Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

Abstract

Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) and histamine (HA) participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA). Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD.

Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact

“…Dopamine (DA) neurotransmission is required for motor control, learning, memory, motivation, and reward (Wise 2004;Iversen and Iversen 2007). DAergic dysregulation is evidenced in numerous neuropsychiatric disorders, including attentiondeficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, addiction, and Parkinson's disease (PD) (Hyman, Malenka, and Nestler 2006;Sharma and Couture 2014;Ashok et al 2017;Howes et al 2017;Eissa et al 2018;Geibl, Henrich, and Oertel 2019). DA signaling is tightly controlled by the presynaptic dopamine transporter (DAT), which rapidly clears synaptically released DA.…”

Clustering by phenotype and genome-wide association study in autism

“…In addition to phenotype and genotype heterogeneities, ASD shows heterogeneous responses to interventions. Several kinds of pharmacological treatments are suggested, but the effects of these treatments are controversial (7).…”

Differential serotonin transporter (5‐HTT) and 5‐HT2 receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy

“…Peripheral hyperserotonemia was the earliest demonstrated neurochemical change in individuals with autism spectrum disorders (ASD) (Schain and Freedman ) and has since become the best replicated biomarker, as recent meta‐analyses conclude that hyperserotonemia is present in 25–45% of the autism population (Gabriele et al ; Chen et al ; Eissa et al ). Furthermore, whole blood maternal serotonin levels during pregnancy are associated with altered cognitive abilities and core neurodevelopmental outcomes in offspring with ASD (Montgomery et al ).…”