Abstract
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.
Similar content being viewed by others
References
Adler, B. A., et al. (2014). Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: A chart review study. Autism. https://doi.org/10.1177/1362361314524641.
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.
Christensen, D. L. (2016). Prevalence and characteristics of autism spectrum disorder among children aged 8 years- autism developmental disabilities monitoring network. Journal of Developmental & Behavioral Pediatrics 37, 1–8.
Constantino, J., & Gruber, C. (2005). Social responsiveness scale. Torrance: WPS Publishing LLC.
Coric, V., et al. (2005). Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: An open-label trial. Biological Psychiatry, 58, 424–428. https://doi.org/10.1016/j.biopsych.2005.04.043.
Delahanty, R. J., et al. (2009). Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Molecular Psychiatry. https://doi.org/10.1038/mp.2009.118.
Doble, A. (1996). The pharmacology and mechanism of action of riluzole. Neurology, 47, S233–S241.
Erickson, C. A., et al. (2011). Open-label riluzole in fragile X syndrome. Brain Research, 1380, 264–270. https://doi.org/10.1016/j.brainres.2010.10.108.
Erickson, C. A., et al. (2017). Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism. Journal of Psychiatric Research, 84, 153–160. https://doi.org/10.1016/j.jpsychires.2016.09.003.
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.
Faridar, A., et al. (2014). Mapk/Erk activation in an animal model of social deficits shows a possible link to autism. Molecular Autism, 5, 57. https://doi.org/10.1186/2040-2392-5-57.
Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 52, 805–810.
Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009). GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism and Developmental Disorders, 39, 223–230. https://doi.org/10.1007/s10803-008-0646-7.
Fumagalli, E., Funicello, M., Rauen, T., Gobbi, M., & Mennini, T. (2008). Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 578, 171–176. https://doi.org/10.1016/j.ejphar.2007.10.023.
Grant, P., Lougee, L., Hirschtritt, M., & Swedo, S. (2007a). An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. Journal of Child and Adolescent Psychopharmacology, 17, 761–767.
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.
Grant, P. J., et al. (2014). 12-week, placebo-controlled trial of add-on riluzole in the treatment of childhood-onset obsessive-compulsive disorder. Neuropsychopharmacology, 39, 1453–1459. https://doi.org/10.1038/npp.2013.343.
Guy, W. (1976). ECDEU assessment manual for psychopharmacology. Washington DC: National Institute of Mantal Health, U.S. Department of Helath, Education and Wellfare.
He, Y., et al. (2002). Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology, 42, 199–209.
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.
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.
Kim, S. A., Kim, J. H., Park, M., Cho, I. H., & Yoo, H. J. (2006). Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios. Neuropsychobiology, 54, 160–165. https://doi.org/10.1159/000098651.
Lecavalier, L., Leone, S., & Wiltz, J. (2006). The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders. Journal of Intellectual Disability Research, 50, 172–183. https://doi.org/10.1111/j.1365-2788.2005.00732.x.
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.
Malhotra, D., & Sebat, J. (2012). CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell, 148, 1223–1241. https://doi.org/10.1016/j.cell.2012.02.039.
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.
McCracken, J. T., et al. (2002). Risperidone in children with autism and serious behavioral problems. The New England Journal of Medicine 347, 314–321.
Menold, M. M., et al. (2001). Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. Journal of Neurogenetics, 15, 245–259. https://doi.org/10.3109/01677060109167380.
Owen, R., et al. (2009). Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics, 124, 1533–1540.
Page, L. A., et al. (2006). In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. American Journal of Psychiatry, 163, 2189–2192. https://doi.org/10.1176/appi.ajp.163.12.2189.
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.
Posey, D. J., Stigler, K. A., Erickson, C. A., & McDougle, C. J. (2008). Antipsychotics in the treatment of autism. Journal of Clinical Investigation, 118, 6–14. https://doi.org/10.1172/JCI32483.
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.
Purcell, A. E., Jeon, O. H., Zimmerman, A. W., Blue, M. E., & Pevsner, J. (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 57, 1618–1628.
Samuels, I. S., et al. (2008). Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. The Journal of Neuroscience, 28, 6983–6995. https://doi.org/10.1523/JNEUROSCI.0679-08.2008.
Samuels, I. S., Saitta, S. C., & Landreth, G. E. (2009). MAP’ing CNS development and cognition: An ERKsome process. Neuron, 61, 160–167. https://doi.org/10.1016/j.neuron.2009.01.001.
Sanacora, G., Kendell, S. F., Fenton, L., Coric, V., & Krystal, J. H. (2004). Riluzole augmentation for treatment-resistant depression. American Journal of Psychiatry, 161, 2132. https://doi.org/10.1176/appi.ajp.161.11.2132.
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.
Siegel, M., et al. (2015). The autism inpatient collection: Methods and preliminary sample description. Molecular Autism 6, 61 https://doi.org/10.1186/s13229-015-0054-8.
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.
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.
Wink, L. K., et al. (2017). Characterization of medication use in a multicenter sample of pediatric inpatients with autism spectrum disorder. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-017-3153-x.
Wink, L. K., Erickson, C. A., Stigler, K. A., & McDougle, C. J. (2011). Riluzole in autistic disorder. Journal of Child and Adolescent Psychopharmacology, 21, 375–379. https://doi.org/10.1089/cap.2010.0154.
Wink, L. K., Pedapati, E. V., Horn, P. S., McDougle, C. J., & Erickson, C. A. (2015). Multiple antipsychotic medication use in autism spectrum disorder. Journal of Child and Adolescent Psychopharmacology, https://doi.org/10.1089/cap.2015.0123.
Zarate, C. A. Jr., et al. (2004). An open-label trial of riluzole in patients with treatment-resistant major depression. American Journal of Psychiatry, 161, 171–174.
Zarate, C. A. Jr., et al. (2005). An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biological Psychiatry, 57, 430–432. https://doi.org/10.1016/j.biopsych.2004.11.023.
Acknowledgments
The authors would like to acknowledge the contributions of Kaela O’Brien and Bridget Crippen for their assistance with study coordination and data collection.
Funding
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
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.
Ethical Approval
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.
Informed Consent
Guardians of all participants provided written informed consent prior to participation.
Electronic Supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wink, L.K., Adams, R., Horn, P.S. et al. A Randomized Placebo-Controlled Cross-Over Pilot Study of Riluzole for Drug-Refractory Irritability in Autism Spectrum Disorder. J Autism Dev Disord 48, 3051–3060 (2018). https://doi.org/10.1007/s10803-018-3562-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-018-3562-5