Elsevier

Brain Research

Volume 1380, 22 March 2011, Pages 264-270
Brain Research

Research Report
Open-label riluzole in fragile X syndrome

https://doi.org/10.1016/j.brainres.2010.10.108Get rights and content

Abstract

Objective. Glutamatergic dysregulation is implicated in the pathophysiology of fragile X syndrome (FXS). Riluzole is hypothesized to have an inhibitory effect on glutamate release, block excitotoxic effects of glutamate, and potentiate postsynaptic GABA(A) receptor function. Extracellular signal-related kinase (ERK) activation is known to be delayed in humans with FXS and knockout animal models of FXS. Correction of delayed ERK activation is a potential biomarker of treatment response in FXS. We conducted a six-week open-label prospective pilot study of riluzole (100 mg/day) in six adults with FXS. Methods. Riluzole was started at 50 mg every evening and then increased to 50 mg twice daily at week 2. The dose was kept constant for the final 4 weeks of the trial. Clinical response was determined by a score of 1 “very much improved” or 2 “much improved” on the Clinical Global Impressions Improvement (CGI-I) scale and a  25% improvement on the Children's Yale-Brown Obsessive Compulsive Scale modified for Pervasive Developmental Disorders. The primary target of treatment in this study was repetitive, compulsive behavior that commonly occurs in persons with FXS. The study incorporated an ERK activation biomarker assay. Potential adverse effects were assessed in a systematic manner at all clinic visits and by phone between visits. Results. Riluzole treatment was associated with clinical response in 1 of 6 subjects (17%). Among a number of secondary outcome measures employed, significant improvement was only noted on the ADHD Rating Scale-IV (became non-significant when corrected for multiple comparisons). Riluzole use was associated with significant correction in ERK activation time in all subjects (mean change from 3.82 ± 0.27 (baseline) to 2.99 ± 0.26 (endpoint) minutes; p = 0.007). Riluzole was well tolerated; mean increases in liver function tests occurred but drug discontinuation was not required. Conclusion. Overall, riluzole use was not associated with significant clinical improvement despite uniform correction of peripheral ERK activation. Future directions of study include testing of riluzole in animal models of FXS and assessment of psychotropic monotherapy on ERK activation.

Research highlights

► Riluzole use was associated in clinical improvement in only 1 of 6 subjects. ► Despite limited clinical change, the ERK activation (a biomarker of treatment response) improved in all cases. ► Riluzole use warrants future systematic study to better predict potential treatment response.

Introduction

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the most common single gene cause of autism spectrum disorders (ASDs).

Among persons with intellectual disability, the prevalence of FXS is estimated to be between 1.9% (Gerard et al., 1997) and 6.0% (Florencia et al., 2006). Approximately 46–67% of males with FXS are thought to additionally meet criteria for an ASD (Bailey et al., 2008, Clifford et al., 2007). FXS is associated with a substantially increased risk of a neurobehavioral phenotype marked by severe interfering behavioral symptoms in addition to cognitive delay, particularly in males. Persons with FXS frequently suffer from behavioral difficulties out-of-proportion to cognitive level (Berry-Kravis and Potanos, 2004). Common behavioral and mood symptoms noted in FXS individuals include anxiety-related symptoms (shyness, social phobia, obsessive–compulsive disorder (OCD)-like symptoms), attention-deficit hyperactivity disorder (ADHD)-like symptoms (overarousal, hyperactivity, distractibility, impulsivity), and aggressive/self-injurious behaviors (SIB) (Berry-Kravis and Potanos, 2004).

FXS is the result of a cysteine–guanine–guanine (CGG) trinucleotide repeat expansion (> 200 repeats) within the fragile X mental retardation gene (FMR1) located near the long arm of the X chromosome. This expansion leads to transcriptional silencing of the FMR1 gene and the absence of fragile X mental retardation protein (FMRP) (Devys et al., 1993). The full mutation gene frequency is 1/2500 (Hagerman, 2008). Lack of FMRP has been associated with glutamatergic dysregulation that has been implicated in the pathophysiology of FXS (Bear et al., 2004, Bear, 2005, Dolen et al., 2007, Dolen and Bear, 2008, Huber et al., 2002). Specifically, excessive neurotransmission at Group 1 metabotropic glutamate receptor 5 (mGluR5) has been associated with failed transcription of FMR1 and subsequent lack of FMRP (Bear et al., 2004, Dolen and Bear, 2008). Treatment with mGluR5 antagonists in animal models of FXS has been shown to reverse phenotypic, neuroanatomical and neurochemical deficits (de Vrij et al., 2008, Dolen et al., 2007, McBride et al., 2005).

In addition to glutamatergic dysregulation at mGluR5 receptors, gamma-aminobutryic acid (GABA) dysregulation has also been noted in FXS animal models. GABA(A) receptors have been shown to be underexpressed in FXS knockout animals (Curia et al., 2008, D'Hulst et al., 2006, D'Hulst and Kooy, 2007, D'Hulst et al., 2008, El Idrissi et al., 2005). Reduced GABA availability in both the synaptic cleft and intracellularly has also been reported in FMR1 knockout mice (Olmos-Serrano et al., 2010). Neuronal hyperexcitability in the amygdala of FMR1 knockout mice has been shown to normalize with treatment with the GABA agonist gaboxadol (Olmos-Serrano et al., 2010).

Given the ability to model FXS in animals, combined with recent findings describing the pathophysiology of the disorder, the potential for quantitative biomarkers of treatment response exists in FXS. Extracellular-signal related kinase (ERK) is a nodal point for several cellular signaling cascades. Delayed early-phase phosphorylation (activation) of ERK has been demonstrated in neurons and thymocytes of FMR1 knockout mice (Weiler et al., 2004). In humans, time to ½ maximum ERK activation measured in lymphocytes was delayed in FXS (mean, 5.5 min) compared to normally developing control subjects (mean, 4.5 min) (Weng et al., 2008). In FXS, correction of delayed ERK activation may potentially be a peripheral measure of normalization of underlying neurobiological dysregulation. ERK activation did normalize (baseline mean, 4.872 min; endpoint mean, 4.109 min; p = 0.007) over 8 weeks of add-on open-label lithium treatment in 15 persons (age range, 6–23 years) with FXS (Berry-Kravis et al., 2008).

Riluzole is United States Food and Drug Administration (FDA)-approved (dosing 100 mg/day) for the treatment of amyotrophic lateral sclerosis (ALS) in adults. While the exact mechanism of riluzole is unknown, the drug is thought to have neuroprotective effects in ALS, potentially related to the attenuation of glutamate induced excitotoxicity (Obrenovitch, 1998). Riluzole is hypothesized to inhibit glutamate release (Martin et al., 1993) and enhance glutamate reuptake (Frizzo et al., 2004, Fumagalli et al., 2008). Preclinical study has also pointed to an impact on GABA neurotransmission, including potentiation of post-synaptic GABA(A) receptor activity (Jahn et al., 2008) and blockage of GABA uptake (Mantz et al., 1994). Riluzole also has anti-epileptic properties potentially related more to anti-glutamatergic than GABAergic effects (Kim et al., 2007).

Riluzole has been studied in several areas of psychopathology. In an open-label monotherapy study, riluzole use (mean dose, 169 mg/day) over 6 weeks was associated with significant improvement in 19 adults with treatment-resistant depression (Zarate et al., 2004). In an open-label report in 14 adults, riluzole (mean dose, 171 mg/day) added to lithium was associated with significant group improvement in bipolar disorder-associated depression over 8 weeks of treatment (Zarate et al., 2005). Seven of 13 (54%) adults with treatment-resistant OCD responded favorably to riluzole (100 mg/day) added to other agents over 6 weeks of open-label treatment (Coric et al., 2005). In a 12-week add-on open-label trial of riluzole (mean dose, 102 mg/day) in 6 youth (mean age, 14.4 years) with treatment-resistant OCD, 4 subjects (67%) were deemed treatment responders (Grant et al., 2007). In a case report, riluzole use was associated with significant improvement in symptoms of trichotillomania (Coric et al., 2007). Major potential adverse effects of riluzole use include elevated liver function tests (up to 50% of treated patients), neutropenia, reductions in hemoglobin, hematocrit, and erythrocyte counts, and interstitial lung disease (Sanofi-Aventis and U.S.L., 2009). These potential adverse events require laboratory monitoring, including testing of liver function at baseline, monthly for three months, then quarterly for the remainder of the first year (Sanofi-Aventis and U.S.L., 2009).

Given the potential mechanisms of action of riluzole, combined with early positive reports on targeting treatment-resistant OCD, we conducted the first study of riluzole in FXS targeting interfering repetitive, compulsive behavior.

Section snippets

Results

All six subjects screened met inclusion criteria. All subjects were male with a mean age of 22.5 years (range, 19–24 years). All subjects successfully completed all study procedures. All subjects met ADI-R criteria for a concomitant diagnosis of autistic disorder. Full scale IQ scores ranged from 40 to 43, with a mean score of 40.5. Each subject received a final dose of riluzole of 100 mg/day (5 subjects tolerated 50 mg twice daily; one subject required 25 mg AM and 75 mg PM dosing).

Discussion

In this pilot report, only 1 of 6 adult subjects with FXS responded to treatment with open-label riluzole. Riluzole was generally well tolerated. However, liver function tests increased in 5 of 6 (83%) subjects, although drug discontinuation was not necessary in any case. While sedation and irritability were noted in some subjects, these adverse effects tended to be time-limited and mild with only one subject requiring a dose schedule change due to moderate sedation. The rate of response to

Study design

A 6-week, prospective, open-label study design was chosen to gather pilot data on riluzole in adults with FXS. In this report, riluzole use primarily targeted the repetitive and compulsive behavior that frequently occurs in persons with FXS. Examples of such behavior include repetitive checking, questioning, touching, and picking. The study design allowed for maintenance dosing for the final 4 weeks of the study. Follow-up visits occurred every 2 weeks throughout the study. Between study visits,

Acknowledgments

Supported in part by The Division of Disability & Rehabilitative Services, Indiana Family and Social Services Administration, (Drs. Erickson, Wink, McDougle); National Institute of Health grant K12 UL1 RR025761 Indiana University Clinical and Translational Sciences Institute Career Development Award (Dr. Erickson); Indiana University Clinical and Translational Sciences Institute Pilot Research Award (Dr. Erickson); Indiana University Department of Psychiatry Research Committee (Dr. Erickson);

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