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There were similarities in the targets of intervention. More than half of the articles focused on ameliorating social impairments Sixteen studies targeted communication Below we will review the studies from each of these four areas. Given that social impairments are a core ASD deficit, it should come as no surprise that most reviewed studies targeted social skills. As a result, in comparison to previous review periods, we are beginning to see improved social skill outcomes for children with ASD.

In fact, the majority of reviewed studies reported improvements in nearly all targeted social skills. Many interventions utilized a group format and reported improvements in these social skills as a result of the experimental intervention. Some social impairment interventions were conducted with younger children. Most studies were carried out in one-on-one interventions rather than groups. Interventions that targeted peer relationships were often carried out in dyads or small groups.

That is, the form was taught, but the function may not have been. Another limitation of reviewed studies was the absence of inclusion and exclusion criteria regarding child participants both typical and the child with ASD. It may be the case that not all children with ASD or their peers are the best candidates for a social skills intervention. Having more information on who may be most responsive to a social skill intervention could inform participant selection for future social skill treatments.


The vast majority of communication and language interventions utilized a single-subject design and focused on the development of spoken communication. In terms of the studies regarding spoken communication, almost all utilized applied behavior analysis and reported improvements in spoken communication. For example, in order to target word acquisition, Koegel et al.

Using a developmentally based behavioral intervention, one of the experimental interventions targeted initiation of joint attention and the other focused on symbolic play skills. Both experimental interventions resulted in better joint engagement between caregiver and child, as well as improved joint attention and play skills.

Children in the ABA condition did not change significantly and made only minimal progress in language development over the follow-up period of 1 year. Interestingly, a subgroup of children who were minimally verbal less than five functional words made the greatest gains if they were randomized to the joint attention intervention.

These data are among the first to find long-term changes in language abilities and also indicate a treatment by aptitude interaction for a communication intervention for children with autism. The period of review also witnessed a number of studies investigating augmentative communication. These studies targeted requests or mands usually for highly preferred items and almost always reported treatment efficacy. What remains unclear from these studies is the extent to which improvement resulting from augmentative communication use generalizes to environments other than the one in which the augmentative communication is taught.

Questions also exist regarding whether augmentative communication leads to improvement in other developmental abilities, such as the understanding and production of spoken communication. Over the past 2 years, there were fewer interventions targeting restricted and repetitive behaviors [ 58 ] and more focusing on aspects of emotions. Whereas some interventions included teaching emotional knowledge within social skills curricula, others targeted anxiety and emotion regulation.

The data from this study are especially promising in suggesting that decreases in anxiety after intervention may result in changes in the social symptoms characteristic of ASD. Given the high anxiety that adolescents and adults with ASD experience, it is important to determine if CBT interventions are as effective for older populations. White and colleagues [ 61 ] reported pilot data that their CBT and social skills intervention was able to significantly reduce anxiety for three of four adolescents with ASD.

A relatively new focus of ASD research is emotion regulation. Emotion regulation, particularly early in development, may have implications for reducing the presence of later anxiety-related disorders.

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One study during this review period focused on treatment-induced changes in the emotion regulation abilities of toddlers with autism [ 64 ]. In this study, a randomized wait-list design of a parent-mediated intervention on joint engagement was employed. Interventions that focus on the development of emotion and behavior regulation strategies of young children appear to be a promising direction of future research.

All reviewed comprehensive treatment studies focused on young children, except one with school-aged children. Almost every study reported using methods that relied on ABA, and most studies were conducted at centers. This study was one of the first methodologically rigorous randomized controlled trials of a comprehensive intervention for toddlers. Data from this study suggest that very young children with ASD may achieve higher cognitive scores, higher adaptive scores, and better autism diagnoses through a comprehensive intervention that includes developmental strategies and family involvement.

Although studies reported improvement, there continue to be some of the same limitations as noted in previous reviews [ 71 ]. For example, the studies often failed to control for dose, both in length of treatment and density of sessions. Also, nearly all comprehensive treatment studies reported a minimum dose of 20 h per week; however, it is not clear whether the 20 h were that similar in approach and content because only a few studies used a treatment manual.

Additionally, it is difficult to compare treatments that vary so drastically in terms of agent parent or therapist mediated and mode of delivery , group, home or clinic. Despite these limitations, some interesting findings emerge. This is consistent with previously published reports of children engaged in comprehensive interventions [ 72 ]. These distinctions highlight the need to more closely monitor the moderators of treatment outcomes e.

An essential question concerns the match between intervention focus and outcome variable. Despite differences in treatment content, IQ was a major outcome for all studies. Using IQ as a primary outcome may be problematic because it is not clear whether reported changes in IQ result from true improvements in cognitive skills or simply better test-taking ability. Therefore, other aspects of cognition will be important to assess in future studies. Additionally, it will be important for future studies to target those behaviors that are core to an ASD diagnosis, such as language ability, social skills, and nonverbal communication e.

A relatively new trend is the addition of parent training to comprehensive treatments. Incorporating parent training into comprehensive treatments may help with the maintenance and generalization of targeted skills. Including parents in comprehensive interventions could also be a way to increase the density of treatment. This instrument has been used in other reviews of behavioral interventions for young children with autism [ 76 , 77 ].

The instrument categorizes behavioral intervention studies as strong, adequate, or weak based upon whether the study satisfies a specified number of quality indicators. Examples of quality indicators include detail regarding participant characteristics, the experimental intervention, as well as the dependent variables. In previously published studies, inter-rater agreement has ranged from Percentage agreement was good The majority of studies were rated as adequate or weak.

In regards to the single subject or case review studies, The articles categorized as strong are noted in the reference section. The studies showed common areas of strength and weakness. Most studies received a high-quality rating for their detailed description of the experimental treatment and dependent variable. Most single-subject or case studies did not conduct kappa or have blind raters. Although we have made much progress in intervention research during the review period, we still have a distance to go. We have only begun to address the multiple priorities in the autism research matrix including randomized controlled trials of intervention, isolation of active ingredients, identification of mediators and moderators, and treatment of core deficits [ 57 ].

Additionally, we are still in need of more studies with high methodological rigor. Continued research on behavioral interventions is critical so that one day we can more effectively match treatments to the unique characteristics of the individual with ASD. We also appreciate the research assistance of Marina Farberov and Janet Bang. List of peer-reviewed, social science journals searched:. Papers of particular interest, published within the annual period of review, have been highlighted as:.

Additional references related to this topic can also be found in the Current World Literature section in this issue pp. Europe PMC requires Javascript to function effectively. Recent Activity. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Curr Opin Neurol. Author manuscript; available in PMC Feb PMID: Connie Kasari and Kathy Lawton. Copyright notice. The publisher's final edited version of this article is available at Curr Opin Neurol.

See other articles in PMC that cite the published article. Abstract Purpose of review The review explores current trends in the behavioral intervention literature for children with an autism spectrum disorder ASD during and Recent findings During and , there was nearly a quarter increase in the number of behavioral intervention studies, as well as more randomized controlled trials and approaches other than applied behavior analysis.

Summary Overall, the reviewed studies suggest that ASD-specific deficits can be improved through behavioral intervention.

Keywords: autism, behavior, intervention. Introduction Although autism spectrum disorder ASD is a neurobiological disorder, behavioral interventions are currently the primary treatments for individuals with ASD. Brief overview of studies We obtained 68 studies from our search. Clearly, this review period witnessed several noteworthy improvements in experimental design, intervention focus, and breadth of intervention strategies The studies in this review period varied in the designs utilized.

Social impairment interventions Given that social impairments are a core ASD deficit, it should come as no surprise that most reviewed studies targeted social skills. Augmentative communication The period of review also witnessed a number of studies investigating augmentative communication. Interventions targeting restricted and repetitive behaviors as well as emotion Over the past 2 years, there were fewer interventions targeting restricted and repetitive behaviors [ 58 ] and more focusing on aspects of emotions.

Emotion regulation A relatively new focus of ASD research is emotion regulation. Conclusion Although we have made much progress in intervention research during the review period, we still have a distance to go. Footnotes List of peer-reviewed, social science journals searched: Journal of Autism and Developmental Disorders. American Psychiatric Association. The effect of therapeutic horseback riding on social functioning in children with autism.

J Autism Dev Disord. A social stories intervention package for students with autism in inclusive classroom settings. J Appl Behav Anal. Cotugno AJ. Social competence and social skills training and intervention for children with autism spectrum disorders. J Dev Phys Disabil. The effects of theory-of-mind and social skill training on the social competence of a sixth-grade student with autism.

J Positive Behav Interv. Implementing visually cued imitation training with children with autism spectrum disorders and developmental delays. Multimedia interfaces for users with high functioning autism: an empirical investigation. Int J Hum Comput Studies. Recess is time-in: using peers to improve social skills of children with autism. Pilot evaluation of the Frankfurt Social Skills Training for children and adolescents with autism spectrum disorder. Eur J Child Adolesc Psychiatry.

Development of symbolic play through the use of virtual reality tools in children with autistic spectrum disorders. Parent-assisted social skills training to improve friendships in teens with autism spectrum disorders. Concept mastery routines to teach social skills to elementary children with high functioning autism. Using time-delay to improve social play skills with peers for children with autism. J Dev Disord.

Autism Spectrum Disorders

Effectiveness of a manualized summer social treatment program for high-functioning children with autism spectrum disorders. Engagement with electronic screen media among students with autism spectrum disorders. Promoting social interactions between students with autism spectrum disorders and their peers in inclusive school settings.

Focus Autism Other Dev Disabil. LEGO therapy and the Social Use of Language Programme: an evaluation of two social skills interventions for children with high functioning autism and Asperger syndrome. The results reflect a lack of improvement in language using the Tomatis sound therapy for children with autism. A total of 62 children with autism were recruited from 6 centers, aged 2 to 7 years mean of 4. Post-hoc analysis indicated that children over the age of 5 years and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated.

The authors concluded that children with autism who received hyperbaric treatment at 1. Moreover, the authors stated that because this study was not designed to measure the long-term outcomes of hyperbaric treatment in children with autism, additional studies are needed to determine if the significant improvements observed in this study last beyond the study period. It is possible that ongoing treatments would be necessary to maintain the improvements observed, but this study was not designed to examine that possibility. Finally, this study was not designed to determine if higher hyperbaric treatment parameters higher atmospheric pressure and oxygen levels, which can only be provided in a clinic setting would lead to better or more long-lasting results.

Additional studies are needed to investigate that possibility. It is interesting to note that Yildiz and colleagues stated that neither the Undersea Hyperbaric Medical Society nor the European Committee for Hyperbaric Medicine "approves" autism as an indication for hyperbaric oxygen therapy.

The authors concluded that there is insufficient evidence to support the use of hyperbaric oxygen therapy in the treatment of children with autism. Moreover, there is a lack of evidence regarding the clinical benefits of weighted blankets for individuals with autism or other pervasive developmental disorders. The authors concluded that while there is only a limited body of research and a number of methodological weaknesses, on balance, indications are that weighted vests are ineffective.

There may be an arguable case for continued research on this intervention but weighted vests can not be recommended for clinical application at this point. Floor time therapy is a series of to min periods during which parents interact and play with their autistic child on the floor. The aim of the interaction is to promote social and communicative abilities. A British Medical Journal Clinical Evidence systematic assessment on autism Parr, concluded that the effectiveness of floor time therapy for autism is unknown.

Ichim and colleagues stated that ASDs are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypo-perfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypo-perfusion with symptomatology was reported.

All charts were included for review where there was a diagnosis of AS or ASD and pre- and post-training testing results were available for one or more of the standardized tests used. For the majority of patients, feedback was contingent on decreasing slow wave activity usually 3 to 7 Hz , decreasing beta spindling if it was present usually between 23 and 35 Hz , and increasing fast wave activity termed sensorimotor rhythm SMR 12 to 15 or 13 to 15 Hz depending on assessment findings. The most common initial montage was referential placement at the vertex CZ for children and at FCz midway between FZ and CZ for adults, referenced to the right ear.

Meta-cognitive strategies relevant to social understanding, spatial reasoning, reading comprehension, and math were taught when the feedback indicated that the patient was relaxed, calm, and focused. Significant improvements were found on measures of attention T. The average gain for the Full Scale IQ score was 9 points.

A decrease in relevant EEG ratios was also observed. Lee et al examined the effectiveness of massage as a treatment option for autism. The references in all located articles were also searched. No language restrictions were imposed. Prospective controlled clinical studies of any type of massage therapy for autistic patients were included. Trials in which massage was part of a complex intervention were also included.

Case studies, case series, qualitative studies, uncontrolled trials, studies that failed to provide detailed results, and trials that compared one type of massage with another were excluded. All articles were read by 2 independent reviewers, who extracted data from the articles according to predefined criteria.

Risk of bias was assessed using the Cochrane classification. Of articles, only 6 studies met inclusion criteria. Two non-RCTs suggested that massage therapy is effective. However, all of the included trials have high risk of bias. The main limitations of the included studies were small sample sizes, predefined primary outcome measures, inadequate control for non-specific effects, and a lack of power calculations or adequate follow-up. The authors concluded that limited evidence exists for the effectiveness of massage therapy as a symptomatic treatment of autism.

Because the risk of bias was high, firm conclusions can not be drawn. They stated that future, more rigorous RCTs are warranted. One new study was found for inclusion. Randomized controlled trials involving adults or children with ASDs were reviewed. Treatment was AIT or other sound therapies involving listening to music modified by filtering and modulation. Control groups could involve no treatment, a waiting list, usual therapy or a placebo equivalent. The outcomes were changes in core and associated features of ASDs, auditory processing, quality of life and adverse events.

Two independent review authors performed data extraction. All outcome data in the included papers were continuous. They calculated point estimates and standard errors from t-test scores and post-intervention means. Meta-analysis was inappropriate for the available data. Two were cross-over trials; 5 trials had fewer than 20 participants. Allocation concealment was inadequate for all studies. Meta-analysis was not possible due to very high heterogeneity or the presentation of data in unusable forms. Three studies Bettison ; Zollweg ; Mudford did not demonstrate any benefit of AIT over control conditions.

The authors concluded that there is no evidence that AIT or other sound therapies are effective as treatments for ASDs.


As synthesis of existing data has been limited by the disparate outcome measures used between studies, there is insufficient evidence to prove that this treatment is ineffective. As such, there is no evidence to support the use of AIT at this time. The literature is lacking on documenting chiropractic care of children with ASD. These researchers stated that at the heart of the core symptoms of ASD i. Preliminary studies indicated that chiropractic adjustment may attenuate sensorimotor integration based on somatosensory evoked potentials studies.

Dissertation Abstracts International was searched on December 10, , but was no longer available to the authors or editorial base in Three authors independently selected studies, assessed them for risk of bias and extracted relevant data. Overall, there was no evidence that omega-3 supplements had an effect on social interaction mean difference MD 0. The authors concluded that to date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD.

Given the paucity of rigorous studies in this area, there is a need for large well-conducted RCTs that examine both high- and low-functioning individuals with ASD, and that have longer follow-up periods. Wuang et al examined the effectiveness of a week Simulated Developmental Horse-Riding Program SDHRP by using an innovative exercise equipment Joba on the motor proficiency and sensory integrative functions in 60 children with autism age of 6 years, 5 months to 8 years, 9 months.

In the 1st phase of 20 weeks, 30 children received the SDHRP in addition to their regular occupational therapy while another 30 children received regular occupational therapy only. The arrangement was reversed in the 2nd phase of another 20 weeks. In addition, the therapeutic effect appeared to be sustained for at least 24 weeks 6 months. This study utilized Joba, an exercise equipment that served as simulated horseback riding; not conventional horseback riding.

A total of 24 participants completed the waiting list period and began the riding program, and 20 participants completed the entire 6 months of riding. Pre-treatment was compared to post-treatment with each child acting as his or her own control. A reduction in the severity of autism symptoms occurred with the therapeutic riding treatment. There was no change in CARS scores during the pre-treatment baseline period; however, there was a significant decrease after treatment at 3 months and 6 months of riding. The Timberlawn Parent-Child Interaction Scale showed a significant improvement in Mood and Tone at 3 months and 6 months of riding and a marginal improvement in the reduction of Negative Regard at 6 months of riding.

The parent-rated quality of life measure showed improvement, including the pre-treatment waiting period. All of the ratings in the Treatment Satisfaction Survey were between good and very good. The authors concluded that these results suggested that children with ASD benefit from equine-assisted activities. The findings of this small study need to be validated by well-designed studies.

In a nonrandomized study, 19 children with autism who participated in 12 weeks of therapeutic horseback riding hippotherapy demonstrated improvements in attention, distractibility, and social motivation compared with 15 wait-list controls. They also searched ClinicalTrials.

This was supplemented by searching reference lists and contacting known experts in the field. Two authors independently selected studies for inclusion, extracted data and appraised each study's risk of bias. A total of 9 RCTs with participants were included. Four SSRIs were evaluated: fluoxetine 3 studies , fluvoxamine 2 studies , fenfluramine 2 studies and citalopram 2 studies. Five studies included only children and 4 studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence quotient of participants; 18 different outcome measures were reported.

Although more than 1 study reported data for Clinical Global Impression CGI and obsessive-compulsive behavior OCB , different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis, except for 1 outcome proportion improvement.

One large, high-quality study in children showed no evidence of positive effect of citalopram; 3 small studies in adults showed positive outcomes for CGI and OCB; 1 study showed improvements in aggression, and another in anxiety. The authors concluded that there is no evidence of effect of SSRIs in children and emerging evidence of harm.

There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear. This study enrolled 32 children and adolescents with either autistic disorder or PDD-not otherwise specified, and a score greater than or equal to 17 on the ABC-Irritability subscale. Arbaclofen was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms.

The authors concluded that placebo-controlled study of arbaclofen is needed. Kyriakopoulos et al stated that in children with ASD, high rates of idiosyncratic fears and anxiety reactions and thought disorder are thought to increase the risk of psychosis.

The critical next step is to identify whether combinations of these symptoms can be used to categorize individual patients into ASD subclasses, and to test their relevance to psychosis. Latent class analysis of individual symptoms was conducted to identify ASD classes. External validation of these classes was performed using as a criterion the presence of hallucinations. Latent class analysis identified 2 distinct classes.

The authors concluded that the findings of this study provided the first empirically derived classification of ASD in relation to psychosis based on 3 underlying symptom dimensions, anxiety, social deficits and thought disorder. They stated that these results can be further developed by testing the reproducibility and prognostic value of the identified classes. Chiocchetti and associates noted that ASD are neurodevelopmental disorders with early onset in childhood.

Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signaling. Mouse models suggested an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections.

A central pathway regulating these mechanisms is glutamatergic signaling. These researchers hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, these investigators performed a systematic review using the literature database "PubMed" and the "AutismKB" knowledgebase. They provided an overview of the glutamatergic system in typical brain function and development, and summarized findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics.

Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signaling, metabolism and transport.

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Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity were able to rescue ASD reminiscent phenotypes. The authors concluded that glutamatergic genetic risk factors for ASD showed a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible.

DeJong et al performed a systematic review to examine the effectiveness of a range of treatments for autistic catatonia. The review identified 22 relevant papers, reporting a total of 28 cases including both adult and pediatric patients. Treatments included electro-convulsive therapy ECT , medication, behavioral and sensory interventions. Quality assessment found the standard of the existing literature to be generally poor, with particular limitations in treatment description and outcome measurement.

The authors concluded that there was some limited evidence to support the use of ECT, high dose lorazepam and behavioral interventions for people with autistic catatonia; however, there is a need for controlled, high-quality trials. They also noted that reporting of side effects and adverse events should also be improved, in order to better evaluate the safety of these treatments.

However, most previous studies were conducted by single-dose administration to adults; and, therefore, the long-term effect of nasal OT on ASD patients and its effect on children remain to be clarified. These researchers conducted a singled-armed, open-label study in which OT was administered intra-nasally over the long term to 8 male youth with ASD 10 to 14 years of age; intelligence quotient [IQ] 20 to A placebo period 1 to 2 weeks was inserted before each step.

In addition, side effects were monitored by measuring blood pressure and examining urine and blood samples. Six of the 8 participants showed improved scores on the communication and social interaction domains of the ADOS-G. However, regarding the T-scores of the CBCL and the scores of the ABC, these investigators could not find any statistically significant improvement, although several subcategories showed a mild tendency for improvement.

Care-givers of 5 of the 8 participants reported certain positive effects of the OT therapy, especially on the quality of reciprocal communication. All participants showed excellent compliance and no side effects. They stated that even though these data were too preliminary to draw any definite conclusions about effectiveness, they do suggest this therapy to be safe, promising, and worthy of a large-scale, double-blind placebo-controlled study.

They participated in a modified maximum tolerated dose study of intra-nasal OT Syntocinon. Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. Among 4 doses tested, the highest dose evaluated, 0. The authors concluded that the findings of this pilot study suggested that daily administration of intra-nasal OT at 0. Moreover, they stated that larger studies are needed. Preti et al noted that little is known about the effectiveness of pharmacological interventions on ASD. A search of computerized databases was supplemented by manual search in the bibliographies of key publications.

The methodological quality of the studies included in the review was evaluated independently by 2 researchers, according to a set of formal criteria. Discrepancies in scoring were resolved through discussion. The main categories of target symptoms tested in the studies were repetitive behaviors, eye gaze, and emotion recognition. The studies had a medium to high risk of bias. All the studies but 1 reported statistically significant between-group differences on at least 1 outcome variable. Most findings were characterized by medium effect size.

Only 1 study had evidence that the improvement in emotion recognition was maintained after 6 weeks of treatment with intra-nasal OT. Overall, OT was well-tolerated and side effects, when present, were generally rated as mild; however, restlessness, increased irritability, and increased energy occurred more often under OT. The authors concluded that RCTs of OT interventions in autism yielded potentially promising findings in measures of emotion recognition and eye gaze, which were impaired early in the course of the ASD condition and might disrupt social skills learning in developing children.

They stated that there is a need for larger, more methodologically rigorous RCTs in this area. They noted that future studies should be better powered to estimate outcomes with medium to low effect size, and should try to enroll female participants, who were rarely considered in previous studies; risk of bias should be minimized. These researchers stated that human long-term administration studies are needed before clinical recommendations can be made. Although intra-nasally delivered OT likely affects behavior, there are conflicting reports as to the exact nature of those behavioral changes: some studies suggested that OT effects are not always "pro-social" and others suggested effects on social behaviors are due to a more general anxiolytic effect.

In this critique, the authors drew from work in healthy human populations and the animal literature to review the mechanistic aspects of intra-nasal OT delivery, and discussed intra-nasal OT effects on social cognition and behavior. They concluded that future work should control carefully for anxiolytic and gender effects, which could underlie inconsistencies in the existing literature. Quintana et al stated that accumulating evidence demonstrated the important role of OT in the modulation of social cognition and behavior.

This has led many to suggest that the intra-nasal administration of OT may benefit psychiatric disorders characterized by social dysfunction, such as ASD and schizophrenia. These investigators reviewed nasal anatomy and OT pathways to central and peripheral destinations, along with the impact of OT delivery to these destinations on social behavior and cognition.

The primary goal of this review is to describe how these identified pathways may contribute to mechanisms of OT action on social cognition and behavior i. The authors proposed a 2-level model involving 3 pathways to account for responses observed in both social cognition and behavior after intra-nasal OT administration and suggested avenues for future research to advance this research field. Owada and colleagues stated that discrepancies in efficacy between single-dose and repeated administration of oxytocin for ASD have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone.

However, repeatable, objective, and quantitative measurement of ASD's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. These researchers tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of ASD. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability i. A recent study by these researchers revealed that increases in these indices characterized autistic facial expression, compared with neurotypical individuals.

The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory effect-size, Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals' facial expressions and demonstrated a time-course change in efficacy.

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The authors concluded that these findings support further development of optimization of objective, quantitative, and repeatable outcome measures for autistic social deficits and to establish optimized regimen of oxytocin treatment for ASD. The authors stated that this study had several potential limitations and methodological considerations that should be considered.

First, subjects in this trials were all adult, male, Japanese individuals with ASD. The majority of the quantification methods were automatically conducted and independent of human labor, facilitating the replication of the current findings. Third, as some autistic characteristics in facial expression at baseline, such as a high mode of neutral facial expression and log-PDF mode of happy facial expression were not significantly improved by oxytocin treatment, these investigators were unable to conclude that oxytocin could treat or recover all characteristics of facial expression in individuals with ASD.

Furthermore, these researchers did not show an association between the effects of oxytocin on the quantified facial expression and those on beneficial therapeutic outcomes, such as Clinical Global Impressions CGI or Global Assessment of Functioning GAF. Fourth, the possibility of further improving the method of quantifying facial expressions, the task used to induce facial expressions in individuals with autism, and the outcome variables, should be considered.

Tonacci and colleagues stated that olfactory function is a well-known early biomarker for neurodegeneration and neural functioning in the adult population, being supported by a number of brain structures that could be dysfunctioning in neurodegenerative processes. Evidence has suggested that atypical sensory and, particularly, olfactory processing is present in several neurodevelopmental conditions, including ASDs. These investigators presented data obtained by a systematic literature review, conducted according to PRISMA guidelines, regarding the possible association between olfaction and ASDs, and analyzed them critically in order to evaluate the occurrence of olfactory impairment in ASDs, as well as the possible usefulness of olfactory evaluation in such conditions.

The results obtained in this analysis suggested a possible involvement of olfactory impairment in ASDs, underlining the importance of olfactory evaluation in the clinical assessment of ASDs. The authors concluded that this assessment could be potentially included as a complementary evaluation in the diagnostic protocol of the condition. Of probands, 24 9.

The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was This included 2 children who received molecular diagnoses from both tests. The authors concluded that among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category.

They stated that if replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD. The drawbacks of this study were:. Brondino et al stated that it has been hypothesized that autism may result from an imbalance between excitatory glutamatergic and inhibitory GABAergic pathways. Commonly used medications such as valproate, acamprosate, and arbaclofen may act on the GABAergic system and be a potential treatment for people with ASD.

These investigators evaluated the state-of-the-art of clinical trials of GABA modulators in autism. The authors concluded that there is insufficient evidence to suggest the use of these drugs in autistic subjects, even if data are promising. They stated that short-term use of all the reviewed medications appeared to be safe; however, future well-designed trials are needed to elucidate these preliminary findings.

Sausmikat and Smollich provided evidence-based data on nutritional interventions for children and adolescents with ASD, thus enabling practitioners to competently assess these diets. Applying defined inclusion and exclusion criteria, a systematic literature research in PubMed, Cinahl and the Cochrane Library was conducted.

Studies published earlier than were excluded. There is no proven efficacy of the widely used gluten-free and casein-free diets GFCF , and no respective predictive marker has been proven significant. The authors concluded that based on available data, no evidence-based recommendations regarding nutritional interventions for children and adolescents with ASD can be made. They stated that future studies need to clarify whether particular patients may yet benefit from certain diets. Wang and associates noted that the reelin gene RELN , which plays a crucial role in the migration and positioning of neurons during brain development, has been strongly posed as a candidate gene for ASD.

Genetic variants in RELN have been investigated as risk factors of ASD in numerous epidemiologic studies but with inconclusive results. To clearly discern the effects of RELN variants on ASD, these researchers conducted a meta-analysis integrating case-control and transmission disequilibrium test TDT studies published through to Evidence is growing for the association between SLC25A12 variants rs and rs and ASD risk, but the results are inconsistent. To clarify the effect of these 2 variants on ASD, these researchers performed a meta-analysis integrating case-control and TDT studies.

A total of cases, controls, and 1, families available from 8 studies concerning rs, and cases, controls, and 1, families available from 7 studies concerning rs were finally included. Sensitivity analysis, cumulative meta-analysis, and publication bias diagnostics confirmed the reliability and stability of these results. The authors concluded that the findings of this meta-analysis suggested that rs and rs in SLC25A12 may contribute to ASD risk. Aoki and Cortese stated that mitochondrial dysfunction has been reported to be involved in the pathophysiology of ASD.

Sensitivity analyses were conducted based on study design family-based or case-control ; 15 out of 79 non-duplicate records were retained for qualitative synthesis. These investigators pooled 10 datasets from 9 studies with 2, families, individuals with ASD and typically developing TD individuals for the meta-analysis of rs, as well as 11 datasets from 10 studies with 2, families, individuals with ASD and 1, TD individuals for the meta-analysis of rs In contrast, sensitivity analyses including case-control design studies only failed to find a significant association.

The authors concluded that further research on the role of SLC25A12 and ASD may pave the way for potential innovative therapeutic interventions. Long and Goldblatt noted that a polymorphism is a variant within a gene that does not necessarily affect its function, unlike a pathogenic mutation. Due to the large, varied and often conflicting data reported on MTHFR, these polymorphisms have been weakly associated with multiple conditions, including autism, schizophrenia, cardiac disease, fetal neural tube defects, poor pregnancy outcomes and colorectal cancer.

These investigators explained the difficulty in translating inconclusive results -- and results of uncertain clinical relevance -- of genetic-association studies on common polymorphisms into clinical practice. They explored why testing for polymorphisms needs to be re-considered in a diagnostic clinical setting. These researchers identified EE of genetic tests for various diseases.

The outcomes used in the EE of the genetic tests were heterogeneous, and results were generally not comparable. The authors concluded that there is no evidence for cost-effectiveness of any genetic diagnostic test for ASD, although such genetic tests are available commercially. They stated that cost-effectiveness analyses for genetic diagnostic tests for ASD are needed; there is a clear lack in research for EE of genetic tests.

These investigators presented a systematic review and narrative synthesis of the determinants of external validity in RCTs on ERT. Generalizability of the findings across situations, populations, settings, treatment delivery, and intervention formats was considered. These researchers identified 13 eligible studies. Participants were predominantly boys with ASD in the normative IQ range IQ over 70 , with an age span from 4 to 18 years across studies.

Interventions and outcome measures were highly variable. Several studies indicated that training may improve ER, but it is still largely unknown to what extent training effects are translated to daily social life. The authors concluded that the generalizability of findings from currently available RCTs remains unclear. In addition, memantine treatment was associated with significant improvement in ADHD and anxiety symptom severity. Memantine treatment was generally well-tolerated and was not associated with any serious adverse events AEs.

The authors concluded that treatment with memantine appeared to be beneficial for the treatment of ASD and associated psychopathology and cognitive dysfunction in intellectually capable adults. Moreover, they stated that future placebo-controlled trials are needed.

In a week, randomized, placebo-controlled, study with a week open-label extension, Aman and associates examined the safety, tolerability, and effectiveness of memantine once-daily extended-release [ER] in children with autism. There was 1 serious adverse event SAE affective disorder, with memantine in the week study and 1 SAE lobar pneumonia in the week extension; both were deemed unrelated to treatment.

Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram ECG. A trend for improvement at the end of the week extension was observed. The authors concluded that this trial did not demonstrate clinical effectiveness of memantine ER in autism; however, the tolerability and safety data were reassuring.

They noted that these findings could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications. Since this was a negative trial, the results have not been published but are posted on ClinicalTrials. In , the U. Food and Drug Administration FDA approved Risperdal risperidone for the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate self-injury, temper tantrums, and quickly changing moods, in children and adolescents aged 5 to 16 years.

This was noted to be the first FDA-approved medication for use in children and adolescents with autism BioSpace, The drug is marketed by Janssen, L. The author performed a systematic review of electronic scientific databases to identify studies of novel and emerging treatments for ASD, including nutritional supplements, diets, medications, and non-biological treatments.

Potential adverse effects for each treatment were also reviewed. Grade A treatments for ASD include melatonin, acetylcholinesterase inhibitors, naltrexone, and music therapy. Grade B treatments include carnitine, tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists, hyperbaric oxygen treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and vision therapy.

The author concluded that the reviewed treatments for ASD are commonly used, and some are supported by prospective RCTs. Promising treatments include melatonin, antioxidants, acetylcholinesterase inhibitors, naltrexone, and music therapy. All of the reviewed treatments are currently considered off-label for ASD and some have adverse effects. The author stated that further studies exploring these treatments are needed.

In , Bristol-Myers Squibb Company announced the FDA approval of Abilify aripiprazole for the treatment of irritability associated with autistic disorder in pediatric patients ages 6 to 17 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods BMS, The ABC-I subscale measured symptoms of irritability in autistic disorder.

Results of the first 8-week trial, contained 98 children and adolescents with autistic disorder. The mean daily dose of Abilify at the end of 8week treatment was 8. The second 8-week trial contained children and adolescents with autistic disorder. Abilify is available as oral tablets, orally-disintegrating tablets, and oral solution for treatment of irritability associated with autistic disorder. According to prescribing information Otsuka, , it is not known if Abilify is safe or effective in children under 6 years of age with irritability associated with autistic disorder.

Crawford and colleagues stated that preliminary studies have indicated that music therapy may benefit children with ASD. Randomization was via a remote service using permuted blocks, stratified by study site. Subjects were children aged between 4 and 7 years with a confirmed diagnosis of ASD and a parent or guardian who provided written informed consent.

These investigators excluded children with serious sensory disorder and those who had received music therapy within the past 12 months. All parents and children received enhanced standard care ESC , which involved three min sessions of advice and support in addition to treatment as usual. The primary outcome was measured using the social affect score derived from the ADOS at 5 months: higher scores indicated greater impairment; secondary outcomes included social affect at 12 months and parent-rated social responsiveness at 5 and 12 months higher scores indicated greater impairment.

A total of participants were randomized between and A total of children were allocated to IMT 90 to high-frequency sessions and 92 to low-frequency sessions , and were allocated to ESC alone. A total of Among those randomized to IMT, From baseline to 5 months, mean scores of ADOS social affect decreased from There were also no differences in the parent-rated social responsiveness score, which decreased from There were 7 admissions to hospital that were unrelated to the study interventions in the 2 IMT arms compared with 10 unrelated admissions in the ESC group.

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  • The authors concluded that adding IMT to the treatment received by children with ASD did not improve social affect or parent-assessed social responsiveness. In an assessor-blinded, randomized clinical trial, conducted in 9 countries, Bieleninik and associates examined the effects of IMT on generalized social communication skills of children with ASD. Children aged 4 to 7 years with ASD were enrolled in this study; they were recruited from November to November , with follow-up between January and November In IMT, trained music therapists sang or played music with each child, attuned and adapted to the child's focus of attention, to help children develop affect sharing and joint attention.

    The primary outcome was symptom severity over 5 months, based on the ADOS, social affect domain range of 0 to 27; higher scores indicate greater severity; minimal clinically important difference, 1. Pre-specified secondary outcomes included parent-rated social responsiveness. All outcomes were also assessed at 2 and 12 months.

    Among participants randomized mean age of 5. Over 5 months, participants assigned to IMT received a median of 19 music therapy, 3 parent counseling, and 36 other therapy sessions, compared with 3 parent counseling and 45 other therapy sessions for those assigned to ESC. From baseline to 5 months, mean ADOS social affect scores estimated by linear mixed-effects models decreased from Of 20 exploratory secondary outcomes, 17 showed no significant difference.

    Brondino and colleagues stated that ciliary neurotrophic factor CNTF is a neurotrophin that could signal neuronal suffering and at the same time acts as a neuroprotective agent. They stated these findings support the hypothesis of neurotrophic imbalance in ASD. However, the currently available results are inconsistent. These researchers used sensitivity analyses and the assessment of publication bias in their meta-analysis.

    An OR of 0. The authors concluded that the findings of this meta-analysis provided strong evidence that different SNPs of GABA receptor B3, A5, and G3 subunit genes located on chromosome 15qq13 are not associated with the development of autism spectrum diseases in different ethnic populations. Lochman and colleagues noted that the immune system may have a role in the pathogenesis of ASD, including typical and atypical autism. These researchers examined if a cytokine and growth factor panel could be identified for the diagnosis and prognosis in children with ASD, including typical and atypical autism.

    There were no statistically significant differences in serum cytokine and growth factor levels between children with ASD and their siblings. Serum levels of cytokines and growth factors showed a positive correlation with CARS and ADOS scores but differed between children with typical and atypical autism and their siblings. The authors concluded that the findings of this study showed that serum measurement of appropriately selected panels of cytokines and growth factors might have a role in the diagnosis of ASD.

    El-Rashidy and colleagues stated that many diet regimens were studied for patients with ASD over the past several years. Ketogenic diet is gaining attention due to its proven effect on neurological conditions like epilepsy in children. In a case-control study, a total of 45 children aged 3 to 8 years diagnosed with ASD based on DSM-5 criteria were enrolled to compare ketogenic diet versus gluten free casein free diet for the treatment of ASD. Patients were equally divided into 3 groups, first group received ketogenic diet as modified Atkins diet MAD , second group received gluten free casein free GFCF diet, and the third group received balanced nutrition and served as a control group.

    The authors concluded that depending on the parameters measured in this study, modified Atkins diet and gluten free casein free diet regimens may safely improve autistic manifestations and could be recommended for children with ASD. Gogou and Kolios stated that a nutritional background has been recognized in the pathophysiology of autism and a series of nutritional interventions have been considered as complementary therapeutic options. As available treatments and interventions are not effective in all individuals, new therapies could broaden management options for these patients. These investigators provided current literature data regarding the effect of therapeutic diets on ASD.

    A systematic review was conducted by 2 reviewers independently; prospective clinical and pre-clinical studies were considered. These researchers were able to identify 8 studies conducted in animal models of autism demonstrating a beneficial effect on neurophysiological and clinical parameters. Only 1 clinical study was found showing improvement in childhood autism rating scale after implementation of ketogenic diet.

    Furthermore, a combination of gluten-free and modified ketogenic diet in a study had a positive effect on social affect scores. No serious adverse events AEs have been reported. The authors concluded that despite encouraging laboratory data, there is controversy regarding the real clinical effect of therapeutic diets in patients with ASD. They stated that more research is needed to provide sounder scientific evidence.

    Kang and colleagues noted that ASD is a heterogeneous neurodevelopmental disorder that affects the developmental trajectory in several behavioral domains, including impairments of social communication, cognitive and language abilities. Transcranial direct current stimulation tDCS is a non-invasive brain stimulation technique, and it was used for modulating the brain disorders. The authors concluded that the findings of this study suggested that tDCS may be helpful in the rehabilitation of children with ASD.

    Moreover, they stated that further research is needed to examine the potential of brain stimulation treatments for ASD and to interpret the mechanisms of these treatments using neuroimaging techniques. The authors stated that this study had several drawbacks. Second, the stimulation region of DLPFC was not confirmed by neuroimaging but rather by using a slightly less accurate F3 placement of the standard international system.

    Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms.

    A Spectrum within a Spectrum: A 2018 Year End Review of Scientific Research

    Collectively, these small molecules and their interactions within a biological system are known as the metabolome. Smith et al [article in press] stated Autism Spectrum Disorder ASD is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD.

    Based on evidence that dysregulation of branch chain amino acids BCAA may contribute to the behavioral characteristics of ASD, the authors tested whether dysregulation of amino acids AA was a pervasive phenomenon in individuals with ASD. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. The authors concluded that identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.

    West et al stated the diagnosis of autism spectrum disorder ASD at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age. The objective of this study was to discover metabolic features present in plasma samples that can discriminate children with ASD from typically developing TD children.

    The ultimate goal is to identify and develop blood-based ASD biomarkers that can be validated in larger clinical trials and deployed to guide individualized therapy and treatment. Samples were analyzed using 5 mass spectrometry-based methods designed to orthogonally measure a broad range of metabolites. Univariate, multivariate and machine learning methods were used to develop models to rank the importance of features that could distinguish ASD from TD. A set of statistically significant features resulting from univariate analysis were used for multivariate modeling.