Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: A randomized, controlled, phase 2 trial

Science Translational Medicine

Volumn 4, Issue 152, 2012, Pages

  Berry Kravis, Elizabeth M ^a   Hessl, David ^b   Rathmell, Barbara ^c   Zarevics, Peter ^c   Cherubini, Maryann ^c   Walton Bowen, Karen ^c   Mu, Yi ^d   Nguyen, Danh V ^d   Gonzalez Heydrich, Joseph ^e   Wang, Paul P ^c   Carpenter, Randall L ^c   Bear, Mark F ^f   Hagerman, Randi J ^b  

^a RUSH UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c Seaside Therapeutics Inc   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e BOSTON CHILDREN S HOSPITAL   (United States)

^f MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARBACLOFEN; PLACEBO;

ADOLESCENT; ADULT; AGGRESSION; ARTICLE; BRAIN FUNCTION; CHILD; CHILD BEHAVIOR; CHILD BEHAVIOR CHECKLIST; CONTROLLED STUDY; CROSSOVER PROCEDURE; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; FEMALE; FRAGILE X SYNDROME; GENE MUTATION; HUMAN; INCREASED APPETITE; IRRITABILITY; MAJOR CLINICAL STUDY; MALE; PATIENT ASSESSMENT; PRESCHOOL CHILD; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; SCHOOL CHILD; SEDATION; SIDE EFFECT; SOCIAL BEHAVIOR; SOCIAL DISABILITY; SOCIAL STATUS; UPPER RESPIRATORY TRACT INFECTION; VISUAL ANALOG SCALE; VOMITING;

ADOLESCENT; ADULT; BACLOFEN; BEHAVIOR; CHILD; FEMALE; FRAGILE X SYNDROME; HUMANS; MALE; NERVOUS SYSTEM; NEUROPSYCHOLOGICAL TESTS; REPRODUCIBILITY OF RESULTS; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84866628742     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3004214     Document Type: Article

References (37)

1. C. Bradley, The behavior of children receiving benzedrine. Am. J. Psychiatry 94, 577-585 (1937).
2. J. T. McCracken, J. McGough, B. Shah, P. Cronin, D. Hong, M. G. Aman, L. E. Arnold, R. Lindsay, P. Nash, J. Hollway, C. J. McDougle, D. Posey, N. Swiezy, A. Kohn, L. Scahill, A. Martin, K. Koenig, F. Volkmar, D. Carroll, A. Lancor, E. Tierney, J. Ghuman, N. M. Gonzalez, M. Grados, B. Vitiello, L. Ritz, M. Davies, J. Robinson, D. McMahon; Research Units on Pediatric Psychopharmacology Autism Network, Risperidone in children with autism and serious behavioral problems. N. Engl. J. Med. 347, 314-321 (2002).
3. D. Ehninger, A. J. Silva, Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol. Med. 17, 78-87 (2011).
4. D. Z. Wetmore, C. C. Garner, Emerging pharmacotherapies for neurodevelopmental disorders. J. Dev. Behav. Pediatr. 31, 564-581 (2010).
5. L. W. Wang, E. Berry-Kravis, R. J. Hagerman, Fragile X: Leading the way for targeted treatments in autism. Neurotherapeutics 7, 264-274 (2010).
6. R. J. Hagerman, E. Berry-Kravis, W. E. Kaufmann, M. Y. Ono, N. Tartaglia, A. Lachiewicz, R. Kronk, C. Delahunty, D. Hessl, J. Visootsak, J. Picker, L. Gane, M. Tranfaglia, Advances in the treatment of fragile X syndrome. Pediatrics 123, 378-390 (2009).
7. D. B. Budimirovic, I. Bukelis, C. Cox, R. M. Gray, E. Tierney, W. E. Kaufmann, Autism spectrum disorder in Fragile X syndrome: Differential contribution of adaptive socialization and social withdrawal. Am. J. Med. Genet. A 140A, 1814-1826 (2006).
8. J. E. Roberts, L. A. Weisenfeld, D. D. Hatton, M. Heath, W. E. Kaufmann, Social approach and autistic behavior in childrenwith fragile X syndrome. J. Autism Dev.Disord. 37, 1748-1760 (2007).
9. A. J. Verkerk, M. Pieretti, J. S. Sutcliffe, Y. H. Fu, D. P. Kuhl, A. Pizzuti, O. Reiner, S. Richards, M. F. Victoria, F. P. Zhang, B. E. Eussen, G.-J. B. van Ommen, L. A. J. Blonden, G. J. Riggins, J. L. Chastain, C. B. Kunst, H. Galjaard, C. T. Caskey, D. L. Nelson, B. A. Oostra, S. T. Warren, Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905- 914 (1991).
10. M. F. Bear, K. M. Huber, S. T. Warren, The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370-377 (2004).
11. G. Dölen, E. Osterweil, B. S. Rao, G. B. Smith, B. D. Auerbach, S. Chattarji, M. F. Bear, Correction of fragile X syndrome in mice. Neuron 56, 955-962 (2007).
12. S. M. McBride, C. H. Choi, Y. Wang, D. Liebelt, E. Braunstein, D. Ferreiro, A. Sehgal, K. K. Siwicki, T. C. Dockendorff, H. T. Nguyen, T. V. McDonald, T. A. Jongens, Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 45, 753-764 (2005).
13. Q. J. Yan, M. Rammal, M. Tranfaglia, R. P. Bauchwitz, Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49, 1053-1066 (2005).
14. A. Suvrathan, C. A. Hoeffer, H. Wong, E. Klann, S. Chattarji, Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome. Proc. Natl. Acad. Sci. U.S.A. 107, 11591-11596 (2010).
15. F. M. de Vrij, J. Levenga, H. C. van der Linde, S. K. Koekkoek, C. I. De Zeeuw, D. L. Nelson, B. A. Oostra, R. Willemsen, Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol. Dis. 31, 127 - 132 (2008).
16. A receptor: A novel target for treatment of fragile X? Trends Neurosci. 30, 425-431 (2007).
17. J. L. Olmos-Serrano, S. M. Paluszkiewicz, B. S. Martin, W. E. Kaufmann, J. G. Corbin, M. M. Huntsman, Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J. Neurosci. 30, 9929-9938 (2010).
18. C. Watson, F. Hoeft, A. S. Garrett, S. S. Hall, A. L. Reiss, Aberrant brain activation during gaze processing in boys with fragile X syndrome. Arch. Gen. Psychiatry 65, 1315-1323 (2008).
19. L. Cordeiro, E. Ballinger, R. Hagerman, D. Hessl, Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: Prevalence and characterization. J. Neurodev. Disord. 3, 57-67 (2011).
20. F. Farzin, S. M. Rivera, D. Hessl, Brief report: Visual processing of faces in individuals with fragile X syndrome: An eye tracking study. J. Autism Dev. Disord. 39, 946-952 (2009).
21. J. L. Olmos-Serrano, J. G. Corbin, Amygdala regulation of fear and emotionality in fragile X syndrome. Dev. Neurosci. 33, 365-378 (2011).
22. S. Chang, S. M. Bray, Z. Li, D. C. Zarnescu, C. He, P. Jin, S. T. Warren, Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat. Chem. Biol. 4, 256-263 (2008).
23. C. L. Gatto, K. Broadie, Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front. Synaptic Neurosci. 2, 4 (2010).
24. B-mediated presynaptic inhibition of excitatory transmission and synaptic vesicle dynamics in cultured hippocampal neurons. Neuron 18, 143-152 (1997).
25. B receptors with arbaclofen. Sci. Transl. Med. 4, 152ra128 (2012).
26. E. Mutschler, Y. Gietl, D. Krauss, Stereospecific analysis and human pharmacokinetics of the enantiomers of drugs administered as racemates, in Chirality and Biological Activity, H. Frank, B. Holmstedt, B. Testa, Eds. (Alan R. Liss, New York, 1990), p. 283.
27. S. M. Sansone, K. F. Widaman, S. S. Hall, A. L. Reiss, A. Lightbody, W. E. Kaufmann, E. Berry-Kravis, A. Lachiewicz, E. C. Brown, D. Hessl, Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment. J. Autism Dev. Disord. 42, 1377-1392 (2012).
28. D. D. Krueger, M. F. Bear, Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med. 62, 411-429 (2011).
29. E. Berry-Kravis, K. Potanos, Psychopharmacology in fragile X syndrome - Present and future. Ment. Retard. Dev. Disabil. Res. Rev. 10, 42-48 (2004).
30. S. Jacquemont, A. Curie, V. des Portes, M. G. Torrioli, E. Berry-Kravis, R. J. Hagerman, F. J. Ramos, K. Cornish, Y. He, C. Paulding, G. Neri, F. Chen, N. Hadjikhani, D. Martinet, J. Meyer, J. S. Beckmann, K. Delange, A. Brun, G. Bussy, F. Gasparini, T. Hilse, A. Floesser, J. Branson, G. Bilbe, D. Johns, B. Gomez-Mancilla, Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3, 64ra1 (2011).
31. M. G. Aman, N. N. Singh, A. W. Stewart, C. J. Field, The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. Am. J. Ment. Defic. 89, 485-491 (1985).
32. S. S. Sparrow, D. V. Cicchetti, D. A. Balla, Vineland Adaptive Behavior Scales, Second Edition (AGS Publishing, Circle Pines, 2005).
33. J.N. Constantino, S. A. Davis, R. D. Todd, M. K. Schindler, M.M.Gross, S. L. Brophy, L.M. Metzger, C. S. Shoushtari, R. Splinter, W. Reich, Validation of a brief quantitativemeasure of autistic traits: Comparison of the social responsiveness scale with the Autism Diagnostic Interview-Revised. J. Autism Dev. Disord. 33, 427-433 (2003).
34. K. S. Lam, M. G. Aman, The Repetitive Behavior Scale-Revised: Independent validation in individuals with autism spectrum disorders. J. Autism Dev. Disord. 37, 855-866 (2007).
35. D. G. Sukhodolsky, L. Scahill, K. D. Gadow, L. E. Arnold, M. G. Aman, C. J.McDougle, J. T. McCracken, E. Tierney, S. Williams White, L. Lecavalier, B. Vitiello, Parent-rated anxiety symptoms in children with Pervasive Developmental Disorders: Frequency and association with core autism symptoms and cognitive functioning. J. Abnorm. Child Psychol. 36, 117-128 (2008).
36. G. J. DuPaul, T. J. Power, A. D. Anastopoulos, D. Reid, ADHD Rating Scale - IV: Checklists, Norms, and Clinical Interpretations (The Guilford Press, New York, 1998).
37. R. Owen, L. Sikich, R.N. Marcus, P. Corey-Lisle, G. Manos, R. D. McQuade, W. H. Carson, R. L. Findling, Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 124, 1533-1540 (2009).