Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions

McCracken, James T.; Anagnostou, Evdokia; Arango, Celso; Dawson, Geraldine; Farchione, Tiffany; Mantua, Valentina; McPartland, James C.; Murphy, Declan; Pandina, Gahan; Veenstra‐VanderWeele, Jeremy; Isctm,

doi:10.1016/j.euroneuro.2021.05.010

Cited by 34 publications

(21 citation statements)

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“…In ASD intervention research, there remains a lack of validated biomarkers that can be used to predict intervention outcomes ( 59 ). Future studies with larger samples should attempt to both replicate these findings and further parse these constructs to move closer to “precision medicine” efforts to individualize intervention and predict which adolescents are most likely to benefit from PEERS.…”

Section: Discussionmentioning

confidence: 99%

Investigating Changes in Reward-Related Neural Correlates After PEERS Intervention in Adolescents With ASD: Preliminary Evidence of a “Precision Medicine” Approach

et al. 2021

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Background: The Social Motivation Hypothesis proposes that individuals with autism spectrum disorder (ASD) experience social interactions as less rewarding than their neurotypical (TD) peers, which may lead to reduced social initiation. Existing studies of the brain's reward system in individuals with ASD report varied findings for anticipation of and response to social rewards. Given discrepant findings, the anticipation of and response to social rewards should be further evaluated, particularly in the context of intervention outcome. We hypothesized that individual characteristics may help predict neural changes from pre- to post-intervention.Methods: Thirteen adolescents with ASD received the Program for the Education and Enrichment of Relational Skills (PEERS) intervention for 16 weeks; reward-related EEG was collected before and after intervention. Fourteen TD adolescents were tested at two timepoints but did not receive intervention. Event-related potentials were calculated to measure anticipation of (stimulus-preceding negativity; SPN) and response to (reward-related positivity; RewP) social and non-social rewards. Additionally, measures of social responsiveness, social skills, and intervention-engagement were collected. Group differences were analyzed as well as individual differences using prediction models.Result: Parent-reported social responsiveness and social skills improved in adolescents with ASD after participation in PEERS. ASD adolescents displayed marginally decreased anticipation of social rewards at post-intervention compared to pre-intervention. Regression models demonstrated that older adolescents and those with lower parent-reported social motivation prior to participation in PEERS displayed marginally increased social reward anticipation (more robust SPN) from pre- to post-intervention. Participants who displayed more parent-reported social motivation before intervention and were more actively engaged in the PEERS intervention evidenced increased social reward processing (more robust RewP) from pre- to post-intervention.Conclusion: Findings suggest that there may be differences in saliency between wanting/anticipating social rewards vs. liking/responding to social rewards in individuals with ASD. Our findings support the hypothesis that identification of individual differences may predict which adolescents are poised to benefit the most from particular interventions. As such, reported findings set the stage for the advancement of “precision medicine.” This investigation is a critical step forward in our ability to understand and predict individual response to interventions in individuals with ASD.

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Section: Discussionmentioning

confidence: 99%

Investigating Changes in Reward-Related Neural Correlates After PEERS Intervention in Adolescents With ASD: Preliminary Evidence of a “Precision Medicine” Approach

et al. 2021

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“…Currently, no medication is approved for the core symptoms of ASD [ 39 ]. However, about half of the individuals with ASD receive psychotropic drugs, mainly for associated symptoms, such as antipsychotics (median prevalence of 18.1%), ADHD medications (16.6%), antidepressants (17.2%), antiepileptics/mood-stabilizers and sleep medication [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our review identified a considerable number of experimental medications (Fig. 3 ) with diverse mechanisms of action, which discussion is out of the scope of this review (e.g., see [ 39 , 76 – 79 ]). The majority of them were investigated exclusively in children/adolescents, except for oxytocin and balovaptan.…”

Section: Discussionmentioning

confidence: 99%

“…The co-primary outcomes were the change in core symptoms measured with validated rating scales: (1) social-communication difficulties (SCD, e.g., ABC-L/SW [ 34 ] or VABS-Socialization [ 35 ]), (2) repetitive behaviors (RB, e.g., ABC-S [ 34 ] or CYBOCS-PDD [ 36 ]), and (3) overall core symptoms (OCS, e.g., SRS [ 37 ] or CARS [ 38 ]). There is yet no optimal outcome measure [ 39 ], and we accepted a wide range of validated scales, giving preference to clinician-ratings and to the commonly used scales mentioned above, similar to our previous review [ 4 ] (Additional file 1 : eAppendix-5.3).…”

Section: Methodsmentioning

confidence: 99%

“…Individual-participant-data meta-analyses could further explore this issue and investigate the potential impact of participant-level covariates [ 108 ], e.g., age, sex, baseline severity of core and associated symptoms. In that direction, there are also efforts to disentangle the neurobiology of subgroups within ASD in order to facilitate biomarker stratification and more targeted treatments [ 39 , 77 ].…”

Section: Limitationsmentioning

confidence: 99%

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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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Budget Impact Analysis of Risperidone Use and Adverse Event Monitoring in Autism Spectrum Disorder in Brazil: Assessment of Theoretical Versus Real Data

Lopes,

Itria,

Lopes

2023

PharmacoEconomics Open

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Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions

Cited by 34 publications

References 324 publications

Investigating Changes in Reward-Related Neural Correlates After PEERS Intervention in Adolescents With ASD: Preliminary Evidence of a “Precision Medicine” Approach

Investigating Changes in Reward-Related Neural Correlates After PEERS Intervention in Adolescents With ASD: Preliminary Evidence of a “Precision Medicine” Approach

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

Budget Impact Analysis of Risperidone Use and Adverse Event Monitoring in Autism Spectrum Disorder in Brazil: Assessment of Theoretical Versus Real Data

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