• 86 • Taiwanese Journal of (Taipei) Vol. 28 No. 2 2014 Overview

DSM-5 on Epidemiological and Genetic Studies of Spectrum Disorder in Taiwan

Luke Y. Tsai, M.D.*

This overview reviews the evolution of the defi nition and diagnostic criteria of disorder (ASD). The author starts to introduce the work on early infantile autism by and the work on autistic psychopathy by Hans Asperger. Then, he describes how infantile autism is defi ned in ICD-9-CM, and pervasive developmental disorders in DSM-III and DSM-III-R, how autistic disorder and Asperger’s disorder as subtypes of pervasive developmental disorders in DSM-IV, as well as how ASD as a single category is listed in DSM-5. With all those background information, the author warns the impacts of DSM-5 ASD on future studies of ASD epidemiology and genetics in Taiwan. Overall, it seems that the implementation of DSM-5 ASD may cause more negative results than provides positive infl uences. Investigators of ASD in Taiwan must be mindful of the poten- tially negative impacts caused by the DSM-5 ASD.

Key words: DSM-IV, ICD-10, autism spectrum disorder, Asperger’s disorder (Taiwanese Journal of Psychiatry [Taipei] 2014; 28: 86-94)

our society. In 1980, the DSM-III [2] moved from Introduction a descriptive or conceptual approach to an opera- tionalized, criteria-defi ning approach to enable To facilitate validation of psychiatric disor- clinicians to make diagnoses based on whether a ders, Robins and Guze [1] proposed a process patient’s symptoms matched the diagnostic crite- which included the following phases: clinical de- ria. The DSM-III also intended to establish a high- scriptions, laboratory studies, follow-up studies, er degree of diagnostic consistency or reliability and family studies. The evolution of the American within the psychiatric community. The expecta- Psychiatric Association’s (APA) Diagnostic and tion of DSM-III and subsequent DSM-III-R [3], Statistical Manual of (DSM) has DSM-IV [4], and DSM-IV-TR [5] was that DSM- closely followed such process. Initially the DSM based research would identify the underlying eti- was developed for who were inter- ologies of the disorders included in the manuals, ested in describing and understanding the fre- which would allow greater refi nement of the crite- quency with which mental illnesses developed in ria and ultimately their validation by the biologi-

Departments of Psychiatry and , University of Michigan Medical School Ann Arbor, Michigan, U.S.A. Received: May 6, 2014; accepted: May 6, 2014 *Corresponding author. 2385 Placid Way, Ann Arbor 48105, Michigan, U.S.A. E-mail: Luke Y. Tsai Tsai LY • 87 •

cal measures and etiologies which in turn can lead sistence on sameness. He adopted the term early to specifi c treatments and even prevention or infantile autism to describe this disorder and cures. But from DSM-III to DSM-IV-TR, the prog- called attention to the fact that its symptoms were ress of research has not led to the defi nitive iden- already evident in infancy. tifi cation of etiologies or the validation of proven biological measures to defi ne the mental disor- Hans Asperger’s autistic psychopathy ders. Now DSM-5 has been developed and offi - Hans Asperger was also born and educated in cially launched in May 2014 [6]. This overview . He was trained as a pediatrician but was focuses only on how and what impact the new later appointed as the director of the Unit for DSM-5 would have on the autism spectrum disor- Special Education at the Children’s Hospital. In der (ASD) 1944, after more than a decade of working at the hospital, he described four boys, aged 6 to 11 Evolution of Defi nition and years, in his German postgraduate thesis, “Die Diagnostic Criteria of Autism Autistischen Psychopathen im Kindesalter” Spectrum Disorder (Autistic Psychopathy in Childhood) [8]. He noted that all his cases exhibited autistic Before discussing the impact on the ASD by withdrawal, a symptom usually seen in schizo- the newly published DSM, it is necessary to re- phrenic patients. Asperger was not aware of view the history of the changes of the defi nition Kanner’s work and the paper published in 1943. and diagnostic criteria of ASD over the years. Both Kanner [7] and Asperger [8] independently used Bleuler’s [9] earlier term “autism” to de- Leo Kanner’s early infantile autism scribe the core clinical feature of their disorders. In 1943, Leo Kanner [7], published his now But Asperger did not consider his newly discov- classic paper, “Autistic Disturbance of Affect ered disorder a form of psychosis. In fact, he ap- Contact,” which described a group of 11 physi- pears to have used the term “psychopathy” to de- cally normal children with a previously unrecog- scribe a , consistent with the nized disorder. He noted many characteristic fea- meaning of the word in German, since, while dis- tures in these children, such as an inability to cussing the paper, he stated that those patients suf- develop relationships with people, extreme aloof- fered “with the type of personality disorder pre- ness, a delay in speech development, and non- sented here.” communicative use of speech. Other features in- According to Asperger, individuals with au- cluded repeated simple patterns of play activities tistic psychopathy usually began to speak at ap- and islets of ability. He described these children as proximately the same time as children without having “come into the world with innate inability this disorder. A full command of grammar was to form the usual, biologically provided affective acquired sooner or later although some children contact with people” [7, p. 250]. showed diffi culty in using pronouns correctly. But Despite the variety of individual differences the content of speech was usually abnormal and that appeared in the case descriptions, Kanner be- pedantic and consisted of lengthy disquisitions on lieved that only two features were of diagnostic favorite subjects. Often a word or phrase was re- signifi cance: autistic aloneness and obsessive in- peated over and over in a stereotyped fashion. • 88 • Autism Spectrum Disorder in DSM-5

Other features he described were impaired two- Statistical Manual of Mental Disorders (DSM), way social interaction, totally ignoring demands 2nd Edition [12]. Although in DSM-II diagnostic of the environment, repetitive and stereotyped information for childhood , there play, and isolated areas of interests. Asperger ob- were a number of symptoms similar to that being served these children talking back at teachers, described as features of Kanner’s syndrome and sometimes verbally abusing and hitting other chil- Asperger’s disorder (e.g., autistic, atypical and dren, and lashing out at objects. Some of them withdrawn behavior” (p. 35), they were not equiv- seemed to gain pleasure from their actions with no alent to the diagnostic features of Kanner’s syn- regard for the feelings of others or the conse- drome and Asperger’s disorder. quences of their actions. Asperger believed that Infantile autism fi rst appeared in DSM-III the condition was never recognized in infancy and and ICD-9-CM [13]. Both the diagnostic systems early childhood and that those with the syndrome had similar defi nitions and diagnostic criteria for had excellent, logical abstract thinking and were infantile autism. But they differed in the way they capable of originality and creativity in chosen conceptualized the disorder. In ICD-9-CM, infan- fi elds. The case histories also indicated the pres- tile autism was classifi ed as a subtype of “psycho- ence of developmental delay and/or social and be- ses with origin specifi c to childhood,” whereas in havioral diffi culties from an early age. DSM-III, infantile autism was viewed as a type of Asperger subtly changed his descriptions of pervasive developmental disorders (PDDs) (de- his syndrome over the years, perhaps affected by fi ned as a group of severe, early developmental the opinions of other authors. In his later paper disorders characterized by delays and distortions [10], he emphasized the high intelligence and spe- in the development of social skills, cognition, and cial abilities in areas of logic and abstraction, communication). whereas, in 1944, he had specifi ed that his syn- In DSM-III, the diagnosis of infantile autism drome could be found in people of all levels of required that the features associated with infantile intelligence, including those with mental retarda- autism (i.e., social problems, communication dif- tion. Asperger’s work remained relatively un- fi culties, and bizarre behavior) be present within known in English-speaking countries until 1981 the fi rst 30 months of life. A childhood-onset PDD when , a British , pub- subtype was also included where symptoms ap- lished an infl uential review of the topic and added peared after 30 months but before 12 years of age, a series of her own [11]. and did not meet all the symptoms for infantile autism. Thus, DSM-III covered the major areas of Infantile Autism in ICD-9-CM developmental concern fi rst described by Kanner and Pervasive Developmental [7], but allowed for later development and for a Disorders in DSM-III and residual state. DSM-III-R When DSM-III was published in 1980, Asperger’s disorder was unknown in the English Despite Kanner’s [7] and Asperger’s [8] literature. Hence, DSM-III did not include clear elucidation of apparently new disorders, Asperger’s disorder as a subtype of PDD. both early infantile autism and autistic psychopa- However, when DSM-III-Revised appeared in thy were not included in the Diagnostic and 1987, Asperger’s work was fairly well-known to Tsai LY • 89 •

professionals in the fi eld of PDD in European individuals. DSM-III-R broadened the diagnostic countries, but not in the . Wing [11] concept of autism from DSM-III, allowing for the suggested that Asperger’s disorder be considered gradation of behavior seen in autistic individuals. as a part of the “autistic continuum.” She believed that Asperger’s disorder could be a mild variant of Autistic disorder and Asperger’s disorder autism. DSM-III-R adopted Wing’s [11] view of as subtypes of DSM-IV PDDs Asperger’s disorder and did not offer any specifi c After the publication of DSM-III, reports defi nition and diagnostic criteria for it. suggested that other developmental disorders such On the other hand, empirical data published as Asperger’s disorder [11], Rett’s disorder [14], after 1980 could not fi nd any signifi cant differ- and disintegrative psychosis [15] should also be ences (except age at onset) between individuals considered as separate subgroups of PDDs. But with infantile autism and those with childhood- the DSM-III-R Work Group on Pervasive onset PDD. In DSM-III-R, the category child- Developmental Disorders did not believe that hood-onset PDD was eliminated. In addition, it there was suffi cient evidence for the taxonomic was found to be diffi cult to differentiate between validity of the additional subgroups of PDDs to atypical PDD and residual infantile autism. The justify the establishment of separate diagnostic DSM-III-R Pervasive Developmental Disorders categories, preferring instead pervasive develop- Work Group therefore decided to take a combin- mental disorder not otherwise specifi ed ing (lumping) approach and to include only two (PDDNOS). This decision generated the concern subcategories under PDDs: autistic disorder that further research on the validity of the sub- (roughly corresponding to infantile autism) and types of PDDs would become virtually impossible PDD not otherwise specifi ed (PDDNOS). Under if these disorders were grouped together [16]. such a system, many cases with features of DSM-IV [4] and ICD-10 [17] diagnostic Asperger’s disorder or cases with disintegrative schemes continue to adopt the term pervasive de- forms were diagnosed as having either an autistic velopmental disorders and include fi ve subcatego- disorder or a PDDNOS. ries: (A) autistic disorder (AD), (B) Asperger’s Although the concept of PDDs was retained disorder (AspD), (C) Rett’s disorder, (D) child- in DSM-III-R, the diagnostic criteria for autistic hood disintegrative disorder, and (E) PDDNOS disorder were revised considerably. The DSM-III (including atypical autism). DSM-IV and ICD-10 criteria were descriptive, whereas the menu like also offer operational diagnostic criteria for all the scheme of DSM-III-R criteria required the pres- subtypes of PDDs except PDDNOS. The DSM-IV ence of a minimum number of criteria in each of diagnostic criteria for autistic disorder resemble the three cardinal areas of defi cits. The revised those of DSM-III-R, but the total number of diag- criteria were much more concrete, observable, nostic criteria has been reduced from 16 to 12, and and operational than those in DSM-III. The re- the required minimum number for a diagnosis of vised criteria did not require raters to determine autistic disorder also has been reduced from 8 to subjectively whether a “pervasive impairment” or 6. These changes were made to facilitate the use a “gross defi cit” was present; hence, clinicians no of the criteria by clinicians while the diagnostic longer hesitated to use the diagnosis of autistic validity and reliability are maintained at a high disorder in older and higher-functioning autistic level. • 90 • Autism Spectrum Disorder in DSM-5

The concept of PDDs in DSM-IV adopts a from mild to severe of autism, rather than a simple “splitters” approach. It supports the taxonomic va- yes or no diagnosis of a specifi c disorder. The lidity of each subtype and aims to facilitate re- Work Group also proposed to remove Rett’s disor- search in the sub-classifi cation of these disorders. der from DSM-5’s ASD category. The APA DSM- Although the DSM-IV diagnostic criteria for 5 Committee accepted the proposed change, the PDDs are based on a well-designed multisite fi eld discrete disorders that formerly included in PDDs trial study in which 977 patients participated [18], (e.g. autism, Asperger’s disorder, PDDNOS, and it is expected that these criteria will not satisfy ev- CDD) were eliminated and all were absorbed eryone and they will be revised when improved into a single category: autism spectrum disorder understanding and further knowledge are gained [6]. to support the taxonomic validity of each subtypes The Work Group proposed to have diagnos- of the newer edition of DSM. tic criteria that included: A. persistent defi cits in During the two decades since the publica- social communication and social interaction tion of the ICD-10 [17] and the DSM IV [4], both across multiple contexts; and B. restricted, repeti- clinicians and researchers, in various settings, tive patterns of behavior, interests, or activities. have used the subtypes of PDD to describe chil- There are three symptom groups under diagnostic dren and adults with a range of social and other criteria A (social-communication domain); and defi cits. More than 500 studies of Asperger’s dis- four symptom groups under diagnostic criteria B order alone [including about 150 comparative (restricted-repetitive domain). The proposed studies of AspD and high function autism (HFA)] DSM-5 ASD required that all three symptom cri- have been published. However, the debate has teria under social-communication domain and at continued between the “splitters” and the “lump- least two symptom criteria under restricted-repet- ers,” with the latter maintaining that AD and itive domain must be present to be endorsed as AspD lie on a “continuum” with AspD at the less having an ASD. impaired end. For unknown reason, the offi cially published DSM-5 ASD does not specifi cally require any DSM-5 autism spectrum disorder as a minimal number of the symptom criteria under di- single category agnostic criteria A (i.e., social-communication do- In 2007, the American Psychiatric Associa- main) must be present to qualify for a diagnosis of tion formed a Work Group on Neurodevelopmental DSM-5 ASD while it specifi cally requires “at least Disorders to review DSM-IV PDDs and to devel- two” symptoms under diagnostic criteria B (i.e., op a new defi nition and diagnostic criteria or to restricted-repetitive domain) must be present to replace the PDDs in DSM-5. The Work Group qualify for a diagnosis of DSM-5 ASD [6, page concluded that there was suffi cient evidence to re- 50]. Although many clinicians and investigators place the term “PDDs” with “autism spectrum assume that all three symptoms are required, but disorder (ASD)” and to subsume Asperger’s dis- some have argued that this is unclear [19]. Some order, childhood disintegrative disorder (CDD), professionals in the fi eld of ASD even consider and PDDNOS into the overarching category of this as a “major” fl aw of DSM-5 ASD (www.huff- ASD. The proposal asserted that symptoms of ingtonpost.com/allen-frances/two-fatal-technical- these three disorders represented a continuum fl aws_b_3337009.html?view=screen) Tsai LY • 91 •

Table 1. Published studies of Autism Spectrum Disorder in Taiwan

Gender Prevalence Cited Diagnostic Studied Age Authors Year ratio Diagnosis reference system population (years) Rate per One per M/F 10,000 population Chien et al. 2007 [20] ICD-10 329,539 3-8 4.1/1 AD 34 294 Chien et al. 2011 [21] DSM-IV-TR 372,642 < 18 NA ASD (1996) 1.8 5,587 (2005) 28.7 348 15.3§ 654 Lai et al. 2012 [22] DSM-IV-TR 4,644,310 3-17 6.3/1 ASD (2004) 4.5 2,222 DSM-IV to 11.2 893 4,044,433 6.6/1 ASD (2010) 14.3 699 to 25.3 395 13.8§ 395 M, male; F, female, AD, autistic disorder; ASD, autism spectrum disorder § Median value

The other decision by DSM-5 ASD that also These are the reasons for expecting future in- has been considered as a “major” fl aw (www.huff- consistent reports of prevalence rates of ASD by ingtonpost.com/allen-frances/two-fatal-technical- various groups of investigators “discretionally” fl aws_b_3337009.html?view=screen) is that at using DSM-5 ASDs “loose” diagnostic criteria. the end of the criteria set of ASD, a note is at- tached which states “individuals with a well-es- Impact on Epidemiological tablished DSM-IV diagnosis of autistic disorder, Study of Autism Spectrum Asperger’s disorder, or pervasive developmental Disorder in Taiwan disorder not otherwise specifi ed should be given the diagnosis of autism spectrum disorder” [6, Impact on fi nding a true and consistent page 51]. This statement may be interpreted by prevalence of ASD in Taiwan many clinicians/raters as “free to choose” how to A recent extensive and comprehensive re- defi ne and diagnose ASD. Those cases with view of the prevalence of ASD between 1966 and “mild” autism who would not qualify for DSM-5 2014 (unpublished manuscript of LY Tsai) shows ASD under “all three symptom criteria” rule would that there are three epidemiological studies of qualify for DSM-5 ASD under the “note” rule. ASD in Taiwan [20-22]. As shown in Table 1, one As Frances [20] has pointed out that “DSM-5 study [20] investigated AD and two studies [21, has essentially made it clinician’s choice how to 22] studied ASD. The prevalences were deter- defi ne and diagnose autism spectrum disorder. mined based on DSM-IV, DSM-IV-TR, or ICD-10. Some will require one item from criterion A; oth- Although there are only two studies of ASD prev- ers two; yet others three; and some will chuck alence in Taiwan, median values of ASD reported DSM-5 altogether and use the very different defi - by the two Taiwanese studies are similar (Table nitions that are contained in DSM-IV.” 1). • 92 • Autism Spectrum Disorder in DSM-5

So far, there has no study of ASD prevalence duce the number of potential “ASD genes” that in Taiwan based on DSM-5 ASD. As described are also being identifi ed as the “potential genes” above, the investigators plan to study the ASD for language disorders (e.g., CNTNAP2 gene). prevalence in Taiwan need to make it clear which The “miss the cut” cases may also include “diagnostic system/how many symptom groups many cases with AspD and co-morbid mood dis- are required under Criteria A” is being used to as- orders as described by Asperger [8] that many of certain the prevalence of ASD in Taiwan. Such an his cases had “most severe tantrum,” “serious approach would help readers of future published rows,” and “for days they may cry desperately.” reports to appreciate the reported discrepancies. The fi eld of PDD/ASD has just begun to appreci- ate the mood problems/disorders in children and Impact on Genetic adolescents with . A recent re- Studies of Autism Spectrum view of the issue of Asperger syndrome and co- Disorder in Taiwan morbid psychiatric disorders [26] shows that as high as 70% of cases with AspD had experienced Impact on fi nding potential genes for ASD at least one episode of major depression. The Bespalova and Buxbaum [23] suggested that “elimination” of AspD by DSM-5 ASD will im- family studies and several genome-wide linkage pede the opportunity of further studying of such analyses supported the hypothesis of complex in- shared genes for both ASD and . heritance of ASD with involvement of as many as Future investigators of ASD genetics in 10-100 genes of moderate effect. A decade later, Taiwan should be mindful of these potential im- Iossifov et al. [24] estimated between 350 and 400 pacts caused by using DSM-5 ASD to select the autism susceptibility genes have been identifi ed subjects and should plan ahead more appropriate and the number is still counting. There are many study methods that would minimize such genetic studies of ASD, concluding that ASD is a impacts. heterogeneous group of neurodevelopmental dis- orders with heterogeneous genetic etiologies [26]. Conclusion So far, there has no published genetic study of ASD based on Taiwan population. The future It is quite clear that whenever there is a major challenges faced by ASD investigators include change of mental health diagnostic system, it will high possibility of having heterogeneous subjects bring with enormous impacts on many areas relat- in the studies due to the use of broad and loose ing to mental health. The present review addresses selection criteria (i.e. DSM-5 ASD) and using a the impact of the newly launched DSM-5 ASD. diagnostic system (i.e. DSM-5 ASD) that has With limited space, the present overview focuses many ‘fl aws” allowing investigators “discretion- only on two areas: ASD epidemiology and genet- ally” use the DSM-5 ASD diagnostic criteria [6]. ics of ASD. AS the new DSM-5 ASD will exclude many All previous studies based on DSM-IV/DSM- mild and borderline cases with severe language/ IV-TR or ICD-10 PDD, or non-offi cial term of speech defi cits because these cases would be diag- ASD, used various defi nitions and inclusion crite- nosed as having “social communicative disor- ria which result the broad range of prevalences of ders.” The future genetic study of ASD may re- PDD/ASD (unpublished manuscript of L. Y. Tsai). Tsai LY • 93 •

In the future, whatever prevalences obtain by vari- ous research groups using “DSM-5 ASD” not only Acknowledgement cannot be used to compare with previously report- ed prevalence rates due to very different defi ni- The author declares no potential confl ict of tions of ASD were used, it most likely will pro- interest in writing this overview. duce inconsistent prevalences due to the reason described earlier. References On the other hand, the DSM-5 ASD Work Group members had argued that one of the 1. Robins E, Guze SB: Establishment of diagnostic va- strengths of the DSM-5 ASD would be its im- lidity in psychiatric illness: Its application to schizo- proved “utility” (i.e., more patients would be tak- phrenia. Am J Psychiatry 1970; 126: 983-7. en care) [28]. But the review by Tsai (unpublished 2. American Psychiatric Association: Diagnostic and manuscript) notes that several recent studies that Statistical Manual of Mental Disorders (3rd ed). compared the utility of DSM-IV/DSM-IV-TR ASD Washington, DC, USA: American Psychiatric Association, 1980. and the proposed DSM-5 ASD (i.e., all three 3. American Psychiatric Association: Diagnostic and symptom criteria under social-communicative do- Statistical Manual of Mental Disorders (3rd ed, main must be present), and reported that about 9% Revised). Washington, DC, USA: American to 54% with a median of 33%, of DSM-IV PDD/ Psychiatric Association, 1987. ASD cases did not qualify for DSM-5 ASD. 4. American Psychiatric Association: Diagnostic and Overall, the mildly impaired (or the higher Statistical Manual of Mental Disorders (4th ed). functioning) end of the autism spectrum has sig- Washington, DC, USA: American Psychiatric nifi cantly “missed” cases [28]. If future clinicians Association, 1994. and researchers in Taiwan require that all three 5. American Psychiatric Association: Diagnostic and symptom groups under diagnostic criteria A (i.e., statistical manual of mental Disorders (4th ed, Text social-communicative domain) must be present to Revision). Washington, DC, USA: American qualify for a diagnosis of DSM-5 ASD, it is ex- Psychiatric Association, 2000. pected that about one third of individuals who 6. American Psychiatric Association: Diagnostic and would qualify for A PDD/ASD diagnosis based on statistical manual of mental Disorders (5th ed.). Arlington, Virginia, USA: American Psychiatric DSM-IV/DSM-IV-TR or ICD-10 would be missed Association, 2013. according to the DSM-5 ASD criteria. 7. Kanner L: Autistic disturbances of affective contact. Learning from last two decades’ research ex- Nervous Child, 1943; 2: 217-50. periences, the fi eld of ASD genetic study is now 8. Asperger H: Die autistischen psychopathen im calling for a need to reduce the heterogeneity of kindesalter. Archiv für Psychiatrie und the ASD population under study by subgrouping Nervenkrankheiten 1944; 117: 76-136, “Autistic psy- individuals according to clinical phenotypes, spe- chopathy” in childhood. Translated and annotated by cifi c traits or even comorbidities, which has been U. Frith. In: Frith U, ed., Autism and Asperger demonstrated to improve logarithm of the odds Syndrome. : Cambridge University Press, (LOD) scores in genome-wide linkage analyses 1991: 37-92. [25]. Such an approach may lead to identifying 9. Bleuler E: Dementia Praecox Oder Gruppe der genes that are unique to subtypes of disorders. Schizophrenien (1911). Translated by Zinkin J. New • 94 • Autism Spectrum Disorder in DSM-5

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