Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial

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

(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

2 A. Ghaleiha et al.

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



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



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

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.


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


[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


[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


[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


[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


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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Documents

Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial