A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder

Laura A Potter, Danielle A Scholze, Hazel Maridith B Biag, Andrea Schneider, Yanjun Chen, Danh V Nguyen, Akash Rajaratnam, Susan M Rivera, Patrick S Dwyer, Flora Tassone, Reem R Al Olaby, Nimrah S Choudhary, Maria J Salcedo-Arellano, Randi J Hagerman, Laura A Potter, Danielle A Scholze, Hazel Maridith B Biag, Andrea Schneider, Yanjun Chen, Danh V Nguyen, Akash Rajaratnam, Susan M Rivera, Patrick S Dwyer, Flora Tassone, Reem R Al Olaby, Nimrah S Choudhary, Maria J Salcedo-Arellano, Randi J Hagerman

Abstract

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799.

Keywords: autism spectrum disorder; controlled trial; nonsyndromic autism spectrum disorder; sertraline; targeted treatment.

Copyright © 2019 Potter, Scholze, Biag, Schneider, Chen, Nguyen, Rajaratnam, Rivera, Dwyer, Tassone, Al Olaby, Choudhary, Salcedo-Arellano and Hagerman.

Figures

Figure 1
Figure 1
CONSORT flow diagram. CONSORT, Consolidated Standards of Reporting Trials.
Figure 2
Figure 2
Clinical Global Impression Scale—Improvement at end-of-treatment. CGI-I, Clinical Global Impression Scale—Improvement.

References

    1. Youssef EA, Berry-Kravis E, Czech C, Hagerman RJ, Hessl D, Wong CY, et al. Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results. Neuropsychopharmacology (2018) 43(3):503–12. 10.1038/npp.2017.177
    1. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature (2014) 515(7526):209–15. 10.1038/nature13772
    1. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. Mmwr Surveill Summ (2018) 67(6):1–23. 10.15585/mmwr.ss6706a1
    1. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature (2014) 515:216. 10.1038/nature13908
    1. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron (2012) 74(2):285–99. 10.1016/j.neuron.2012.04.009
    1. Lo SQ, Sng JCG, Augustine GJ. Defining a critical period for inhibitory circuits within the somatosensory cortex. Sci Rep (2017) 7(1):7271–. 10.1038/s41598-017-07400-8
    1. Reinhard SM, Razak K, Ethell IM. A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders. Front Cell Neurosci (2015) 9:280–. 10.3389/fncel.2015.00280
    1. Su T, Fan H-X, Jiang T, Sun W-W, Den W-Y, Gao M-M, et al. Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology (2011) 215(2):291–300. 10.1007/s00213-010-2130-2
    1. Ismail FY, Fatemi A, Johnston MV. Cerebral plasticity: Windows of opportunity in the developing brain. Eur J Paediatric Neurology (2017) 21(1):23–48. 10.1016/j.ejpn.2016.07.007
    1. Meredith RM. Sensitive and critical periods during neurotypical and aberrant neurodevelopment: A framework for neurodevelopmental disorders. Neurosci Biobehavioral Rev (2015) 50:180–8. 10.1016/j.neubiorev.2014.12.001
    1. LeBlanc JJ, Fagiolini M. Autism: a "critical period" disorder? Neural plasticity (2011) 2011:921680–. 10.1155/2011/921680
    1. He Q, Arroyo ED, Smukowski SN, Xu J, Piochon C, Savas JN, et al. Mol Psychiatry (2018). 10.1038/s41380-018-0048-y
    1. Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics (2010) 125(1):e17–23. 10.1542/peds.2009-0958
    1. Dawson G, Jones EJH, Merkle K, Venema K, Lowy R, Faja S, et al. Early behavioral intervention is associated with normalized brain activity in young children with autism. J Am Acad Child Adolesc Psychiatry (2012) 51(11):1150–9. 10.1016/j.jaac.2012.08.018
    1. Chandana SR, Behen ME, Juhasz C, Muzik O, Rothermel RD, Mangner TJ, et al. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci (2005) 23(2-3):171–82. 10.1016/j.ijdevneu.2004.08.002
    1. Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism (2013) 4(1):16. 10.1186/2040-2392-4-16
    1. Bianchi P, Ciani E, Guidi S, Trazzi S, Felice D, Grossi G, et al. Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. J Neurosci (2010) 30(26):8769–79. 10.1523/JNEUROSCI.0534-10.2010
    1. Mei F, Nagappan G, Ke Y, Sacktor TC, Lu B. BDNF Facilitates L-LTP Maintenance in the Absence of Protein Synthesis through PKMζ. PloS One (2011) 6(6):e21568. 10.1371/journal.pone.0021568
    1. Greenberg ME, Xu B, Lu B, Hempstead BL. New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci: Off J Soc Neurosci (2009) 29(41):12764–7. 10.1523/JNEUROSCI.3566-09.2009
    1. Qin XY, Cheng Y. Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder-Reply. JAMA Pediatr (2017) 171(5):493. 10.1001/jamapediatrics.2017.0110
    1. Jansson LC, Louhivuori L, Wigren HK, Nordström T, Louhivuori V, Castrén ML, et al. Brain-derived neurotrophic factor increases the motility of a particular N-methyl-d-aspartate /GABA-responsive subset of neural progenitor cells. Neuroscience (2012) 224:223–34. 10.1016/j.neuroscience.2012.08.038
    1. Lauterborn JC, Rex CS, Kramár E, Chen LY, Pandyarajan V, Lynch G, et al. Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome. J Neurosci (2007) 27(40):10685–94. 10.1523/JNEUROSCI.2624-07.2007
    1. Abdallah MW, Michel TM. Matrix metalloproteinases in autism spectrum disorders. J Mol Psychiatry (2013) 1(1):16. 10.1186/2049-9256-1-16
    1. Hasan M, Seo JE, Rahaman KA, Kang MJ, Jung BH, Kwon OS. Increased levels of brain serotonin correlated with MMP-9 activity and IL-4 levels resulted in severe experimental autoimmune encephalomyelitis (EAE) in obese mice. Neuroscience (2016) 319:168–82. 10.1016/j.neuroscience.2016.01.045
    1. Saghazadeh A, Rezaei N. Brain-Derived neurotrophic factor levels in autism: a systematic review and meta-analysis. J Autism Dev Disord (2017) 47(4):1018–29. 10.1007/s10803-016-3024-x
    1. Williams K, Brignell A, Randall M, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database systematic Rev (2013) (8), Cd004677. 10.1002/14651858.CD004677.pub3.
    1. Winarni TI, Schneider A, Borodyanskara M, Hagerman RJ. Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile x syndrome. Case Rep Genet (2012) 2012:280813. 10.1155/2012/280813
    1. Chugani DC, Chugani HT, Wiznitzer M, Parikh S, Evans PA, Hansen RL, et al. Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial. J Pediatr (2016) 170:45–53. 10.1016/j.jpeds.2015.11.033
    1. Greiss Hess L, Fitzpatrick SE, Nguyen DV, Chen Y, Gaul KN, Schneider A, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome. J Dev Behav Pediatr (2016) 37(8):619–28. 10.1097/DBP.0000000000000334
    1. Yoo K, Burris J, Gaul K, Hagerman R, Rivera S. Low-Dose Sertraline Improves Receptive Language in Children with Fragile X Syndrome when Eye Tracking Methodology is used to Measure Treatment Outcome. J Psychol Clin Psychiatry (2017) 7(6). 10.15406/jpcpy.2017.07.00465.
    1. AlOlaby RR, Sweha SR, Silva M, Durbin-Johnson B, Yrigollen CM, Pretto D, et al. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome. Brain Dev (2017) 39(6):483–92. 10.1016/j.braindev.2017.01.012
    1. Tassone F, Choudhary NS, Tassone F, Durbin-Johnson B, Hansen R, Hertz-Picciotto I, et al. Identification of expanded alleles of the FMR1 Gene in the CHildhood Autism Risks from Genes and Environment (CHARGE) study. J Autism Dev Disord (2013) 43(3):530–9. 10.1007/s10803-012-1580-2
    1. Dink J, Ferguson B, (2015). eyetrackingR: An R Library for Eye-Tracking Data Analysis.
    1. Hoenig JM, Heisey DM. The Abuse of Power. Am Statistician (2001) 55(1):19–24. 10.1198/000313001300339897
    1. Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest (2016) 126(6):2221–35. 10.1172/JCI84877
    1. Lucchelli JP, Bertschy G. Low-Dose Fluoxetine in Four Children with Autistic Spectrum Disorder Improves Self-Injurious Behavior, ADHD-Like Symptoms, and Irritability. Case Rep Psychiatry (2018) 2018:6278501–. 10.1155/2018/6278501
    1. Coleman DM, Adams JB, Anderson AL, Frye RE. Rating of the Effectiveness of 26 Psychiatric and Seizure Medications for Autism Spectrum Disorder: Results of a National Survey. J Child Adolesc Psychopharmacology (2019) 29(2):107–23. 10.1089/cap.2018.0121
    1. Basson MA, Wingate RJ. Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences. Front neuroanatomy (2013) 7:29–. 10.3389/fnana.2013.00029
    1. Baer S, Afenjar A, Smol T, Piton A, Gérard B, Alembik Y. Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: a study of 33 French cases. Clin Genet (2018) 94(1):141–52. 10.1111/cge.13254
    1. Ziats MN, Goin-Kochel RP, Berry LN, Ali M, Ge J, Guffey D, et al. The complex behavioral phenotype of 15q13.3 microdeletion syndrome. Genet In Med (2016) 18:1111. 10.1038/gim.2016.9
    1. Wenger TL, Miller JS, DePolo LM, de Marchena AB, Clements CC, Emanuel BS, et al. 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening. Mol Autism (2016) 7:27. 10.1186/s13229-016-0090-z
    1. Beesdo K, Knappe S, Pine DS. Anxiety and anxiety disorders in children and adolescents: developmental issues and implications for DSM-V. Psychiatr Clinics North America (2009) 32(3):483–524. 10.1016/j.psc.2009.06.002
    1. Salum GA, Desousa DA, Rosario MC, Pine DS, Manfro GG. Pediatric anxiety disorders: from neuroscience to evidence-based clinical practice. In: Revista brasileira de psiquiatria., vol. 35 Suppl 1 , Sao Paulo, Brazil: (2013). p. S03–21. 10.1590/1516-4446-2013-S108.
    1. White SW, Oswald D, Ollendick T, Scahill L. Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol review (2009) 29(3):216–29. 10.1016/j.cpr.2009.01.003
    1. Kerns CM, Kendall PC, Berry L, Souders MC, Franklin ME, Schultz RT, et al. Traditional and atypical presentations of anxiety in youth with autism spectrum disorder. J Autism Dev Disord (2014) 44(11):2851–61. 10.1007/s10803-014-2141-7
    1. Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord (2011) 3(1):57–67. 10.1007/s11689-010-9067-y
    1. Roberts JE, Ezell JE, Fairchild AJ, Klusek J, Thurman AJ, McDuffie A, et al. Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder. Am J Med Genet Part B: Neuropsychiatr Genet (2018) 177(7):665–75. 10.1002/ajmg.b.32674
    1. Ezell J, Hogan A, Fairchild A, Hills K, Klusek J, Abbeduto L, et al. Prevalence and Predictors of Anxiety Disorders in Adolescent and Adult Males with Autism Spectrum Disorder and Fragile X Syndrome. J Autism Dev Disord (2018) 49(3):1131–41. 10.1007/s10803-018-3804-6
    1. Abbeduto L, Thurman AJ, McDuffie A, Klusek J, Feigles RT, Ted Brown W, et al. ASD Comorbidity in Fragile X Syndrome: Symptom Profile and Predictors of Symptom Severity in Adolescent and Young Adult Males. J Autism Dev Disord (2019) 49(3):960–77. 10.1007/s10803-018-3796-2
    1. Miller LJ, McIntosh DN, McGrath J, Shyu V, Lampe M, Taylor AK, et al. Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report. Am J Med Genet (1999) 83(4):268–79. 10.1002/(SICI)1096-8628(19990402)83:4<268::AID-AJMG7>;2-K

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