A Randomized Placebo-Controlled Cross-Over Pilot Study of Riluzole for Drug-Refractory Irritability in Autism Spectrum Disorder
- 385 Downloads
Riluzole is a glutamatergic modulator of particular interest in autism spectrum disorder (ASD). In this 12-week randomized, double-blind, placebo-controlled, crossover pilot study we evaluated the safety and tolerability of 5-week of adjunctive riluzole treatment (vs. 5-week of placebo, with 2-week washout period) targeting ASD-associated drug-refractory irritability in eight individuals age 12–25 years. All participants tolerated riluzole 200 mg per day, however there were no statistically significant findings for the overall treatment effect, the treatment effect by week within period of the study, or a cross-over effect across the periods of the study on the Clinical Global Impression Improvement Scale or the Aberrant Behavior Checklist Irritability subscale. The results of this trial indicate that 5-week of riluzole treatment was well tolerated, but had no significant effect on the target symptoms. Trial Registration ClinicalTrials.gov Identifier NCT02081027, Registered 5 August 2013, First participant enrolled 19 September 2013.
KeywordsAutism Autism spectrum disorder Riluzole Irritability Extracellular signal related kinase ERK
The authors would like to acknowledge the contributions of Kaela O’Brien and Bridget Crippen for their assistance with study coordination and data collection.
LKW participated in study design, study execution, and drafted the manuscript. RA and PH completed the statistical analysis and assisted with drafting the statistical portion of the manuscript. CT and APB completed the ERK biomarker analysis. MH drafted the ERK analysis portion of the manuscript. RCS and EVP assisted in study execution, assisted in drafting the manuscript and reviewed the data analysis. CAE participated in study design, study execution, and oversaw manuscript development. All authors read, edited, and approved the final manuscript.
This study was funded by the Center for Clinical and Translational Science and Training at the University of Cincinnati via an Institutional Clinical and Translational Science Award, NIH/NCRR Grant No. 8UL1TR000077-04.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no interests that compete directly with this work, though LKW, CRT, RSC, EVP, and CAE do receive research support from various sources for other work. LKW’s current and/or past research is supported by the Simons Research Foundation, Autism Speaks, Riovant Sciences Ltd, and Cures Within Reach. Dr. Wink is currently a NICHM-NIMH supported T32 fellow. She is an inventor on intellectual property held by Cincinnati Children’s Hospital Research Foundation for a treatment in autism spectrum disorder. LKW has also served as a past consultant for Otsuka and Ovid. CRT has been a past one-time consultant for Confluence Pharmaceuticals. His current and/or past research has been supported by the National Institute of Mental Health and Indiana University School of Medicine. RCS receives research support from the Rubenstein foundation. EVP receives research support from Cincinnati Children’s Hospital Research Foundation and the National Institutes of Health. CAE has received current and/or past research support from the National Institutes of Health, the United States Department of Defense, the United States Centers for Disease Control, the John Merck Fund, Autism Speaks, the Simons Foundation, Cincinnati Children’s Hospital Research Foundation, the FRAXA Research Foundation, the National Fragile X Foundation, the Roche Group, Seaside Therapeutics, Novartis, Neuren, Alcobra, and Indiana University School of Medicine. He is a past consultant to Alcobra, the Roche Group, and Novartis. He is a current consultant to Fulcrum Therapeutics. He holds equity interest in and is a consultant for Confluence Pharmaceuticals. He is the inventor on intellectual property held by Cincinnati Children’s Hospital Research Foundation and Indiana University describing methods for diagnosis and treatment methods in autism spectrum disorder and fragile X syndrome. RA, PH, APB, and MH have no conflicts to report.
This study was approved by the Cincinnati Children’s Hospital institutional review board. All procedures performed in this study were in accordance with the ethical standards of the institution and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Guardians of all participants provided written informed consent prior to participation.
- Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985). The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. American Journal of Mental Deficiency, 5, 485–491.Google Scholar
- Constantino, J., & Gruber, C. (2005). Social responsiveness scale. Torrance: WPS Publishing LLC.Google Scholar
- Erickson, C. A., Posey, D. J., Stigler, K. A., & McDougle, C. J. (2008). Glutamatergic function in autism. In U. Heresco-Levy (Ed.), Glutamate in neuropsychiatric disorders. (pp. 197–212). Trivandrum: Research Signpost.Google Scholar
- Grant, P., Lougee, L., Hirschtritt, M., & Swedo, S. E. (2007b). An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. Journal of Child Adolescent Psychopharmacology, 17, 761–767. https://doi.org/10.1089/cap.2007.0021.CrossRefPubMedGoogle Scholar
- Guy, W. (1976). ECDEU assessment manual for psychopharmacology. Washington DC: National Institute of Mantal Health, U.S. Department of Helath, Education and Wellfare.Google Scholar
- Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & Lasalle, J. M. (2007). 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics, 16, 691–703. https://doi.org/10.1093/hmg/ddm014.CrossRefPubMedPubMedCentralGoogle Scholar
- Jahn, K., Schlesinger, F., Jin, L. J., Dengler, R., Bufler, J., & Krampfl, K. (2008). Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABA(A)-receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 378, 53–63. https://doi.org/10.1007/s00210-008-0290-y.CrossRefPubMedGoogle Scholar
- Lord, C., Rutter, M., DiLavore, P., Risis, S., Gotham, K., & Bishop, S. (2012). Autism diagnostic observation schedule (ADOS-2), (2nd ed). Portland: Western Psychological Services.Google Scholar
- Marcus, R. N., et al. (2009). A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 48, 1110–1119. https://doi.org/10.1097/CHI.0b013e3181b76658.CrossRefPubMedGoogle Scholar
- Pittenger, C., Kelmendi, B., Wasylink, S., Bloch, M. H., & Coric, V. (2008). Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: A series of 13 cases, with long-term follow-up. Journal of Clinical Psychopharmacology, 28, 363–367. https://doi.org/10.1097/JCP.0b013e3181727548.CrossRefPubMedGoogle Scholar
- Pucilowska, J., Vithayathil, J., Tavares, E. J., Kelly, C., Karlo, J. C., & Landreth, G. E. (2015). The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. The Journal of Neuroscience 35, 3190–3200. https://doi.org/10.1523/JNEUROSCI.4864-13.2015.CrossRefGoogle Scholar
- Scahill, L., et al. (2006). Children’s yale-brown obsessive compulsive scale modified for pervasive developmental disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1114–1123. https://doi.org/10.1097/01.chi.0000220854.79144.e7.CrossRefPubMedGoogle Scholar
- Wang, S. J., Wang, K. Y., & Wang, W. C. (2004). Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience, 125, 191–201. https://doi.org/10.1016/j.neuroscience.2004.01.019.CrossRefPubMedGoogle Scholar
- Weng, N., Weiler, I. J., Sumis, A., Berry-Kravis, E., & Greenough, W. T. (2008). Early-phase ERK activation as a biomarker for metabolic status in fragile X syndrome. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 1253–1257. https://doi.org/10.1002/ajmg.b.30765.CrossRefGoogle Scholar