Riluzole in Fragile X Syndrome

The purpose of this study is to investigate the effectiveness and tolerability of riluzole in adults with Fragile X Syndrome.

Fragile X Syndrome (FXS) represents the most common inherited form of intellectual disability. FXS is more common in males and the symptoms associated with the disorder are more marked in males. FXS is associated with characteristic physical features, behaviors, and comorbidities. Those with FXS often suffer from behavioral difficulties that include anxiety-related symptoms (shyness, social phobia, obsessive-compulsive disorder (OCD) symptoms), attention deficit hyperactivity symptoms (overarousal, hyperactivity, distractibility, impulsivity) and aggressive/self-injurious behaviors. Riluzole is approved by the FDA for use in treating amyotrophic lateral sclerosis (ALS) in adults. Recently, riluzole has been the subject of several open-label studies describing the use of the drug in treatment-resistant depression and OCD. Given the overlap between repetitive behavior in FXS and symptoms of OCD, it is logical to study riluzole in FXS given the compound's promise in ameliorating treatment-refractory symptoms of OCD.

The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse

The CY-BOCS PDD has been utilized in a largescale clinical treatment study of repetitive behavior in idiopathic ASDs. CYBOCS-PDD scores range from 0 to 20 and measure repetitive/compulsive behavior and not obsessions. Higher score indicate worse outcome.

The Aberrant Behavior Checklist (ABC) is a 58-item measure of maladaptive behaviors and is used as a measure of drug effects. The ABC has 5 subscales: Social Withdrawal (16 items) ranging from 0 (not at all) to 48 (severe), Irritability (15 items) ranging from 0 (not at all) to 45 (severe), Inappropriate Speech (4 items) ranging from 0 (not at all) to 12 (severe), Hyperactivity (16 items) ranging from 0 (not at all) to 48 (severe), and Stereotypy (7 items) ranging from 0 (not at all) to 21 (severe). Items are rated from 0 (not at all) to 3 (severe).

The ADHD Rating Scale is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder. The ADHD Rating Scale-IV is completed by the parent and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. The total score can range from 0 to 54, with a higher score indicating greater severity

The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill

The Peabody Picture Vocabulary Test is one of the most commonly used assessment tests that measure verbal ability in standard American English vocabulary. This test has been nationally standardized using examinees from various age groups, from children to adults. Thus, the raw scores are equated to mental age, using the norms obtained from standardization. The total standard scores range from 40 (worse receptive vocabulary) to 160 (better receptive vocabulary). The scores can also be converted to percentile rank.

The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each individual item is summed to create a total raw score. A total scores results are as follows: 0-62: Within normal limits 63-79: Mild range of impairment 80-108: Moderate range of impairment 109-149: Severe range of impairment.

ERK activations times, as defined as the time in minutes for ERK phosphorylation to reach the half maximal level.

Inclusion Criteria: Males and females age 18 years or older. Confirmed molecular diagnosis of Fragile X Syndrome. Clinical Global Impression Severity (CGI-S) score of 3 or greater. Significant interfering repetitive behavior as determined by the principal investigator. Must be in good health as determined by screening procedures including a detailed medical history, and complete physical and neurological examination. Dosing of concomitant medications during the study must remain stable. Exclusion Criteria: Pregnancy. Concomitant use of another glutamatergic agent (memantine, topiramate, amantadine, among others. Evidence of prior trial of riluzole and/or hypersensitivity/allergic reaction to riluzole. Abnormal baseline liver function tests at screen or by history; or complete blood count abnormalities at screen or by history.

Erickson CA, Weng N, Weiler IJ, Greenough WT, Stigler KA, Wink LK, McDougle CJ. Open-label riluzole in fragile X syndrome. Brain Res. 2011 Mar 22;1380:264-70. doi: 10.1016/j.brainres.2010.10.108. Epub 2010 Nov 5.