A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders

Díaz‐Caneja, Covadonga M.; State, Matthew W.; Hagerman, Randi J.; Jacquemont, Sébastien; Marı́n, Oscar; Bagni, Claudia; Umbricht, Daniel; Simonoff, Emily; Andrés-Trelles, F; Kaale, Anett; Pandina, Gahan; Gomez‐Mancilla, Baltazar; Wang, P P; Cusak, J; Siafis, Spyridon; Leucht, Stefan; Parellada, Mara; Loth, Eva; Charman, Tony; Buitelaar, Jan K.; Murphy, Declan; Arango, Celso

doi:10.1016/j.euroneuro.2021.02.020

Cited by 34 publications

(26 citation statements)

References 307 publications

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“…Neurodevelopmental disorders (NDDs) are severe clinical consequences of abnormal brain development [ 1 ]. The phenotypic manifestations of NDDs include sleep disorders, learning disabilities, delayed ascertainment of developmental milestones, intellectual disabilities, behavioral disturbances and epilepsy among others.…”

Section: Introductionmentioning

confidence: 99%

Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome

et al. 2021

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Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children’s Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies—Phelan–McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1–46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1–64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1–17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome

et al. 2021

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“…Medications with different mechanisms of action have been examined in randomized controlled trials (RCTs) [ 3 – 5 ], and some of them have been found efficacious for associated symptoms, such as aripiprazole, risperidone and haloperidol for irritability, methylphenidate, atomoxetine, clonidine and guanfacine for attention-deficit/hyperactivity disorder (ADHD) symptoms and melatonin for sleep disorders [ 2 , 6 ]. However, prior late-stage clinical trials failed to identify efficacious treatments for the core symptoms of neurodevelopmental disorders [ 5 , 7 ]. Despite lack of clear evidence in efficacy, about half of the individuals with ASD receive psychotropic drugs [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite lack of clear evidence in efficacy, about half of the individuals with ASD receive psychotropic drugs [ 8 ]. The current synthesis of literature is restricted to medication classes or target symptoms [ 9 – 19 ], hence failing to combine the huge amount of recently conducted RCTs [ 3 – 5 ]. In order to better inform clinical practice and identify medications potentially efficacious for ASD, we combined evidence from pharmacological and dietary-supplement ASD trials in a network meta-analysis.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

et al. 2022

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Background There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. Methods We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. Results We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. Limitations Most of the studies were inadequately powered (sample sizes of 20–80 participants), with short duration (8–13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. Conclusions Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

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“…There is still no approved medication for the core symptoms of autism spectrum disorder (ASD) (i.e., social communication difficulties and repetitive restricted behaviors [ 1 ]), yet a large number of medications are being investigated in an increasing number of randomized controlled trials (RCTs), with this number increasing sharply after 2008 [ 2 ]. Many of these trials are pilot trials with small sample sizes and cannot provide definite answers, and given their increasing number, there is an ongoing need to comprehensively synthesize their evidence [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder

et al. 2021

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Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence. Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland–Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis. Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [−8.1%, 16.74%]; no subgroup differences χ2 = 1.24, p-value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [−0.87, 1.04]; χ2 = 0.02, p-value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used. Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed.

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A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders

Cited by 34 publications

References 307 publications

Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome

Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder

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