RESEARCH UPDATE REVIEW

This series of 10-year updates in child and adolescent psychiatry began in July 1996. Zpics are selected in consultation with the AACAP Committee on Recert$cation, both for the importance of new research and its clinical or developmental significance. The authors have been asked to place an asterisk before the 5 or G most seminal rPferences. M.RD.

Pervasive Developmental Disorders: A 10-Year Review

PETER E. TANGUAY, M.D.

ABSTRACT Objective: To summarize recent advances about the nature, diagnosis, and treatment of pervasive developmental disorders. Method: Review of Medhe databases, books, and book chapters published between July 1989 and November 1999. Results: Clinical and genetic studies support expansion of the concept of autism to indude a broader spectrum of social com- munication handicaps. The prevalence of autism is approximately 1 per 2,000;the prevalence of autism and Aspergets dis- order together is 1 per 1,000. The Checklist fw Autism in Toddlers is a useful screening instrument for l&monthdd children; the Autism Diagnostic interview-Revised and the Autism Diagnostic Observation Schedule are instruments of choice for research. Although twin and family studies dearly support genek factors as important in autism, linkage analysts studies indi- cate that many genes may be invdved.There is no one treatment of choice.Sodal-pragmatic approaches, augmented by indi- vidualized strategies and social coaching, may be best for teaching soda1 communication skills. Pharmacological interventions have a limited role in improving social communication, but selective serotonin reuptake inhibitors and atypical neurdeptic med- ications may help ameliorate aggression, hyperactivity, and other secondary problems. Condwlons: Private and government agencies must continue to support basic and applied research. J. Am. Acad. ChiMAdolesc. Psychiatry; 2OO0, 39(9):107% 1095. Keywords: pervasive developmental disorders, autism, Aspergets disorder, review.

A review of the National Library of Medicine database PERVASIVE DEVELOPMENTAL DISORDERS indicates that more than 2,000 articles about autism and Five diagnoses are included under pervasive devel- Asperger's disorder have been published over the past 10 opmental disorders (PDDs) in DSM-IV (American years. This does not include books and book chapters Psychiatric Association, 1994).These are autism, Reds dis- about autism, which number in the hundreds. This order, childhood disintegrative disorder (CDD),Aspergets review differs from the Practice Parameters (American disorder (ASP), and pervasive developmental disorder not Academy of Child and Adolescent Psychiatry, 1999) in otherwise specified (PDD-NOS) (including atypical that it focuses primarily on research, and especially on autism). Autism is the prototypic disorder in the category. studies that have been clinically important in the past For convenience, Rett's and CDD will be discussed first. decade. This review will focus on research issues and con- Rett's Disorder troversies, especially as they answer clinical questions. The diagnostic criteria for Rett's disorder derive from those agreed upon by an international work group in 1988 Accepted March 13, 2000. (Rett Syndrome Diagnostic Criteria Work Group, 1988). Dr. Tanguay is Spafird Ackrrb Endowed I'rofmsor of Child and AdoL-scmt Aychiav, Diuuton of ChildandAdoLscmt &hiaq, Dtpammt of Aychiaq, There is an initial period of normal development, in- Uniumiry of Louisuillc School of Medicine, Louisville?KI: cluding normal perinatal head circumference. Between 5 Comsponhcc to Dr. Tanguay, Bingham Child Guidance Cmtm 200 E. months and 4 years there is a deceleration of head growth, Chestnut Strcet, Louisville, KY 40202; e-mail:[email protected]. 0890-8567/00/3903-107902000 by the American Academy of Child followed by a loss of hand skills and the appearance of ster- and Adolcsccnt Psychiatry. eotypic hand-wringing movements. Social skills and

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER ZOO0 1079 TAN G U AY expressive and receptive language development also dete- differ in the 2 groups, but children with CDD were more riorate at 2 or 3 years of age. Ataxia and apraxia become likely to be mute and to have an IQscore of less than 40. prominent, and gait becomes broad-based and jerlq with The age of onset is the most important differentiating stiff legs and side-to-side swaying. Breathing dysfunctions characteristic. The prevalence of CDD is considered to may be severe. be much lower than that of autism. The prevalence rate of Rett‘s disorder is approximately 1 in 10,000 to 15,000 females (Hagberg, 1985). A British Autism, Asperger‘s Disorder, and Pervasive survey (Kerr et al., 1997) found an annual mortality rate Developmental Disorder Not Otherwise Specified of 1.2%. Forty-eight percent of deaths occurred in persons (Including Atypical Autism) already debilitated by respiratory and motor dysfunctions. The DSM-Nfield trials have established that autism is There was a 26% incidence of sudden and unexpected one of the most robust diagnoses in the system, with a sen- death. sitivity of 0.82 and a specificity of 0.87 (Volkmar et d., There is a 100% concordance of Rett’s disorder in 1994). Of the almost 1,000 cases studied in the DSM-N monozygotic wins and a 100% discordance in dizygotic field trials for PDD, 163 cases appeared to fit within the twins. Because Rett’s disorder occurs almost exclusively in category but did not meet all of the criteria for autism. females, it was proposed that the syndrome was caused by These were given a subthreshold diagnosis of either PDD- an X-liked dominant mutation with lethality in hemizy- NOS or “atypical autism.” In some instances this diagnosis gous males. On the basis of previous family studies indi- was given because insufficient information was available cating a locus at Xq28, Amir et al. (1999) found that about peer relationships or imaginative play, but 38 cases mutations in a gene called MeCP2 are responsible for failed to meet the strict criteria for autism (Klin et al., nearly a third of the Rett cases. Previous studies had 1995a) despite having some degree of autistic-like symp- shown that MeCP2 plays a role in the epigenetic regula- toms. The existence of “autistic-like” or “subthreshold tion of gene expression. The manner in which the gene cases had already been anticipated in the literature. defect leads to the myriad of Rett‘s disorder defects is Asperger‘s case histories (Asperger, 1991) are very similar to unknown, but study of mice in whom the MeCP2 genes what is currently called high-fiznctioning autism or autism are knocked out shows that they develop symptoms sim- spectrum disorder. Even as young children, many of ilar to Rett’s disorder symptoms (Gura, 1999). Asperger‘s patients had normal language development, but their facial expression, prosody, and social gestures were Childhood Disintegrative Disorder ofien deficient, as was their social interaction. They lacked In 1930, Heller described a disorder that he called an “intuitive knowledge” of how to approach others. If infantile dementia (Heller, 1969). The children in ques- highly intelligent, they might become intensely interested tion had 2 to 4 years of normal development, after which in one or two subjects, such as astronomy, genealogy, or they markedly regressed in social, communicative, and geology. Some were able to use this knowledge quite suc- adaptive skills. The condition has been associated with cessfully, so that despite their very inept social skills they various medical conditions including metachromatic leu- became quite successll in earning a living. In addition to kodystrophy and Schilder‘s disease, but in most cases no having normal language development, persons with ASP specific neuropathological process has been identified. A are described as having delayed motor milestones and recent comparison (Mouridsen et al., 1998) of 13 cases of motor clumsiness but no significant delays in cognitive disintegrative psychosis (defined as having normal or development or in development of age-appropriate self- near-normal development for several years followed by help skills and adaptive behavior. the loss of social skills and speech) showed that compared Atypicalautism is often used to designate persons with with 39 matched autism cases, significantly more chil- PDD whose symptoms developed after 30 months of age dren with disintegrative disorders had developed seizures or who show atypical or subthreshold symptoms. Two (77% versus 33%). As part of the DSM-IV field trials studies (Ghaziuddin et al., 1994; Manjiviona and Prior, (Volkmar and Rutter, 1995), 26 children with CDD 1995) compared persons with high-functioning (IQ> 70) were compared with a group of children with autism. autism (HFA) and ASP. Neither motor impairments nor The median age of onset for the children with CDD was clumsiness distinguished HFA from ASP subjects. Cog- 36 months (range 24-70 months). The sex ratio did not nitively, children with ASP have better Verbal and poorer

1080 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER ZOO0 PDD REVIEW

Performance scores than children with HFA on standard- persons with PDD, the clinical and experimental usell- ized IQtests (Ehlers et al., 1997; Min et al., 1995b). Other ness of the exercise is uncertain. Few clinicians appear to studies have investigated whether expert clinicians can be using it in their everyday work. reliably classify subjects into HFA or ASP groups. In one Nonverbal Learning Disorh. Nonverbal learning dis- (Eisenmajer et al., 1996), a logistic regression analysis was order (NVLD) is a diagnostic category developed outside used to determine which variables from a standard check- of the DSM-Wnomenclature by Rourke (1989). It is list of items best predicted clinician's diagnosis. Among characterid by deficits in perception, psychomotor coor- family and developmental variables, only delayed lan- dination, visual-spatial organization, nonverbal problem- guage onset predicted diagnosis. The ASP group also had solving, and appreciation of conceptual incongruities and significantly higher verbal mental age than the autistic humor. The neuropsychological model of hemispheric subjects. In a further study (Mahoney et al., 1998), data specialization has been invoked to categorize NVLD as a fiom the Autism Diagnostic Interview-Revised (ADI-R), form of right hemisphere dysfunction. Previously a sim- the Autism Diagnostic Observation Schedule (ADOS), ilar cluster of neuropsychological traits had been identi- IQ, and other clinical instruments were independently fied as Irarning disability of the rigbt hnnirphm (Denckla, assessed by 3 experienced raters, each of whom then made 1999). Klin et al. (1995b) compared ASP and NVLD. a separate, blind diagnosis. The clinicians had little diffi- They found a robust overlap between the neuropsycho- culty differentiating autism from ASP but had more dif- logical profiles of persons with ASP and those with ficulty identifying children with atypical autism. A latent NVLD, suggesting that from a clinical viewpoint, the class analysis showed that the average error rates of the 3 groups are quite similar. On a related topic, Siege1 et al. raters for a differentiation of atypical autism from autism (1996) examined whether rigorously diagnosed HFA sub were unacceptably high. Sevin et al. (1995), using a num- jects had a uniform pattern of Performance versus Verbal ber of instruments, studied 34 children with autism and scores on the WISC-R. They found no characteristic autistic-like conditions. Four subgroups were identified. PerformanceVerbd relationships, though autistic sub They differed mainly in their IQand the severity of their jects did tend to have lower Comprehension and higher social handicaps. The authors concluded that while the Block Design subtest scores. children's symptoms were quantitatively different, they Multiple Comph Developmental Disordn: This cat- did not represent discrete categories. egory, which has also been called mditplcx Irarningdisoh Additional attempts to identify new entities within and mulridimcnsionally impaiwddisordn; may include chil- PDD have not fired well. Wing (1997) proposed a "triad dren labeled in the 1950s and 1960s as having atypical of subtypes" based on social interaction, communication, developmental disorder, symbiotic pTcbosu, and bo&litu imagination, and behavior. The subtypes were aloof (per- conditions of chiUood. Although the clinical features of sons who actively avoid interaction), pasive (who accept multiple complex developmental disorder (MCDD) social interaction but do not seek it), and active but odd include symptoms of autism, especially social and inter- (who accept social interaction but interact in odd and personal difficulties, persons with MCDD also show dis- eccentric ways). Vohar et al. (1989a) classified autistic turbed anxiety modulation and peculiarities in thinking persons into Wing subtypes using questionnaire-based in- and language (Klin et al., 1995a; Kumra et al., 1998; formation gathered fiom teachers or caretakers. Although Towbin et al., 1993). Using standardized instruments, a clinicians were able to reliably group both autistic and retrospective chart review indicated that in comparison nonautistic cases into the 3 subtypes, the subtypes were with children with dysthymia or with conduct disorder, mainly related to IQ. Lower-functioning individuals were children with MCDD had earlier symptom onset, earlier mostly classified as aloof, and the highest-functioning age of first hospitalization, higher psychopathology scorn ones exhibited features of the active but odd group. The on the Child Behavior Checklist, poorer peer relation- passive category fell between these two extremes. As such, ships, and greater psychopathology ('Towbin et al., 1993). it appears that a classification based on IQalone would Compared with subjects with very-early-onset schizophre- have been as useful as one using Wing's subtypes. Other nia (VEOS), subjects with MCDD are similar to the investigators who studied Wings system (Borden and VEOS subjects in the proportion of family members hav- Ollendick, 1994; Castelloe and Dawson, 1993; O'Brien, ing schizotypal or paranoid personality disorder and in 1996) showed that although it can be used to reliably group their not being abIe to understand what they read despite

1. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 39:9, SEPTEMBER 2000 1081 TANGUAY having adequate word recognition skills. They differ from 12-month-old infants learn to look to their mother‘s face the VEOS group in that they have a less deviant pattern of to determine what they should do (Sore et al., 1985). If autonomic reactivity and no progression to schizophrenia. their mothers pose joy or interest, the children will cross; However, 3 of the 11 subjects in the MCDD group re- if the mothers pose fear or anger, few infants cross. ceived the diagnosis of schizoaffective disorder (bipolar Persons with dassic forms of autism may fail to engage type) at 2-year follow-up. The investigators noted that only in the nonverbal social communication interactions typ- transient features of PDD were found in the MCDD ically seen in young children (Baron-Cohen et al., 1993; group (Kumra et al., 1998). In a more direct comparison Sigman and Capps, 1997). It is not that autistic children (Van der Gaag et al., 1995), 105 MCDD subjects were ret- fail to attach to their caretakers or that they avoid prox- rospectively compared with 32 HFA subjects. Each child imity. Like normal children and children with Down was rated on 189 developmental, behavioral, neurological, syndrome, children with autism are clearly attached to cognitive, and affective items. In comparison with MCDD their mothers and they attempt to remain close to them subjects, HFA subjects had significantly poorer social (Dissanayake and Crossley, 1996). In the Ainsworth interactions and more stereotyped and rigid behaviors, Strange Situation they seek proximity and contact with while the children with MCDD had significantly more their mothers as much as normal children matched on age psychotic thinking, anxiety, and aggression. Research indi- and IQ(Rogers et al., 1991). What they do not do, how- cates that children with MCDD do show differences from ever, is engage in attention-sharing behaviors, such as children with autism or ASE but it is not dear that the cat- pointing or showing objects (Sigman et al., 1986). We egory is unique. Perhaps MCDD represents an early man- have no evidence that this is because autistic persons fail ifestation of major affective disorder or schizophrenia. to perceive normally: they can distinguish between pic- tures of objects and various sounds as well as age- and IQ- AUTISM AND SOCIAL COMMUNICATION matched nonautistic subjects (Hobson, 1986), and they Our understanding of the development of children’s appear not to have any deficits in perception of faces as social and emotional interactions with others in the first stimulus objects (Volkmar et al., 1989b). They do not 2 years of life has been substantially augmented in the seem to recognize the emotional and contextual meaning past 2 decades. Newborn infants come into the world of facial expression, gesture, and the nonverbal vocal- with an innate set of behavioral propensities that maxi- izations of emotion (Hobson, 1986). mize the infant’s interaction with caretakers. Children, In comparison with children with “mental handicap” like other higher primates, emit various innate, univer- matched on mental age, autistic children fail to use the sal, facial expressions (Izard, 1994; Malatesta and Izard, speaker‘s direction of gaze to orient themselves to objects 1984) and can discriminate their mother’s face from that (Baron-&hen et al., 1997). In comparison with children of a stranger (Field et al., 1984). Newborn infants can with Down syndrome (Attwood et al., 1988), autistic discriminate and imitate facial expressions (Field et al., persons rarely use emotional gestures, even though they 1983).Afectattunemnzt (Szajnberg et al., 1989) describes usually can initiate them upon request. Autistic children a phenomena in which an infant expresses affect and a are better at expressing their physical needs than at mother responds cross-modally, matching duration, engaging in eye contact or pointing and showing an intensity, and rhythm. Mothers talk to their infants in object to someone else (Mundy et al., 1992). They may “motherese,” using exaggerated tone of voice, body lan- recognize and label emotions demonstrated to them, guage, gestures, and facial expressions. Their infants learn though less well than normal children (Yirmiya et al., to respond with their own set of nonverbal communica- 1992). Autistic children do not chat, nor do they become tive behaviors. Mother-inhnt vocal interactions, which proficient at give-and-take conversation, even when they tend to be overlapping around 7 to 13 weeks of age, develop language. change to an alternative to-and-fro pattern by 18 weeks. Put succinctly, persons with autism do not showjoint At 2 to 4 months of age, 30% of children automatically attmtian (McArthur and Adamson, 1996), and they fail follow their mother’s line of sight to an object, but by 14 to develop a cheoly of mind (Baron-Cohen, 1995). Joint months of age all children do so,without verbal prompt- attention develops prelinguistidy, and it involves a triadic ing or gesture on the part of their mother (Scaife and coordination of attention between the infant, another Bruner, 1975). Faced with an experimental “visual cliff,” person, and an object or event. In its narrowest definition,

1082 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER 2000 PDD REVIEW theory of mind signifies an understanding that people cation, and play; questions about restricted and repeti- have minds which differ from their own and that one tive behaviors; and questions about general behavioral can learn from others by reading their social signals and difficulties. Raters use probes to formulate their queries listening to what they say. Not all autistic persons lack a and are required to record specific instances and exam- theory of mind in an absolute sense, but even those who ples of the behaviors on which the rating is based. Each have normal intelligence and language may fail to acquire question is scored on an anchored 0 to 3 scale, with 0 social knowledge. They do not know the social (prag- being normal and 3 being severe disability. An algorithm matic) rules of interpersonal communication (e.g., how permits overall scores to be calculated for the 3 diagnos- do you start a conversation, choose a topic of discourse, tic categories for autism in the DSM-ZV. The ADI-R is take turns or end a conversation, etc.) nor can they cor- both reliable and valid (Lord et al., 1994). The ADOS rectly impute motives to others, understand another‘s (Lord et al., 1989) is a standardized protocol for the goals, or respond with alacrity to the nonverbal signals of observation of social and communicative behaviors asso- others. The autistic person’s lack of social knowledge is ciated with autism. It consists of a series of structured shown by the inability to form context-relevant communi- and semistructured “presses” for social interaction, initi- cative intentions (ma,1993), engage in spontaneous sym- ated by the rater, accompanied by coding of specific tar- bolic play (Jarrold et al., 1993), or generate original actions get behaviors and by general ratings about the quality of in play (Lewis and Boucher, 1995), despite the ability to social and interpersonal behaviors. The interrater relia- follow instructions in play. bility of the instrument is good. A diagnostic algorithm It should be noted that deficits in theory of mind are not has been developed for the ADOS. The ADOS was orig- specific to autism, but may be found in severely hearing- inally developed for use with verbal children, but a Pre- impaired children (Russell et al., 1998) and in persons Linguistic version has since been published (PL-ADOS) who have Down syndrome (Yirmiya et al., 1996; &lam (DiLavore et al., 1995). et al., 1996). The difference between autistic and hearing- Several additional instruments have been proposed for impaired or Down syndrome children may be that the use in autism and in developmental disorders, including latter two groups do not show deficits in joint attention. the Kiddie-Inht Descriptive Instrument for Emotional States (Tmd et al., 1992), the Behavioral Summarized Eva- RATING SCALES luation (Barthelemy et al., 1992), the Parent Interview Two popular rating scales for PDD are the Childhood for Autism (Stone and Hogan, 1993), and the Real Life Autism Rating Scale (CARS) (Schopler et al., 1988) and Rating Scale (Freeman et al., 1986). None has been used the Autism Behavior Checklist (ABC) (Krug et al., 1980). in more than a few projects to date. Both have good interrater reliability. The CARS contains It appears that for screening purposes, the CARS may 15 items and uses a 7-point Liken scale ranging from 1.O be the best instrument: it is easily learned and admin- to 4.0, with intermediate values between units. The ABC istered, has good interrater reliability, and seems to have has 57 items which are rated as either absent or present. reasonable sensitivity in distinguishing autistic fiom non- Several studies have compared the CARS and the ABC autistic subjects. For research purposes, only the ADI-R (Eaves and Milner, 1993; Sevin et al., 1991). In both in- and the ADOS/PL-ADOS can be considered adequate. stances the CARS was superior to the ABC in correctly Their advantages are that they provide a very detailed view identifting autistic subjects; however, the study of Eaves of social, language, and interpersonal haioning (in addi- and Milner appears to have been biased in that the tion to information about restrictive and repetitive behav- CARS was rated from direct observation whereas the iors), and they have algorithms for overall diagnosis as well ABC was scored from parent report. as for each of the 3 DSM-Nautism domains. Their draw- Two new interviews, the ADI-R (Lord et al., 1994) back is that raters must be fully trained and they are time- and the ADOS (Lord et al., 1989), have been published consuming to administer (up to 2 hours for the MI-R in the past decade. The ADI-R is a standardized investi- and 45 minutes for the ADOS and PL-ADOS). gator-based interview intended for use in the diagnosis of the PDDs. It consists of a series of initial questions AUTISM AS A SPECTRUM DISORDER about schooling, treatment history, and hmily constella- The spectrum model views autism as a disorder whose tion, followed by inquiries about social skills, communi- manifestations can vary fiom severe to mild. The model

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9, SEPTEMBER 2000 1083 TANGUAY might, of course, be incorrect. Autism could represent (Gurling et al., 1997; Hallmayer et al., 1994). Autism and several discrete genetic disorders with a common over- atypical autism have been reported in approximately 40% lapping phenotype. Nonetheless, the spectrum model is of persons with tuberous sclerosis (Gutierrez et al., 1998; a way of making sense of those individuals, including Hunt and Shepherd, 1993), but mostly in autistic persons relatives of persons who are autistic (Piven et al., 1994), who have moderate to severe mental retardation and/or a who have significant impairments in social knowledge seizure disorder. Bolton and Griffiths (1997) found that and pragmatic communication and whose behaviors, the number of tubers seen on magnetic resonance imag- interests, and activities are socially nonfunctional but ing (MRI) was correlated with degree of mental retarda- whose symptoms are not severe enough to meet the crite- tion. Eight of the 9 patients with autism or atypical ria for autism. autism in their sample had tubers located in the temporal One recent attempt to study the model used “social lobes, in contrast to none of the nonautistic patients. communication” as the spectrum variable, with the There have also been a few reports of autism in Williams ADI-R and the ADOS serving as rating instruments syndrome (Gillberg and Rasmussen, 1994) and in neuro- (Robertson et al., 1999; Tanguay et al., 1998). A factor fibromatosis and Hersh, 1998), but the coinci- analysis of the “social communication” items resulted in a dence of autism and these disorders is quite rare. Although 3-factor solution, with symptoms filling into 3 domains: an association has been postulated between celiac disease affective reciprocity, joint attention, and theory of mind. and autism, a study (Pavone et al., 1997) of 120 patients Mective reciprocity was thought to represent the behav- with celiac disease indicated none had DSM-III-R symp- ioral propensity of the children to use facial, gestural, toms of autism, nor was there evidence of celiac disease vocal, and body language cues in 2-way communication among 11 autistic patients. Stefanos et al. (1995) described with others. Theory of mind appeared to represent “social a 6-year-old child with profound expressive-receptive knowledge” in the broad sense. The most severely affected aphasia whose language and behavior had regressed at 22 autistic children had moderate to severe abnormalities in months. They diagnosed both PDD-NOS and Landau- all 3 domains, while children with ASP and PDD-NOS Kleffner syndrome (Mouridsen, 1995). Corticosteroid had better affective reciprocity scores than joint attention therapy led to amelioration of his language and social def- or theory of mind scores. The least impaired subjects were icits. Subsequent correspondence (Volkmar et al., 1996) ones whose impairments were mostly in theory of mind. established that the child did not appear to have autism Although the results are interesting, the study is prelimi- (though he had some symptoms of PDD-NOS) nor did nary and needs replication and improvement. he have classic Landau-Klefher syndrome, inasmuch as his EEG was normal. A major issue raised by this report COMORBIDITY STUDIES was whether it is medically justifiable to treat young autis- General Medical Conditions tic children with high-dose steroids whose effect on brain development may not be entirely benign. A thorough review of the literature (Rutter et al., 1994) has concluded that most of autism are not secondary cases Other Psychiatric Disorders to, or associated with, specific medical disorders. When concomitant medical disorders are found, they are seen Several studies have reported a higher incidence of most often in profoundly retarded autistic persons or in major depression and social phobia in the first-degree rel- atypical cases of autism which differ from ones diagnosed atives of persons with autism (Bolton et al., 1998; Piven using DSM-Ncriteria With the discovery that fragde X et al., 1991; Piven and Palmer, 1999; Smalley et al., 1995). syndrome is caused by a CGG triplet repeat insertion in The latter reported that 37% of 96 first-degree relatives the region near the FMR-1 gene at Xq27, it has been pos- of autistic probands had a major depressive disorder, com- sible to identif) accurately how many persons with autism pared with 11% of the 45 relatives of control subjects. have a Fra-X mutation. The number is no more than 2% Likewise, the frequency of social phobia in the relatives to 5% (Bailey et al., 1993). Examination of multiplex of the autistic persons was 20%, 10 times higher than in autism families (i.e., ones in which there are 2 or more the relatives of controls. Sixty-four percent of the de- autistic probands) has established that none of the FMR- pressed parents had their first episode prior to the birth of 1 mutations identified to date is associated with autism the autistic child.

1084 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 39~9.SEPTEMBER 2000 PDD REVIEW

PREVALENCE RATES important. The Checklist for Autism in Toddlers (CHAT) Within the past 30 years there have been some 20 (Baron-Cohen et al., 1992) has been developed to screen epidemiological studies of autism (see Fombonne et al., for autism. Initial studies indicate that the key psycho- 1997; Honda et al., 1996). Fombonne et al. calculated logical predictors at 18 months of a later diagnosis of that the mean estimated prevalence rate for all the studies autism are the presence of 2 or more of the following: lack of pretend play, lack of protodeclarative pointing, was 4.8 per 10,000, or approximately 1 per 2,000 persons. lack of social interest or social play, and lack of joint Recently, however, much higher prevalence rates have attention. Sixteen thousand British 18-month-old chil- been reported by several groups-as much as 1 per 250 dren were screened with the CI-MT, with follow-up dies persons. If the increase were real it could be alarming, at 20 and 42 months (Baron-&hen et al., 1996; Charman though no persuasive reason has been advanced to explain et al., 1997; Cox et al., 1999). Almost all children iden- it. A comparison of studies reported in the past decade tified autistic at 18 months were found to have either shows that they differ greatly in screening methods, diag- as autism or a major language delay by 42 months. But the nostic instruments, and diagnostic criteria. If one exam- CHAT appears to lack sensitivity at 18 to 20 months, ines them in terms of diagnostic criteria, there appears to i.e., it missed 60% of the children who were later found be a possible explanation for the differing results. Three to be autistic. An unrelated study (Lord, 1995) empha- projects, one from France (Fombonne et al., 1997), one sized how important it is to use direct observations of from Norway (Sponheim and Skjeldal, 1998), and one the infant as well as parental descriptions when screen- from Japan (Honda et al., 1996) used strict ICD-20 Re- ing for autism in infants. search Diagnostic Criteria. The French group reported a prevalence rate for autism of 1 per 2,000 and of 1 per 600 ANTECEDENT FACTORS INFLUENCING THE for autism and other PDDs taken together. The Norwegian DEVELOPMENT OF AUTISM group reported a prevalence of 1 per 2,000 for autism. In contrast, the Japanese investigators reported a prev- Season of Birth alence rate of roughly 1 per 500. But they also noted that Two recent studies (Bolton et al., 1992; Mouridsen more than 50% of their subjects had IQscores greater et al., 1994) used complex time-series analysis to exam- than 85, which suggests that their population may have ine seasonal variations in the births of persons with been more akin to HFA than to most cases of DSM-IV autism. Such variations might point to seasonal factors autism. Three studies have been reported in which less such as infections, weather, or diet as important in autism. rigorous criteria were used: Bryson et al. (1988) used the No consistent seasonal trends emerged. Mouridsen et al. ABC and other nonstandard criteria, Sugiyama and Abe examined season of birth in 328 in children with autism, (1989) used the more liberal DSM-lllcriteria, and Elders autism-like conditions, or “borderline child psychosis.” and Gillberg (1993) used a set of criteria specifically de- Children with autism had a significantly greater inci- signed for the diagnosis of ASP All 3 studies reported dence of births in March and in August, and those with prevalence rates for autism ranging from 1 per 250 to 1 autistic-like conditions were most often born in May and per 1,000. A parsimonious explanation for the apparent November. It would seem that if there are seasonal influ- increase in the prevalence of autism is that higher rates ences on the development of autism, these are fairly weak include varying numbers of persons with atypical autism, and inconsistent. ASP, and PDD-NOS as well as autism. A conservative estimate for the prevalence of autism would appear to be Severe Early Global Deprivation 1 per 2,000 persons, and for autism plus ASP, 1 per 1,000 After the fall of the Ceaucescu regime in Romania, a persons. large number of children were discovered to be living under extremely poor conditions in institutions, many SCREENING INFANTS AND CHILDREN FOR AUTISM of them having been placed there in early infancy. There There has been a consensus among clinicians that if is no evidence that any child was sent to an institution treatment is started by 24 to 36 months of age, the prog- because of an existing handicap. The conditions in the nosis in autism may be better than if treatment is post- institutes ranged from poor to appalling. A cohort of poned until age 4. If true, early diagnosis would be very such children arrived in the United Kingdom in the early

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER 2000 1085 TANGUAY

1990s (Rutter et al., 1998). A randomly selected, age- role-taking, a task which is also markedly impaired in stratified sample of 165 of these children are being sys- autism and ASP. tematically monitored. Of 111 children assessed at age 4 and again at age 6, some showed an attachment disorder NEUROBIOLOGICAL STUDIES IN AUTISM (O'Connor et al., 1999) and 7 children (6.3%) met the Genetic Studies criteria for autism on the Autism Screening Questionnaire, an instrument based on the ADI. They appeared to be Twin and Family Studies. Several studies have con- quite similar to autistic children in general, but further firmed Folstein and Rutter's (1977) findings of a markedly evaluation and follow-up revealed important differences. increased concordance of infintile autism in monozygotic (MZ) compared with dizygotic (DZ) twins. In a study of Three of the children were severely retarded, but despite this they had learned some sign language, which they 21 twin pairs, Steffenburg et al. (1989) found the con- cordance rate for autism (using DSM-ZZZcriteria but with- spontaneously used to communicate, and 2 made con- out standardized diagnostic interviews) to be 91% for siderable social approaches, albeit deviant in quality. MZ and 0% for DZ twins. Bailey et al. (1995) reexamined What these findings emphasize is that very severe social the subjects seen in the first British twin study of Folstein deprivation may occasionally lead to social and emotional and Rutter, adding subjects to increase the number of handicaps that meet the diagnostic criteria for autism. pairs to 48 and using the AD1 for diagnosis. They found Antecedent Neuropsychological Deficits that 60% of MZ twins and 0% of DZ twins were concor- dant for the ZCD-10 diagnosis of autism. When they Minshew et al. (1997) administered a battery of neu- examined a broader spectrum of related cognitive and ropsychological tests to 33 rigorously diagnosed autistic social abnormalities, they found that 92% of the MZ persons of normal intelligence and compared them with twins versus 10% of DZ wins were concordant. Behav- normal controls. Autistic persons had intact or superior ioral and cognitive manifestations of autism were also performance in tasks measuring attention, simple mem- compared both within and between pairs. The variation ory, simple language, and visual-spatial domains. In con- was as great within MZ twin pairs as between pairs. trast, they were impaired in skilled motor tasks, complex Because MZ twins share all of their genes, this finding memory, complex language, and reasoning. This profile su%gestedthat the varying symptoms seen in autism were of deficits will need refining before it can be of use in not a result of different sets of genes acting to produce dif- understanding the nature of autism. ferent clinical features. It appears that autism is under a Executive functions (EF), which are defective in per- high degree of genetic control, but what is inherited is a sons with frontal lobe damage, have been defined as the broader spectrum of related cognitive and social abnor- ability to maintain an appropriate problem-solving set malities (Bailey et al., 1995). for the attainment of future goals. They include the abil- Family studies suggest that there is an increased load- ity to formulate goals, to plan an action sequence to reach ing for both autism and autistic-like disorders in the the goals, and to maintain memory traces needed for first-degree relatives of persons with autism (Bolton et al., these processes. Even this concept may still be too broad 1994; Piven et al., 1997a,b; Spiker et al., 1994; Szatmari for the understanding of a specific disorder such as autism. et al., 1996).These studies used the AD1 and the ADOS A recent review (Pennington and OzonofT, 1996) con- for diagnosis, with the addition of other structured inter- cluded that EF deficits are consistently found in both views for broader symptom assessment. Bolton et al. (1994) attention-deficidhyperactivity disorder and autism, but reported an increased family loading for autism and for not in conduct disorder. Other investigators have reported more broadly defined PDDs in the siblings of 99 autistic more specific EF deficits in autism: impairment in cog- probands compared with the siblings of Down syndrome nitive flexibility (Ozonoff et al., 1994) and in shifting cog- subjects. They also found evidence for a lesser variant of nitive set (Hughes et al., 1994). Pennington and Ozonoff autism, comprising more subtle communication/social (1996) argued that EF deficits may underlie theory of impairments or stereotypic behaviors, but not mental re- mind deficits and cite an intriguing study (Price et al., tardation alone, in 12.4%to 20.4%of the autism siblings, 1990) of 2 individuals who sustained widespread pre- compared with 1.6% to 3.2% of the Down syndrome frontal damage early in development. Neither was autis- siblings. Szatmari et al. (1996) found a high intraclass tic, but both exhibited severe deficits in interpersonal correlation of social behavior abnormalities (measured

1086 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER 2000 PDD REVIEW using the Vineland and the ABC) between affected chil- Neuropharmacological Studies dren from the same fimilies, but a low correlation between Although various neuropharmacological substrates in affected and unaffected siblings. Piven et al. (1997a,b), autism have been investigated in the past several decades, using a semistructured family history interview, reported most abnormal findings have not been substantiated. Con- higher rates of social and communication deficits and vergent findings in the past decade from behavioral neu- stereotypic behaviors in the relatives in families with roscience, platelet, pharmacological, and genetic studies multiple-incidence autism in comparison with relatives indicate the involvement of serotonin in many of the in Down syndrome families. They also reported that the symptoms of autism (Cook and Leventhal, 1996). Cir- parents of autistic subjects had higher rates of aloof, culating blood serotonin is carried on the platelets; but rigid, hypersensitive, and anxious personality traits and despite numerous studies, the reason for the increased of speech and pragmatic language deficits. They also had serotonin levels in the platelets remains unknown. Hyper- more limited friendships. Taken together, these studies serotonemia in autism may be heterogenous, with one suggest that there are genetic factors which influence the subgroup of subjects having increased 5-HT uptake and development of autism and that these factors can result another group having decreased 5-HT2binding (Cook in a variety of subtle and not-so-subtle social and com- et al., 1993).That autistic persons have autoantibodies to munication deficits and stereotypic behaviors. brain serotonin receptors (Todd and Ciaranello, 1985) Chromosome Studies and Linkage Analysis. Using data was initially exciting. Two studies have not confirmed it from 38 multiplex hilies, Hallmayer et al. (1996) per- (Todd et al., 1988; Yuwiler et al., 1992). Singh et al. (1997) formed a sib-pair lmkage analysis between autism and 35 reported that autistic children’s plasma inhibits the spe- microsatellite markeb on the X chromosome. None of the cific binding of serotonin to its receptor, which they inter- reached a positive level of significance, leading lod scores pret as indicating the presence of serotonin-blocking them to conclude that there was no major gene effect on antibodies. Two recent studies focused on the serotonergic the X chromosome causing autism. Because 2% to 5% of receptor gene. Herault et al. (1996) reported no differences persons with fragde X show symptoms of autism, several in allele and genotype frequencies for the 5-HTL receptor, projects have investigated whether autistic children might but Cook et al. (1997) found evidence of linkage and show abnormalities in the FMR gene or in the fragile X association between the serotonin transporter gene and region (Gurling et al., 1997; Holden et al., 1996; Vincent autistic disorder. The latter finding could not be replicated et al., 1996). None have been found. Sporadic reports of (Klauck et al., 1997). singlecase abnormalities in other chromosomes are ques- tionable. Exceptions are the numerous reports of deletions Electroencephalography and Event-Related Potentials and duplications of chromosome 15, especially in the Persons with autism are likely to show more EEG 15qll-13 region (see Cook, 1998). No candidate genes abnormalities than are seen in a normal population, but have been identified, however. Investigators from the In- the findings are varied, are nonspecific, and do not lead ternational Molecular Genetic Study of Autism Consor- to a better understanding of the nature of brain dysfunc- tium carried out a 2-stage genome search for susceptibility tion in the syndrome. Advances in EEG techniques have loci for autism on 87 affected sib pairs and 12 non-sib not overcome the inherent shortcomings of the technol- affected relatives (International Molecular Genetic Study ogy: brain activity at any one electrode represents the of Autism Consortium, 1998).The highest lod scores were summed activity of numerous electrical generators whose obtained for regions on chromosome 7q and lbp, with location is difficult to pinpoint, and uncontrolled and lesser scores of interest on chromosomes 4,10, 19, and 22. often unquantifiable changes in subject attention may Another multicenter group (Risch et al., 1999) reported greatly affect the EEG or event-related potential (ERP) that the results of their linkage analysis studies were com- response. Few EEG and ERP studies have been reported patible with a model specifying a large number of loci in the past decade. Those that have appeared (Buchwald (>15), and less so with models specifying fewer than 10 et al., 1992; Dawson et al., 1988, 1995; Strandburg et al., loci. They concluded that the task of identifjmg genetic 1993) have led to no more than modest increases in knowl- abnormalities by positional cloning of susceptibility loci edge. Even brainstem evoked responses, which are rel- using linkage analysis could be a formidable one and that atively simple to record and whose neural generators are other approaches may be necessary. known, have led to negative or inconclusive results (Klin,

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1993).They remain an excellent tool with which to study not been correlated with IQ, verbal ability, seizure disor- hearing acuity, however. der, or medical illness. Using retrospective data, Lainhart et al. (1997) found that the macrocephaly was not present Neural Imaging at birth, but developed in early and middle childhood. MRI studies of autistic persons in the past 15 years Two MRI studies (Piven et al., 1995,1996) confirmed the have not identified or confirmed brain abnormalities in increase in brain volume. The former reported that the autism (see Deb andThompson, 1998).Courchesne et al. increase was present in the temporal, parietal, and occip (1994) reported cerebellar vermal hypoplasia or hyper- ital, but not frontal lobes. The cause of the increase in plasia in subgroups of autistic persons, but others (Garber size has not yet been explained, but longitudinal MRI and Ritvo, 1992; Kleiman et al., 1992; Piven et al., 1997c) studies of the phenomena are warranted. have not been able to confirm this finding. Autistic per- sons have been reported to have larger third ventricles and TREATMENT OF AUTISM AND ASPERGER’S DISORDER smaller caudates than normal subjects (Jacobson et al., Social and Behavioral Therapies 1988), abnormal forebrain structures (Gaffney et al., It is generally accepted that early intervention, tailored 1989), smaller right anterior cingulate gyrus (Haznedar to the child’s individual patterns of strengths and hand- et al., 1997), and smaller parietal lobes (Courchesne et al., icaps, can enable a child to develop better social and emo- 1993). Skepticism is warranted with regard to neural imag- tional relationships, learn better communicative skills, and ing results. decrease the intensity of stereotypic and bizarre behaviors. There is no one treatment that works with everyone, Neuropathological Studies though some treatments may be more effective than others Kemper and Bauman (1993) and Raymond et al. in improving social, interpersonal, and pragmatic skills. In (1996), who used whole-brain serial sections, reported some parts of the United States there is still a severe short- increased neuronal density in the hippocampus, amyg- age of teachers trained to meet the needs of autistic chil- dala, and limbic system in 6 brains of persons who had dren. There is also a lack of understanding by educators autism. They as0 reported decreased numbers of Purkinje that early intervention is important and that persons with cells and evidence of a fetal cerebellar circuitry. In a study HFA or ASP have special needs. There are few comparison of 4 autistic brains, Ritvo et al. (1986) reported lower studies between methods of treatment and few investiga- Purkinje cell counts. Bailey et al. (1998) examined brain tions designed to identifjr when and where a particular tissue from 6 mentally handicapped persons with autism. approach works best. Whiie it is beyond the scope of thii Four of the brains were megalocephalic, and they found article to review specific techniques of therapy, important developmental abnormalities, including evidence of ab- studies, as well as theoretical issues, will be reviewed. normal neuronal cell migration, in the brainstem and Twatmtnts Not Shown To Be Efictivc. Auditory integra- cerebellum. Numbers of Purkinje cells were reduced in tion training (AIT) (Stehli, 1991) entails listening to 10 the adult cases. Kemper and Bauman’s finding of elevated hours of music which has been filtered to dampen fie- neuronal density was not confirmed. Although the num- quencies to which the person is hypersensitive. A pilot ber of subjects in each of these investigations was small, study (Rimland and Edelson, 1995) reported that AIT the coincidence of certain findings, in particular the low decreased subject irritability, stereotypy, and hyperactivity Purkinje cell count, is intriguing. The difficulty of obtain- 3 months after treatment, but statistical flaws (the baseline ing suitable study material may constrain the develop- measures of the control and experimental groups were sig- ment of this line of research. nificantly different) make it difficult to assess the validity of these results. Bettison (1996) found that AIT signifi- Study of Brain Volume cantly improved psychometric and social ratings for both There has been a convergence of evidence in the past AIT subjects and controls (the latter listened to unfiltered decade in support of the observation that an unex- music), without there being any significant between- pectedly large portion of autistic persons (ranging from group differences. Gillberg et al. (1997) reported no sig- 14% to 30%) have a marked increase in head circumfer- nificant changes in autistic symptoms as a result of AIT ence (Davidovitch et al., 1996; Fombonne et al., 1999; In ficilitated communication, the ficilitator guides the Woodhouse et al., 1996). Increased head cihrencehas arm,wrist, or fingers of the autistic person as helshe types

1088 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 39:9. SEPTEMBER 2000 PDD REVIEW messages on a keyboard. Nonverbal and intellectually young persons, the core social skills they lack. Applied handicapped autistic persons have been reported to have behavior analysis or the Lovaas approach, at least in terms become suddenly capable of sending emotionally moving of its earlier descriptions (Lovaas, 1987; Maurice, 1994), and grammatically complex messages to their parents, but appears to be a prototypic example of the massed, discrete- studies have shown that the messages come largely from trial learning, while treatments advocated by Greenspan the facilitator and not from the handicapped person (1995), Rogers and Lewis (1989), Lewy and Dawson (Bomba et al., 1996; Eberlin et al., 1993; Smith et al., (1992), or McGee et al. (1992) are examples of social- 1994). pragmatic teaching. What must be kept in mind is that Two other treatment programs, daily life therapy, prac- proponents of the various named therapies (including ticed in the Higashi schools (Gould et al., 1991), and the Lovaas treatment) may have evolved their approaches Kaufman’s “Options” (Kauhan, 1981), have been cham- to the point at which they now include elements of both pioned on the basis of anecdotal observations and testimo- discrete-trial learning and social-pragmatic therapy. nials, but neither has been subject to rigorous scientific Clinicians and parents must ask therapists for a specific study. description of their philosophy, goals, and techniques if Massed Discrete- Teal Learning Versus Intense Social- they are to judge properly whether the treatment is suit- Pragmatic Tcacbing. Recent passionate debates about the able for a particular child. merits of one or other school of treatment for autism Dismte Elnnena of Twatment. Most autistic children appear to reflect 2 fundamentally different approaches need a combination of individual teaching strategies and to teaching. Each may be useful in certain circumstances broad educational goals. Social and interactional hand- (see Prizant and Wetherby, 1998, for a detailed discus- icaps, intellectual and language deficits, and motor skill sion). Massed, discrete-trial learning (also called teacher- abnormalities require expert remedial approaches (Mundy or therapist-centered learning or traditional behavioral and Crowson, 1997). “Challenging” behaviors (e.g., aggres- learning) focuses on teaching discrete and objectively sion, self-injury, and ritualistic stereotyped activities) defined behaviors, skills, and facts; the teaching struc- must be dealt with (Dawson et al., 1998; Howlin, 1993). ture is highly prescribed; the focus of the learning is Some children learn better if materials are presented vis- determined by the teacher-therapist; predetermined ually rather than verbally (Hodgdon, 1996; Quill, 1997). criteria are provided for correctness of the response; ini- Autistic persons may be treated in special Head Start tial focus is on adult control and child compliance; rewards programs or therapeutic preschools, assisted by home are given for correct answers or behaviors; “aversive stim- therapy programs administered by their parents. They uli” may be given for incorrect answers or inappropriate may benefit from the newer technologies designed for behaviors; and teaching is largely directed through oral augmented communication. Memory devices (as simple language. In contrast, social-pragmatic teaching (also as a felt-board with coded symbols) may relieve the anx- called child-centered therapy, pivotal-behavior therapy, iety of not knowing what is next in their daily routine. or incidental teaching) emphasizes following the child’s Some will benefit from social coaching, as represented attentional focus and motivations; it builds on the person’s by Gray’s Social Stories and Comic Strip Conversations current repertoire of social and communicative behav- (Gray and Garand, 1993). Social coaching can be given iors (even if this is only nonverbal); it uses visual, verbal, by teachers, teacher‘s aides, or wen the child’s peers (McGee and tactile cues; it seeks to motivate learning through et al., 1992).Treatment should begin early and may need shared emotional experiences; it relies on naturally occur- to be continued, in one form or another, into adulthood ring events rather than a set curriculum; and it views the as described in Project TEACCH (Mesibov, 1997). child as an active learner and social participant. The former is perhaps best suited to teaching discrete skills and facts, Pharmacotherapy of Autism such as vocabulary and grammar or reading and math- There is, as yet, no medication that is effective in treat- ematical concepts. The latter appears similar to the way ing the social and relationship problems in autism. Stim- in which very young children learn joint attention, prag- ulants may be effectivein treating impulsivity, overactivity, matic language skills, and theory of mind and social and short attention span. Traditional antidepressants, knowledge. As such, it appears to be a more suitable ap- mood stabilizers, and antianxiety medications may be proach to teaching persons with autism, especially very used as they would be in a nonautistic population. Unfix-

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER ZOO0 1089 TANG WAY tunately, we know little about the long-term effects of Corticostcroidr. Although recommended by Stefanos some of the newer, and perhaps more promising, med- et al. (1995), there is little evidence that the treatment is ications for autism. The continuing arrival of new psycho- effective (Volkmar et al., 1996). The effect of long-term tropic agents, as well as the increased use of the present use of steroids on brain development is not known. ones, suggests that many more medication studies will Antidepressants. Although imipramine and desipra- need to be carried out in the coming years. mine were initially popular for treatment of depression, What follows is a brief review of the pharmacological aggression, and irritability in autism, potential cardio- interventions for which there are sufficient experimental vascular side effects and a realization that they are not data, either with regard to their effectiveness or lack very effective have led to their being supplanted by clo- thereof. mipramine. A double-blind study (Gordon et d., 1993) Vitamin B6 and Magnesium. Proponents (Rimland, reported that clomipramine was superior to both desip 1988) of megavitamin treatment for autism frequently ramine and placebo in reducing stereotypies, anger, and cite the study by Martineau et al. (1988) as supportive of compulsive behaviors and that both tricyclics were supe- their belief. In fact, only 30% of the children in that rior to placebo in decreasing hyperactivity. A second study showed improvement, most to only a modest degree. double-blind study (Brodkin et al., 1997) reported that Two recent reviews (Kleijnen and Knipschild, 1991; 18 of 33 subjects receiving clomipramine experienced a Pfeiffer et al., 1995) concluded that there are no data to decrease in repetitive thoughts and behaviors, and in back the megavitamin claims. A recent double-blind, aggression, and that the social relatedness of a few sub- placebo-controlled study concluded that high-dose pyri- jects also seemed to improve. Three patients, 2 of whom doxine and magnesium were ineffective in ameliorating were known to have epilepsy, had a seizure while being autistic behaviors (Martineau et al., 1988). treated. The results of an open trial of clomipramine Fenfuramine. Originally proposed as a treatment for (Sanchez et al., 1996) indicated that the target symp- autism because it lowers blood serotonin levels, and ini- toms of stereotypies and aggression improved in only 1 tially greeted with excitement, it has proven disappointing. of 6 subjects. One child developed acute urinary reten- While it may lead to modest decreases in hyperactivity, it tion while taking the medication. With the advent of is not useful in ameliorating other symptoms (Campbell the selective serotonin reuptake inhibitors (SSRIs), there et al., 1988; Leventhal et al., 1993). Concern has also been has been a shift of interest to these medications, though expressed about its safety (see Campbell, 1988). as yet there have been too few SSRI studies to permit Naltrexone. Although a few studies reported modest any conclusions to be reached. SSRIs appear to be mod- improvements in behavior (Kolmen et al., 1995, 1997) or erately effective in decreasing hyperactivity, restlessness, moderate improvement in hyperactivity and restlessness and agitation and in decreasing obsessive thoughts and (Campbell et al., 1990; Feldman et al., 1999; Willemsen- preoccupations (Awad, 1996; Cook et al., 1992; McDougle Swinkels et al., 1996, 1999), naltrexone is not effective et al., 1998; Posey et al., 1999). No one SSRI has been in reducing self-injurious behavior (Willemsen-Swinkels shown to be superior for these purposes. et al., 1995; Zingarelli et al., 1992) or in increasing learn- Neurokpics. Older neuroleptics were not found to be ing (Campbell et al., 1990; Kolmen et al., 1995). especially effective in treating autism (Campbell and Cfonidinc. P-Blockers were initially suggested as a Cueva, 1995), and their potential to produce tardive treatment for self-injurious behaviors. Studies of their dyskinesia (Campbell et al., 1997) has limited their use. use in autism (Fankhauser et al., 1992; Jaselskis et al., Of the newer “atypical” neuroleptics, risperidone has 1992) indicate that although clonidine can effect a mod- been the most frequently studied (McDougle et al., est reduction in hyperactivity and irritability, it is less 1997; Nicolson et al., 1998; Perry et al., 1997). These beneficial in ameliorating social behaviors. Drowsiness studies, which were all open-label trials, indicate that ris- has been reported as a main side effect. peridone may be effective in reducing hyperactivity, Secretin. Secretin, an endogenous gastrointestinal pol- impulsivity, obsessive preoccupations, and aggressive- ypeptide, was widely touted in 1999 as a treatment for ness. It may also increase socialization in some children. the social and communication handicaps of autism. Con- The major side effect of risperidone has been weight gain. trolled studies (Sander et al., 1999) have found single- In a 12-week open-label study of olanzapine (Potenza dose secretin to be ineffective for this purpose. et al., 1999), of the 7 patients who completed the study,

1090 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER 2000 PDD REVIEW

6 were judged to be responders on the basis of their 'Bailey A. Luthcrt P, Dean A et al. (1998), A dinicoparhological study of autism. Bmin 121:889-905 improvement in hyperactivity, repetitive behaviors, self- 'Baron-Cohcn S (1995). Mindblindness: An Esuy on Autism and Theory of injurious behaviors, and social relatedness (Potenza et al., Mind Cambridge. MA: MlT Press 1999). Baron-&hen S, Baldwin DA, Crowson M (1997). Do children with autism uy the speaker's dircction of guc srratcgy to crack the code of language? In summary, it appears that pharmacological interven- Child DN 68:48-57 tions have a limited role to play in improving the social and 'Baron-Cohcn S, Cox A, Baird G ct al. (1996). Psychological markers in the detection of autism in infancy in a large population. Br] Prychiany communication handicaps of persons with autism and 168: 158-163 ASP They may be helpfd in decreasing hyperactivity and Baron-Cohcn S, Tagcr-Flusberg H. Cohcn D (1993), Undmtanding Orhrr Mind. NmYork: Oxford University Pm impulsivity and in reducing aggression and obsessive pre- Baron-Cohcn S, Allen J, Gillberg C (1992). Can autism be detected at 18 occupations. The SSRIs appear to be well suited for this months? The needle. the haystack, and the CHAT. Br J Prychiany role, though there have been too few studies to confirm 161:833-843 Banhclcmy C. Adrien J-L, Roux S. Garrcau B, Pcrrot A, Lclord G (1992), this or to identify which SSRI medication may be best. Sensitivity and specificity of the Behavioral Summarize Evaluation (BSE) Except for their propensity to induce weight gain, the for the assessment of autistic behaviors. /Autism Dn, Dirord22:23-31 Benison S (1996),The long-term effects of auditory training on children with atypical neuroleptics also appear promising in this regard. autism. JAutLm DN DLod26:36-374 Bolton P, MacDonald H, Pickles A et al. (1994).A use-control family history FUTURE CONSIDERATIONS study of autism. 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Evaluating the genes may influence the phenotypic manifestations of impact of facilitated communication on the communicative competence of founcen students with autism. JAurirm Dn, Dirord26:43-58 the disorder suggest that it may be many years before Bordcn MC, Ollcndick TH (1994).An cumination of the validity of wid they bear hit. If specific genes are identified, there can subtypcs in autism. JAutim DN Disord24:23-37 Brodkin Es, McDouglc CJ, Naylor ST. &hen DJ, Price LH (1997),Clomi- be hope for very early identification of persons at risk. pramine in adults with pervasive developmental disorders: a prospmivc Brain imaging studies using functional MRI could be open-label investigation. J ChildAdohc f~ychophurmucol7:109-121 Bryron SE, Clark BS, Smith IM (1988),First report of a Canadian epidcmio- promising, but we will first need to better understand logical study of autistic syndromes. J ChikipIyrhol Psychiuny 29:433-445 normal brain-behavior relationships. 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The Dynamics ofAlcohol and Marijuana Initiation: Patterns and Predictors of First Use in Adolescence. Rick Kostennan, PhD, J. David Hawkins, PhD, Jie Guo, PhD, Richard F. Cadano, PhD, Robert D. Abbott, PhD 06jrcrjvrs: Thii study, guided by the social development model, examined the dynamic panems and predictors of alcohol and mari- juana use onset. M&: Survival analysis and complcmentary log-log regression wcrc used to modcl hazard rates and ctiology of ini- tiation with timevarying covariatcs. The sample was dcrived from a longitudinal study of 808 youth interviewed annually from 10 to 16 years of agc and at 18 ycars of age. hh:Alcohol initiation mse steeply up to thc agc of 13 years and thcn increased more grad- ually; most participants had initiated by 13 years of agc. Marijuana initiation shawcd a different pancrn, with more participants ini- tiating after the agc of 13 years. ConrhioncThis study showed that: (1) the risk of initiation spans the entire coursc of adolacent dcvcloprnenr; (2) young pmplc exposed to others who w substances arc at highcr riik for carly initiation; (3) proactive parents can help delay initiation; and (4) clear family standards and pmactivc family managcmcnt are imporrant in delaying alcohol and marijuana use, qdasof how closely bonded a child is to his or hcr mother. Am J Public Hal& 2000;3033W366. Copyright 2000 by the American Public Health Association.

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 39:9. SEPTEMBER 2000 1095