Riluzole to Treat Child and Adolescent Obsessive-Compulsive Disorder With or Without Autism Spectrum Disorders

Condition(s) targeted: Obsessive-Compulsive Disorder; Autism Spectrum Disorder; Autism; Asperger Disorder; Development Disorder

Intervention: Riluzole (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institute of Mental Health (NIMH)

Overall contact:
Lorraine Lougee, L.C.S.W., Phone: (301) 496-5323, Email: ocdnimh@intra.nimh.nih.gov

This study will examine the effectiveness of riluzole for treating Obsessive-Compulsive Disorder in Youth, Including those with Autism Spectrum Disorders.

Official title: An Investigation of the Efficacy in Childhood Obsessive-Compulsive Disorder of Riluzole: An Antiglutamatergic Agent

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Primary outcome: Reduction of 30% or more in Children's Yale-brown Obsessive-Compulsive Scale (CY-BOCS) and Repetitive Behavior Scale

Secondary outcome: Much/Very much improved on Clinical Global Impressions - Improvement score (CGI-I)

Detailed description: Obsessive-Compulsive Disorder (OCD) is a chronic psychiatric disorder characterized by the presence of intrusive and unwanted obsessional thoughts and images and of compulsive behaviors. Its presentation during childhood is similar to that seen in adulthood, except that children sometimes lack insight into the senselessness of the thoughts and behaviors. Although many patients benefit from treatment with selective serotonin reuptake inhibitors (SSRIs), a significant proportion have limited or no response to these medications. Additionally, these medicines have been associated with a slight but significant increase in onset of suicidal thoughts among adolescents being treated for depression or OCD. Cognitive behavioral therapy (CBT) may also be effective for OCD, alone or in combination with SSRIs, but there is a shortage of qualified therapists, and many patients and families cannot participate effectively in the therapy. Further, in a recent report on a multi-site study of childhood OCD, CBT alone at one site fared little better than placebo (March and et al, 2004).

There is a pressing need, then, for the development of alternative, novel treatments for pediatric OCD. Neuropsychological and neuroimaging data suggest that OCD may arise from dysfunction of orbitofronto-striato-thalamocortical circuitry. Glutamate plays a crucial role in the regulation of excitatory activity within this circuit and may be involved in the etiopathogenesis of OCD. If so, then agents which reduce glutamatergic neurotransmission may provide unique antiobsessional benefits. Studies in adults with OCD are already in progress. To evaluate the possibility of benefit in children, we propose to conduct a two-stage study of a novel pharmaceutical, riluzole, an agent that reduces glutamatergic effect via inhibition of its release and perhaps via other mechanisms. Riluzole is Food and Drug Administration (FDA)-approved for treatment of amyotrophic lateral sclerosis (ALS), and is currently under investigation at the NIMH for treatment of acute depression.

This proposal is for a 12-week, single-arm, open-label study that will evaluate safety and estimate dose in 6 children, ages 7 to 17 years, with a primary diagnosis of OCD, including those who previously have tried one or more psychopharmacologic agents with Food and Drug Administration (FDA) indication for childhood OCD but who have found that treatment ineffective or poorly tolerated. Riluzole will be added to current regimen or used as sole agent. Following this feasibility and dose-finding study, a second stage will enroll 30 additional subjects with OCD as well as 30 additional subjects who have both autistic spectrum disorder (ASD) and OCD. These 60 subjects will participate in a double-blind, placebo-controlled 12-week trial of riluzole as a sole agent or as an augmentation to their currently inadequate therapy. Patients will be followed at regular intervals until one year from baseline, for safety monitoring.

Minimum age: 7 Years. Maximum age: 17 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

Subjects may be included in the study only if they meet all of the following criteria:

1. Male or female subjects, 7 to 17 years of age.

2. Female subjects of childbearing potential must be using a medically accepted means of contraception or must remain abstinent.

3. Each legal guardian must have a level of understanding sufficient to agree to all required tests and examinations. Each legal guardian must understand the nature of the study. Each legal guardian must consent to study protocol.

4. Subjects must fulfill DSM-IV criteria for (OCD) and have a CY-BOCS score of greater than 16. In the double-blind phase, subjects enrolled in the combined OCD and ASD cohort must also meet DSM-IV criteria for Pervasive Developmental Disorder as well as OCD.

5. Each subject already taking medicine must be taking usually effective doses of a medicine demonstrated to be effective in childhood OCD, must have been stable on that dose for at least six weeks, and must have no newly recognized or intolerable adverse effects from that medicine. Subjects who are currently not taking such a medication must have had adequate trial in the past of at least one medicine with FDA indication for childhood OCD, and must have failed to see improvement or must have had intolerable adverse effects from the medicine.

6. Subjects must be able to swallow capsules.

EXCLUSION CRITERIA:

Subjects will be excluded from the study for any of the following reasons:

1. Presence of psychotic symptoms or lifetime history of schizophrenia, bipolar disorder, other psychotic disorder, or other serious unstable psychiatric illness. Mecially unstable due to binging, purging, or starvation.

2. Judged clinically to be at risk for suicide (suicidal ideation, severe depression, or other factors). Diagnosis of DSM-IV Major Depressive Disorder is not necessarily an exclusion criterion.

3. Disabling Tic Disorder requiring contraindicated medicines.

4. Female subjects who are either pregnant or nursing.

5. Serious unstable illnesses, including gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

6. Renal or hepatic dysfunction that would interfere with excretion or metabolism of riluzole as evidenced by increase above upper limits of normal for BUN/creatinine, or two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT), gamma glutamate (GGT), or bilirubin.

7. Documented history of hypersensitivity or intolerance to riluzole.

8. DSM-IV Substance Abuse Disorder within the past 90 days or Substance Dependence Disorder within the past 5 years, or any use of tobacco.

9. Taking contraindicated drugs.

10. Unable to swallow capsules.

11. In addition, patients will not receive cognitive-behavior therapy during the period of the study.

Lorraine Lougee, L.C.S.W., Phone: (301) 496-5323, Email: ocdnimh@intra.nimh.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

Sasso DA, Kalanithi PS, Trueblood KV, Pittenger C, Kelmendi B, Wayslink S, Malison RT, Krystal JH, Coric V. Beneficial effects of the glutamate-modulating agent riluzole on disordered eating and pathological skin-picking behaviors. J Clin Psychopharmacol. 2006 Dec;26(6):685-7. No abstract available.

Zarate CA Jr, Quiroz JA, Singh JB, Denicoff KD, De Jesus G, Luckenbaugh DA, Charney DS, Manji HK. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005 Feb 15;57(4):430-2.

Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3;330(9):585-91.

Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology (Berl). 2003 May;167(2):219-20. Epub 2003 Mar 26. No abstract available.

McGrath MJ, Campbell KM, Parks CR, Burton FH. Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder. Brain Res. 2000 Sep 15;877(1):23-30.

Moore GJ, MacMaster FP, Stewart C, Rosenberg DR. Case study: caudate glutamatergic changes with paroxetine therapy for pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1998 Jun;37(6):663-7.

Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1096-103.

Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005 Sep 1;58(5):424-8.

Russman BS, Iannaccone ST, Samaha FJ. A phase 1 trial of riluzole in spinal muscular atrophy. Arch Neurol. 2003 Nov;60(11):1601-3.

Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-4.

Starting date: August 2005
Last updated: September 15, 2008