JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 25, Number 4, 2015 ª Mary Ann Liebert, Inc. Pp. 282–285 DOI: 10.1089/cap.2015.28999.mga
Guest Editorial
Assessing Change in Core Autism Symptoms: Challenges for Pharmacological Studies Michael G. Aman, PhD, L. Eugene Arnold, MD, and Jill A. Hollway, Ph.D.
T
hese days, there is considerable interest in attempts to treat certain developmental disabilities pharmacologically. In this discussion, we periodically step outside the fields of psychopharmacology or autism to see what lessons can be learned for the study of core autism features. If we explore Clinicaltrials.gov, we see approximately 20 studies underway or recently completed among patients with autism spectrum disorder (ASD), Down syndrome, or Fragile X syndrome. Recently, we completed a small trial of mecamylamine in children with autism and pervasive developmental disorder not otherwise specified (Arnold et al., 2012). This trial was the occasion for reflections on the issue of how to measure change in the core symptoms of autism in the context of pharmacological intervention. The purpose of this editorial is to make some observations, pose questions, and offer some suggestions regarding the measurement of ASD core symptoms. We also comment on the clinical and research context in which such investigations must take place. Autism Spectrum Disorder as a Developmental Disability: Implications for Pharmacotherapy
ASD is a neurodevelopmental disorder—i.e., it becomes evident in the course of development, usually within the first three years of life. As a developmental disability, we see three areas of profound social impairment involving failure to develop normally. First, there are profound deficits in social-emotional reciprocity (APA, 2013). The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), gives the following examples of deficits in social and emotional reciprocity: Poor social approach, failure to engage in reciprocal conversations, reduced sharing of thoughts, experiences, and emotions. Second, there are deficits in nonverbal communication, including the ability to integrate gesture, eye contact, facial expressions, and body language when communicating with others. Third, there are deficits in the development and understanding of relationships, which may include a lack of interest in others and lack of joint interactive imaginative play (APA, 2013). Also included in the diagnostic criteria are behavioral excesses encompassing restricted, repetitive, or narrow patterns of behaviors and interests, including repetitive physical movements or speech, insistence on sameness or routines, narrow or fixated interests, and odd reactions (often increased or muted) to sensory aspects of the environment. The key issue here is that these developmental deficits suggest months and (usually) years of failure to develop and progress at normal rates. When practiced in the general population, the field of psychopharmacology tends to focus on recovery to the premorbid
status (i.e., on reversible symptoms, such as major depression or significant anxiety disorder). In the case of ASD, there is usually no premorbid period in which patients had essentially normal behavior or development, unless we count the first months of life before the problems are noted. The study participants have not ‘‘stored up’’ the relevant developmental information to be released later with the onset of successful pharmacotherapy. Hence, true therapeutic success for individuals with ASD is likely to require months or even years to reach the patient’s new adaptive level. This has obvious implications for pharmacological trials, including matters related to duration of the trial, ideal age of the participants (younger children may be more ‘‘plastic’’ than older adults), and therapeutic medium in which participants are embedded (e.g., rich and educational environment vs. bland environment lacking educational value). Relevant questions to ask when contemplating treatments for people with ASD include the following: (a) Should we be looking for mastery of new developmental milestones? (b) Is it realistic to expect change in the absence of active ASD psychosocial or educational intervention? (c) Should the form of change measurement be focused on core ASD symptoms or developmental course (e.g., language development, adaptive behavior), or both? (d) What is a reasonable time frame in which to witness changes in core ASD symptoms or in developmental indices? (e) Should the focus be on reduction of behavioral excesses (restricted, repetitive, or narrow patterns of behaviors and interests) rather than on expansion of the person’s social deficits? Past Struggles with Assessing ASD Symptoms In our study of mecamylamine (Arnold et al., 2012), we encountered some obstacles that we did not anticipate. Here are a few of them. We hope that these are instructive little lessons to others as they attempt to assess promising therapeutic agents. 1. AbstruseTerminology a Barrier. Most of us are very accustomed to using complex terminology from the DSM, from psychology, and from neuroscience in general. However, we did not fully anticipate the challenges in ‘‘translating’’ our questions into language that the parents of our patients readily understood. One instrument that we worked with was the unpublished OSU Autism Rating Scale—DSM-IV (OARS-4), which appears on our Web site: http://psychmed.osu.edu/resources.htm. This is a checklist of 12 symptoms of autistic disorder that were listed in the DSM-IV. We have already employed some of that language in this editorial, such as ‘‘social-emotional reciprocity,’’ as discussed earlier; ‘‘spontaneous impairments in seeking to share
The Nisonger Center UCEDD, Ohio State University, Columbus, Ohio.
282
GUEST EDITORIAL enjoyment, interests, or achievements with other people,’’ the third rating item on the OARS-4, is another such expression. Although all of the parents of our patients have been ‘‘through the drill’’ before, such as when their children were originally diagnosed with ASD, suffice it to say that our shorthand language is a barrier and is not always easy to modify and make comprehensible to parents within the confines of a short visit. At some stage, such interview questions usually need to be made simpler, more concrete, and expressed in everyday language. The extent to which this translation takes place ‘‘on the fly’’ poses a risk to the reliability of the transaction. 2. Coarseness in Our Clinical Global Impressions- Improvement Format. One instrument that we worked with was the Ohio Autism Clinical Impressions Scale (OACIS) (Butter & Mulick, 2006), whose format is modeled on the ubiquitous Clinical Global Impressions (CGI) Scale used in most psychopharmacological trials (Guy, 1976). Like the CGI-Improvement Scale, the OACIS improvement scale is scored on a metric that extends from 7 (very much worse) through 4 (no change), to 1 (very much improved). The main problem with this metric tended to occur between a score of 3 (minimally improved) to 2 (much improved). There were several times when we felt that a child’s improvements extended beyond modest gains, connoted by a 3, but that they did not reach the rather stellar level suggested by a score of 2. In some ways, our conundrum was probably due to the largely inert effects of the drug on ASD symptoms. However, we strongly felt that we needed some middle ground between scores of 2 and 3 on this scale. Later efforts to assess core ASD symptoms coincided with an additional score that effectively resided midway between former 2 and 3 of this scale (making an 8-point scale with 5 = no change). 3. NormalReactivity to Assessment. Many investigators rightly fear that placebo responses will obfuscate any true signal that may emerge from the study intervention. To take an historical example, many of the secretin studies that took place in the late 1990s and early 2000s occurred in an era of ebullient personal testimonials and unrealistic hope, often resulting in trials that showed improvements with all experimental interventions, including placebo (Sturmey, 2005). However,not all change that is non-pharmacological is placebo response in nature. In our mecamylamine ASD trial, we routinely reviewed all of the main symptoms of ASD with the subjects’ parents. This directed some parents’ attention to the targets of treatment. At least one participating family decided to address some of the most troublesome symptoms exhibited by their son, and they chose a rational approach to doing so. The child concerned had very intense interests, and he would frequently lapse into periods when all he wanted to do was to focus on that activity. Following a few study assessments, the child’s parents decided to ‘‘break into’’ these periods of overfocus, with the result that these episodes were much shorter and less common. Consequently, our assessment of this symptom of ASD showed substantial change but that change was externally imposed by the parents. Interestingly,this boy’s parents also became aware of the importance of spontaneous play and of verbal and nonverbal communication. The child’s parents, who were very diligent, obtained DVDs for teaching sign language, and both the child and his mother began to learn to communicate by signing. The moral is obvious: The assessment process can actually have a teaching function. Furthermore, there may well be reactivity to the assessment process that results in growth for study participants and that has nothing whatsoever to do with the treatment under study!
283 4. Overspecificityof Symptoms. Certain symptoms appearing on the OARS-4 were too specific for routine use in a pharmacological study of this type. For instance, the last item in section C of the scale probed about overly focused interests and asked about ‘‘preoccupation with parts of objects.’’ This item did not occur commonly in our sample, and it seemed to be developmentally specific in that it tended to occur during particular phases of the children’s lives. Hence, several of our children displayed this type of overfocus with parts of objects, but this tended to occur primarily in their earlier years. On reflection, we realized that the overarching concept might be captured better by using a modification, such as the following: ‘‘Child fails to use toys and other objects imaginatively and/or uses them in a nonfunctional manner.’’ The advantages of such expanded terms is that they should be relevant throughout subjects’ lives and not be dependent on the presence of particular ‘‘props,’’ such as toys. Autism Spectrum Disorder: Final Common Pathway or Multiple Distinctive Conditions? As a syndrome, ASD is characterized by a distinctive set of symptoms, an early developmental course that is reasonably well described, and an early—but now rapidly becoming dated—literature on its natural course with the aging process. With time, we will almost certainly discover a few (unlikely) or many (highly likely) genetic and other etiological factors that collectively predispose to and cause ASD. From the perspective of pharmacological research, it is important to be mindful of this issue. If the intervention is active somewhere other than the ‘‘final common pathway,’’ this suggests that only some members of the active treatment group will show true change from the intervention. That, in turn, has important implications for sample selection, determination of sample size, and a variety of other methodological issues. Multiple Comorbidities Obscuring Target Symptoms Treatments that have been demonstrated effective in the ASD population generally target associated symptoms or disorders, such as irritability/aggression or attention-deficit/hyperactivity. Other common comorbidities are anxiety, obsessive-compulsive disorder, and stereotyped self-injury. These complicate assessment of core autism symptoms in several ways. If they preoccupy the caregiver, they can distract from noticing improvements in core symptoms. Also, if they improve from the treatment, ratings of core symptoms may reflect a halo effect. Finally, they may moderate or mediate improvement in core symptoms. Must Selection of Suitable Tools Await Proven Treatments in Autism Spectrum Disorder (or ‘‘What Came First, The Chicken or the Egg?’’) When attempting to identify optimal instruments for assessing change in symptoms of ASD, it is fairly common to hear professionals say that we will not know the value of our outcome measures until we have therapeutic agents that truly reduce ASD symptoms. To us this seems an unfortunate position and one that is unlikely to be true. The real crux of the issue seems to be the sensitivity of existing instruments to change or, perhaps more accurately, how quickly existing instruments will detect change. When choosing an outcome tool for assessing change in core ASD symptoms, the paramount considerations should concern the instrument’s psychometric characteristics. Psychologists have become quite sophisticated in determining how to evaluate
284 psychometric characteristics, and cutting-edge psychometric methods continue to evolve. In any case, the best indicators for selecting a sound outcome tool will include presence of wellestablished reliability and validity, suitability for repeated administration, and ease of use. Of necessity, the optimal instruments will assess current functioning; those that dwell on developmental history will be bad candidates because a focus on recent change cannot be determined through knowledge of the past. There are several good candidates for assessing change in core symptoms of ASD, and we shall mention just two of them here. The Autism Impact Measure (AIM; Kanne et al., 2014) is a recent candidate that appears to hold good promise for assessing change in ASD severity in children. The Social Responsiveness Scale (Constantino et al., 2003) may prove to be a good outcome measure in children, adolescents, and adults. A myriad of other possible measures were discussed in a review by Aman and colleagues (Aman et al., 2004). In that review, the authors pointed out that appraisal of change should not necessarily be confined to ASD-specific symptoms. Adaptive behavior, IQ, and language are three examples of domains that are very important to individuals with ASD. Glass Half Full There have now been numerous studies of early intensive behavior intervention (EIBI), and these have been reviewed in several meta-analyses (Reichow, 2012; Virue´s-Ortega, 2010). Basically, EIBI entails the use of a number of specific interventions derived from applied behavior analysis (ABA) to teach skills to young children with ASD using detailed curricula that break down a host of skills into smaller discrete steps. EIBI is usually intense, comprising 20 hours or more of contact per week, and durations of a year or more are quite common. Virue´s-Ortega (2010) reviewed 25 EIBI studies, and he documented the use of the following outcome measures: (a) full-scale IQ (18 studies), (b) nonverbal IQ (9 studies), (c) receptive language (10 studies), (d) expressive language (9 studies), (e) adaptive behavior (including communication, daily living skills, and socialization; 10 studies each), and (f) overall composite adaptive behavior (14 studies). It is clear that building IQ and skill acquisition have been major objectives in studies of EIBI. As noted earlier, there have also been numerous studies of secretin in ASD. As reported in one review (Sturmey, 2005), these included (a) measures of ASD symptoms from paper instruments (e.g., Gilliam Autism Rating Scale, Autism Behavior Checklist, others), (b) live interactive assessments of autism symptoms using social prompts, (c) behavior problem assessments (e.g., Aberrant Behavior Checklist), (d) language and communication scales, (e) visual perception scales, and (f) adaptive behavior scales. We note that there are other ongoing trials mentioned in our introduction with samples of individuals having ASD, Fragile X syndrome, and Down syndrome, and these are employing a mix of outcome measures, some of which may be highly relevant to pharmacological treatment of ASD symptoms. Also, there are other trials of high interest such as ABA investigations of joint attention, functional communication treatment, and problem behavior. Recently, researchers at Vanderbilt University performed critical analyses of most of the intervention research in ASD. Their original meta-analysis encompassed 159 studies (Warren et al, 2011), and their update included an additional 65 studies (Weitlauf et al., 2014). Thus, we know that there have been at least 224 investigations in people with ASD, and each of these has employed a selection of outcome measures. The upshot is that different dis-
GUEST EDITORIAL ciplines (e.g., psychopharmacology, EIBI, joint attention, behavioral management of problem behavior) has made its own contribution to outcomes assessment. This lends itself to systematic study and an opportunity to evaluate assessment approaches. By careful study of these outcomes, we should be able to learn valuable lessons about placebo effects, practice effects, stability over time, reliability. and variability of measurement over time. With luck, we may also learn about temporal responsiveness to treatment effects and sensitivity to treatment. In so doing, we shall begin to develop a true science of outcome measures for ASD symptoms and so begin to put ourselves on solid true footing for launching pharmacological trials with confidence. The glass is at least half full! Acknowledgment The authors thank Professor Luc Lecavalier (The Nisonger Center UCEDD, Ohio State University) for critical suggestions on this document. Disclosures Dr. Arnold has received research funding from CureMark, Forest, Lilly, and Shire; advisory board honoraria from Biomarin, Novartis, Noven, Otsuka, Roche, Seaside Therapeutics, and Shire; consulting fees from Gowlings, Pfizer, and Tris Pharma; and travel support from Noven. Dr. Aman has received research contracts from, consulted with, or served on advisory boards of Biomarin Pharmaceuticals, Bristol-Myers Squibb, CogState, Confluence Pharmaceutica, Coronado Bioscience, Forest Research, Hoffman LaRoche, Johnson & Johnson, MedAvante Inc., Neuren Pharmaceuticals, Novartis, ProPhase LLC, and Supernus Pharmaceutica. Dr. Hollway has received research support from Forest Research, Young Living, Supernus Pharmaceutica, and Sunovian Pharmaceuticals. References Aman MG, Novotny S, Samango-Sprouse C, Lecavalie, L, Leonard E, Gadow KD, King BH, Pearson DA, Gernsbacher MA, Chez M: Outcome measures for clinical drug trials in autism. CNS Spectrums 9:36–48, 2004. Arnold LE, Aman MG, Hollway J, Hurt E, Bates B, Li X, Farmer C, Anand R, Thompson S, Ramadan Y, Williams C: Placebocontrolled pilot trial of mecamylamine for treatment of autism spectrum disorders. J Child Adolesc Psychopharmacol 22:198–205, 2012. Butter EM, Mulick JA: Assessing the core symptoms of autism spectrum disorders: The development of the Ohio Autism Clinical Impressions Scale. Poster presented at the New Clinical Drug Evaluation Unit Conference, Boca Raton, FL, June, 2006. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W: Validation of a brief quantitative measure of autistic traits: Comparison of the Social Responsiveness Scale with the Autism Diagnostic Interview-Revised. J Autism Developmental Dis 33:427– 433, 2003. Guy W, editor:ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, 1976. Kanne SM, Mazurek MO, Sikora D, Bellando J, Branum-Martin L, Handen B, Katz K, Freedman B, Powell MP, Warren Z: The Autism Impact Measure (AIM): Initial development of a new tool for treatment outcome measurement. J Autism Developmental Dis 44:168–179, 2014.
GUEST EDITORIAL Reichow B: Overview of meta-analyses on early intensive behavioral intervention for young children with autism spectrum disorders. J Autism Developmental Dis 42:512–520, 2012. Sturmey P: Secretin is an ineffective treatment for pervasive developmental disabilities: A review of 15 double-blind randomized controlled trials. Res Developmental Disabilities 26:87–97, 2005. Virue´s-Ortega J: Applied behavior analytic intervention for autism in early childhood: Meta-analysis, meta-regression and dose-response meta-analysis of multiple outcomes. Clin Psychology Rev 30:387– 399, 2010. Warren Z, Veenstra-VanderWeele J, Stone W, Bruzek JL, Nahmias AS, Foss-Feig JH, Jerome RN, Krishnaswami S, Sathe NA, Glasser AM, Surawicz T, McPheeters ML. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2007-10065-I.) AHRQ Publication No. 11-EHC029-EF. Rockville, MD: Agency for Healthcare Research and Quality. April 2011. Available at: www.effectivehealth care.ahrq.gov/reports/final.cfm.
285 Weitlauf AS, McPheeters ML, Peters B, Sathe N, Travis R, Aiello R, Williamson E, Veenstra-VanderWeele J, Krishnaswami S, Jerome R, Warren Z. Therapies for Children With Autism Spectrum Disorder: Behavioral Interventions Update. Comparative Effectiveness Review No. 137. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2012-00009-I.) AHRQ Publication No. 14-EHC036-EF. Rockville, MD: Agency for Healthcare Research and Quality; August 2014. www.effectivehealth care.ahrq.gov/reports/final.cfm.
Address correspondence to: Michael G. Aman, PhD Professor Emeritus of Psychology The Nisonger Center (OCEDD) Ohio State University 1581 Dodd Drive Columbus, Ohio 43210 E-mail: [email protected]
Guest Editorial
Assessing Change in Core Autism Symptoms: Challenges for Pharmacological Studies Michael G. Aman, PhD, L. Eugene Arnold, MD, and Jill A. Hollway, Ph.D.
T
hese days, there is considerable interest in attempts to treat certain developmental disabilities pharmacologically. In this discussion, we periodically step outside the fields of psychopharmacology or autism to see what lessons can be learned for the study of core autism features. If we explore Clinicaltrials.gov, we see approximately 20 studies underway or recently completed among patients with autism spectrum disorder (ASD), Down syndrome, or Fragile X syndrome. Recently, we completed a small trial of mecamylamine in children with autism and pervasive developmental disorder not otherwise specified (Arnold et al., 2012). This trial was the occasion for reflections on the issue of how to measure change in the core symptoms of autism in the context of pharmacological intervention. The purpose of this editorial is to make some observations, pose questions, and offer some suggestions regarding the measurement of ASD core symptoms. We also comment on the clinical and research context in which such investigations must take place. Autism Spectrum Disorder as a Developmental Disability: Implications for Pharmacotherapy
ASD is a neurodevelopmental disorder—i.e., it becomes evident in the course of development, usually within the first three years of life. As a developmental disability, we see three areas of profound social impairment involving failure to develop normally. First, there are profound deficits in social-emotional reciprocity (APA, 2013). The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), gives the following examples of deficits in social and emotional reciprocity: Poor social approach, failure to engage in reciprocal conversations, reduced sharing of thoughts, experiences, and emotions. Second, there are deficits in nonverbal communication, including the ability to integrate gesture, eye contact, facial expressions, and body language when communicating with others. Third, there are deficits in the development and understanding of relationships, which may include a lack of interest in others and lack of joint interactive imaginative play (APA, 2013). Also included in the diagnostic criteria are behavioral excesses encompassing restricted, repetitive, or narrow patterns of behaviors and interests, including repetitive physical movements or speech, insistence on sameness or routines, narrow or fixated interests, and odd reactions (often increased or muted) to sensory aspects of the environment. The key issue here is that these developmental deficits suggest months and (usually) years of failure to develop and progress at normal rates. When practiced in the general population, the field of psychopharmacology tends to focus on recovery to the premorbid
status (i.e., on reversible symptoms, such as major depression or significant anxiety disorder). In the case of ASD, there is usually no premorbid period in which patients had essentially normal behavior or development, unless we count the first months of life before the problems are noted. The study participants have not ‘‘stored up’’ the relevant developmental information to be released later with the onset of successful pharmacotherapy. Hence, true therapeutic success for individuals with ASD is likely to require months or even years to reach the patient’s new adaptive level. This has obvious implications for pharmacological trials, including matters related to duration of the trial, ideal age of the participants (younger children may be more ‘‘plastic’’ than older adults), and therapeutic medium in which participants are embedded (e.g., rich and educational environment vs. bland environment lacking educational value). Relevant questions to ask when contemplating treatments for people with ASD include the following: (a) Should we be looking for mastery of new developmental milestones? (b) Is it realistic to expect change in the absence of active ASD psychosocial or educational intervention? (c) Should the form of change measurement be focused on core ASD symptoms or developmental course (e.g., language development, adaptive behavior), or both? (d) What is a reasonable time frame in which to witness changes in core ASD symptoms or in developmental indices? (e) Should the focus be on reduction of behavioral excesses (restricted, repetitive, or narrow patterns of behaviors and interests) rather than on expansion of the person’s social deficits? Past Struggles with Assessing ASD Symptoms In our study of mecamylamine (Arnold et al., 2012), we encountered some obstacles that we did not anticipate. Here are a few of them. We hope that these are instructive little lessons to others as they attempt to assess promising therapeutic agents. 1. AbstruseTerminology a Barrier. Most of us are very accustomed to using complex terminology from the DSM, from psychology, and from neuroscience in general. However, we did not fully anticipate the challenges in ‘‘translating’’ our questions into language that the parents of our patients readily understood. One instrument that we worked with was the unpublished OSU Autism Rating Scale—DSM-IV (OARS-4), which appears on our Web site: http://psychmed.osu.edu/resources.htm. This is a checklist of 12 symptoms of autistic disorder that were listed in the DSM-IV. We have already employed some of that language in this editorial, such as ‘‘social-emotional reciprocity,’’ as discussed earlier; ‘‘spontaneous impairments in seeking to share
The Nisonger Center UCEDD, Ohio State University, Columbus, Ohio.
282
GUEST EDITORIAL enjoyment, interests, or achievements with other people,’’ the third rating item on the OARS-4, is another such expression. Although all of the parents of our patients have been ‘‘through the drill’’ before, such as when their children were originally diagnosed with ASD, suffice it to say that our shorthand language is a barrier and is not always easy to modify and make comprehensible to parents within the confines of a short visit. At some stage, such interview questions usually need to be made simpler, more concrete, and expressed in everyday language. The extent to which this translation takes place ‘‘on the fly’’ poses a risk to the reliability of the transaction. 2. Coarseness in Our Clinical Global Impressions- Improvement Format. One instrument that we worked with was the Ohio Autism Clinical Impressions Scale (OACIS) (Butter & Mulick, 2006), whose format is modeled on the ubiquitous Clinical Global Impressions (CGI) Scale used in most psychopharmacological trials (Guy, 1976). Like the CGI-Improvement Scale, the OACIS improvement scale is scored on a metric that extends from 7 (very much worse) through 4 (no change), to 1 (very much improved). The main problem with this metric tended to occur between a score of 3 (minimally improved) to 2 (much improved). There were several times when we felt that a child’s improvements extended beyond modest gains, connoted by a 3, but that they did not reach the rather stellar level suggested by a score of 2. In some ways, our conundrum was probably due to the largely inert effects of the drug on ASD symptoms. However, we strongly felt that we needed some middle ground between scores of 2 and 3 on this scale. Later efforts to assess core ASD symptoms coincided with an additional score that effectively resided midway between former 2 and 3 of this scale (making an 8-point scale with 5 = no change). 3. NormalReactivity to Assessment. Many investigators rightly fear that placebo responses will obfuscate any true signal that may emerge from the study intervention. To take an historical example, many of the secretin studies that took place in the late 1990s and early 2000s occurred in an era of ebullient personal testimonials and unrealistic hope, often resulting in trials that showed improvements with all experimental interventions, including placebo (Sturmey, 2005). However,not all change that is non-pharmacological is placebo response in nature. In our mecamylamine ASD trial, we routinely reviewed all of the main symptoms of ASD with the subjects’ parents. This directed some parents’ attention to the targets of treatment. At least one participating family decided to address some of the most troublesome symptoms exhibited by their son, and they chose a rational approach to doing so. The child concerned had very intense interests, and he would frequently lapse into periods when all he wanted to do was to focus on that activity. Following a few study assessments, the child’s parents decided to ‘‘break into’’ these periods of overfocus, with the result that these episodes were much shorter and less common. Consequently, our assessment of this symptom of ASD showed substantial change but that change was externally imposed by the parents. Interestingly,this boy’s parents also became aware of the importance of spontaneous play and of verbal and nonverbal communication. The child’s parents, who were very diligent, obtained DVDs for teaching sign language, and both the child and his mother began to learn to communicate by signing. The moral is obvious: The assessment process can actually have a teaching function. Furthermore, there may well be reactivity to the assessment process that results in growth for study participants and that has nothing whatsoever to do with the treatment under study!
283 4. Overspecificityof Symptoms. Certain symptoms appearing on the OARS-4 were too specific for routine use in a pharmacological study of this type. For instance, the last item in section C of the scale probed about overly focused interests and asked about ‘‘preoccupation with parts of objects.’’ This item did not occur commonly in our sample, and it seemed to be developmentally specific in that it tended to occur during particular phases of the children’s lives. Hence, several of our children displayed this type of overfocus with parts of objects, but this tended to occur primarily in their earlier years. On reflection, we realized that the overarching concept might be captured better by using a modification, such as the following: ‘‘Child fails to use toys and other objects imaginatively and/or uses them in a nonfunctional manner.’’ The advantages of such expanded terms is that they should be relevant throughout subjects’ lives and not be dependent on the presence of particular ‘‘props,’’ such as toys. Autism Spectrum Disorder: Final Common Pathway or Multiple Distinctive Conditions? As a syndrome, ASD is characterized by a distinctive set of symptoms, an early developmental course that is reasonably well described, and an early—but now rapidly becoming dated—literature on its natural course with the aging process. With time, we will almost certainly discover a few (unlikely) or many (highly likely) genetic and other etiological factors that collectively predispose to and cause ASD. From the perspective of pharmacological research, it is important to be mindful of this issue. If the intervention is active somewhere other than the ‘‘final common pathway,’’ this suggests that only some members of the active treatment group will show true change from the intervention. That, in turn, has important implications for sample selection, determination of sample size, and a variety of other methodological issues. Multiple Comorbidities Obscuring Target Symptoms Treatments that have been demonstrated effective in the ASD population generally target associated symptoms or disorders, such as irritability/aggression or attention-deficit/hyperactivity. Other common comorbidities are anxiety, obsessive-compulsive disorder, and stereotyped self-injury. These complicate assessment of core autism symptoms in several ways. If they preoccupy the caregiver, they can distract from noticing improvements in core symptoms. Also, if they improve from the treatment, ratings of core symptoms may reflect a halo effect. Finally, they may moderate or mediate improvement in core symptoms. Must Selection of Suitable Tools Await Proven Treatments in Autism Spectrum Disorder (or ‘‘What Came First, The Chicken or the Egg?’’) When attempting to identify optimal instruments for assessing change in symptoms of ASD, it is fairly common to hear professionals say that we will not know the value of our outcome measures until we have therapeutic agents that truly reduce ASD symptoms. To us this seems an unfortunate position and one that is unlikely to be true. The real crux of the issue seems to be the sensitivity of existing instruments to change or, perhaps more accurately, how quickly existing instruments will detect change. When choosing an outcome tool for assessing change in core ASD symptoms, the paramount considerations should concern the instrument’s psychometric characteristics. Psychologists have become quite sophisticated in determining how to evaluate
284 psychometric characteristics, and cutting-edge psychometric methods continue to evolve. In any case, the best indicators for selecting a sound outcome tool will include presence of wellestablished reliability and validity, suitability for repeated administration, and ease of use. Of necessity, the optimal instruments will assess current functioning; those that dwell on developmental history will be bad candidates because a focus on recent change cannot be determined through knowledge of the past. There are several good candidates for assessing change in core symptoms of ASD, and we shall mention just two of them here. The Autism Impact Measure (AIM; Kanne et al., 2014) is a recent candidate that appears to hold good promise for assessing change in ASD severity in children. The Social Responsiveness Scale (Constantino et al., 2003) may prove to be a good outcome measure in children, adolescents, and adults. A myriad of other possible measures were discussed in a review by Aman and colleagues (Aman et al., 2004). In that review, the authors pointed out that appraisal of change should not necessarily be confined to ASD-specific symptoms. Adaptive behavior, IQ, and language are three examples of domains that are very important to individuals with ASD. Glass Half Full There have now been numerous studies of early intensive behavior intervention (EIBI), and these have been reviewed in several meta-analyses (Reichow, 2012; Virue´s-Ortega, 2010). Basically, EIBI entails the use of a number of specific interventions derived from applied behavior analysis (ABA) to teach skills to young children with ASD using detailed curricula that break down a host of skills into smaller discrete steps. EIBI is usually intense, comprising 20 hours or more of contact per week, and durations of a year or more are quite common. Virue´s-Ortega (2010) reviewed 25 EIBI studies, and he documented the use of the following outcome measures: (a) full-scale IQ (18 studies), (b) nonverbal IQ (9 studies), (c) receptive language (10 studies), (d) expressive language (9 studies), (e) adaptive behavior (including communication, daily living skills, and socialization; 10 studies each), and (f) overall composite adaptive behavior (14 studies). It is clear that building IQ and skill acquisition have been major objectives in studies of EIBI. As noted earlier, there have also been numerous studies of secretin in ASD. As reported in one review (Sturmey, 2005), these included (a) measures of ASD symptoms from paper instruments (e.g., Gilliam Autism Rating Scale, Autism Behavior Checklist, others), (b) live interactive assessments of autism symptoms using social prompts, (c) behavior problem assessments (e.g., Aberrant Behavior Checklist), (d) language and communication scales, (e) visual perception scales, and (f) adaptive behavior scales. We note that there are other ongoing trials mentioned in our introduction with samples of individuals having ASD, Fragile X syndrome, and Down syndrome, and these are employing a mix of outcome measures, some of which may be highly relevant to pharmacological treatment of ASD symptoms. Also, there are other trials of high interest such as ABA investigations of joint attention, functional communication treatment, and problem behavior. Recently, researchers at Vanderbilt University performed critical analyses of most of the intervention research in ASD. Their original meta-analysis encompassed 159 studies (Warren et al, 2011), and their update included an additional 65 studies (Weitlauf et al., 2014). Thus, we know that there have been at least 224 investigations in people with ASD, and each of these has employed a selection of outcome measures. The upshot is that different dis-
GUEST EDITORIAL ciplines (e.g., psychopharmacology, EIBI, joint attention, behavioral management of problem behavior) has made its own contribution to outcomes assessment. This lends itself to systematic study and an opportunity to evaluate assessment approaches. By careful study of these outcomes, we should be able to learn valuable lessons about placebo effects, practice effects, stability over time, reliability. and variability of measurement over time. With luck, we may also learn about temporal responsiveness to treatment effects and sensitivity to treatment. In so doing, we shall begin to develop a true science of outcome measures for ASD symptoms and so begin to put ourselves on solid true footing for launching pharmacological trials with confidence. The glass is at least half full! Acknowledgment The authors thank Professor Luc Lecavalier (The Nisonger Center UCEDD, Ohio State University) for critical suggestions on this document. Disclosures Dr. Arnold has received research funding from CureMark, Forest, Lilly, and Shire; advisory board honoraria from Biomarin, Novartis, Noven, Otsuka, Roche, Seaside Therapeutics, and Shire; consulting fees from Gowlings, Pfizer, and Tris Pharma; and travel support from Noven. Dr. Aman has received research contracts from, consulted with, or served on advisory boards of Biomarin Pharmaceuticals, Bristol-Myers Squibb, CogState, Confluence Pharmaceutica, Coronado Bioscience, Forest Research, Hoffman LaRoche, Johnson & Johnson, MedAvante Inc., Neuren Pharmaceuticals, Novartis, ProPhase LLC, and Supernus Pharmaceutica. Dr. Hollway has received research support from Forest Research, Young Living, Supernus Pharmaceutica, and Sunovian Pharmaceuticals. References Aman MG, Novotny S, Samango-Sprouse C, Lecavalie, L, Leonard E, Gadow KD, King BH, Pearson DA, Gernsbacher MA, Chez M: Outcome measures for clinical drug trials in autism. CNS Spectrums 9:36–48, 2004. Arnold LE, Aman MG, Hollway J, Hurt E, Bates B, Li X, Farmer C, Anand R, Thompson S, Ramadan Y, Williams C: Placebocontrolled pilot trial of mecamylamine for treatment of autism spectrum disorders. J Child Adolesc Psychopharmacol 22:198–205, 2012. Butter EM, Mulick JA: Assessing the core symptoms of autism spectrum disorders: The development of the Ohio Autism Clinical Impressions Scale. Poster presented at the New Clinical Drug Evaluation Unit Conference, Boca Raton, FL, June, 2006. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W: Validation of a brief quantitative measure of autistic traits: Comparison of the Social Responsiveness Scale with the Autism Diagnostic Interview-Revised. J Autism Developmental Dis 33:427– 433, 2003. Guy W, editor:ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, 1976. Kanne SM, Mazurek MO, Sikora D, Bellando J, Branum-Martin L, Handen B, Katz K, Freedman B, Powell MP, Warren Z: The Autism Impact Measure (AIM): Initial development of a new tool for treatment outcome measurement. J Autism Developmental Dis 44:168–179, 2014.
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285 Weitlauf AS, McPheeters ML, Peters B, Sathe N, Travis R, Aiello R, Williamson E, Veenstra-VanderWeele J, Krishnaswami S, Jerome R, Warren Z. Therapies for Children With Autism Spectrum Disorder: Behavioral Interventions Update. Comparative Effectiveness Review No. 137. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2012-00009-I.) AHRQ Publication No. 14-EHC036-EF. Rockville, MD: Agency for Healthcare Research and Quality; August 2014. www.effectivehealth care.ahrq.gov/reports/final.cfm.
Address correspondence to: Michael G. Aman, PhD Professor Emeritus of Psychology The Nisonger Center (OCEDD) Ohio State University 1581 Dodd Drive Columbus, Ohio 43210 E-mail: [email protected]
