Responses to NIH Questions
Question 1: What are the most important goals for future research on medical interventions?
There are two overriding objectives for future research on medical interventions: (a) rigorous evaluation of the effectiveness of currently available medical approaches to treatment: (b) facilitation of the creation of newer approaches to treatment that utilize advances in neuroscience, genetics, immunology, and other associated fields.
Evaluation of Treatment.
The development and testing of biological interventions is a complex process that requires collaboration among clinicians and basic biological and behavioral scientists, including pharmacologists, psychologists, statisticians, and other neuroscientists. This process of clinical research should be embedded within suitable institutional contexts in which clinical care and investigation can be integrated, and in which there can be state of the art pharmacological and behavioral assessments of individuals with autism, at different phases of development and longitudinally. The infrastructure for this program includes the following components: (a) well-trained investigators familiar with the phenomenology and natural history of autism and with sophisticated methods of psychopharmacological research; (b) centers in which individuals with autism can be engaged in long-term biological research protocols, including inpatient and outpatient facilities, laboratories for biological and behavioral assessment, nursing and other staff for monitoring overall response, concurrent treatments, and support to assure long-term engagement of families in the research; (c) development and refinement of methodologies for assessment and for monitoring changes in various domains of functioning (including clinical rating procedures. behavioral observational methods, studies of functioning in important contexts, and laboratory-based assessments of cognition. attention, and other domains).
Advances in genetics, neuroscience, pharmacology, and other areas will continue to suggest new approaches to intervention. It is important to have investigators who are familiar with emerging areas of knowledge that may be relevant to autism (e.g., to new agents that are under development). Also, there should be increased emphasis on finding treatments that are specifically related to the core problems of autism. Currently, all medications used with individuals with autism were screened on test systems that are not specific for core symptoms of autism (e.g., screened in relation to antipsychotic and antidepressant potential). They have been used with children and with individuals with autism, in particular, as orphan indications. There is no current program aimed at developing and testing agents that may specifically relate to core areas of autistic disturbance—social and communicative impairments. The development of new approaches may be based on increasing understanding of the biological preconditions for social attachment, for example, the role of hormonal systems in modulating attachment, on important systems (e.g., dopaminergic, serotonergic, noradrenergic, and peptidergic systems and their interactions) that are implicated in specific classes of symptoms, and on genetic factors in behavioral development and disorder (as these are elucidated). In the future, the field of genetic pharmacology will play an increasingly important role. This field integrates molecular genetics and biological interventions that are specifically targeted at changing the expression of genes. With the localization of specific genes and characterization of gene products that may be related to autism, a new era of biological intervention will be opened.
Recommendations of the Working Group on Medical Intervention
The design of biological intervention studies is complicated by heterogeneity among individuals with autism, the importance of following the effect of treatments over long periods of time to determine changes in developmental course, the many different agents and procedures that are available for study, and questions of informed consent.
- A task force is needed to study improved approaches to the evaluation of treatment to complement the standard, double-blind, placebo-controlled trials. In addition to efficacy, it is important to have studies that relate to clinical effectiveness for diverse groups of individuals with autism and over longer periods. New statistical methods for assessment of developmental course (e.g., individual growth curve analysis) may be helpful, and statisticians, methodologists, pharmacologists, parents, and clinicians need to be able to work together as teams to design suitable approaches.
- The use of medication is rarely appropriate without other treatment approaches, including educational and behavioral interventions. This collaborative approach will provide maximum benefit for the patients and data normally collected in educational settings can prove useful in evaluating medical interventions in "real life." Once efficacy of a single aspect of treatment (i.e., medical or behavioral) is demonstrated, drug behavioral intervention interactions can be tested, but increases in sample sizes needed to test such effects tend to be exponential in numbers and cost.
- Currently available assessment methodologies are perhaps more useful for baseline assessment than for monitoring change. New methods for assessment may be needed for "lower functioning" individuals and for carefully following the course of treatment response in various positive domains (learning, social, emotional, cognitive) as well as on target symptoms (e.g., aggression, activity level). Functioning in situations of daily living needs to be assessed as well as symptom severity. Short- and long-term side effects need to be monitored.
- Response to treatment may help define new subtypes of individuals with autism and lead to further understanding of biological subtyping.
- In the assessment of individuals with autism, epidemiological study of dietary history and current functioning is needed. Studies are needed of the unusual eating behavior of individuals with autism (e.g., limited diets, craving for or avoidance of certain foods, eating unusual substances) which has been shown in other disorders to lead to elevated levels of lead or reductions in important dietary components. Such study may also reveal possible undiagnosed symptoms related to diet (e.g., MSG or lactose intolerance) or reflect metabolic disorders.
- Pharmacological interventions may require the use of more than one medication at a time. For example, the treatment of some nonautistic individuals with obsessive-compulsive disorder may sometimes be improved by the augmentation of a serotonin reuptake inhibitor with a neuroleptic (e.g., fluvoxamine + pimozide). Similar clinical needs are presented by some individuals with autism. Systematic research is needed to understand the biological and behavioral effects of multiple drug use.
- A coordinated plan for supporting rigorous, sustained clinical research on biological interventions in autism is needed. This includes (a) facilitation of training programs and career development in the field of pediatric neuropsychopharmacology and associated fields of clinical research; (b) creation of centers for long-term engagement in the field of biological clinical research. This initiative might be undertaken as an expansion of the current NICHD networks on pediatric pharmacology. Centers involved in this work should have the capacity for rigorous behavioral and biological assessment, integration of biological and behavioral interventions, and long-term follow-up; (c) establishment of multicenter collaborations for evaluation of biological and behavioral interventions (in which studies can be implemented, monitored, and carefully assessed over longer periods of time, including short-term improvements as well as long-term effects on developmental course); (d) NIH should work with advocacy and professional organizations to increase the awareness of parents, professionals, and government about the importance of rigorous scientific research on biological interventions. This includes helping parents and advocates recognize the value of volunteering for studies (including placebo-controlled designs) that may delay the onset of treatment for certain individuals but will ultimately benefit the individual involved as well as the advancement of the field by promoting authentic scientific knowledge that can inform treatment.
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