Riluzole in Autistic Disorder

Abstract

To the Editor:

A utistic disorder (autism) is a neurodevelopmental disorder presenting in early childhood with characteristic social deficits, impaired communication, and repetitive behavior (American Psychiatric Association 1994). Individuals with autism often also suffer from interfering behavioral symptoms, including severe tantrums, aggression, self-injurious behavior (SIB), and hyperactivity. Significant progress has been made in the pharmacologic management of interfering symptoms associated with autism in recent years. The atypical antipsychotics risperidone and aripiprazole have been shown to be efficacious in reducing irritability (defined as aggression, SIB, and severe tantrums) in youth with autism, leading to U.S. Food and Drug Administration approval of these two drugs for treatment of irritability in this population (Research Units on Pediatric Psychopharmacology Autism N 2002; Marcus et al. 2009; Owen et al. 2009). The stimulant methylphenidate was found to be efficacious in treating inattention and hyperactivity in youth with autism spectrum disorders (Research_Units_On_Pediatric_Psychopharmacology_Autism_Unit 2005). However, treatment of the core defining symptoms of autism continues to remain elusive.

To date, drugs with prominent effects on serotonin (5-HT) neurotransmission have been the focus of pharmacologic management of repetitive behavior in autism. The serotonin reuptake inhibitor (SRI) clomipramine has shown mixed results (McDougle et al. 1992; Remington et al. 2001). The selective SRI fluvoxamine has been associated with significant reduction in repetitive behavior in adults (McDougle et al. 1996) but not in children (Posey and McDougle 2000). Recent large-scale, double-blind, placebo-controlled trials of the selective SRIs citalopram and fluoxetine in youth with autism have not demonstrated significant reduction in repetitive behavior (Autism Speaks, 2009; King et al. 2009). A solid evidence base guiding drug treatment of core repetitive behavior characteristic of autism does not yet exist.

The glutamate system has been hypothesized to play a role in the pathophysiology of autism (Carlsson 1998). Conflicting evidence regarding peripheral glutamate levels in individuals with autism has been demonstrated (Rolf et al. 1993; Moreno-Fuenmayor et al. 1996; Dhossche et al. 2002; Aldred et al. 2003). Disequilibrium in the glutamate receptor 6 (GluR6) gene and the glutamate receptor ionotropic kainite 2 (GRIK2) gene in individuals with autism has also been reported (Jamain et al. 2002). The GRIK2 gene has been identified as a potential autism-susceptibility genetic region (Philippe et al. 1999). Postmortem investigation of brain tissue from individuals with autism has also identified potential abnormalities in glutamate-associated genes and proteins (Blatt et al. 2001; Purcell et al. 2001; Fatemi et al. 2002).

Riluzole is U.S. Food and Drug Administration approved for the treatment of the neurodegenerative disorder amyotrophic lateral sclerosis in adults. In amyotrophic lateral sclerosis, riluzole is thought to have neuroprotective effects secondary to attenuation of glutamate-induced excitotoxicity (Obrenovitch 1998). Although the exact mechanism of riluzole is unknown, the drug is thought to inhibit the release of glutamate at the presynaptic nerve cell terminus (Urbani and Belluzzi 2000), enhance glutamate reuptake (Frizzo et al. 2004; Fumagalli et al. 2008), and have antiepileptic effects (Kim et al. 2007).

Three open-label reports of riluzole in the treatment of mood disorders have noted positive treatment response (Zarate et al. 2004, 2005; Sanacora et al. 2007). Zarate et al. (2004) performed a 6-week open-label study of riluzole monotherapy (mean dose 168.8 mg/day) in 19 adults aged 18-years and older with treatment-resistant recurrent major depression (Zarate et al. 2004). Significant improvement on the Montgomery-Asberg Depression Rating Scale was noted for all patients completing the study. Common adverse events included headache, gastrointestinal distress, and decreased salivation. One subject was removed from the study due to increased liver function tests (LFTs) three times greater than the upper limit of normal. Zarate et al. (2005) again undertook an open-label study of riluzole in combination with lithium for the treatment of bipolar depression (Zarate et al. 2005). In an 8-week open-label add-on-to lithium study of 14 acutely depressed adults with bipolar disorder, riluzole use (mean dose 171.4 mg/day) was associated with significant reduction in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale. No mania or hypomania was observed in these patients, and no significant adverse effects were reported. Sanacora et al. (2007) investigated riluzole as an add-on therapy in 10 adult patients with treatment-resistant depression (Sanacora et al. 2007). This 12-week open-label study of riluzole demonstrated a significant decline on the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). The most frequent adverse event in this study was fatigue, and no elevations in LFTs were observed in study participants.

Four open-label studies of riluzole for treatment of symptoms associated with anxiety disorders have also demonstrated promising results (Coric et al. 2005; Mathew et al. 2005; Grant et al. 2007; Pittenger et al. 2008). Coric et al. (2005) investigated riluzole (fixed dose 100 mg/day) augmentation of SRI treatment in 13 adults aged 18–65 with treatment-resistant obsessive-compulsive disorder (OCD). Scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) improved significantly, with seven (54%) patients demonstrating a >35% reduction in Y-BOCS scores. No serious adverse events were reported in this trial. Mathew et al. (2005) undertook an 8-week, open-label, fixed-dose (100 mg/day) study of riluzole in 18 adults with generalized anxiety disorder after a 2-week drug-free period. Twelve patients (67%) showed significant improvement on the HAM-A. The most common adverse event reported was insomnia. Three patients (20%) experienced a transient increase in alanine aminotransferase. Grant et al. (2007) investigated riluzole (mean dose 101 mg/day) in six children aged 8–16 years with treatment-resistant OCD. In this 12-week, open-label trial, four subjects (67%) demonstrated clinical response marked by a reduction of >39% overall on the Children's Yale-BOCS (CY-BOCS). No adverse events leading to discontinuation or reduction in dose were noted. Pittenger et al. (2008) undertook an open-label study of riluzole add-on therapy (100–200 mg/day) in 13 adults with OCD including 9 of whom had current major depression. Six of the 13 (46%) participants had a >35% reduction on the Y-BOCS. Again, no major adverse events were noted.

Grant et al. (2010) recently reported preliminary results of a 12-week double-blind, placebo-controlled trial of riluzole (100 mg/day) in youth aged 7–17 years with moderate to severe OCD, half of whom may have an autism spectrum disorder diagnosis. Reportedly, to date, every child has entered an open-label extension, with many electing to continue riluzole after the 1-year study duration. Importantly, one adolescent developed pancreatitis during the double-blind phase 6-weeks after initiation of treatment. A second child is reported to have developed pancreatitis after the 1-year protocol while taking open-label riluzole. Other adverse effects have been laboratory abnormalities including elevation of LFTs. Erickson et al. (2011) reported on riluzole use targeting repetitive behavior in a 6-week, open-label study in 6 adults with fragile X syndrome. In this article, although the biomarker extracellular signal-related kinase activation time normalized in all subjects, only one in six adults (17%) with fragile X syndrome was judged a clinical responder to riluzole (50 mg twice daily). Veenstra-VanderWeele (2010) described a single case of add-on riluzole in a 13-year-old girl with autistic disorder and interfering compulsive behavior. At the dose of 100 mg/day, she demonstrated decreased compulsivity and screaming. However, after 1 month of riluzole treatment, she was noted to be listless and fatigued and was found to have an elevated valproic acid level of 160 μg/mL (levels before riluzole initiation ranged from 100 to 120 μg/mL). Riluzole was discontinued, and her compulsive behaviors returned to baseline over the next 3 months. In a report on use of riluzole in two persons with autism, Wachtel (2009) noted sustained remission of symptoms of depression and self-injury in a 20-year-old man and affective stabilization and reduction in self-injury in a 9-year-old boy.

In this article, we describe our initial clinical experience with riluzole targeting severe repetitive behavior in three persons with autism.

Materials and Methods

The sample included three individuals, a 15-year-old adolescent male (A), an 18-year-old male (B), and a 20-year-old adult male (C), all with autistic disorder and moderate or severe mental retardation. Diagnoses of autistic disorder were made by a board-certified child and adolescent psychiatrist (C.A.E.) using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994). Two individuals (A and C) suffered from intense repetitive behaviors, including repetitive self-injury, marked by skin-picking. One individual (B) suffered from intense repetitive movements and touching behaviors that inhibited his ability to partake in school activities. All subjects remained on stable concomitant psychotropic medication dosing throughout the trial of riluzole. Each patient's parent or legal guardian consented to the treatment. This study was approved by our local Institutional Review Board and, thus, has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

In two cases (A and C), riluzole was initiated at 50 mg in the evening for 7 days, increased to 50 mg twice daily for 4 weeks, and then increased to 100 mg twice daily thereafter. Patient B was maintained on a maximum 50 mg twice daily dose due to sufficient treatment improvement on this dose. Vital signs including weight, blood pressure, and pulse were obtained at follow-up visits at 4 and 8 weeks, and then quarterly thereafter. The duration of treatment in each case is reflective of the time each individual has been seen in follow up. Each patient currently continues to take riluzole. Labs including complete blood count with platelets and differential and LFTs were obtained at baseline, 4 weeks, and then quarterly. The Clinical Global Impressions (CGI) Severity (CGI-S) Scale was prospectively obtained at baseline, 4- and 8-week visits, and at every subsequent visit; and the CGI Improvement (CGI-I) Scale was also prospectively obtained at 4 and 8 weeks and every visit thereafter. The CGI-S scale measures illness relative to the patient's previous visit on a scale from 1 to 7, with 1 being “not ill” and 7 equivalent to “extremely ill” (Guy 1976). In this article, the CGI-I scale focused on target symptoms of repetitive behavior and was rated from 1 to 7 with 1 equal to very much improved and 7 equal to very much worse. Individuals were deemed responders to treatment if they were given a final rating of 1 “very much improved” or 2 “much improved” on the CGI-I.

Results

Case 1

A is a 15-year-old male with diagnoses of autistic disorder, severe mental retardation, and seizure disorder with a long history of repetitive behaviors, aggression, and SIB. A is engaged in repetitive ordering of objects, speech, and compulsive food-seeking. Caregivers report that A's intense repetitive behavior historically has resulted in aggressive behavior if he is interrupted during his rituals or compulsions. Before treatment with riluzole, previous adequate psychotropic medication trials targeting A's repetitive behavior and irritability included quetiapine, aripiprazole, and risperidone. Each medication was discontinued due to lack of efficacy. At initiation of treatment with riluzole, A's medication regimen included paliperidone 12 mg daily, fluoxetine 60 mg daily, and clonidine 0.3 mg daily for behaviors, as well as levetiracetam 500 mg daily and valproic acid 375 mg daily for seizure disorder.

After 2 months of treatment with riluzole, A experienced a global decrease in repetitive behaviors, including food-seeking, ordering objects, and repetitive speech, as well as increased tolerance of school-related activities. A also experienced a reduction in aggression and SIB related to interruption of compulsions. A's caregivers reported a 75% reduction in compulsive behavior post-treatment. He received a score of 5 or “markedly ill” on the CGI-S at baseline and a score of 4 or “moderately ill” after 2 months of treatment. On the CGI-I, he received a score of 4 or “no change” at 4 weeks (50 mg twice daily dosing), but was “very much improved” with a score of 1 at 8 weeks (100 mg twice daily dosing). A experienced no change in his vital signs or LFTs during initial treatment with riluzole.

After 10 months of treatment with riluzole, A was noted to “look pale” on clinical exam. A CBC revealed mild anemia with a hemoglobin of 11.5 g/dL (normal 14–18 g/dL), hematocrit of 33.6% (normal 40%–54%), and red blood cell count of 3.53 million/mm³ (normal 4.6–6.0 million/mm³). White blood cell count, absolute neutrophil count, platelets, and LFTs remained within normal limits. A was subsequently evaluated by a hematologist, who felt his anemia was likely secondary to riluzole but was not severe enough to indicate discontinuation of the medication. However, as a precaution, A's riluzole dose was decreased to 50 mg twice daily in an attempt to find the minimal dose necessary to provide adequate symptom relief. This dose reduction resulted in increased intensity of his repetitive behaviors and an increase in aggression and SIB. After 8 weeks on the lower dose, riluzole was again increased to 100 mg twice daily with a subsequent decrease in repetitive behavior and improvement in irritability. A underwent treatment with riluzole for a total of 12 months, with a final CGI-S score of 4 and a CGI-I score of 1. A's anemia persisted but remained stable throughout treatment with riluzole.

Case 2

B is an 18-year-old male with diagnoses including autistic disorder and moderate mental retardation. B has a history of severe repetitive behaviors, including repetitive movements such as kicking and getting up and down from a chair and repetitive touching of objects. B's repetitive behaviors significantly impaired his ability to participate in classroom work at school. B also has a history of significant irritable behavior marked by aggression and SIB. In recent years, B's irritability had been well controlled with the use of aripiprazole 20 mg daily. B had minimal benefit from previous adequate trials of multiple psychotropic medications for treatment of his interfering behaviors including guanfacine, risperidone, sertraline, and fluoxetine.

B was treated with riluzole for a total of 6 months. After the first month of treatment, B demonstrated a reduction in repetitive behavior. At this time, B's guardian reported a 50% reduction in his repetitive movements and repetitive touching. His guardian reported that the reduction in repetitive behavior was associated with an increased ability to participate in school activities. He received a CGI-S score at baseline of 5 or “markedly ill” and a CGI-S score at 1 month of 4 or “moderately ill.” Based on B's global decrease in repetitive behaviors, he was judged to be “much improved” with a CGI-I score of 2 at 4 weeks and at all subsequent visits. B experienced no side effects or laboratory abnormalities during treatment with riluzole.

Case 3

C is 20-year-old male with diagnoses including autistic disorder and severe mental retardation. C has a long history of severe repetitive behaviors, including repetitive play with fecal matter, touching of objects, ordering of objects, and skin-picking. C also has a history of intense SIB, including repetitive head-banging and slapping himself, necessitating use of a protective helmet and padded room. C also exhibits aggression toward others, including hitting, kicking, and biting others.

C has had previous adequate trials of multiple psychotropic medications for treatment of his repetitive behaviors and intense irritability, including risperidone, aripiprazole, ziprasidone, quetiapine, citalopram, sertraline, fluvoxamine, venlafaxine, clonazepam, gabapentin, propranolol, and methylphenidate. C's medication regimen at the time of addition of riluzole was paliperidone 9 mg daily, naltrexone 50 mg daily, olanzapine 40 mg daily, clonidine 0.6 mg daily, amitriptyline 75 mg at bedtime, and carbamazepine 800 mg daily for behavior. This medication regimen remained stable throughout treatment with riluzole.

C was treated with riluzole for a total of 4 months. After the first month of treatment, C demonstrated a reduction in aggression and SIB but no change in repetitive behavior. After a dosage increase to 100 mg twice daily, C became easier to redirect away from his compulsions and more cooperative with activities of daily living, including dressing himself. C's caregivers reported a 50% reduction in his compulsive picking, ordering, and touching behaviors. He received a CGI-S score at baseline of 5 or “markedly ill,” and a CGI-S score at 2 months of 4 or “moderately ill.” Based on C's global decrease in repetitive behaviors, as well as reduction in aggression and SIB, he was judged to be “very much improved” with a CGI-I score of 1 at 2 months and all subsequent visits. C experienced no side effects or laboratory abnormalities during treatment with riluzole (Table 1).

Table 1.

Clinical Demographics and Treatment Response Data for Three Persons with Autism Treated with Riluzole

Patient	Diagnosis	Age (years)	Final riluzole dose (mg/day)	Duration of treatment (weeks)	Concomitant psychotropic drugs	Treatment response (CGI-I)	Adverse effects
A	Autistic disorder, severe intellectual disability	15	200	48	Clonidine, fluoxetine, paliperidone; Levitiracetam and valproic acid for seizures	1	Anemia
B	Autistic disorder, moderate intellectual disability	18	100	24	Aripiprazole	2	None
C	Autistic disorder, severe intellectual disability	20	200	16	Amitriptyline, carbamazepine, clonidine, naltrexone, olanzapine	1	None

CGI = Clinical Global Impressions Improvement.

Discussion

This article illustrates our initial clinical experience with riluzole in three individuals with autistic disorder and severe interfering behavioral symptoms. All patients were judged to be “very much improved” or “much improved” on the CGI-I and had a reduction in CGI-S scores based on a clinically meaningful reduction in repetitive behaviors and irritability. These preliminary results suggest that riluzole should be investigated for the treatment of repetitive behavior in individuals with autistic disorder, as no drug has been identified that consistently results in improvement in this core symptom domain. Riluzole may also be of interest for the treatment of irritability in individuals with autism.

Overall, riluzole was well tolerated with no changes noted in vital signs or LFTs in any patient. In case 1, mild anemia occurred; however, it was not severe enough to necessitate discontinuation of the medication.

Limitations

Factors that limit this article include the small number of patients included and the open-label nature of the treatment. All patients also received a number of other medications throughout the trial of riluzole. Finally, only the CGI-S and CGI-I were used as outcome measures in these cases.

Clinical implications

These preliminary data on the use of riluzole targeting interfering behaviors in individuals with autism is promising. The results suggest the importance of future large-scale systematic trials of riluzole to investigate its safety and efficacy in patients with autistic disorder and interfering symptoms. Future work should focus on determining which interfering symptoms associated with autism may respond best to riluzole use. Standard measures of repetitive behavior in addition to global symptom inventories should be included. Potential use of biomarkers of treatment response may also prove useful in future investigations of riluzole in autism.

Footnotes

Disclosures

Logan K. Wink has no conflicts of interest or financial ties to disclose. Craig A. Erickson is a current or past consultant to F. Hoffman-La Roche, Ltd., McNeil Pediatrics, and Novartis. He has received grant support from F. Hoffman-La Roche, Ltd., Novartis, Bristol-Myers Squibb Co., and Seaside Therapeutics. Christopher J. McDougle is a member of the Speakers Bureau for Bristol-Myers Squibb Co. Kimberly A. Stigler has received research grant support from Forest, Bristol-Myers Squibb, and Janssen. The work was supported in part by The Division of Disability and Rehabilitative Services, Indiana Family and Social Services Administration (Drs. Erickson, Wink, McDougle); National Institute of Health Grant KL2 UL1 RR025761 Indiana University Clinical and Translational Sciences Institute Career Development Award (Dr. Erickson); Daniel X. and Mary Freedman Fellowship in Academic Psychiatry (Dr. Stigler); NIMH grant K23 MH082119 (Dr. Stigler); and NIMH grants R01 MH072964, R01 MH077600, and R01 MH083739 (Dr. McDougle).

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