations (Akhondzadeh et al. 2004, 2010 ; Asadabadi
et al. 2012; Rezaei et al. 2010). The rater followed
standardized instructions when using the ABC-C rating
scale. The mean decrease in the ABC-C irritability sub-
scale score from baseline was used as the main outcome
measure for response to treatment. Extrapyramidal
symptoms were assessed using the Extrapyramidal
Symptoms Rating Scale (Chouinard et al. 1980). Patients
were randomized to receive memantine or placebo
in a 1:1 ratio using a computer-generated code. The
assignments were kept in sealed, opaque envelopes until
data analysis. Each child was rated at baseline and at
weeks 2, 4, 6, 8 and 10 (end-point) by the ABC-C rating
scale. Throughout the study, the person who adminis-
tered the medications, the rater and the patients were
blind to assignments. Patients were assessed by a resi-
dent of psychiatry (M. S.) with input from the children’s
parents (behaviour was rated by M. S. and their parents
every 2 wk). M. S. was trained by a child psychiatrist in
the use of the translated versions of ABC-C rating scales
and she completed the ABC-C after interviewing study
participants ’ parents.
Side-effects
Side-effects were recorded every 2 wk, starting at the
second week of the trial using a checklist administered by
a medical student. Entries were based on responses from
parents. The behaviour appraisals and side-effects were
completed by independent raters.
Statistical analysis
Results are presented as mean¡S.D. differences and were
considered significant at pf0.05. A two-way repeated
measures analysis of variance was used. The two groups
were considered as a between subjects factor (group)
and the five measurements during treatment were
considered as a within-subjects factor (time) in the
analyses. To compare the baseline data, differences in
frequency of side-effects and frequency of extra-
pyramidal symptoms with the two treatments were
assessed using Fisher’s exact test. With a type 1 error
a=0.05 and b=0.2 and a final difference in score
between the two groups of at least 5 units on the ABC-C
irritability subscale, the sample size necessary was
calculated to be at least 15 patients in each group.
Results
Forty children were randomized to the trial. Patients
of both groups (risperidone+memantine vs. risper-
idone+placebo) were statistically identical according to
basic demographic data, including age and gender (Fig. 1
and Table 1). All children completed the trial and there
were no missing data.
Memantine vs. placebo : irritability subscale
The mean (S.D.) scores of the two groups of patients are
shown in Table 2. The difference between the two treat-
ments was significant, as indicated by the effect of
groupsrtime interaction (F=21.48, d.f.=1.78, pf0.001).
Memantine vs. placebo : lethargy/social withdrawal
subscale
The mean (S.D.) scores of the two groups of patients are
shown in Table 2. The difference between the two treat-
ments was not significant, as indicated by the effect of
groupsrtime interaction (F=2.56, d.f.=1.43, p=0.10).
Memantine vs. placebo : stereotypic behaviour subscale
The mean (S.D.) scores of the two groups of patients are
shown in Table 2. The difference between the two treat-
ments was significant, as indicated by the effect of
groupsrtime interaction (F=30.42, d.f.=1.53, pf0.01).
Memantine vs. placebo : hyperactivity/non-compliance
subscale
The mean (S.D.) scores of the two groups of patients
are shown in Table 2. The difference between the
two treatments was significant, as indicated by the
effect of groupsrtime interaction (F=153.50, d.f.=1.53,
pf0.01).
Memantine vs. placebo : inappropriate speech subscale
The mean (S.D.) scores of the two groups of patients
are shown in Table 2. The difference between the two
protocols was not significant, as indicated by the effect of
groupsrtime interaction (F=2.04, d.f.=2.20, p=0.13).
Memantine in the treatment of autism 3
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Extrapyramidal symptoms rating scale
Extrapyramidal symptoms were observed in five and six
patients in the memantine and placebo groups respect-
ively. No significant difference was observed between
the two groups.
Clinical complications and side-effects
Eight side-effects were observed over the trial, out of the
25 side-effects that the checklist included. The difference
between the two groups in the frequency of side-
effects was not significant (Table 3 and Supplementary
Table S1).
Discussion
Over the last two decades, there has been significant
progress in the development of treatment strategies for
both core and associated symptoms of ASD (Currenti,
2010 ; Nazeer, 2001). Several lines of evidence support
Table 1. Characteristics of the patients
Risperidone+memantine Risperidone+placebo p
Age [mean (S.D.)] (yr) 7.42 (1.48) [11 (max) & 4 (min)] 7.97¡(1.68) [11 (max) & 5 (min)] 0.32
Gender Boys : 11 ; Girls : 9 Boys : 12 ; Girls : 8 1.00
Baseline weight, kg, mean¡S.D. 25.30¡6.98 24.95¡7.12 0.87
Mean dose of risperidone at the
end of week 3
2.00 mg/d 2.00 mg/d 1.00
History of previous medication Risperidone: 17 ; Haloperidol : 2 Risperidone : 16 ; Haloperidol : 4 1.00
Irritability subscale week 0 (mean¡S.D.) 18.25¡1.55 17.65¡3.74 0.51
Lethargy/social withdrawal subscale
week 0 (mean¡S.D.)
16.55¡4.26 16.85¡3.48 0.80
Stereotypic behaviour subscale week 0
(mean¡S.D.)
8.83¡3.08 8.26¡2.67 0.53
Hyperactivity/noncompliance subscale
week 0 (mean¡S.D.)
23.00¡4.69 22.45¡7.91 0.79
Inappropriate speech subscale week 0
(mean¡S.D.)
6.00¡1.36 5.85¡1.46 0.73
67 patients screened
40 randomized
20 assigned to risperidone + memantine
20 completed trial 20 completed trial
20 assigned to risperidone + placebo
27 patients excludedNot meeting inclusion criteria: 10Meeting exclusion criteria: 12Refused to participate: 5
Fig. 1. CONSORT diagram showing the disposition of all subjects screened for the study.
4 A. Ghaleiha et al.
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the hypothesis that abnormalities in glutamatergic
neurotransmission are involved in autistic disorders
(Shinohe et al. 2006; Smith et al. 2011). Indeed, NMDA
antagonists have become the focus of increasing interest
in the treatment of obsessive–compulsive disorder,
schizophrenia and mood disorders (Zdanys & Tampi,
2008). In agreement with the hypothesis of this study, the
results of this trial based on analysis of multiple subscales
of ABC-C show that treatment with memantine as adju-
vant to risperidone for 10 wk results in significantly
greater reduction in ABC-C subscale scores for irrita-
bility, hyperactivity and stereotypic behaviour compared
to placebo. These findings suggest that memantine can
be an effective treatment for behavioural problems in
children with autism. Clinical characteristics of the
patients, such as gender, age and illness duration, did not
differ between groups and cannot explain differences in
the therapeutic outcome. To the best of our knowledge,
there is no report regarding pharmacokinetic interaction
between risperidone and memantine. We started both
drugs (memantine and risperidone) simultaneously to
prevent any loss to follow-up due to long duration of
the study. However, this did not affect our results
as memantine was superior to placebo in improving
Table 2. Mean¡S.D. of the two treatment arms on the five subscales of Aberrant Behavior Checklist–Community rating scale
Subscales Week 0 Week 2 Week 4 Week 6 Week 8 Week 10
TimerTreatment
Irritability
Risperidone+memantine
[mean (S.D.)]
18.25 (1.55) 17.25 (1.74) 15.20 (1.67) 12.90 (1.80) 9.85 (2.39 8.90 (1.55) p<0.01
Risperidone+placebo
[mean (S.D.)]
17.65 (3.74) 16.75 (3.36) 15.90 (3.38) 14.95 (3.13) 13.70 (2.92) 12.75 (3.05)
Lethargy/social withdrawal
Risperidone+memantine
[mean (S.D.)]
16.55 (4.26) 15.30 (3.85) 14.45 (3.80) 13.25 (3.24) 12.00 (3.46) 11.65 (3.39) p=0.10
Risperidone+placebo
[mean (S.D.)]
16.85 (3.48) 15.90 (2.88) 15.50 (2.30) 14.75 (2.04) 14.05 (2.03) 13.85 (2.10)
Stereotypic behaviour
Risperidone+memantine
[mean (S.D.)]
8.83 (3.08) 7.94 (2.79) 7.05 (2.45) 5.75 (2.02) 4.20 (1.73) 3.30 (1.30) p<0.01
Risperidone+placebo
(mean¡S.D.)
8.26 (2.67) 8.08 (2.71) 7.62 (2.40) 7.35 (2.13) 7.09 (2.00) 6.99 (1.97)
Hyperactivity/non-compliance
Risperidone+memantine
[mean (S.D.)]
23.00 (4.69) 21.00 (4.70) 17.20 (3.53) 13.95 (3.26) 9.00 (2.71) 8.25 (2.19) p<0.01
Risperidone+placebo
[mean (S.D.)]
22.45 (7.91) 21.20 (6.89) 18.70 (5.51) 16.85 (4.41) 15.50 (4.23) 13.85 (3.28)
Inappropriate speech
Risperidone+memantine
[mean (S.D.)]
6.00 (1.36) 5.82 (1.31) 5.76 (1.54) 5.16 (1.73) 4.80 (1.98) 4.50 (1.75) p=0.13
Risperidone+placebo
[mean (S.D.)]
5.85 (1.46) 5.56 (1.42) 5.21 (1.42) 4.99 (1.44) 4.74 (1.59) 4.69 (1.60)
Table 3. Number of patients with side-effects
p Risperidone+placebo Risperidone+memantine Side-effect
1.00 1 (5%) 1 (5%) Abdominal pain
1.00 1 (5%) 1 (5%) Decrease in appetite
1.00 2 (10%) 2 (10%) Increase in appetite
1.00 3 (15%) 3 (15%) Dizziness
1.00 1 (5%) 1 (5%) Insomnia
0.66 2 (10%) 4 (10%) Nausea
0.66 2 (10%) 4 (15%) Sedation
1.00 1 (5%) 2 (10%) Rash
Memantine in the treatment of autism 5
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irritability, hyperactivity and stereotypic behaviour
symptoms of autism.
Owley et al. (2006) enrolled 14 subjects aged 3–12 yr in
an 8-wk study of memantine for PDD (Owley et al. 2006).
Patients received up to 20 mg/d memantine. In addition
to cognitive assessments, the ABC-C version for behav-
ioural outcomes was also used. Of these measures,
patients showed significant improvement only in
memory and behaviour change, including improvements
in irritability, lethargy, stereotypy, hyperactivity and
inappropriate speech (Owley et al. 2006). Results
of this study with regard to irritability, hyperactivity
and stereotype behaviours are in line with Owley et al.
Nevertheless, their study was an open-label trial.
A retrospective study by Erickson et al. (2007)
analysed the use of memantine in 18 patients aged 6–19
yr with PDD. The maximum dose of memantine was
20 mg/d. Outcomemeasures included the Clinical Global
Impression–Severity and Clinical Global Impression–
Improvement (CGI-I) subscales and Aberrant Behavior
Checklist data. Subjects for whom Aberrant Behavior
Checklist data were available showed significant im-
provement in hyperactivity relative to baseline (Erickson
et al. 2007), which is in line with the results of the present
study. However, it should be noted that their study was
retrospective and small. Chez et al. (2007) conducted an
open-label study of 151 patients with autism or PDD–Not
Otherwise Specified with an age range of 2.58–26.33 yr.
Patients received a maximum dosage of 30 mg/d mem-
antine. Clinical improvement was demonstrated in 70%
of patients, with significant improvement demonstrated
in language, behaviour and self-stimulatory stereotypic
behaviour, as rated by the CGI-I (Chez et al. 2007).
Nevertheless, objective assessments were not used in
this study. Chez et al. (2007) observed worse irritability,
hyperactivity and manic-type behaviours in 18/150
(11.84%) of patients, whereas the present study reports
improvements in the irritability subscale. In addition,
unlike the results of the present study, they reported
improvements in receptive language and social behav-
iour. Niederhofer (2007) described a case series study
investigating the effect of memantine in the treatment of
autism. Four patients were enrolled: two with Asperger
type; one with Kanner type; one with atypical autism.
Subjects received memantine at doses of 20 mg/d for
4 wk and outcomes were measured by the Aberrant
Behavior Checklist. Significant improvement was noted
for irritability, hyperactivity and inappropriate speech
(Niederhofer, 2007).
To our knowledge, this study represents the first
double-blind, placebo-controlled study of memantine in
children with autism. However, the present study is in
line with previous reports regarding the role of NMDA
antagonist in the treatment of autism (Erickson et al. 2007;
Niederhofer, 2007; Owley et al. 2006). In the present
study, the period of follow-up was relatively short
and requires that the results be confirmed in longer,
randomized, controlled trials. There was no significant
difference in the frequency of side-effects and extra-
pyramidal effects. Nevertheless, it may be possible
that the study was relatively small to determine differ-
ences in side-effect rates and this should be considered
as a limitation of the present study. In conclusion, the
present study indicates memantine as a potentially
well-tolerated adjunctive treatment strategy for autism.
Nevertheless, monotherapy studies with memantine are
warranted to further assess its efficacy in the treatment of
autism.
Supplementary material
For supplementary material accompanying this paper,
visit http ://dx.doi.org/10.1017/S1461145712000880
Acknowledgements
This study was Dr Maryam Shahei’s postgraduate thesis
toward the Iranian Board of Psychiatry. This study was
supported by a grant from Tehran University of Medical
Sciences to Professor Shahin Akhondzadeh (Grant No:
6964).
Statement of Interest
None.
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