Abstract
Sertraline is one among several selective serotonin reuptake inhibitors (SSRIs) that exhibited improvement of language development in Autism Spectrum Disorder (ASD); however, the molecular mechanism has not been elucidated. A double blind, randomized, 6-month, placebo-controlled, clinical trial of low-dose sertraline in children ages (3–6 years) with ASD was conducted at the UC Davis MIND Institute. It aimed at evaluating the efficacy and benefit with respect to early expressive language development and global clinical improvement. This study aimed to identify molecular biomarkers that might be key players in the serotonin pathway and might be predictive of a clinical response to sertraline. Fifty eight subjects with the diagnosis of ASD were randomized to sertraline or placebo. Eight subjects from the sertraline arm and five from the placebo arm discontinued from the study. Furthermore, four subjects did not have a successful blood draw. Hence, genotypes for 41 subjects (20 on placebo and 21 on sertraline) were determined for several genes involved in the serotonin pathway including the serotonin transporter-linked polymorphic region (5-HTTLPR), the tryptophan hydroxylase 2 (TPH2), and the Brain-Derived Neurotrophic Factor (BDNF). In addition, plasma levels of BDNF, Matrix metallopeptidase 9 (MMP-9) and a selected panel of cytokines were determined at baseline and post-treatment. Intent-to-treat analysis revealed several primary significant correlations between molecular changes and the Mullen Scales of Early Learning (MSEL) and Clinical Global Impression Scale – Improvement (CGI-I) of treatment and control groups but they were not significant after adjustment for multiple testing. Thus, sertraline showed no benefit for treatment of young children with ASD in language development or changes in molecular markers in this study. These results indicate that sertraline may not be beneficial for the treatment of children with ASD; however, further investigation of larger groups as well as longer term follow-up studies are warranted.
Highlights
According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, version-5, Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in two domains: (1) communication and social interaction and (2) restricted, repetitive, and stereotyped patterns of behaviors and interests (APA, 2013)
Plasma samples derived from age and gender matched control children were utilized for measuring Brain-Derived Neurotrophic Factor (BDNF) and Matrix metallopeptidase 9 (MMP-9) levels for comparison
In this study we investigated the predictive efficacy of molecular biomarkers of sertraline, including BDNF, MMP-9, TPH-2 and cytokines to determine whether sertraline normalizes the expression of any of these genes in young children with ASD
Summary
According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, version-5, Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in two domains: (1) communication and social interaction and (2) restricted, repetitive, and stereotyped patterns of behaviors and interests (APA, 2013). 30% of individuals with ASD require psychological and psychiatric treatments for behavioral problems including hyperactivity, impulsivity, inattention, aggression, property destruction, self-injury, mood disorders, psychosis, and tic disorders (Lecavalier, 2006; Butler et al, 2012). Several neuroimaging and genetic studies indicate dysregulation of serotonin in the pathogenesis of ASD. Dysregulation in serotonin is associated with aggression, anxiety, mood, impulsivity, sleep, ingestion behavior, and reward systems (Cook and Leventhal, 1996; Chugani, 2002). Reduction in uptake of tryptophan (the precursor of 5-HT) and 5-HT synthesis, decreased 5-HT2A receptor binding, and binding capacity of 5-HT transporter molecules (SERT, 5-HTT) have been detected in autistic brain using positron emission tomography and single-photon emission computed tomography (Chugani et al, 1999; Chandana et al, 2005; Makkonen et al, 2008; Goldberg et al, 2009; Oblak et al, 2013)
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