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Harvard Review of Psychiatry:
doi: 10.1097/HRP.0000000000000028
Special Issue


Frazier, Jean A. MD*; McDougle, Christopher J. MD

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From the *University of Massachusetts Health Care, University of Massachusetts Medical School. Email: Jean.Frazier@umassmed.edu; †Massachusetts General Hospital, Harvard Medical School. Email: cmcdougle@partners.org

This special issue of the Harvard Review of Psychiatry focuses on Autism Spectrum Disorders (ASDs), a heterogeneous group of disorders characterized by impairment in social communication and language and by repetitive behaviors and restricted interests.1 The prevalence of ASDs has been rising over the years, with the most recent estimate from the CDC indicating that 1 out of 88 youth are affected.2 The disorder is highly heritable, yet the etiology in the vast majority of cases remains elusive. Autism is one of the most challenging disorders to treat, and the public health concerns associated with the disorder are numerous due to its burden on the individual, the family, and society. Therefore, a special issue focused on various aspects of etiology, clinical presentations, and evidence-based therapeutics could not be more timely or more needed. This issue contains thorough reviews by experts in the field on six topics that will inform clinical practice: the genetics of the disorder; evidenced-based psychopharmacologic interventions for maladaptive behaviors and psychiatric comorbidities; obesity in children with ASD; gastrointestinal (GI) comorbidities in ASD; sensory issues seen in these youth, along with available interventions; and issues in the transition from secondary school to college.

In their comprehensive, yet accessible, review of ASD genetics, Talkowski and colleagues3 describe the tremendous progress that has been made in this field in the last decade, but they also remind us that a lot of work remains to be done. They believe that the rising prevalence of ASD relates to both genetic and environmental factors. The lack of a quantitative diagnostic biomarker poses a significant challenge to determining the exact reasons for the increased prevalence. In addition, the authors suggest that hundreds of genes are capable of conferring varying degrees of risk for ASD, depending on their nature and the predisposing variation. While this situation is somewhat overwhelming in and of itself, many genes associated with ASD also confer shared risk for a wide range of neurodevelopmental abnormalities and psychopathology beyond ASD. Thus, a highly heterogeneous collection of genes can contribute to a similar clinical presentation, and at the same time, particular genetic lesions can be associated with widely variable clinical outcomes. As progress continues to be made along these lines, we may see the diagnostic process for ASD and other neuropsychiatric disorders move in the direction of increasing objectivity and away from schemas based on groupings of clinical phenomenology.4 Finally, the article helps the reader understand commonly used terms in the field of ASD genetics, such as whole-exome sequencing (WES), loss-of-function (LoF) mutations, copy-number variations (CNVs), and non-allelic homologous recombination (NAHR). It will be important for clinicians to begin to master this language and knowledge base as the discoveries being made today in our leading institutions’ laboratories begin to make their way into our day-to-day clinical practice. Within the next few years, we will likely be making more specific diagnoses in our patients, like 16p11.2 duplication disorder, rather than ASD.

The second article in this special issue, by Politte and colleagues,5 is a thoughtful review of the evidence for pharmacologic interventions for maladaptive behavior or psychiatric comorbidities in ASD. While psychotropics are routinely prescribed in clinical practice, limited rigorous research has been conducted on prescribing medications to target most areas of impairment in individuals on the spectrum. Many published clinical trials are limited due to small sample sizes and various methodologic issues. This article systematically discusses medications by class, outlining the benefits and side effects as well as highlighting the differences in response rates seen in youth versus adults. For example, while double-blind studies of selective serotonin reuptake inhibitors in adults on the spectrum have been positive, studies in youth have been less promising, and the side effects of agitation and aggression are a greater concern in youth. Stimulants have been well studied for treating symptoms of attention-deficit/hyperactivity disorder in youth with ASDs. Generally, while studies of stimulants are positive, studies in youth with ASDs show lower response rates than studies in youth with ADHD who are not on the spectrum. In addition, youth on the spectrum typically experience more side effects, particularly irritability, on stimulants. The class of medication with the strongest evidence base for use in individuals with ASD are atypical antipsychotics, which are considered first-line agents for irritability and aggression. In fact, two agents (risperidone and aripiprazole) have been approved by the Federal Drug Administration for treating irritability in youth on the spectrum. Weight gain and metabolic syndrome, however, remain concerns with these agents. Finally, limited evidence is available on the efficacy of mood stabilizers and anticonvulsants to treat mood lability and aggression. The article ends with a thoughtful discussion of studies of oxytocin6 and some of the novel agents that target glutamate and GABA—which hold the promise of targeting the core deficits in ASD. The authors conclude by emphasizing the need for more clinical trials with larger samples to inform clinical practice.

Curtin and colleagues7 provide a thorough review of obesity in children with ASD. They discuss a number of risk factors making obesity in children with ASD a public health challenge as great as or greater than for typically developing children. For example, specific genetic abnormalities, such as duplications and deletions at chromosomal region 16p11.2, make an individual vulnerable not only to ASD and other neuropsychiatric disorders, but also to early-onset obesity. In addition, many children with ASD develop irritability (aggression, self-injury, severe tantrums, mood lability), which interferes with important behavioral and educational interventions. Unfortunately, the two atypical antipsychotics that are approved for treating irritability in children and adolescents with autism are associated with increased appetite and weight gain, which iatrogenically compounds the baseline problem.8 As children eat more and gain weight, the impact of their irritability on themselves and those around them becomes more damaging because they are larger physically. Because food is often used as a reinforcer for persons with ASD, withholding food in an effort to reduce the child’s caloric intake can result in heightened maladaptive behavior, creating a problematic cycle. By and large, other types of medications that may have a more favorable weight-gain profile have not been found to be effective for irritability. Until efficacious agents with a reduced propensity toward weight gain are identified, clinicians should prescribe atypical antipsychotics only after behavioral approaches and medications with more benign side-effect profiles have been tried. Because ideal medications for this indication may be a number of years from the market, controlled trials of concomitant administration of appetite- and weight-limiting medications should be pursued in clinical research studies. In addition, the authors of this article present data that link short sleep duration with increased body weight. Children with ASD are known to have significant sleep dysregulation and disturbances in serotonin and melatonin pathways, which contribute to sleep physiology.9 Reduced sleep affects the child’s behavior as well as family functioning. That sleep disturbance is related to obesity further underscores the importance of sleep regulation in ASD. Recently, results of systematic studies of sleep hygiene in ASD have been reported.10 With regard to medications to help with sleep disturbance, only melatonin has been studied in a placebo-controlled trial. It will be important that other medications, including trazodone and clonidine, be investigated in a rigorous manner, for those children that do not improve with more conservative interventions. Finally, in addition to the numerous challenges facing adults with ASD,11 obesity in childhood represents yet another threat to their independent living, self-care, quality of life, and health as they age.

Elaine Hsiao has provided a thoughtful review of gastrointestinal issues in ASD.12 She emphasizes the challenge to research in ASD presented by the vast clinical heterogeneity across individuals with the disorder. She posits that it will be necessary to identify well-delineated subtypes of persons with ASD in order to make meaningful progress on the search for etiologies and targeted treatments. Dr. Hsiao notes that the majority of children described by Leo Kanner13 in his landmark description of autism showed eating/feeding or dietary problems. She summarize studies of the prevalence of GI symptoms in ASD. The prevalence ranges from 9% to 91%, depending on the study, but an expert panel asserted that the preponderance of data are consistent with the likelihood of a high prevalence of GI symptoms and disorders associated with ASD. Dr. Hsiao next discusses the effects of two genes that have been implicated in ASD that may relate to GI disturbances. One of these genes, c-Met, is a proto-oncogene that encodes the MET receptor tyrosine kinase. Importantly, the c-Met promoter variant rs1858830 reflects a common single-nucleotide polymorphism that increases the risk for ASD, distinctively in individuals with ASD with co-occurring GI dysfunction. MET protein expression was also found to be decreased in the temporal cortex of postmortem brains from individuals with ASD, providing evidence for involvement of gut and brain. Dr. Hsiao then reviews evidence for another susceptibility gene for ASD, SLC6A4, which encodes for the serotonin transporter (SERT), and for how it may also be linked to GI dysfunction. SERT coding variants have been shown to result in hyperfunction of SERT activity. When this overactivity occurs on the membrane of circulating platelets, increased whole blood serotonin, or hyperserotonemia, results. Hyperserotonemia is the most well replicated biomarker for ASD.14 Because endocrine cells of the GI tract produce over 90% of the body’s serotonin, ASD-associated SERT polymorphisms are likely to disrupt GI serotonin metabolism and GI function. Finally, it is well known that the immune compartments of the GI tract contain about 80% of all immune cells in the body. Immune dysfunction has been identified in a large subset of persons with ASD.4 It seems likely that those persons with ASD and immune dysregulation may also have a higher prevalence of GI disturbances. Dr. Hsiao describes the bidirectionality of the communication between the GI tract and the brain stem via the vagus nerve, and provides further evidence of why the gut-brain connection may be so important in the pathophysiology of a subgroup of those with ASD. She concludes her article with a proposed model for a subtype of ASD that brings together genetic risk factors, hyperserotonemia, immune dysfunction, and GI abnormalities. Dr. Hsiao’s model sets the stage for testable hypotheses in a potentially meaningful subtype of ASD—something our field has been lacking.

Next, Dr. Hazen and colleagues15 provide a review of the literature on sensory symptoms in ASD. While difficulties responding appropriately to sensory stimuli in the environment have been documented dating back to Kanner’s first description of the disorder, it was not until recently that sensory dysfunction came to be seen as a more central component of ASD, by virtue of being associated with social and linguistic impairment, repetitive behaviors, and anxiety. The prevalence of sensory symptoms in ASD has been estimated to be between 69% and 95% across studies. Differences in degree of sensory symptoms may be associated with age, severity of autism, and IQ as well as other features of ASD, though studies are mixed and further research is warranted. What is already clear, however, is that sensory dysfunction is associated with more problem behaviors and lower adaptive functioning. The authors describe the three subtypes of disorders of sensory modulation: sensory overresponsivity, sensory underresponsivity, and sensory-seeking behavior. Some individuals suffer from a combination of overresponsivity and underresponsivity. Despite the prevalence of these difficulties, the field lacks assessment instruments that are specifically tailored to individuals with ASD. In addition, the pathophysiology and underlying neurobiology of the sensory symptoms in ASD remain unknown. The authors thoughtfully outline studies that have explored the relationship of sensory symptoms to attentional issues and anxiety, and describe a recent article documenting that both anxiety and sensory overresponsivity predict the number of GI difficulties in youth with ASDs. The authors conclude by reviewing the various treatments available for sensory symptoms, highlighting that the best current intervention involves an occupational therapy program that is tailored to the individual. Further research is warranted in this particular area.

The final article in this special issue focuses on an increasingly important topic: identifying the unmet needs of college students on the ASD spectrum. A recently released document entitled the Massachusetts Autism Commission Report (2013) indicated—based on a survey of institutions of higher education—that the number of individuals with ASD enrolling in college has increased over the past five years, creating the need for greater professional development on the social and communication challenges of individuals with ASD.16 Other publications highlight this rise across the nation. The numbers of college students on the spectrum will continue to rise as the prevalence of the disorder continues to increase and as individuals who are higher functioning continue to be appropriately diagnosed.17 Stephanie Pinder-Amaker’s review18 tackles the important question as to how to accommodate the needs of youth on the spectrum as they matriculate to college. She emphasizes the importance of supporting the core deficits of ASD and monitoring for the emergence or worsening of comorbid psychopathologies as youth transition from the therapeutic supports of their secondary school settings to the complex and unfamiliar milieu of the college campus. As a framework for understanding the transitional challenges for ASD students, Dr. Pinder-Amaker uses a bioecological systems theory of development. In this approach, multiple systems—ranging from the immediate family milieu up to the broad level of social, economic, and political forces—influence the individual and, in the context of transitioning ASD students, need to be taken into account when creating efforts to enhance their success at the college level.

Students on the ASD spectrum are at heightened risk for school and social failure and for withdrawal from college. Dr. Pinder-Amaker reviews the evidence base for interventions and supports for college students with mental illness and for those with ASD, drawing upon similarities and differences to establish a foundation for supporting youth who confront these challenges. The article highlights the importance of enhancing the transition from secondary school to college by having professionals at both levels working to coordinate the transition, thereby providing cross-fertilization of knowledge and practice. The article also highlights the increased vulnerability to stress around transition points, the need for sexual education and appropriate interaction, and the need for attention to health disparities. Dr. Pinder-Amaker indicates that further population-based research should examine the influence of race, ethnicity, socioeconomic status, and culture on transitioning to college. During secondary school, parents, teams, and teachers routinely interact to develop individualized educational plans (IEPs) for youth on the spectrum. But when this type of support is most needed—as students embark on the unfamiliar academic and social challenges of the college environment—the available services are fragmented and not designed with the ASD student in mind. The sharp divide between child and adult services further exacerbates the situation. While recent literature has begun to examine the needs of college students with ASD and to propose potential supports, none of the available research has evaluated the effectiveness of those proposed supports in enhancing the successful college outcomes for students on the spectrum. The evidence-based literature for students with disabilities may offer some insights, but the approaches will need to be more fully tailored and validated in the ASD student group. Promising interventions include video modeling, multisystemic therapy, and the Transition to Independence Process model, but further research is indicated.

In general, ASD students who are successful in college have an understanding of their disability and are able to seek assistance and to advocate for their needs. Dr. Pinder-Amaker recommends that the ideal transition plan would include evidence-based practices of both the secondary and college educational systems, that individual adjustments be made as necessary, and that those adjustments be integrated into a coordinated overall plan. She also recommends identifying who or what on the college level could serve as the counterparts of the secondary school support system—which would presumably require a shift from school-parent-IEP constellation at the secondary level to a more flexible approach at the college level in which the student and support team work together within an overall plan but also deal with new problems as they arise. Finally, Dr. Pinder-Amaker suggests some sort of bridging process that would begin in secondary school with a “student-in-training”; in addition to reframing their IEPs into an individualized plan for the college level, students would engage in a summer program specifically designed to facilitate their matriculation to, and subsequent success in, college.

In closing, we hope you find this compilation of reviews of various dimensions of ASD both informative and useful in your clinical practice. The increasing numbers of individuals with ASD mandate such a special journal issue. Clearly, more research is needed on every level for the field to help support and treat individuals on the spectrum so that they can optimize their developmental trajectory and, as adults, become integral members of our society and work force.

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