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A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome

Greiss Hess, Laura PhD, OTR/L; Fitzpatrick, Sarah E. BS; Nguyen, Danh V. PhD; Chen, Yanjun MS; Gaul, Kimberly N. BS; Schneider, Andrea PhD; Lemons Chitwood, Kerrie PhD, CCC-SLP; Eldeeb, Marwa Abd Al Azaim MD; Polussa, Jonathan BS; Hessl, David PhD; Rivera, Susan PhD; Hagerman, Randi J. MD

Journal of Developmental & Behavioral Pediatrics: October 2016 - Volume 37 - Issue 8 - p 619–628
doi: 10.1097/DBP.0000000000000334
Original Articles
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Objective: Observational studies and anecdotal reports suggest that sertraline, a selective serotonin reuptake inhibitor, may improve language development in young children with fragile X syndrome (FXS).

Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS aged 2 to 6 years.

Results: Eighty-one subjects were screened for eligibility, and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and 3 from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language (EL) age equivalent and Clinical Global Impression Scale—Improvement. However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred.

Conclusion: This randomized controlled trial of 6 months of sertraline treatment showed no primary benefit with respect to early EL development and global clinical improvement. However, in secondary exploratory analyses, there were significant improvements seen on motor and visual perceptual subtests, the cognitive T score sum on the MSEL, and on one measure of social participation on the Sensory Processing Measure—Preschool. Furthermore, post hoc analysis found significant improvement in early EL development as measured by the MSEL among children with autism spectrum disorder on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but the authors do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

*Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis Medical Center, Sacramento, CA;

Department of Occupational Therapy, Dominican University of California, San Rafael, CA;

Department of Neuroscience, The Ohio State University, Columbus, OH;

§Department of Medicine, University of California, Irvine School of Medicine, Orange, CA;

Institute for Clinical and Translational Science, University of California, Irvine, CA;

Department of Psychology, University of California, Davis, Davis, CA;

**Department of Pediatrics, University of California, Davis Medical Center, Sacramento, CA;

††Department of Special Education, California State University, Monterey Bay, CA;

‡‡Department of Psychiatry and Behavioral Sciences, University of California, Davis Medical Center, Sacramento, CA.

Address for reprints: Randi J. Hagerman, MD, MIND Institute, University of California, Davis Medical Center, 2825 50th St, Sacramento, CA 95817; e-mail: rjhagerman@ucdavis.edu.

This project was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number R40MC22641. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. Other support includes, the MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125), and the National Fragile X Foundation. This publication was also made possible by grants UL1 TR000002 and linked award TL1 TR000133, UL1 TR000153, and UL1 TR001414 from the National Center for Advancing Translational Sciences, National Institutes of Health, through the Biostatistics, Epidemiology, and Research Design Unit.

Disclosure: R. J. Hagerman has consulted with Roche/Genentech, Novartis, Alcobra, Zynerba, and Neuren, and she has been funded by Roche, Novartis, Alcobra, and Neuren to carry out treatment studies in fragile X syndrome. The remaining authors declare no conflict of interest.

L. Greiss Hess and S. E. Fitzpatrick contributed equally to this study.

See the related commentary by Desmond Kelly on page 657.

Received December , 2015

Accepted May , 2016

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