ORIGINAL RESEARCH ARTICLE

Riluzole as an Adjunctive Therapy to Risperidonefor the Treatment of Irritability in Children with AutisticDisorder: A Double-Blind, Placebo-Controlled, Randomized Trial

Ali Ghaleiha • Effat Mohammadi • Mohammad-Reza Mohammadi •

Mehdi Farokhnia • Amirhossein Modabbernia • Habibeh Yekehtaz •

Mandana Ashrafi • Elmira Hassanzadeh • Shahin Akhondzadeh

� Springer International Publishing Switzerland 2013

Abstract

Background A hyperglutamatergic state has been shown

to play a possible role in the pathophysiology of autistic

disorders. Riluzole is a glutamate-modulating agent with

neuroprotective properties, which has been shown to have

positive effects in many neuropsychiatric disorders.

Objective The aim of this study was to assess the efficacy

and tolerability of riluzole as an adjunctive to risperidone

in the treatment of irritability in autistic children who were

not optimally responding to previous medications.

Study Design This was a 10-week, randomized, double-

blind, parallel-group, placebo-controlled trial.

Participants The study enrolled male and female outpa-

tients aged 5–12 years with a diagnosis of autistic disorder

based on the DSM-IV-TR criteria and a score of C12 on

the Aberrant Behavior Checklist-Community (ABC-C)

irritability subscale who had discontinued other medica-

tions because of a lack of efficacy.

Interventions Subjects received riluzole (titrated to 50 or

100 mg/day based on bodyweight) or placebo in addition

to risperidone (titrated up to 2 or 3 mg/day based on

bodyweight) for 10 weeks.

Outcome Patients were assessed at baseline, week 5, and

week 10. The primary outcome measure was the difference

in the change in the ABC-C irritability subscale score from

baseline to week 10 between the two groups. We also

compared changes in other ABC-C subscale scores and

Clinical Global Impressions-Improvement (CGI-I) scale

scores between the two groups.

Results Forty-nine patients were enrolled in the study, and

forty children completed the trial (dropouts: placebo = 4,

riluzole = 5). A significantly greater improvement in the

study primary outcome (the ABC-C irritability subscale

score) was achieved by the riluzole-treated children com-

pared with the placebo group (P = 0.03). Patients in the ril-

uzole group also showed significantly greater improvement

on the lethargy/social withdrawal (P = 0.02), stereotypic

behavior (P = 0.03), and hyperactivity/non-compliance

subscales (P = 0.005), but not on the inappropriate speech

subscale (P = 0.20) than patients in the placebo group.

Eleven patients in the riluzole group and five patients in the

placebo group were classified as responders based on their

CGI-I scores [v2(1) = 3.750, P = 0.05]. Children in the

riluzole group experienced significantly more increases in

their appetite and bodyweight than children in the placebo

group by the end of the study.

Conclusion Riluzole add-on therapy shows several thera-

peutic outcomes, particularly for improving irritability, in

children with autism. However, its add-on to risperidone also

results in significantly increased appetite and weight gain.

1 Introduction

Autism is a neurodevelopmental disorder characterized by

severe impairments in reciprocal social interaction, aber-

rant communication, and restricted, repetitive, and/or

Clinical Trial Registration: Iranian Registry of Clinical Trials

(http://www.irct.ir), IRCT201107281556N27.

A. Ghaleiha

Research Center for Behavioral Disorders and Substance Abuse,

Hamadan University of Medical Sciences, Hamadan, Iran

E. Mohammadi � M.-R. Mohammadi � M. Farokhnia �A. Modabbernia � H. Yekehtaz � M. Ashrafi � E. Hassanzadeh �S. Akhondzadeh (&)

Psychiatric Research Center, Roozbeh Psychiatric Hospital,

Tehran University of Medical Sciences, South Kargar Street,

13337 Tehran, Iran

e-mail: s.akhond@neda.net

Pediatr Drugs

DOI 10.1007/s40272-013-0036-2

stereotyped behaviors and interests [1]. While the absolute

cause of autism spectrum disorders (ASD) remains unclear,

these disorders are believed to be influenced by genetic,

environmental, and immunological factors in conjunction

with neurobiological components [2, 3]. Considerable lines

of evidence indicate that abnormalities in neurotransmitter

pathways occur in autism. Glutamate, the principal excit-

atory neurotransmitter in the brain, plays a central role

in cortical development and plasticity [4]. High levels of

glutamate during brain development result in formation of

defective neural pathways and negatively affect higher

cortical functions [5]. Some authors have hypothesized that

a hyperglutamatergic state and glutamate-induced excito-

toxicity play key roles in the pathophysiology of ASD [6,

7]. This hypothesis is supported by findings of elevated

levels of glutamate in the blood, cerebrospinal fluid, and

brains of autistic individuals [8, 9] as well as mutations

in genes related to glutamate receptors and glutamate

regulatory pathways [10, 11]. The beneficial effect of

glutamate-modulating drugs, such as piracetam [12],

amantadine [13], and topiramate [14], on autistic disorders

further supports the role of glutamate in the pathophysi-

ology of this disorder.

The anti-glutamate drug riluzole is a neuroprotective

agent originally developed for treatment of amyotrophic

lateral sclerosis (ALS) [15]. Although the exact mechanism

of action is unknown, riluzole can reduce extracellular

glutamate through several complex processes. At the

presynaptic nerve cell terminal, riluzole inhibits the release

of glutamate [16] and enhances glutamate reuptake [17].

Riluzole also interferes with postsynaptic effects of gluta-

mate by noncompetitive blockade of a-amino-3-hydroxy-

5-methyl-4-isoxazolepropionic acid (AMPA) glutamate

receptors [18, 19]. AMPA receptors play a prominent role in

fast excitatory synaptic transmission, information process-

ing, and behavioral plasticity in mammalian brains [20]. The

efficacy of AMPA receptor modulators has been established

in many psychiatric and neurological diseases [21]. Altered

density of AMPA receptors [22, 23] has also been demon-

strated in human subjects with ASD, suggesting these

receptors as novel appealing drug targets for autism.

Promising benefits of riluzole have been demonstrated

in animal models of disorders affecting the central nervous

system (CNS) [24, 25] as well as numerous trials and case

reports of riluzole treatment in psychiatric patients [26, 27].

Grant et al. [28] reported significant improvement in four

of six individuals with treatment-resistant obsessive-com-

pulsive disorder (OCD) after riluzole administration. A

double-blind, placebo-controlled trial of riluzole in youth

aged 7–17 years with moderate to severe OCD is currently

ongoing, in which ASD has not been an exclusion criterion

[27]. Several lines of evidence support the existence of

shared behavioral traits between ASD and OCD in addition

to considerable neurochemical, genetic, neuroimaging, and

pharmacological similarities [29]. It can be hypothesized

that riluzole would be of benefit in improving at least some

autism-related symptoms, based on the existing literature.

Veenstra-VanderWeele [30] reported decreased compul-

sivity and screaming in a single case of add-on riluzole in a

13-year-old female with autism and interfering compulsive

behavior. In another report on use of riluzole in ASD,

Watchel noticed constant remission of symptoms in two

autistic males with mood disturbances and self-injurious

behaviors [31]. A report on three autistic individuals aged

15–20 years who were treated with riluzole exhibited

promising results as well. All patients showed significant

reductions in repetitive behaviors and irritability, and two

demonstrated improvement in aggression and self-injurious

behaviors [32]. Since the therapeutic response to current

medications such as risperidone is not fully satisfactory,

augmentative treatment strategies with agents targeting

different underlying dysfunctions are emerging for the

treatment of autism. The aim of this study was to investi-

gate the effects of riluzole plus risperidone in the treatment

of irritability associated with autistic disorder. To our

knowledge, this study is the first double-blind, placebo-

controlled clinical trial assessing the adjunctive role of

riluzole in managing the associated symptoms of autism.

2 Materials and Methods

2.1 Trial Design and Setting

This was a 10-week, randomized, double-blind, parallel-

group, placebo-controlled trial. The study was conducted at

the autism specialty clinic in the children’s outpatient

clinic of Roozbeh Hospital (Tehran University of Medical

Sciences, Tehran, Iran) from August 2011 to September

2012. Each patient attended the clinic on three occasions:

at the baseline/screening visit and at weeks 5 and 10. The

study was authorized by the institutional review board

(IRB) of Tehran University of Medical Sciences (TUMS)

[grant number 14037], performed in accordance with the

Declaration of Helsinki, and approved by the ethics com-

mittee at TUMS (reference number 14009). Written

informed consent was obtained from the child’s parent or

legal representative before enrollment in the study. This

trial is registered with the Iranian Registry of Clinical

Trials (http://www.irct.ir; IRCT201107281556N27).

2.2 Participants

Male and female outpatients aged 5–12 years were eligible

if they had a diagnosis of autistic disorder based on the

Diagnostic and Statistical Manual of Mental Disorders, 4th

A. Ghaleiha et al.

Edition, Text Revision (DSM-IV-TR) criteria (six or more

DSM-IV-TR symptoms) [33] and a score of 12 or higher on

the Aberrant Behavior Checklist-Community (ABC-C)

irritability subscale [34] at screening/baseline. The diag-

nosis of autistic disorder was confirmed by an expert child

psychiatrist (Professor M.-R. Mohammadi), based on

behavioral observations of the child and semi-structured

interviews with the parents. In addition, administration of

the Autism Diagnostic Interview-Revised [35] by an

experienced child psychiatrist backed up the diagnosis.

Subjects were excluded if they had any significant medical

problem, hepatic disease, seizure disorder, or any other

psychiatric disorder on DSM-IV axis I or II (base on a

structured diagnostic interview) except for mental retar-

dation. Severe mental retardation, which makes the diag-

nosis of autism inconclusive, was also an exclusion

criterion. A history of hypersensitivity to riluzole, drug or

alcohol abuse, and tardive dyskinesia were other exclusion

criteria. Subjects were also excluded if they had received

any psychotropic medication within 6 weeks prior to

enrollment. Patients were included in the study only if they

had responded suboptimally to previous medications. Due

to ethical concerns raised by the IRB, we did not discon-

tinue the patients’ treatment to make them drug free prior

to entry. Instead, we included those patients who were drug

free for at least 6 weeks prior to entry due to other reasons,

such as discontinuation of treatment by the patients’

parents.

2.3 Interventions

Eligible patients were equally randomized (1:1) to two

groups to receive either riluzole (Rliutek�; Sanofi-Aventis)

plus risperidone (Risperdal�; Janssen Pharmaceuticals) or

placebo plus risperidone for 10 weeks. The starting dose of

risperidone was 0.5 mg/day, with subsequent weekly dose

increases in increments of 0.5 mg. The dose of risperidone

was titrated up to 2 mg/day for children weighing between

10 and 40 kg and 3 mg/day for those weighing above

40 kg. The initial riluzole dosage was 12.5 mg twice-daily

for the first week followed by 25 mg twice-daily for

patients under 40 kg and 50 mg twice-daily for patients

above 40 kg for the subsequent 9 weeks. Riluzole tablets

were put into capsules. The placebo was identical in

appearance (shape, size, color, and taste) to riluzole and

was dispensed by the investigational drug pharmacist.

Patients did not receive any behavior intervention therapy

during the course of the trial. Other than the trial drugs,

participants were not allowed to receive concomitant

medications during the course of the study, and all patients

were drug free for at least 6 weeks prior to the study.

Compliance with the study medications was assessed

through checking with the parents and also a pill count at

each visit. As we selected the study participants from

patients with moderate to high ABC-C irritability subscale

scores as an inclusion criterion, the ethics committee did

not allow us to give placebo alone to one group and riluzole

to the other group. All patients therefore received risperi-

done, and we could only assess the additional effects of

riluzole in comparison with placebo.

2.4 Randomization, Allocation, Concealment,

and Blinding

A computer-generated code was used in order to randomly

assign the patients to the riluzole or placebo group in a 1:1

ratio. The assignments were kept in sequentially numbered,

sealed, opaque envelopes until the end of the study. The

patients, their parents, and the physicians who referred

them were all blind to the treatment assignments, as were

the rater and the person who administered the medications.

Separate persons were responsible for random allocation

and rating of the patients.

2.5 Outcomes

The efficacy assessment measures in this study included

(i) ABC-C scores [34] as the parent-rated measure; and (ii)

Clinical Global Impressions-Improvement (CGI-I) scale

scores [36] as the clinician-rated measure. The ABC-C

rating scale has been designated for evaluation of devel-

opmental impairments and consists of 58 items that assess

the existence and severity of disruptive behaviors. Five

types of behavioral aberration are rated by the checklist,

including irritability, lethargy/social withdrawal, stereo-

typic behavior, hyperactivity/noncompliance, and inap-

propriate speech. Each child was scored at baseline, week

5, and week 10 (the study endpoint) by the ABC-C rating

scale and at week 10 by the CGI-I, a 7-item scale ranging

from 1 = ‘‘very much improved’’ to 7 = ‘‘very much

worse’’. The ABC-C rating scale has been used in several

studies in Iranian populations [37–40]. The CGI rating

scales are commonly used to assess the severity of illness,

global improvement, and the efficacy of treatment. The

mean decrease in the ABC-C irritability subscale score

from baseline was used as the main outcome measure.

Changes in other subscale scores and CGI-I scores were

considered as secondary outcome measures.

2.6 Side Effects

Parents were encouraged to immediately inform the

research team about any unexpected symptom in their child

after enrollment in the study. Possible adverse events were

checked via a phone call 1 week after the start of the

medication. Side effects were documented at each visit,

Riluzole Adjunctive to Risperidone for Irritability in Autistic Children with Autism

using a thorough checklist administered by a psychiatry

resident. The behavior appraisals and documentation of

side effects were completed by independent raters. Addi-

tionally, a complete blood count (CBC) was taken and

serum aminotransferases were measured at baseline and at

each post-baseline visit.

2.7 Sample Size

Based on our pilot study and previous trials, we assumed a

difference of 5 between the two groups on the ABC-C

irritability subscale, with a standard deviation (SD) of 5, a

power of 90 %, a two-sided significance level of 5 %, and

an attrition rate of 20 %. Therefore, a total sample size of

50 was calculated.

2.8 Statistical Methods

IBM SPSS Statistic 20 software (IBM Corporation) was

used for data analysis. A linear mixed model for repeated

measures with unstructured repeated covariance type was

used to assess the effect of time 9 treatment interaction for

each outcome measure. In this model, each ABC-C sub-

scale was entered as a dependent variable, considering time

and treatment as fixed effects. Partial and complete

responses were defined as C25 and C50 % reductions in

the irritability subscale score, respectively. The number of

patients with a partial or complete response was compared

between the two trial groups, using Fisher’s exact test.

Cohen’s d effect sizes were determined by dividing the

mean difference of the two groups at each time point by

their pooled standard deviation. Analyses were based on

the intention-to-treat (ITT). Categorical variables were

described as n (%) values and continuous variables as mean

(SD) values. Mean differences were reported with 95 %

confidence interval (CI) values. A two-sided significance

level of \0.05 was considered statistically significant.

3 Results

3.1 Participants

Sixty-one patients were screened for the eligibility criteria,

and 49 patients were randomized to two groups. Nine

patients (placebo = 4, riluzole = 5) dropped out before

the first post-baseline visit and so were not included in the

analysis. Forty patients (placebo = 20, riluzole = 20)

completed the 10-week trial, and their data were analyzed

(Fig. 1). No significant differences in the baseline charac-

teristics of patients in the two study groups were detected,

although the difference in bodyweight between the two

Fig. 1 Flow diagram of the

study

A. Ghaleiha et al.

groups was near significance [mean difference (95 %

CI) = 9.350 (-0.179 to 18.879), t(38) = 1.986, P = 0.054]

(Table 1). The mean dose of risperidone throughout the

study was 1.2 (0.6) mg/day in the riluzole group and 1.6

(0.9) mg/day in the placebo group (P = 0.106).

3.2 Outcomes

3.2.1 ABC-C Scores

The scores of the two study groups on different ABC-C

subscales at baseline and at the two post-baseline visits are

presented in Table 2. By the study endpoint, a partial

response was achieved by 8 patients (40 %) in the placebo

group compared with 17 patients (85 %) in the riluzole group

(v2(1) = 8.640, P = 0.003). A complete response was also

reported in 3 patients (15 %) in the placebo group compared

with 7 patients (35 %) in the riluzole group (v2(1) = 2.133,

P = 0.14). The repeated measure linear mixed model (-2

log likelihood [-2LL] = 694.06, Akaike information cri-

terion [AIC] = 706.06, Bayesian information criterion

[BIC] = 722.48) revealed a significant effect for the

time 9 treatment interaction on the ABC-C irritability

subscale as the primary study outcome (F5,43.13 = 20.06,

P \ 0.001). Cohen’s effect size values suggested a moderate

to high practical significance by week 5 (d = 0.66,

r = 0.31) and week 10 (d = 0.70, r = 0.33) as well (Fig. 2).

Considering other ABC-C subscales, a significant effect for

the time 9 treatment interaction was seen on the lethargy/

social withdrawal subscale (F5,39.66 = 13.08, P \ 0.001),

the stereotypic behavior subscale (F5,40.97 = 3.51, P =

0.01), and the hyperactivity/noncompliance subscale

(F5,38.81 =9.14, P \ 0.001), but this effect was not signifi-

cant on the inappropriate speech subscale (F5,38.60 = 1.01,

P = 0.42). Based on Cohen’s effect sizes at the study end-

point, practical significance was evaluated to be high for the

hyperactivity/noncompliance subscale (d = 0.94, r =

0.42), moderate to high for the lethargy/social withdrawal

subscale (d = 0.76, r = 0.35) and the stereotypic behavior

subscale (d = 0.67, r = 0.32), and low to moderate for the

inappropriate speech subscale (d = 0.40, r = 0.19).

3.2.2 CGI-I Scores

Ratings of ‘‘very much improved’’ were applied to three

patients (15 %) in the riluzole group and one patient

(5 %) in the placebo group. Eight patients (40 %) in the

riluzole group and four patients (20 %) in the placebo

group were rated as ‘‘much improved’’ during the course

of the trial. Eleven patients (55 %) in the riluzole and five

patients (25 %) in the placebo group were classified as

responders, based on their CGI-I scores [v2(1) = 3.750,

P = 0.05].

Table 1 Baseline characteristics of the patients in the two treatment

groups

Variable Riluzole ?

risperidone

Placebo ?

risperidone

Age [years; mean (SD)] 8.4 (2.3) 7.6 (1.7)

Gender [n (%)]

Male 17 (85) 16 (80)

Female 3 (15) 4 (20)

Baseline bodyweight [kg;

mean (SD)]

36.6 (18.2) 27.3 (10.6)

Past medical history [n]

Epilepsy 1 3

Nocturia 1

Bicuspid aortic valve 1

Past drug history [n]a

Risperidone 16 18

Ritalin 6 7

Biperiden 5 3

Haloperidol 1 2

Clonidine 2 3

Fluoxetine 2 2

Levocarnitine 2

Valproic acid 1 1

Lamotrigine 1 2

Lithium 1

Perphenazine 1

Ginseng 1

Desmopressin 1

Pentoxifylline 1

a All patients were drug free for at least 6 weeks prior to the study

SD standard deviation

Fig. 2 Comparison of Aberrant Behavior Checklist-Community

(ABC-C) irritability subscale scores [mean (standard error of the

mean)] over time between the riluzole group and the placebo group

Riluzole Adjunctive to Risperidone for Irritability in Autistic Children with Autism

3.3 Clinical Complications and Side Effects

A total number of 16 side effects were observed over the

course of the trial. Increased appetite occurred signifi-

cantly more frequently in patients in the riluzole group

than in the placebo group (60 vs. 15 %, v2(1) = 8.640,

P = 0.003). Children in the riluzole group also experi-

enced significantly more weight gain than those in the

placebo group by the end of the study [2.1 (3.1) vs. 0.2

(0.8) kg, P = 0.03]. There was no significant differ-

ence in the frequency of other side effects between the

two groups (Table 3). CBC elements and serum

Table 2 Scores of patients in the two treatment groups on the five subscales of the Aberrant Behavior Checklist-Community (ABC-C) rating

scale, and results of linear mixed model analysis

ABC-C subscale Week Patient scores [mean (SD)] P values

Riluzole ? risperidone Placebo ? risperidone Effect of time Effect of

treatment group

Effect of

time 9 treatment

interaction

Irritability 0 21.40 (4.18) 22.10 (9.98) <0.001 0.13 <0.001

5 14.40 (8.15) 19.00 (10.76)

10 11.85 (5.57) 16.25 (7.86)

Lethargy/social withdrawal 0 23.95 (8.04) 24.30 (10.98) <0.001 0.01 <0.001

5 20.90 (7.74) 23.10 (10.65)

10 17.10 (5.98) 21.45 (9.43)

Stereotypic behavior 0 7.80 (3.43) 8.25 (4.93) 0.01 0.16 0.01

5 5.80 (3.95) 8.05 (5.30)

10 4.90 (3.49) 7.75 (5.10)

Hyperactivity/

noncompliance

0 26.35 (7.67) 27.95 (10.68) <0.001 0.23 <0.001

5 22.10 (7.90) 26.75 (10.58)

10 20.35 (9.15) 26.65 (9.97)

Inappropriate speech 0 5.85 (3.38) 5.80 (3.10) 0.26 0.53 0.42

5 5.20 (3.10) 5.60 (2.82)

10 4.95 (3.20) 5.70 (2.51)

A P value of \0.05 was considered statistically significant

SD standard deviation

Table 3 Frequency of side

effects in the two treatment

groups

A P value of \0.05 was

considered statistically

significant

Side effect Riluzole ? risperidone

[n (%)]

Placebo ? risperidone

[n (%)]

P value

Constipation 2 (10) 2 (10) 1.00

Nervousness 3 (15) 1 (5) 0.60

Restlessness 4 (20) 1 (5) 0.34

Increased appetite 12 (60) 3 (15) 0.003

Decreased appetite 2 (10) 0 (0) 0.48

Morning drowsiness 7 (35) 4 (20) 0.48

Daytime drowsiness 2 (10) 1 (5) 1.00

Increased salivation 6 (30) 6 (30) 1.00

Urinary retention 1 (5) 0 (0) 1.00

Vomiting 1 (5) 0 (0) 1.00

Fatigue 1 (5) 1 (5) 1.00

Twitches 2 (10) 0 (0) 0.48

Abdominal pain 5 (25) 2 (10) 0.40

Tremor 2 (10) 1 (5) 1.00

Diarrhea 2 (10) 0 (0) 0.48

Difficulty in walking 0 (0) 2 (10) 0.48

A. Ghaleiha et al.

aminotransferase levels did not differ significantly

between the two groups during the trial and at the study

endpoint (Table 4).

4 Discussion

In agreement with our hypothesis, riluzole alleviated many

of the behavioral problems associated with autistic disor-

der. Ratings by the parents on the ABC-C scale showed

that improvements in irritability, lethargy/social with-

drawal, stereotypic behavior, and hyperactivity/non-

compliance were significantly greater in the riluzole-

treated children than in the placebo-treated children at the

study endpoint. Furthermore, significance was reached on

the irritability and hyperactivity/noncompliance subscales

scores by the middle of the trial, suggesting an early impact

of riluzole on behavioral disturbances. This finding is

congruent with the formerly evident concept that pharma-

cological treatments are more efficient in ameliorating

comorbid symptoms than in ameliorating core deficits in

patients with autism [41]. Inappropriate speech was the

only area that had no significant change over the trial

period. Ratings by the clinicians on the CGI-I scale also

showed significantly more clinical improvement in chil-

dren who received riluzole, indicating the drug’s probable

beneficial effects on autism core symptoms as well. The

baseline characteristics of the patients, along with their past

medical and drug history and illness duration, did not differ

significantly between the two groups. Therefore, we cannot

explain the significant difference in therapeutic outcomes

between the riluzole-treated and placebo-treated individu-

als based on differences in baseline data. To the best of our

knowledge, this study represents the first double-blind,

placebo-controlled clinical trial evaluating the therapeutic

effects of riluzole in autistic children. Promising results of

riluzole have been reported in six patients with autism in

three separate studies [30–32] to date. Some other clinical

trials have shown favorable effects of riluzole in different

psychiatric disorders, including unipolar and bipolar

depression, generalized anxiety disorder (GAD), and OCD

[26].

Riluzole’s ability to target multiple underlying molec-

ular defects in ASD may explain the amelioration of

several autism-related dysfunctions in the present study.

Excitotoxic injury plays a central role in the pathophysi-

ology of ASD, and riluzole primarily interrupts this del-

eterious cascade through two independent mechanisms

[7]. First, it inhibits the activity of voltage-dependent

sodium channels, and a part of its neuroprotective prop-

erties may be attributed to stabilizing these channels [42].

Second, riluzole blocks neurotransmission of the excit-

atory amino acid glutamate by reducing glutamate release

[16] and increasing its reuptake [17] pre-synaptically,

along with interaction with post-synaptic ionotropic glu-

tamate receptors [18]. The noncompetitive antagonistic

effect of riluzole has been demonstrated on AMPA,

N-methyl-D-aspartate (NMDA), and kainate glutamate

receptors without a direct receptor interaction [43, 44],

although it seems to be more potent against AMPA

receptors [19, 44]. Electrophysiological studies have

demonstrated moderate antagonist activity for riluzole at

Table 4 Results of laboratory

tests at baseline and during the

study

ALT alanine aminotransferase,

AST aspartate aminotransferase,

HB hemoglobin, Hct

hematocrit, RBC red blood cell,

WBC white blood cell

Laboratory data Week Riluzole ? risperidone Placebo ? risperidone

RBC [91012/L; mean (SD)] 0 4.8 (0.7) 5.00 (0.9)

5 4.9 (0.9) 5.1 (0.8)

10 4.8 (0.8) 5.2 (0.9)

WBC [9109/L; mean (SD)] 0 8.3 (2.5) 8.0 (1.8)

5 8.1 (2.2) 8.2 (1.9)

10 8.4 (2.0) 8.1 (2.0)

HB [g/dL; mean (SD)] 0 14.6 (1.9) 14.3 (1.6)

5 14.9 (1.6) 14.6 (1.9)

10 14.8 (1.7) 14.9 (1.8)

Hct [mean (SD)] 0 48.2 (6.1) 47.3 (6.8)

5 48.6 (7.2) 47.7 (7.00)

10 48.3 (7.0) 47.4 (6.9)

AST [IU/L; mean (SD)] 0 20.5 (8.1) 21.1 (7.3)

5 21.0 (8.3) 21.2 (7.1)

10 20.9 (5.9) 21.4 (6.2)

ALT [IU/L; mean (SD)] 0 18.9 (7.2) 19.3 (6.5)

5 19.4 (7.8) 19.4 (6.2)

10 20.3 (6.8) 19.1 (6.2)

Riluzole Adjunctive to Risperidone for Irritability in Autistic Children with Autism

NMDA receptors, but radioligand binding data failed to

prove this [43]. Abnormal activation of NMDA receptors

might be a cause of problems in higher brain functions,

such as in autism [45]. Interestingly, a sufficient number

of active NMDA receptors were available during riluzole

therapy, suggesting that an additional therapeutic response

and reduced side effects would be obtainable by combi-

nation therapy with riluzole and another NMDA receptor

antagonist [46]. On the other hand, a close relation exists

between glutamate-induced excitotoxicity and immune

system dysregulation in ASD [7]. Overactivation of the

inflammatory response and immune changes within the

brain seem to play a critical role in autism development

[47, 48]. Beneficial effects of riluzole may be mediated,

in part, via interference with inflammatory and immune

processes. Gilgun-Sherki et al. [25] demonstrated that

riluzole can reduce inflammation and axonal damage in

the CNS and can suppress experimental autoimmune

encephalomyelitis in a mouse model. They found fewer

T-cells in the spinal cords of riluzole-treated mice, which

could have been due to a reduction of inflammation by

this agent. Finally, at least a fraction of the neuropro-

tective effects of riluzole is mediated by enhanced pro-

duction of neurotrophic factors. Different abnormalities in

neurotrophic factors, especially brain-derived neurotrophic

factor (BDNF), have been proven in autism [49]. BDNF

plays a critical role in synaptic development and plastic-

ity, which is impaired in individuals with autism [50].

Importantly, riluzole stimulates the synthesis of nerve

growth factor (NGF), BDNF, and glial cell line-derived

neurotrophic factor (GDNF) [51, 52].

Treatment with riluzole was generally well tolerated in

our study, and this is consistent with previous safety

reports on the drug [53]. No pharmacokinetic interaction

between riluzole and risperidone has been reported, and

these two agents are metabolized by different cytochrome

P450 isoenzymes (CYPs) in the liver. CYP2D6 and

CYP1A are the main isoenzymes involved in the metab-

olism of risperidone and riluzole, respectively [54, 55].

Most of the observed adverse events in this trial did not

require any intervention, as they tended to be mild and

transient. Although mild elevation in liver enzymes,

especially alanine transaminase (ALT), has been reported

in some riluzole trials previously [15, 26, 27, 32, 53], no

laboratory adverse event was seen in our study. There was

no significant difference between the two groups in the

frequency of side effects, except for significant increases

in the appetite and bodyweight of the patients receiving

riluzole. Parents of many (12/20) of the riluzole-treated

patients complained about increased appetite in their child

over the trial course. A higher degree of weight gain was

observed in riluzole-treated children compared with the

placebo group. To the best of our knowledge, this is the

first study documenting such a side effect after riluzole

intake [26]. Increased appetite and subsequent weight

gain have been observed in risperidone-treated children

with autism [56]. In our study, patients treated with ris-

peridone and placebo experienced significantly less

weight gain than children who received add-on riluzole,

and only three patients in the placebo group had a slight

increase in their appetite. Therefore, this phenomenon

cannot be explained by the risperidone effect, but it could

be proposed that riluzole has a synergistic effect with

risperidone-induced weight gain. Although follow-up

studies are warranted to assess metabolic outcomes of

riluzole, a dietary regimen and adequate physical activity

seem to be crucial for children with autism receiving this

medication.

There are a number of limitations to this study. The

small sample size and the short observational period are the

major limitations of the study and require that the results be

confirmed in larger and more extended trials. The use of

riluzole as an add-on to risperidone restricts our findings

and could not provide information about the effectiveness

of riluzole without an additional neuroleptic drug in chil-

dren with autism. However, the use of an add-on regimen,

rather than riluzole monotherapy, was necessary due to

ethical considerations. ASD is categorized by DSM-IV-TR

under pervasive developmental disorders (PDDs), a group

of heterogeneous developmental disorders with many

similarities in terms of clinical manifestations and phar-

macological interventions. It remains unclear whether

patients with other forms of PDD can benefit from riluzole,

as our study included only children with a diagnosis of

autism. Although the ABC-C rating scale is widely used

and accepted for the assessment of treatment effects in

autism research [34], application of this tool limited our

study to assessment of behavioral problems. Therefore, we

could not assess the effect of riluzole on adaptive and

cognitive function in children with autism.

5 Conclusion

Riluzole adjuvant therapy showed promising therapeutic

outcomes for the management of autism-related symptoms,

particularly irritability, in children. Nevertheless, the long-

term efficacy and safety of riluzole, as well as its optimal

dosing, requires further investigation.

Acknowledgments This study was Dr. Effat Mohammadi’s post-

graduate thesis toward the Iranian Board of Psychiatry. The study was

supported by a grant from Tehran University of Medical Sciences to

Prof. Shahin Akhondzadeh (grant number 14037). The funding

organization had no role in the design and conduct of the study; in the

collection, analysis, and interpretation of the data; or in the prepara-

tion, review, or approval of the manuscript and the decision to submit

the paper for publication.

A. Ghaleiha et al.

Conflict of Interest Statement Drs. Ghaleiha, E. Mohammadi,

M.-R. Mohammadi, Farokhnia, Modabbernia, Yekehtaz, Ashrafi,

Hassanzadeh and Akhondzadeh have no conflicts of interest associ-

ated with this manuscript, and there was no source of extra-institu-

tional commercial funding.

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