6.12 Pharmacological Treatments for the Core Symptoms of Autism Spectrum Disorder: A Systematic Review

Abstract Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

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Improved symptoms following bumetanide treatment in children aged 3 to 6 years with autism spectrum disorder: a randomized, double-blind, placebo-controlled trial

10.1101/2020.09.18.20197640 ◽

2020 ◽

Author(s):

Yuan Dai ◽

Lingli Zhang ◽

Juehua Yu ◽

Xin Zhou ◽

Hua He ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Clinical Significance ◽

Controlled Trial ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Double Blind ◽

Global Improvement ◽

Double Blind Placebo ◽

The Core ◽

Core Symptoms

AbstractWith the drug therapy for the core symptoms of autism spectrum disorder (ASD) currently limited, here we reported a randomised, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3 to 6 years old. There were 120 children entered into the study and randomly assigned to either 0.5mg bumetanide or placebo. In the final sample, 119 received at least one dose of bumetanide (59 children) or placebo (60 children). The primary outcome was the score reduction of Childhood Autism Rating Scale (CARS) and the secondary outcomes were the score of Clinical Global Impressions Scale (CGI) -Global Improvement (CGI-I) at 3 months and the change from baseline to 3-month in Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with the decrease in insular GABA in the bumetanide group. In conclusion, this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD. However, the clinical significance remains uncertain and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.

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Pharmacotherapy of emotional and behavioral symptoms associated with autism spectrum disorder in children and adolescents

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2017.19.4/rfindling ◽

2017 ◽

Vol 19 (4) ◽

pp. 395-402 ◽

Cited By ~ 5

Keyword(s):

Autism Spectrum Disorder ◽

Selective Serotonin Reuptake Inhibitors ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Behavioral Symptoms ◽

Treatment Modalities ◽

The Core ◽

Patterns Of Behavior ◽

New Treatment ◽

Core Symptoms

Autism spectrum disorder (ASD) is characterized by impairment in social communication and restricted patterns of behavior. Although there is no pharmacological treatment approved by the US Food and Drug Administration (FDA) for the core symptoms of ASD, there is mounting support in the literature for the management of behavioral symptoms associated with this developmental disorder, in particular, irritability and hyperactivity. Aripiprazole and risperidone are currently approved by the FDA for the treatment of irritability in youth with ASD. Though not FDA-approved, methylphenidate and guanfacine are effective for the management of hyperactivity in children with ASD. Selective serotonin reuptake inhibitors are often used in clinical practice to target anxiety and compulsions; however, there is little evidence to support its use in this population. There is a great need for further research on the safety and efficacy of existing psychotropic medications in youth with ASD, as well as the development of new treatment modalities for the core and associated behavioral symptoms.

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Behavioral aspects and neurobiological properties underlying medical cannabis treatment in Shank3 mouse model of autism spectrum disorder

Translational Psychiatry ◽

10.1038/s41398-021-01612-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shani Poleg ◽

Emad Kourieh ◽

Angela Ruban ◽

Guy Shapira ◽

Noam Shomron ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Wide Spectrum ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Mutant Mice ◽

Medical Cannabis ◽

Neurodevelopmental Disease ◽

The Core ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication, and restricted and repetitive patterns of behavior, interests, or activities. These are often accompanied by intellectual disabilities. At present, there is no designated effective treatment for the core symptoms and co-morbidities of ASD. Recently, interest is rising in medical cannabis as a treatment for ASD, with promising clinical data. However, there is a notable absence of basic pre-clinical research in this field. In this study, we investigate the behavioral and biochemical effects of long-term oral treatment with CBD-enriched medical cannabis oil in a human mutation-based Shank3 mouse model of ASD. Our findings show that this treatment alleviates anxiety and decreases repetitive grooming behavior by over 70% in treated mutant mice compared to non-treated mutant mice. Furthermore, we were able to uncover the involvement of CB1 receptor (CB1R) signaling in the Avidekel oil mechanism, alongside a mitigation of cerebrospinal fluid (CSF) glutamate concentrations. Subsequently, RNA sequencing (RNA seq) of cerebellar brain samples revealed changes in mRNA expression of several neurotransmission-related genes post-treatment. Finally, our results question the relevancy of CBD enrichment of medical cannabis for treating the core symptoms of ASD, and emphasize the importance of the THC component for alleviating deficits in repetitive and social behaviors in ASD.

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Drug treatment of autism spectrum disorder and its comorbidities in children and adolescents

BJPsych Advances ◽

10.1192/apt.bp.115.014597 ◽

2016 ◽

Vol 22 (3) ◽

pp. 151-161 ◽

Cited By ~ 10

Author(s):

Paramala J. Santosh ◽

Jatinder Singh

Keyword(s):

Autism Spectrum Disorder ◽

Drug Treatment ◽

Children And Adolescents ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Comorbid Conditions ◽

The Core ◽

Drug Treatments ◽

Core Symptoms ◽

Underlying Pathogenesis

SummaryAutism spectrum disorder (ASD) is a complex, multifactorial disorder, the prevalence of which is rising. Specific biomarkers are yet to be identified for the classic ASD phenotypes, so despite treatment advances, most interventions focus on the comorbid disorders of ASD and have little impact on the underlying pathogenesis of the disorder. This article describes drug treatments that target the core symptoms of ASD and its comorbid conditions in children and adolescents. Difficulties and challenges encountered when treating the most frequent comorbidities are discussed, with emphasis on the safety, tolerability and efficacy of medications. In view of its widespread use, complementary and alternative medicine is also described.

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What are we targeting when we treat autism spectrum disorder? A systematic review of 406 clinical trials

Autism ◽

10.1177/1362361319854641 ◽

2019 ◽

Vol 24 (2) ◽

pp. 274-284 ◽

Cited By ~ 6

Author(s):

Umberto Provenzani ◽

Laura Fusar-Poli ◽

Natascia Brondino ◽

Stefano Damiani ◽

Marco Vercesi ◽

...

Keyword(s):

Systematic Review ◽

Autism Spectrum Disorder ◽

Clinical Trials ◽

Outcome Measures ◽

Rating Scale ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Social Responsiveness ◽

Comprehensive Overview ◽

Core Symptoms

The number of trials aimed at evaluating treatments for autism spectrum disorder has been increasing progressively. However, it is not clear which outcome measures should be used to assess their efficacy, especially for treatments which target core symptoms. The present review aimed to provide a comprehensive overview regarding the outcome measures used in clinical trials for people with autism spectrum disorder. We systematically searched the Web of KnowledgeSM database between 1980 and 2016 to identify published controlled trials investigating the efficacy of interventions in autism spectrum disorder. We included 406 trials in the final database, from which a total of 327 outcome measures were identified. Only seven scales were used in more than 5% of the studies, among which only three measured core symptoms (Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale, and Social Responsiveness Scale). Of note, 69% of the tools were used in the literature only once. Our systematic review has shown that the evaluation of efficacy in intervention trials for autism spectrum disorder relies on heterogeneous and often non-specific tools for this condition. The fragmentation of tools may significantly hamper the comparisons between studies and thus the discovery of effective treatments for autism spectrum disorder. Greater consensus regarding the choice of these measures should be reached.

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Treatment Effect of Bumetanide in Children With Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.751575 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tiantian Wang ◽

Ling Shan ◽

Chunyue Miao ◽

Zhida Xu ◽

Feiyong Jia

Keyword(s):

Systematic Review ◽

Autism Spectrum Disorder ◽

Therapeutic Effect ◽

Rating Scale ◽

Meta Analysis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Children With Asd ◽

Core Symptoms ◽

Positive Effect

Background: The therapeutic effect of bumetanide on autism spectrum disorder (ASD) seems to be controversial. To obtain better evidence on the efficacy of bumetanide, a systematic review and meta-analysis were performed.Methods: Randomized, placebo-controlled trials (RCTs) of bumetanide treatment in children with ASD were identified through systematic review from database inception to January 17, 2021. Subsequently, a meta-analysis was carried out to examine the effect of bumetanide on the severity of symptoms of ASD as assessed by the Childhood Autism Rating Scale (CARS) and Social Responsive Scale (SRS); core symptoms according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 of the American Psychiatric Association [social affect (SA), restricted, repetitive patterns of behavior, interests, or activities (RRB) and sensory symptoms]; and the therapeutic effect as assessed by Clinical Global Impressions-Efficacy (CGI-E).Results: In total, six RCTs involving 496 participants with ASD were identified in our study. The results showed that bumetanide could significantly improve the severity of the ASD symptoms measured by CARS and SRS. There was also evidence that bumetanide had positive effect on the core symptoms of ASD such as the SA and RRB, but there was no statistically significant effect on sensory symptoms. A significant positive effect on CGI-E scores in ASD patients was also observed.Conclusion: Our meta-analysis provided some support that bumetanide could improve the symptoms of children with ASD. However, additional large-scale longitudinal studies that provide clearer information and better control for confounding factors are needed to confirm our findings.

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Isolated Congenital Alacrima in a Child with Autism Spectrum Disorder

Integrative Pediatrics and Child Care ◽

10.18314/ipcc.v1i1.1339 ◽

2018 ◽

Vol 1 (1) ◽

pp. 49-53

Author(s):

Anutosh Shee

Keyword(s):

Autism Spectrum Disorder ◽

Tear Film ◽

Rare Condition ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Lacrimal Glands ◽

Emotional Stimuli ◽

Social Emotional ◽

The Core ◽

Core Symptoms

Isolated congenital absence of lacrimal glands is a very rare condition in children, only few cases were reported so far. Its symptoms can be quite variable depending on the other associated factors like absence of accessary lacrimal glands and/or salivary glands. Children with isolated absence of lacrimal gland can have normal tear film but lack tear production upon emotional stimuli. Although, alacrima can be a part of other rare syndromes, isolated absence has never been reported in the literature in association with autism spectrum disorder. In this article we present a case of alacrima with autism spectrum disorder, never reported in the literature to our knowledge. With increasing recognition of autism spectrum disorder, it is important to report common and rare association of other clinical co-morbidities as this may influence the initial presentation posing diagnostic challenges to the diagnosticians. In this case the lack of tears with the emotional stimuli was considered exclusively caused by the lack of social-emotional reciprocity, which is one of the core symptoms of autism spectrum disorder.

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