This project is a controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI), for the treatment of children with fragile X syndrome (FXS) between 24-68 months of age. FXS is the most common inherited cause of intellectual disabilities and the most common known genetic cause of autism. It can be recognized early with prenatal testing in utero and through newborn screening, although the majority of children are diagnosed by the pediatrician or geneticist at ages 2-3 years. Currently, there is no treatment that has demonstrated efficacy in young children with FXS. These children experience severe anxiety, sensory integration deficits, language delays and attention problems, and these issues usually emerge from 2 years of age onward. Our clinical experience and preliminary data showed that early use of sertraline (Zoloft), which increases serotonin levels at the synapse, helps with the development of language and alleviation of anxiety and behavioral problems in children with FXS. These effects appear to reduce the autistic symptoms, which we believe improves long term outcomes. These benefits are consistent with the research in autism where a deficit in the production of serotonin has been shown by Chugani, 2002 and Chandana, et al., 2005, suggesting that there is a developmental window in the first 5 to 6 years of life when an SSRI can be most beneficial. There is also emerging evidence regarding the stimulation of brain-derived neurotrophic factor (BDNF) and the stimulation of neurogenesis when an SSRI is given early on in the development of animal models of Down syndrome (Bianchi, et al., 2010).
This project will recruit 20 children with FXS per year for 3 years into a 6 month controlled trial of sertraline. Children will be randomized to either placebo or sertraline treatment. The dose of sertraline will be low beginning at 2.5 mg/ day for those 2 to 4 years and at 5 mg/day at 4 years to 5 years 8 months. Weekly phone calls to the family will document any side effects and the dose will be adjusted if necessary. Outcome measures will include the CGI, a visual analogue scale for the top 2 behavior problems, the Mullen Scales of Early Learning, the Preschool Language Scale, and novel outcome measures utilizing infra-red eyetracking. We also anticipate improvement on the Autism Diagnostic Observation Scale, especially social reciprocity, over the treatment period since clinically these children are less socially anxious with sertraline. We have also hypothesized that the children homozygous for the L allele of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) (L/L) will demonstrate a greater reduction of anxiety symptoms, improvement on language and social gaze behavior, and improvement in social reciprocity than those with the S (S/S or S/L) phenotype. The results of this study will significantly impact the field of FXS and we plan to expand these studies in the future to include those with idiopathic autism.
Listed is descending order by year published.
Hagerman RJ. Translating treatments from the laboratory to the clinic. In: Hagerman RJ, Hendren RL, eds. Treatment of neurodevelopmental disorders: targeting neurobiological mechanisms. New York, NY: Oxford University Press; 2014.
Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X Syndrome: implications for treatment. Intractable Rare Dis Res. 2014;3(4):110-117.
Developmental Disabilities, Special Health Care Needs, Autism