Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

Aman, Michael G.; Findling, Robert L.; Hardan, Antonio Y.; Hendren, Robert L.; Melmed, Raun D.; Kehinde-Nelson, Ola; Hsu, Hai An; Trugman, Joel M.; Palmer, Robert H.; Graham, Stephen M.; Gage, Allyson; Perhach, James L.; Katz, Ephraim

doi:10.1089/cap.2015.0146

Cited by 77 publications

(49 citation statements)

References 31 publications

(33 reference statements)

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“…Placebo responses are frequently reported in psychiatric clinical trials (30), including trials in ASD (19,22,31). Placebo responses can compromise trial outcomes, rendering medications that otherwise might have been deemed efficacious as "failed" interventions.…”

Section: Discussionmentioning

confidence: 99%

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

Parker

Oztan

Libove

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.A utism spectrum disorder (ASD) is a brain disorder of early childhood onset. ASD is characterized by core social communication impairments as well as restricted, repetitive behaviors, which jeopardize the development of appropriate social skills and the maintenance of social relationships (1). Despite being one of the most devastating childhood disorders in terms of prevalence [1 in 68 US children (2)] and societal cost [$236 billion expended annually in the United States (3)], ASD pathophysiology remains poorly understood. Consequently, there are no approved medications that enhance social abilities in individuals with ASD.

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Section: Discussionmentioning

confidence: 99%

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

Parker

Oztan

Libove

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

269

250

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“…The Aberrant Behavior Checklist (ABC), a measure of disruptive behaviors, is most common, while trials focusing on social symptoms, commonly used the Social Responsiveness Scale (SRS). Despite some trials demonstrating a large placebo effect with the SRS [ 107 ], a meta-analysis of outcomes for the controlled group, social skills intervention trials found that the SRS demonstrated a large effect size [ 108 ]. Given the large heterogeneity in symptoms in children with ASD as well as the fact that some symptoms are more important to parents than other symptoms, an innovative approach is to individualize outcomes by rating targeted behaviors selected by parents [ 109 ].…”

Section: Outcome Measures For Assessing Social Functionmentioning

confidence: 99%

“…A medium-sized ( n = 40) DBPC add-on to risperidone study of children with ASD reported improvements in ABC Irritability, Stereotypy, and Hyperactivity, but not Social Withdrawal, subscales [ 148 ]. In a large ( n = 121) DBPC 12-week study, once-daily extended-release memantine did not significantly affect the SRS owing to a large improvement in the placebo group [ 107 ]. Thus, DBPC studies do not show improvement in social symptoms with memantine, although they do suggest an excellent safety profile.…”

Section: Drug Treatments For Improving Social Interaction In Autism Smentioning

confidence: 99%

Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents

Frye

2018

CNS Drugs

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Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.

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“…evaluating the safety and efficacy of memantine in autistic children, found that based on Social Responsiveness Scale, no significant difference between groups in the primary efficacy outcome of caregiver/parent ratings, was observed; however, it was improved at week 12 in both groups compared to preintervention. [ 33 ]…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Memantine as Adjunct Therapy for Autism Spectrum Disorder in Children Aged <14 Years

et al. 2018

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Background:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a recent increase in prevalence. A timely appropriate treatment for the disorder may play a crucial role in improvements in behaviors, interactions, and communications in an individual's life. It appears that evaluation of therapeutic approaches to the patients is essential and of importance. Thus, the aim of this study was to evaluate the efficacy of memantine as adjunct therapy in children with ASD.Materials and Methods:This randomized single-blind clinical trial included 60 children with ASD aged <14. The children undergoing applied behavior analysis (ABA) were divided into two groups of placebo and memantine (5 mg/day: a half of tablet in the morning and a half in the evening). After a 3-month course, improvements in symptoms of ASD were evaluated in both groups based on Gilliam autism rating scale. The collected data were analyzed with SPSS (version 20) using independent samples t-test, paired samples t-test, Chi-squared test and Fisher's exact test.Results:Both groups were similar in baseline characteristics including age, gender, and ASD symptoms (P > 0.05) but post intervention, total scores of ASD symptoms in both groups of memantine (mean score1 =95.20 ± 14.49; mean score2=73.50 ± 9.81) and control group (mean scorebefore = 91.50 ± 14.35; mean scoreafter = 89.63 ± 13.95) showed a decrease which was only significant in intervention group (P < 0.001).Conclusion:Accordingly, memantine administration as adjunct therapy can be more effective in improvement of ASD symptoms in children than ABA alone. Thus, it can be considered as a new selective adjunct therapy.

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Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

Cited by 77 publications

References 31 publications

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents

Efficacy of Memantine as Adjunct Therapy for Autism Spectrum Disorder in Children Aged <14 Years

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