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Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

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.

SUBMITTER: Alolaby RR

PROVIDER: S-EPMC7174723 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

Alolaby Reem Rafik RR Jiraanont Poonnada P Durbin-Johnson Blythe B Jasoliya Mittal M Tang Hiu-Tung HT Hagerman Randi R Tassone Flora F

Frontiers in genetics 20200415

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 develop ...[more]

PMID: 32346385

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Project description:Autism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology.

Project description:Introduction: Clinicians working with children with autism spectrum disorder (ASD) occupy an important position between parents and the wide-ranging research findings. However, it is not widely known how clinicians view and experience ASD in children, even though their perspective has been shown to significantly influence their work. Material and methods: Sixteen physicians working with preschool children without a diagnosis of (intellectual or other) disability with a (presumed) diagnosis of ASD participated in a semistructured interview. They described their professional views on ASD, and how they experienced its use in their clinical practice. The data were analyzed by applying the qualitative research method of interpretative phenomenological analysis of the data through Nvivo 11. Results: The main topic of the interviewed physicians' views and experiences of ASD in a young child comprised three inductively established themes: 1) physicians' views on ASD are multifaceted but fit within their personal clinical styles; 2) the ASD diagnosis is a "descriptive" part of a clinical trajectory; and 3) ASD treatment is a mix of "standard" approaches and a personalized search. These physicians' perspectives on ASD are composed of multiple and sometimes ambiguous facets. However, their views are embedded in their personal clinical styles in general (i.e., beyond ASD) and are experienced as clinically "workable." With the aim of finding an adequate approach to the problems parents bring to their office, many interviewed physicians say that-complementary to or rather than a classificatory diagnosis-they prefer using a personalized "profile" of a child in a therapeutic "process." Conclusions: The interviewed physicians consider doubts and concerns to be an inherent part of their clinical work with ASD in young children, but do not experience this ambiguity as an obstacle to clinical care. These physicians deal with the multiplicity of their views on ASD by basing their eclectic views on their generally adopted clinical styles, and by selecting what works for them, and for the parents and child, from what they regard as the 'textbook knowledge' on ASD. We discuss the implications of these findings for translating research results to the clinic.

Dataset Information

Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

Publications

Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

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