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

Provenzani, Umberto; Fusar-Poli, Laura; Brondino, Natascia; Damiani, Stefano; Vercesi, Marco; Meyer, Nicholas; Rocchetti, Matteo; Politi, Pierluigi

doi:10.1177/1362361319854641

Cited by 57 publications

(46 citation statements)

References 58 publications

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“…Standardized measures were used only in a few studies, and in some cases, the authors reported only the proportion of improvement for each symptom. This important issue confirms the findings of a recent systematic review of 406 clinical trials [ 85 ], which pointed out that the tools used in autism research are heterogeneous and non-specific. This fragmentation might significantly hamper the comparison between studies and the understanding of the real effectiveness of cannabinoids in the ASD population.…”

Section: Discussionsupporting

confidence: 86%

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

et al. 2020

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The etiopathogenesis of autism spectrum disorder (ASD) remains largely unclear. Among other biological hypotheses, researchers have evidenced an imbalance in the endocannabinoid (eCB) system, which regulates some functions typically impaired in ASD, such as emotional responses and social interaction. Additionally, cannabidiol (CBD), the non-intoxicating component of Cannabis sativa, was recently approved for treatment-resistant epilepsy. Epilepsy represents a common medical condition in people with ASD. Additionally, the two conditions share some neuropathological mechanisms, particularly GABAergic dysfunctions. Hence, it was hypothesized that cannabinoids could be useful in improving ASD symptoms. Our systematic review was conducted according to the PRISMA guidelines and aimed to summarize the literature regarding the use of cannabinoids in ASD. After searching in Web of KnowledgeTM, PsycINFO, and Embase, we included ten studies (eight papers and two abstracts). Four ongoing trials were retrieved in ClinicalTrials.gov. The findings were promising, as cannabinoids appeared to improve some ASD-associated symptoms, such as problem behaviors, sleep problems, and hyperactivity, with limited cardiac and metabolic side effects. Conversely, the knowledge of their effects on ASD core symptoms is scarce. Interestingly, cannabinoids generally allowed to reduce the number of prescribed medications and decreased the frequency of seizures in patients with comorbid epilepsy. Mechanisms of action could be linked to the excitatory/inhibitory imbalance found in people with ASD. However, further trials with better characterization and homogenization of samples, and well-defined outcomes should be implemented.

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Section: Discussionsupporting

confidence: 86%

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

et al. 2020

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show abstract

“…Standardized measures were used only in few studies, and in some cases, authors have reported only the proportion of improvement for each symptom. This important issue confirms the findings of a recent systematic review of 406 clinical trials [81], which has pointed out that the tools used in autism research are heterogeneous and non-specific. This fragmentation may significantly hamper the comparison between studies and the understanding of the real effectiveness of cannabinoids in the ASD population.…”

Section: Limitation: Heterogeneity Of Studiessupporting

confidence: 85%

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

Fusar-Poli

Cavone

Tinacci

et al. 2020

Preprint

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The etiopathogenesis of autism spectrum disorder (ASD) remains largely unclear. Among other biological hypotheses, researchers have evidenced an imbalance in the endocannabinoid (eCB) system, which regulates some functions typically impaired in ASD, such as emotional responses and social interaction. Also, cannabidiol (CBD), the non-intoxicating component of Cannabis sativa, has been recently approved for treatment-resistant epilepsy. Seizures represent frequent medical comorbidities of ASD and could be responsible for the onset or worsening of behavioral problems. Thus, it has been hypothesized that cannabinoids could be useful in improving some ASD symptoms. Our systematic review was conducted according to the PRISMA guidelines and aimed to summarize the literature regarding the use of cannabinoids in ASD. After searching in Web of KnowledgeTM, PsycINFO, and Embase, we included ten studies (eight papers and two abstracts). Four ongoing trials were retrieved in ClinicalTrials.gov. Findings are promising, as cannabinoids appeared to improve problem behaviors, sleep, hyperactivity, and communication deficits, with limited cardiac and metabolic side effects. Interestingly, they generally allowed to reduce the number of prescribed medications and decreased the frequency of seizures in epileptic patients. Mechanisms of action could be linked to the excitatory/inhibitory imbalance found in people with ASD. However, further trials need to be implemented with better characterization and homogenization of samples, and well-defined outcomes.

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“…In addition, many of the existing scales were not designed to measure change but rather as screening (e.g., SRS [ 31 ]) or diagnostic tools (CARS [ 32 ] and ADOS [ 78 ]), and efforts have been made for their improvement and adaptation, such as the ADOS calibrated severity score [ 79 ]. Given the lack of optimal scales, CGI has been extensively used and it is recommended for all trials irrespective of their target in order to investigate global autism symptoms and incorporate both core and associated symptoms [ 80 , 81 ]. However, the anchoring system of CGI should be clearly reported, since it could vary materially among trials with different target symptoms (Table-S).…”

Section: Discussionmentioning

confidence: 99%

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

et al. 2020

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Background: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. Methods: We searched ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a randomeffects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317. Results: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = − 0.32, 95% CI [− 0.39, − 0.25], in repetitive behaviors − 0.23[− 0.32, − 0.15] and in scales measuring overall core symptoms − 0.36 [− 0.46, − 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. Limitations: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers.

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

Cited by 57 publications

References 58 publications

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

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