Serotonin dysregulation in Fragile X Syndrome: implications for treatment

Hanson, Alicia C; Hagerman, Randi J.

doi:10.5582/irdr.2014.01027

Cited by 29 publications

(34 citation statements)

References 70 publications

(108 reference statements)

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“…Serotonin levels are abnormally low during early development (under 5 years) when synapse formation is most rapid, suggesting a developmental window in the first several years of life in which a selective serotonin reuptake inhibitor (SSRI) could be beneficial 24 . Evidence also shows that SSRIs stimulate brain-derived neurotrophic factor (BDNF) when given early in development in mouse models of Down syndrome 32 .…”

Section: Introductionmentioning

confidence: 99%

“…Evidence also shows that SSRIs stimulate brain-derived neurotrophic factor (BDNF) when given early in development in mouse models of Down syndrome 32 . Given the lack of maturation of synapses in FXS along with BDNF’s role in synaptic maturation, plasticity, and neurogenesis 33,34 , SSRIs are of particular interest for the treatment of FXS 24 .…”

Section: Introductionmentioning

confidence: 99%

“…This study emphasized the need for a controlled trial of low dose sertraline in young children with FXS. Sertraline may be an optimal SSRI for FXS because it is less activating than fluoxetine, has minimal interaction with the metabolism of other medications compared to other SSRIs, and prevents re-uptake of dopamine, particularly in the striatum 24,38–40 . Dopamine is dysregulated in FXS because of impaired dopamine-receptor modulation in cells lacking FMRP 41 .…”

Section: Introductionmentioning

confidence: 99%

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

Hess

Fitzpatrick

Nguyen

et al. 2016

J Dev Behav Pediatr

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Objective Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 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 three 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 age equivalent and Clinical Global Impression-Improvement (CGI-I). 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 six-months of sertraline treatment showed no primary benefit with respect to early expressive language 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. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hess

Fitzpatrick

Nguyen

et al. 2016

J Dev Behav Pediatr

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“…Thus, introducing selective serotonin reuptake inhibitors (SSRI) within the first years of life might be effective for those with ASD (5,6). Further, treatment with SSRIs early in postnatal development, paired with appropriate behavioral intervention may have the ability to stimulate neurogenesis and improve clinical symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, to alleviate maladaptive or disruptive behaviors and social deficits that manifest as anxiety-related symptoms, SSRIs are often prescribed to patients with FXS (7,8). According to medication usage surveys, approximately 50% of patients over five years old with FXS are prescribed an SSRI to treat in particular, anxiety, irritability, and socialization deficits (6–8). Similarly, several studies demonstrated positive responses in anxiety, mood and irritability, with minimal adverse effects in children with ASD, with and without FXS, following low-dose sertraline treatment (9–11).…”

Section: Introductionmentioning

confidence: 99%

Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome

AlOlaby

Sweha

Silva

et al. 2017

Brain and Development

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Objectives Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS. Methods Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24 to 68 months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models. Results A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P= 0.008) and the Cognitive T Score (P= 0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study. Conclusion This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings.

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