Abstract
Increasing evidence suggests that the function of the GABAergic system is abnormally low in autism spectrum disorder (ASD). Baclofen, which functions as a selective agonist for GABAB receptors, does appear promising for the treatment of ASD. We conducted a 10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD. Sixty-four children (3–12 years) with moderate-to-severe irritability symptoms of ASD were included. We used the Aberrant Behavior Checklist-Community Edition (ABC-C) for the outcome measures on each of the follow-up visits (weeks 0, 5, and 10). Analysis of the combined data revealed significant improvement for all the ABC subscales (irritability: F = 51.644, df = 1.66, p < 0.001, lethargy: F = 39.734, df = 1.38, p < 0.001, stereotypic behavior: F = 25.495, df = 1.56, p < 0.001, hyperactivity: F = 54.135, df = 1.35, p < 0.001, and inappropriate speech: F = 19.277, df = 1.47, p = 0.004). Combined treatment with baclofen and risperidone exerted a greater effect on improvement of hyperactivity symptoms at both midpoint [Cohen’s d, 95% confidence interval (CI) = − 3.14, − 5.56 to − 0.72] and endpoint (d, 95% CI = − 4.45, − 8.74 to − 0.16) when compared with treatment with placebo plus risperidone. The two treatments achieved comparable results for other outcome measures. Our data support safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD.
Similar content being viewed by others
References
American Psychiatric A (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Publishing, Wachington, DC
Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M et al (2010) Brain serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gene Pychiatry 67(1):59–68
Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P et al (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Dugs 20(5):389–409
De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU (2011) Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry 26(3):144–158
Research Units on Pediatric Psychopharmacology Autism N (2005) Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months. Am J Psychiatry 62(7):1361–1369
Benarroch EE (2012) GABAB receptors: structure, functions, and clinical implications. Neurology 78(8):578–584
Cryan JF, Kaupmann K (2005) Don’t worry ‘B’happy!: a role for GABAB receptors in anxiety and depression. Trends Pharmacol Sci 26(1):36–43
Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD (2009) GABA A receptor downregulation in brains of subjects with autism. J Autism Dev Disord 39(2):223
Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD (2009) Expression of GABA B receptors is altered in brains of subjects with autism. Cerebellum 8(1):64–69
Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 31(6):537–543
Samaco RC, Hogart A, LaSalle JM (2005) Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Gen 14(4):483–492
Oblak AL, Gibbs TT, Blatt GJ (2010) Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem 114(5):1414–1423
Gaetz W, Bloy L, Wang DJ, Port RG, Blaskey L, Levy SE et al (2014) GABA estimation in the brains of children on the autism spectrum: measurement precision and regional cortical variation. Neuroimage 86:1–9
Mori T, Mori K, Fujii E, Toda Y, Miyazaki M, Harada M et al (2012) Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study. Brain Dev 34(8):648–654
Yip J, Soghomonian Jean J, Blatt Gene J (2009) Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res 2(1):50–59
Blatt GJ, Fatemi SH (2011) Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications. Anatomical Rec 294(10):1646–1652
Dhossche D, Applegate H, Abraham A, Maertens P, Bland L, Bencsath A et al (2002) Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monitor 8(8):PR1–PR6
Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben HM, Baker S et al (2015) GABA B receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in Two mouse models of autism. Neuropsychopharmacol 40(9):2228
Stoppel LJ, Kazdoba TM, Schaffler MD, Preza AR, Heynen A, Crawley JN et al (2018) R-baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11. 2 deletion mice. Neuropsychopharmacol 43(3):513
Erickson CA, Veenstra-Vanderweele JM, Melmed RD, McCracken JT, Ginsberg LD, Sikich L et al (2014) STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord 44(4):958–964
Veenstra-VanderWeele J, Cook EH, King BH, Zarevics P, Cherubini M, Walton-Bowen K et al (2017) Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacol 42(7):1390–1398
General Assembly of the World Medical Association (2014) World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent 81(3):14
Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub; 2013
Aman MG, Burrow WH, Wolford PL (1995) The Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homes. Am J Mental Retard 100(3):283–292
Lord C, Rutter M, Le Couteur A (1994) Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24(5):659–685
Aman MG, Singh NN, Stewart AW, Field CJ (1985) The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 89(5):485–491
Collins AL, Ma D, Whitehead PL, Martin ER, Wright HH, Abramson RK et al (2006) Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics 7(3):167–174
Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA et al (2000) Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Gen 96(1):43–48
McCauley JL, Olson LM, Delahanty R, Amin T, Nurmi EL, Organ EL et al (2004) A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genetics B Neuropsychiatric Gen 131(1):51–59
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H et al (2005) Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Gen 77(3):377–388
Collins AL, Ma D, Whitehead PL, Martin ER, Wright HH, Abramson RK et al (2006) Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics 7(3):167–174
Kim SA, Kim JH, Park M, Cho IH, Yoo HJ (2006) Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios. Neuropsychobiology 54(3):160–165
Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM (2007) 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Gen 16(6):691–703
Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hübner CA, Represa A et al (2006) Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314(5806):1788–1792
Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S et al (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343(6171):675
Wang DD, Kriegstein AR (2011) Blocking Early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex 21(3):574–587
Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al (2010) Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67(7):692–694
Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L et al (2007) Oxytocin increases retention of social cognition in autism. Biol Psychiatry 61(4):498–503
Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR et al (2003) Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmaco 28(1):193
Fatemi SH, Reutiman TJ, Folsom TD, Rooney RJ, Patel DH, Thuras PD (2010) mRNA and protein levels for GABA A α4, α5, β1 and GABA B R1 receptors are altered in brains from subjects with autism. J Autism Develop Disord 40(6):743–750
Laurence JA, Fatemi SH (2005) Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 4(3):206–210
DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res 187(2):207–220
DeLorey TM, Sahbaie P, Hashemi E, Li WW, Salehi A, Clark DJ (2011) Somatosensory and sensorimotor consequences associated with the heterozygous disruption of the autism candidate gene, Gabrb3. Behav Brain Res 216(1):36–45
Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V et al (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69(9):875–882
Banerjee A, Garcia-Oscos F, Roychowdhury S, Galindo LC, Hall S, Kilgard MP (2013) Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. Int J Neuropsychopharmacol 16(6):1309–1318
Bertelsen F, Moller A, Folloni D, Drasbek KR, Scheel-Kruger J, Landau AM (2017) Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats. Acta Neuropsychiatr 29(5):309–314
Han S, Tai C, Jones CJ, Scheuer T, Catterall WA (2014) Enhancement of inhibitory neurotransmission by GABAA receptors having alpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81(6):1282–1289
Nakamura T, Arima-Yoshida F, Sakaue F, Nasu-Nishimura Y, Takeda Y, Matsuura K et al (2016) PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking. Nat Commun 7:10861
Cohen BI (2002) Use of a GABA-transaminase agonist for treatment of infantile autism. Med Hypotheses 59(1):115–116
Kratsman N, Getselter D, Elliott E (2016) Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacol 102:136–145
Olmos-Serrano JL, Corbin JG, Burns MP (2011) The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci 33(5):395–403
Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B et al (1989) Intrathecal baclofen for severe spinal spasticity. New Engl J Med 320(23):1517–1521
Omari TI, Benninga MA, Sansom L, Butler RN, Dent J, Davidson GP (2006) Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J Pediatrics 149(4):468–474
Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA (2010) Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcoholism Clin Exp Res 34(11):1849–1857
Lal R, Sukbuntherng J, Tai EH, Upadhyay S, Yao F, Warren MS et al (2009) Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J Pharmacol Exp Therapeutics 330(3):911–921
Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR et al (2012) Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Translational Med 4(152):152ra28
Qin M, Huang T, Kader M, Krych L, Xia Z, Burlin T, Zeidler Z, Zhao T, Smith CB (2015) R-Baclofen reverses a social behavior deficit and elevated protein synthesis in a mouse model of fragile X syndrome. Int J Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyv034
Sinclair D, Featherstone R, Naschek M, Nam J, Du A, Wright S, Pance K, Melnychenko O, Weger R, Akuzawa S, Matsumoto M, Siegel SJ (2017) GABA-B Agonist baclofen normalizes auditory-evoked neural oscillations and behavioral deficits in the Fmr1 knockout mouse model of Fragile X syndrome. eNeuro. https://doi.org/10.1523/ENEURO.0380-16.2017
Berry-Kravis E, Hagerman R, Visootsak J, Budimirovic D, Kaufmann WE, Cherubini M et al (2017) Arbaclofen in fragile X syndrome: results of phase 3 trials. J Neurodevelop Disord 9:3
Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben HM, Baker S et al (2015) GABAB receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacol 40(9):2228–2239
Port RG, Gajewski C, Krizman E, Dow HC, Hirano S, Brodkin ES et al (2017) Protocadherin 10 alters gamma oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits. Neurobiol Dis 108:324–338
Acknowledgements
This study was funded by Tehran University of Medical Sciences and Health Services (Grant number: 32601).
Funding
This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant No: 32601).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Mahdavinasab, SM., Saghazadeh, A., Motamed-Gorji, N. et al. Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry 28, 1619–1628 (2019). https://doi.org/10.1007/s00787-019-01333-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00787-019-01333-5