Rutter's Child and Adolescent Psychiatry Book 2

737 Schizophrenia is one of the most devastating psychiatric disorders to affect children and adolescents. Although extremely rare before the age of 10, the incidence of schizophrenia rises steadily though adolescence to reach its peak in early adult life. The clinical severity, impact on development and poor prognosis of child- and adolescent-onset schizophrenia reinforce the need for early detection, prompt diagnosis and effective treatment. The current concept of schizophrenia in children and adolescents evolved from a different perspective held during much of the 20th century. Until the early 1970s, the term childhood schizophrenia was applied to children who would now be diagnosed with autism. Until the 1990s, there was doubt about the validity of diagnosing schizophrenia in children and younger adolescents. However, in DSM-III and ICD-9 the separate category of childhood schizophrenia was removed, and the same diagnostic criteria for schizophrenia were applied across the age range. Good evidence for the validity of the diagnosis of schizophrenia in childhood and adolescence comes from the Maudsley Child and Adolescent Psychosis Follow-up Study (Hollis, 2000). First, a DSM-III-R diagnosis of schizophrenia in childhood and adolescence predicted a significantly poorer adult outcome compared to other nonschizophrenic psychosis. Second, the diagnosis of schizophrenia showed a high level of stability, with 80% having the same diagnosis recorded at adult follow-up (Jarbin, Ott, & Van Knorring, 2003). Clinical Features Schizophrenia is characterized by psychotic symptoms as follows. 1 Hallucinations These are sensory perceptions in the absence of external stimuli. Auditory hallucinations (hearing voices) are by far the most common type of hallucination in schizophrenia. Typically, their content is threatening, derogatory or commanding. Auditory hallucinations are classified according to their form: voices addressing the patient directly (second person); voices discussing or commenting on the patient’s actions in the third person (third person or running commentary); and voices speaking the patient’s thoughts aloud (thought echo). 2 Delusions These are false beliefs, incompatible with the patient’s social, religious and educational background, arising from an incorrect inference about external reality and not amenable to reason. Paranoid delusions (belief that one is persecuted), delusions of reference (belief that events or people’s behavior refer to oneself) or delusions of control (belief that one’s own thoughts, emotions or movements are controlled by external forces) are particularly common in schizophrenia. 3 Passivity phenomena These include the experience of one’s own thoughts becoming automatically available to others (thought broadcast); alien thoughts being inserted into one’s mind (thought insertion); and the experience of one’s thoughts being removed from one’s mind (thought withdrawal). 4 Disordered thought and speech This may present as incoherent speech (loosening of associations), neologisms or a paucity of content and ideas (poverty of speech). 5 Reduced or inappropriate emotional reactivity and lack of volition People with schizophrenia may demonstrate reduced emotional expression (flattened affect) or incongruous emotional reactions, lack of drive and initiative, and social withdrawal. 6 Motor abnormalities These phenomena may include posturing, mannerisms, stereotopies and catatonic immobility or excitement. Symptoms in schizophrenia can be seen as representing either an excess or distortion of normal function (positive symptoms) or a reduction or loss of normal function (negative symptoms). Positive symptoms include hallucinations, delusions, passivity phenomena, thought disorder, disorganized behavior and inappropriate affect. Negative symptoms include poverty of thought and speech, blunted affect, impaired volition and social withdrawal. Liddle (1987) showed that symptoms in chronic schizophrenia cluster into three syndromes: psychomotor poverty (negative symptoms); reality distortion (hallucinations and delusions); and disorganization (bizarre behavior, inappropriate affect and disorganized thought). The relationship between these different groups of symptoms and underlying brain function in schizophrenia is considered in more detail below. A wide variety of anomalous perceptual experiences may occur at the onset of an episode of schizophrenia, leading to a sense of fear or puzzlement which may constitute a delusional mood and herald a full psychotic episode. These anomalous experiences may include the sense that familiar places and Schizophrenia and Allied Disorders 45 Chris Hollis 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 737 Rutter’s Child and Adolescent Psychiatry, 5th Edition, Edited by M. Rutter, D. V. M. Bishop D. S. Pine, S. Scott, J. Stevenson, E. Taylor and A. Thapar © 2008 Blackwell Publishing Limited. ISBN: 978-1-405-14549-7

people and their reactions have changed in some subtle way. These experiences can result from a breakdown between perception and memory (for familiar places and people) and associated affective responses (salience given to these perceptions). For example, a young person at the onset of illness may study their reflection in the mirror for hours because it looks strangely unfamiliar, misattribute threatening intent to an innocuous comment or experience family members or friends as being unfamiliar, leading to a secondary delusional belief that they have been replaced by doubles or aliens. In summary, some clinical phenomena in schizophrenia can be understood in terms of a loss of normal contextualization and co-ordination of cognitive and emotional processing. Clinical Phases of Schizophrenia Premorbid Social and Developmental Impairments Child- and adolescent-onset schizophrenia is associated with poor premorbid functioning and early developmental delays (Alaghband-Rad, McKenna, Gordon et al., 1995; Hollis, 1995, 2003). Similar developmental and social impairments in childhood have been reported in adult-onset schizophrenia, but premorbid impairments appear to be more common and severe in the child- and adolescent-onset forms of the disorder. In the Maudsley study (Hollis, 2003), significant early delays were particularly common in the areas of language (20%), reading (30%) and bladder control (36%). Just over 20% of cases of adolescent schizophrenia had significant early delays in either language or motor development. In contrast, language and motor developmental delays have been reported in only about 10% of individuals who develop schizophrenia in adult life (Jones, Rogers, Murray, & Marmot, 1994). A consistent characteristic in the premorbid phenotype is impaired sociability. For example, in the Maudsley study of child- and adolescentonset psychoses (Hollis, 2003), about one-third of cases with schizophrenia had significant difficulties in social development affecting the ability to make and keep friends. Premorbid IQ in child- and adolescent-onset schizophrenia is in the mid to low 80s, some 10–15 points lower than in the adult form of the disorder (Alaghband-Rad, McKenna, Gordon et al., 1995; Asarnow, Thompson, Hamilton, Goldstein, & Guthrie, 1994; Hollis, 2000). In the Maudsley study (Hollis, 2000), one-third of child- and adolescent-onset cases had an IQ below 70, with the whole distribution of IQ shifted down compared to both adolescent affective psychoses and adult schizophrenia. Cannon, Caspi, Moffitt et al. (2002) reported a specific association between adult schizophreniform disorder and an antecedent pattern of childhood pan-developmental impairments involving motor development, receptive language and IQ. These findings are consistent with the view that premorbid impairments are manifestations of a genetic and/or developmental liability to schizophrenia. It seems clear that the premorbid phenotype does not just represent non-specific psychiatric disturbance. Looking backward from schizophrenia to early impairment, subtle problems of language, attention and social relationships are typical, whereas, in contrast, conduct problems are rare. However, looking forward from childhood impairments to later schizophrenia, prediction is much weaker. In addition, premorbid social and behavioral difficulties are not unique to schizophrenia and occur in other psychoses. Are Premorbid Impairments a Risk or Precursor of Psychosis? Premorbid impairments could lie on a causal pathway for psychosis or, alternatively, they could be markers of an underlying neuropathological process, such as aberrant neural connectivity, which may be the cause of both premorbid social impairment and psychosis. Frith (1994) has speculated on the possible cognitive mechanisms that might link deficits in social cognition or “theory of mind” in a causal pathway to both positive and negative psychotic symptoms. If these characteristics are causally related then modifying the “primary” cognitive or social deficits may reduce the risk of psychosis. Alternatively, cognitive and social deficits, although often present, may not be necessary in the pathogenesis. The fact that individuals may develop schizophrenia without obvious premorbid impairments supports this view. In these circumstances, an intervention aimed at the neurobiological level (e.g., antipsychotic medication) may be necessary. Only a high-risk longitudinal intervention study can adequately address the issue of causality, and this would require an intervention that had benefits for individuals who had the premorbid phenotype but did not develop psychosis. Premorbid Psychopathology A diverse range of clinical diagnoses, including attention deficit/hyperactivity disorder (ADHD), conduct disorder, anxiety, depression and autism spectrum disorders, may precede the diagnosis of schizophrenia in children and adolescents (Schaeffer & Ross, 2002) and in adults (Kim-Cohen, Caspi, Moffitt et al., 2003). However, there is a lack of any specific premorbid diagnosis that could practically aid early clinical identification of those at high risk for schizophrenia. A more promising line of research has demonstrated a strong link between self-reported psychotic symptoms in childhood and later schizophrenia (Poulton, Caspi, Moffitt et al., 2000). In the Dunedin cohort, psychotic symptoms at age 11 increased the risk of schizophreniform disorder at age 26 but not other psychiatric diagnoses. Relative to the rest of the cohort, those identified at age 11 with “strong” psychotic symptoms also had significant impairments in motor development, receptive language and IQ (Cannon, Caspi, Moffitt et al., 2002). Whereas none of these cases met criteria for a diagnosis of schizophrenia during adolescence, it appears that isolated or attenuated psychotic symptoms, in combination with pandevelopmental impairment, constitute a significant high-risk premorbid phenotype. Prodromal Symptoms and Onset of Psychosis People who develop schizophrenia typically enter a prodromal CHAPTER 45 738 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 738

phase characterized by a gradual but marked decline in social and academic functioning that precedes the onset of active psychotic symptoms. An insidious deterioration prior to the onset of psychosis is typical of the presentation of schizophrenia in children and adolescents (Werry, McClellan, Andrews, & Ham, 1994), and is more common in schizophrenia than in affective psychoses (Hollis, 1999). Non-specific behavioral changes including social withdrawal, declining school performance and uncharacteristic and odd behavior began, on average, over a year before the onset of positive psychotic symptoms. In retrospect, non-specific behavioral changes were frequently early negative symptoms, which had their onset well before positive symptoms such as hallucinations and delusions. Early recognition of disorder is difficult, as premorbid cognitive and social impairments gradually shade into prodromal symptoms before the onset of active psychotic symptoms (Hafner & Nowotny, 1995). Prodromal symptoms can include odd ideas, eccentric interests, changes in affect, unusual experiences and bizarre perceptual experiences. Whereas these are also characteristic features of schizotypal personality disorder, in a schizophrenic prodrome there is usually progression to more severe dysfunction. Diagnosis of Schizophrenia in Childhood and Adolescence Diagnostic Criteria for Schizophrenia The two dominant diagnostic systems (DSM and ICD) have slightly different definitions for schizophrenia, although both require the clear evidence of psychosis (in the absence of predominant affective symptoms) with minimum duration criteria. The reader should refer to the original manuals (DSM-IV and ICD-10) when making diagnoses in clinical or research practice. ICD-10 criteria are closer to the Schneiderian concept of schizophrenia and place more reliance than DSM-IV on the presence of first-rank symptoms. In contrast, the DSM-IV definition reflects Kraepelin’s concept of a psychotic disorder with a chronic and deteriorating course (Maj, 1998). In addition, DSM-IV stipulates a 6-month duration of disturbance, which makes it more restrictive than the 1-month duration criterion of ICD-10. The DSM-IV category of schizophreniform disorder is used for cases with the same symptoms but an overall duration of disturbance of less than 6 months. As a result, the DSM-III-R/DSM-IV definition of schizophrenia has greater specificity but lower sensitivity than ICD-10 in firstepisode psychoses (Mason, Harrison, Croudace, Glazebrook, & Medley, 1997). Not surprisingly, cases of schizophrenia defined using DSM-IV have a worse prognosis than those defined using ICD-10. DSM-IV also describes various subtypes of schizophrenia defined by the most prominent symptomatology: 1 Paranoid type characterized by delusions and hallucinations; 2 Disorganized type characterized by disorganization of speech, behavior and negative symptoms (i.e., flat or inappropriate affect); 3 Catatonic type characterized by motor abnormalities; and 4 Residual type. Clinical Characteristics of Schizophrenia in Childhood and Adolescence Even if strict adult definitions of schizophrenia (DSM-IIIR/DSM-IV or ICD-10) are applied, there are age-dependent variations in phenomenology. Child- and adolescent-onset cases are characterized by a more insidious onset, negative symptoms, hallucinations in different modalities and fewer systematized or persecutory delusions (Green, Padron-Gayol, Hardesty et al., 1992; Werry, McClellan, Andrews et al., 1994). Early-onset schizophrenia is characterized by greater disorganization (incoherence of thought and disordered sense of self) and more negative symptoms, while in later-onset cases there is a higher frequency of systematized and paranoid delusions (Hafner & Nowotny, 1995). Course and Outcome Short-Term Course Child- and adolescent-onset schizophrenia characteristically runs a chronic course, with only a minority of cases making a full symptomatic recovery from the first psychotic episode. Hollis (1999) found that only 12% of schizophrenic cases were in full remission at discharge compared to 50% of cases with affective psychoses. The short-term outcome for schizophrenia presenting in early life appears to be worse than that of firstepisode adult patients (Robinson, Woerner, Alvir et al., 1999). If full recovery does occur then it is most likely within the first 3 months of the onset of psychosis. In the Maudsley study, those adolescent-onset patients who were still psychotic after 6 months had only a 15% chance of achieving full remission, whereas over half of all cases that made a full recovery had active psychotic symptoms for less than 3 months (Hollis, 1999). The clinical implication is that the early course over the first 6 months is the best predictor of remission and that longer observation over 6 months adds relatively little new information. Long-Term Outcome A number of long-term follow-up studies of child- and adolescent-onset schizophrenia describe a typically chronic unremitting long-term course with severely impaired functioning in adult life (Eggers & Bunk, 1997; Fleischhaker, Schulz, Tepper et al., 2005; Hollis, 2000; Jarbin, Ott, & Von Knorring, 2003; Lay, Blanz, Hartmann, & Schmidt, 2000; Schmidt, Blanz, Dippe, Koppe, & Lay, 1995; Werry, McClellan, & Chard, 1991). Referral bias towards selecting more severe cases is a potential problem in clinical follow-up studies. However, population-based studies have yielded similar results (Hollis, 2000). Several common themes emerge from these studies. First, the generally poor outcome of early onset schizophrenia conceals considerable heterogeneity. About one-fifth of patients in most studies have a good outcome with only mild impairment, whereas at the other extreme about one-third of patients are SCHIZOPHRENIA AND ALLIED DISORDERS 739 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 739

severely impaired, requiring intensive social and psychiatric support. Second, after the first few years of illness there is little evidence of further progressive decline. Third, child- and adolescent-onset schizophrenia has a worse outcome than either adolescent-onset affective psychoses or adult-onset schizophrenia. Fourth, social functioning, in particular the ability to form friendships and love relationships, appears to be very impaired in early-onset schizophrenia. Taken together, these findings confirm that schizophrenia presenting in childhood and adolescence lies at the extreme end of a continuum of phenotypic severity. Prognostic Factors The predictors of poor outcome in adolescent-onset affective psychoses include premorbid social and cognitive impairments (Fleischhaker, Schulz, Tepper et al., 2005; Hollis, 1999), a prolonged first psychotic episode (Schmidt, Blanz, Dippe et al., 1995), extended duration of untreated psychosis and the presence of negative symptoms (Hollis, 1999). Premorbid functioning and negative symptoms at onset provide better prediction of long-term outcome than categorical diagnosis (Fleischhaker, Schulz, Tepper et al., 2005; Hollis, 1999). Mortality The risk of premature death is increased in child- and adolescent-onset psychoses. In the Maudsley study (Hollis, 1999), there were nine deaths out of the 106 cases followedup (8.5%), corresponding to a 12-fold increase in the risk of death compared to an age and sex matched general UK population over the same period. Of the nine deaths in the cohort, seven were male and seven had a diagnosis of schizophrenia. Three subjects suffered violent deaths, two died from self-poisoning and three had unexpected deaths from previously undetected physical causes (cardiomyopathy and status epilepticus) and were possibly associated with high-dose antipsychotic medication. Epidemiology Incidence and Prevalence Good population-based incidence figures for child- and adolescent-onset schizophrenia are lacking, although there are data for broader categories of psychosis, with diagnoses made without the benefit of standardized assessments. Gillberg, Wahlstrom, Forsman, Hellgren, and Gillberg (1986) calculated age-specific prevalence for all psychoses (including schizophrenia, schizophreniform psychosis, affective psychosis, atypical psychosis and drug psychoses) in the age range 13–18 years using case-register data from Goteborg, Sweden. Of the cases, 41% had a diagnosis of schizophrenia. At age 13 years, the prevalence for all psychoses was 0.9 in 10,000, showing a steady increase during adolescence, reaching a prevalence of 17.6 in 10,000 at age 18 years. Sex Ratio Males are overrepresented in many clinical studies of childhoodonset schizophrenia (Russell, Bott, & Sammons, 1989; Spencer & Campbell, 1994). However, other studies of predominantly adolescent-onset schizophrenia have described an equal sex ratio (Gordon, Frazier, McKenna et al., 1994; Hollis, 2000; Werry, McClellan, Andrews et al., 1994). The interpretation of these studies is complicated by the possibility of referral biases to clinical centers. In an epidemiological study of first admissions for schizophrenia and paranoia in children and adolescents there was an equal sex ratio for patients under the age of 15 (Galdos, van Os, & Murray, 1993). The finding of an equal sex distribution with adolescent-onset is intriguing as it differs from the consistent male predominance (ratio 2:1) reported in incident samples of early adult-onset schizophrenia (Castle & Murray, 1991). Clearly, future studies require population-based samples free from potential referral biases. Etiology and Risk Factors Pregnancy and Birth Complications Pregnancy and birth complications (PBC) have long been implicated as a risk factor in schizophrenia, although the evidence is mixed (Geddes & Lawrie, 1995; Kendall, McInneny, Juszczak, & Bain, 2000). In two independent case–control studies of childhood-onset schizophrenia, Matsumoto, Takei, Saito et al. 1999; Matsumoto, Takei, Saito et al., 2001 reported an odds ratio of 3.2–3.5 for PBC, suggesting a greater risk in very early-onset cases. However, in the National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia, PBCs were no more common in cases than in sibling controls (Nicolson, Giedd, Lenane et al., 1999). Insofar as there is a significant association, it seems likely that PBCs are consequences rather than causes of abnormal neurodevelopment (Goodman, 1988). This view is supported by the finding that people with schizophrenia have smaller head size at birth than controls (McGrath & Murray, 1995), which is likely to be a consequence of either defects in genetic control of neurodevelopment or earlier environmental factors such as viral exposure. Prenatal Famine Severe maternal intrauterine nutritional deficiency may increase the risk for schizophrenia in adult life. Evidence of a two-fold increase for schizophrenia in children born to the most malnourished mothers comes from studies of the 1944–1945 Dutch Hunger Winter (Susser & Lin, 1992) and the Chinese famine of 1959–1961 (St. Clair, Xu, Wang et al., 2005). Cannabis and Schizophrenia There is little doubt that acute intoxication with cannabis and other illicit substances such as stimulants and hallucinogens can precipitate psychotic symptoms or exacerbations of existing psychotic illness. However, there is controversy whether cannabis use in particular is a risk factor for the development of schizophrenia. A meta-analysis of four well-conducted longitudinal population-based studies from Sweden (Swedish conscript cohort), the Netherlands (NEMESIS) and New Zealand CHAPTER 45 740 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 740

(Dunedin and Christchurch cohorts) concluded that, at an individual level, cannabis confers an overall two-fold increased risk for later schizophrenia (Arseneault, Cannon, Witton, & Murray, 2004). In the Dunedin cohort, Arseneault, Cannon, Poulton et al. (2002) showed that the association was strongest for the youngest cannabis users (after controlling for prior psychotic symptoms), with 10.3% of the cannabis users at age 15 developing schizophreniform disorder at age 26. So far, cannabis use has not been directly implicated in child- and adolescent-onset schizophrenia – possibly because of the relatively lower prevalence of cannabis use in younger adolescents and a short duration between exposure and psychotic outcome. However, cannabis use is associated with earlier age of onset of schizophrenia in adults (Arendt, Rosenberg, Foldager, Perto, & Munk-Jorgensen, 2005). The mechanism and causal direction for this association remain unclear. It is possible that subtle social and developmental impairments that precede schizophrenia are also risk factors for cannabis use (reverse causality or a third factor). Perhaps a more plausible explanation is a gene × environment interaction effect whereby cannabis exposure causes schizophrenia only in those with a pre-existing susceptibility. Caspi, Moffitt, Cannon et al. (2005) provided evidence for such a gene × environment interaction specific to adolescent cannabis exposure: The COMT val158met polymorphism moderated the link between psychosis and adolescent-onset cannabis use, but not adult-onset cannabis use. The COMT val allele is associated with greater COMT activity (relative to the COMT met allele) and reduced dopamine transmission in the prefrontal cortex. These results, taken together with human (Dean, Bradbury, & Copolov, 2003) and animal (Pistis, Perra, Pillolla et al., 2004) neuropharmacological studies suggest that cannabis may enhance the risk of schizophrenia in vulnerable individuals during a critical period of adolescent brain development. Psychosocial Risks Expressed Emotion High levels of expressed emotion (EE) among relatives of adults with schizophrenia predict psychotic relapse and poor outcome (Leff & Vaughn, 1985), raising the question of whether high EE might act to “bring forward” the onset of the disorder in a vulnerable individual. Goldstein (1987) reported that measures of parental criticism and overinvolvement taken during adolescence were associated with an increased risk of schizophrenia spectrum disorders in young adulthood. However, a causal link was not proven, and the association may reflect either an expression of some common underlying trait or a parental response to premorbid disturbance in the preschizophrenic adolescent. More direct comparisons between the parents of adult- and childhood-onset cases of schizophrenia fail to support the hypothesis of higher parental EE in childhood-onset cases. Asarnow, Thompson, Hamilton et al. (1994) used the Five Minute Speech Sample to measure parental EE and found that people with childhood-onset schizophrenia were no more likely to have “high EE” parents than normal controls. It appears that, on average, the parents of children with schizophrenia generally express lower levels of criticism and hostility than parents of adult-onset patients, because of a greater tendency to attribute their children’s behavior to an illness that is beyond their control (Hooley, 1987). Migration and Social Class Two variables, migration and social class, are associated with significant variation in the incidence of schizophrenia. First and second generation migrants have a 2–4-times greater risk of schizophrenia (Cantor-Graae & Selten, 2005). The relative risk is highest in migrants from developing countries and where the majority population is Black. Adjustment for social class reduces, but does not eliminate, the effects of migration. Migrants living in deprived inner cities are exposed to a range of psychosocial adversities including increased exposure to drugs, violence and crime. The mechanisms linking social adversity to psychosis are unclear – but one suggestion is that experience of social defeat and isolation increases liability to dopamine dysregulation and cognitive distortions (Broome, Woolley, Tabraham et al., 2005). Childhood Abuse and Neglect A causal link between child abuse and psychosis, in particular hallucinations, in adult life has been proposed (Read, van Os, Morrison, & Ross, 2005). While strong claims have been made for this link, the evidence to date remains inconclusive, with most studies supporting the link having serious methodological weaknesses (Morgan & Fisher, 2007). Concepts of Schizophrenia Neurodevelopmental Model Over the last two decades, the concept of schizophrenia as a neurodevelopmental disorder has been the dominant explanatory model with a tension between “early” and “late” versions of the model. However, more recently these positions have converged as it has been recognized that both early events (during pre- and perinatal brain development) and late events (during adolescent brain maturation) contribute to schizophrenia (Hollis & Taylor, 1997; Rapoport, Addington, & Frangou, 2005). The “early” neurodevelopmental model views the primary cause of schizophrenia as a static “lesion,” either neurogenetic or environmental in origin, occurring during fetal brain development (Weinberger, 1987). Two main lines of evidence support this model. First, Roberts, Colter, Lofthouse et al. (1986) reported an absence of gliosis, suggesting aberrant neurodevelopment rather than neurodegeneration. Second, schizophrenia is associated with premorbid social and cognitive impairments (Jones, Rogers, Murray et al., 1994), pregnancy and birth complications (Lewis & Murray, 1987) and minor physical anomalies (Gualtieri, Adams, & Chen, 1982). According to this “early” model, during childhood this lesion is relatively silent, giving rise only to subtle social and cognitive SCHIZOPHRENIA AND ALLIED DISORDERS 741 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 741

impairments. However, in adolescence, or early adult life, the lesion interacts with the process of normal brain maturation (e.g., myelination of cortico-limbic circuits, and/or synaptic pruning and remodeling) and leads to psychotic symptoms. A limitation of the “early” model is that a neurodevelopmental insult on its own cannot account for the finding of increased extracerebral (sulcal) cerebrospinal fluid (CSF) space in schizophrenia. Diffuse loss of brain tissue limited to the preor perinatal periods would result in enlargement of the lateral ventricles but not increased extracerebral CSF space (Woods, 1998). The “late” neurodevelopmental model, first proposed by Feinberg (1983), argues that the key neuropathological events in schizophrenia occur as a result of abnormal brain development during adolescence. The current formulation of the “late” neurodevelopmental model proposes that excessive synaptic and/or dentritic elimination occuring during adolescence produces aberrant neural connectivity (McGlashan & Hoffman, 2000; Woods, 1998). This “late” model characterizes schizophrenia as a progressive late-onset neurodevelopmental disorder and predicts that progressive structural brain changes and cognitive decline will be seen in adolescence around the onset of psychosis. Excessive synaptic pruning is regarded as an amplification of the normal process of progressive pruning and elimination of synapses that begins in early childhood and extends through late adolescence (Purves & Lichtmen, 1980). In the “late” model, premorbid abnormalities in early childhood are viewed as non-specific risk factors rather than early manifestations of an underlying schizophrenic neuropathology. Both the “early” and “late” models suppose that there is a direct and specific expression of the eventual brain pathology as schizophrenic disorder. A third viewpoint, the neurodevelopmental “risk” model, proposes that early and/or late brain pathology acts as a risk factor rather than a sufficient cause, so that its effects can only be understood in the light of an individual’s exposure to other risk and protective factors (Hollis & Taylor, 1997). This latter formulation provides a probabilistic model of the onset of schizophrenia in which aberrant brain development is expressed as neurocognitive impairments that interact with environmental risk factors to produce psychotic symptoms. Over the last decade, further evidence has emerged to refine the neurodevelopmental model of schizophrenia. Data from premorbid social and developmental impairments, brain morphology, neuropsychology and genetics all suggest an aberrant neurodevelopmental process resulting from an interplay of genetic and environmental factors that is set in train before the onset of psychotic symptoms and continues into late adolescence. Neurobiology of Schizophrenia Neuropathology In the postmortem brains of people with schizophrenia there is an absence of gliosis, which is the necessary hallmark of neurodegeneration (Roberts, Colter, Lofthouse et al., 1986). The prominent neuropathology in schizophrenia is not the classic form involving neuronal cell death, but instead a loss or reduction in dendritic spines and synapses, which are the elements of neural connectivity (Glantz & Lewis, 2000). As a result, the brain in schizophrenia is characterized by increased neuronal density, decreased intraneuronal space and reduced overall brain volume. Furthermore, the decrease in dentritic spine density appears to be both region- and diseasespecific, being found in the dorsolateral prefrontal cortex (layer 3 pyramidal cells), but not in the visual cortex (Glantz & Lewis, 2000). These findings are compatible with the hypothesis of reduced cortical and/or thalamic excitatory inputs to the dorsolateral prefrontal cortex in schizophrenia. However, early postmortem findings of aberrant neuronal migration have not been replicated. Hence, while there is a broad consensus that reduced dendritic arborization and synaptic density are core neuropathological features in schizophrenia, there is much less certainty regarding the timing of these changes during development. Structural Brain Abnormalities Neuroimaging and postmortem studies have shown that the brain as a whole and the frontal and temporal cortices in particular are smaller than normal in people with schizophrenia (Nopoulos, Torres, Flaum et al., 1995). Brain volume reductions are specific to gray matter (Gur, Turetsky, Cowell et al., 2000b), which supports neuropathological findings of increased neuronal density and reduced intraneuronal neuropil rather than neuronal loss (Selemon, Rajkowska, & GoldmanRakic, 1995). The volume of the hippocampus and amygdala is reduced bilaterally by 4.5–10% (Gur, Turetsky, Cowell et al., 2000b; Nelson, Saykin, Flashman, & Riodan, 1998), and prefrontal gray matter volume is reduced by about 10% (Gur, Cowell, Latshaw et al., 2000a). Enlargement of the third and lateral ventricles is a consistent finding, with ventricular volume increased by about 40% bilaterally (Lawrie & Abukmeil, 1998). Ventricular enlargement and frontal gray matter abnormalities are associated with neuropsychological impairment and negative symptoms (Vita, Dieci, Giobbio et al., 1991). The brain changes reported in childhood-onset schizophrenia appear to be very similar to those described in adult schizophrenia, supporting the idea of an underlying neurobiological continuity. In the NIMH study of childhood-onset schizophrenia (onset less than 13 years of age), subjects had smaller brains than controls, with larger lateral ventricles and reduced prefrontal lobe volume ( Jacobsen & Rapoport, 1998). As in adult studies, reduced total cerebral volume is associated with negative symptoms (Alaghband-Rad, Hamburger, Giedd, Frazier, & Rapoport, 1997). Midsagittal thalamic area is decreased while midsagittal area of the corpus callosum is increased (Giedd, Castellanos, Rajapaske, Vaituzis, & Rapoport, 1996) suggesting that the reduction in total cerebral volume in childhood-onset schizophrenia is caused by relative reduction in gray matter with relative sparing of CHAPTER 45 742 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 742

white matter. Childhood-onset patients have a higher rate of developmental brain abnormalities than controls, including an increased frequency of an enlarged cavum septum pellucidum (Nopoulos, Giedd, Andreasen, & Rapoport, 1998). Abnormalities of the cerebellum have also been found, including reduced volume of the vermis, midsagittal area and inferior posterior lobe (Jacobsen, Giedd, Berquin et al., 1997a). Associated with reports of reduced cortical thickness are gyrification abnormalities including more flattened curvature in the sulci and more peaked or steep curvature in the gyri (White, Andreasen, Nopoulos, & Magnotta, 2003), consistent with a neurodevelopmental origin of cortical abnormalities. In adolescent-onset schizophrenia patients, there is evidence of ventricular enlargement and reduced volume of the prefrontal cortex and reduced thalamic volume (Dasari, Friedman, Jesberger et al., 1999; James, Smith, & Jayaloes, 2004). Progressive Brain Changes Two different types of progressive brain change have been described in schizophrenia. First, treatment with traditional antipsychotics appears to cause progressive enlargement of the basal ganglia, with these structures returning to their original size when patients are transferred to the atypical antipsychotic clozapine (Frazier, Giedd, Kaysen et al., 1996). Second, there is evidence of progressive volume reductions in the temporal and frontal lobes during the first 2–3 years after the onset of schizophrenia (Gur, Cowell, Turetsky et al., 1998). In the NIMH study of childhood-onset schizophrenia, longitudinal repeated magnetic resonance imaging (MRI) scans through adolescence revealed a progressive increase in ventricular volume and progressive decrease in cortical volume with frontal (11% decrease), parietal (8.5% decrease) and temporal lobes (7% decrease) disproportionately affected (Rapoport, Giedd, Blumenthal et al., 1999; Sporn, Greenstein, Gogtay et al., 2003). Overall, this represents a four-fold greater reduction in cortical volume than in healthy adolescents. A similar progressive loss in cerebellar volume has been reported in the same NIMH childhood-onset schizophrenia sample (Keller, Castellanos, Vaituzis et al., 2003). Age-related volume reduction across adolescence has also been reported for the anterior cingulate gyrus (Marquardt, Levitt, Blanton et al., 2005). Progressive changes appear to be time-limited to adolescence, with the rate of volume reduction in frontal and temporal structures associated with premorbid developmental impairment and baseline symptom severity (Sporn, Greenstein, Gogtay et al., 2003) and declining as subjects reach adult life (Giedd, Jeffries, Blumenthal et al., 1999). The pattern of progressive cortical volume reduction described in the NIMH childhood-onset schizophrenia sample appears to be an exaggeration of the normal “back to front” pattern of cortical volume reduction seen during adolescence (Gogtay, Sporn, Clasen et al., 2004). At present, it is unclear whether the dramatic findings from the NIMH childhood-onset schizophrenia sample, which is atypical in terms of very early onset (<13 years) and neuroleptic treatment resistance, can be generalized to other samples of children and adolescents with schizophrenia (cf. James, Javaloyes, James, & Smith, 2002). Because progressive brain changes have been described after the onset of psychosis, it is possible that they are a consequence of neurotoxic effects of psychosis. Evidence that progressive brain changes precede the onset of psychosis is very limited. Pantelis, Velakoulis, McGorry et al. (2003) have reported brain MRI findings in high-risk subjects scanned before and after the transition into psychosis. The baseline crosssectional comparison found that those about to develop psychosis had reduced cortical gray matter in the right temporal, inferior frontal cortex and cingulate bilaterally. When rescanned, those subjects who developed psychosis had further volume reductions in gray matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices and cingulate gyri. The only significant longitudinal changes in cases who remained non-psychotic were in the cerebellum. These are important findings, and if replicated would provide strong support for the idea that excessive developmental reductions in gray matter both predate and accompany the onset of psychotic symptoms. Functional Brain Imaging The emergence of functional brain imaging technology has provided a unique opportunity to link symptoms and cognitive deficits in schizophrenia to underlying brain activity. In studies of adults with schizophrenia, there are associations between: 1 Negative symptoms, cognitive executive function deficits and abnormal frontal activity; 2 Disorganization symptoms (thought disorder and inappropriate affect) and anterior cingulate activity; and 3 Thought disorder/hallucinations and activity in the superior temporal gyrus (Liddle & Pantellis, 2003). Reduced activity of the anterior cingulate cortex in schizophrenia is associated with impaired ability to monitor response errors and response to conflict (Kerns, Cohen, MacDonald et al., 2005), which may underlie psychotic symptoms (Frith, 1994). Reduced activity in the right dorsolateral prefrontal cortex has also been associated with working memory impairments and disorganization symptoms (Perlstein, Carter, Noll, & Cohen, 2001). The notion of “hypofrontality” has been proposed to account for schizophrenia, but is certainly an oversimplification. Evidence suggests that frontal activation is diminished only when processing load is high and task performance diminishes (Perlstein, Carter, Noll et al., 2001). In contrast, baseline resting frontal activation may be increased in acute schizophrenia relative to healthy subjects as a result of abnormal self-generated mental activity associated with psychotic symptoms. When an external task places an increased processing load on an individual with psychosis, the prefrontal cortex may be unable to meet the demand, resulting in reduced performance and activation (Liddle & Pantellis, 2003). In a positron emission tomography (PET) study in childhoodonset schizophrenia using the Continuous Performance Test (CPT), Jacobsen, Hamburger, Van Horn et al. (1997b) reported SCHIZOPHRENIA AND ALLIED DISORDERS 743 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 743

reduced activation compared to healthy controls in the mid and superior frontal gyrus, and increased activation in the inferior frontal, supramarginal gyrus and insula. Clearly, a simple description of “hypofrontality” does not capture the complex pattern of changes involving interconnected frontal areas. Older, localizationist, models based on focal cerebral dysfunction in schizophrenia have tended to give way to models of cerebral disconnectivity (Bullmore, O’Connell, Frangou et al., 1997) that fit well with both neuropathological and functional neuroimaging findings. This may be one reason for inconsistent neuroanatomical findings in schizophrenia, as “lesions” in different areas of a widely distributed neural system could produce similar functional disturbance. Magnetic Resonance Spectroscopy: Abnormal Neuronal Metabolism Magnetic resonance spectroscopy (MRS) is an imaging technique that can be used to extract in vivo information on dynamic biochemical processes at a neuronal level. Proton (1 H) MRS focuses on changes in the neuronal marker N-acetylaspartate (NAA). Studies in adult schizophrenic patients have shown reductions in NAA in the hippocampal area and dorsolateral prefrontal cortex (DLPFC). Similar reductions in NAA ratios specific to the hippocampus and DLPFC (Bertolino, Kumra, Callicott et al., 1988) and frontal gray matter (Thomas, Ke, Levitt et al., 1998) have been reported in childhood-onset schizophrenia, suggesting neuronal damage or malfunction in these regions. Pettegrew, Keshavan, Panchalingam et al. (1991) used 31P MRS with non-medicated patients during a first episode of schizophrenia and found reduced phosphomonoester (PME) resonance and increased phosphodiester (PDE) resonance in the prefrontal cortex. This result is compatible with reduced synthesis and increased breakdown of connective processes in the prefrontal cortex. A similar finding of reduced PME and increased PDE resonance has been reported in adults with autism, although they showed increased prefrontal metabolic activity, which was not seen in people with schizophrenia (Pettegrew, Keshavan, Panchalingam et al., 1991). Keshavan, Stanley, Montrose et al. (2003) reported reduced PME moieties (e.g., synaptic vesicles and phosphorylated proteins) in the prefrontal cortex using 31P MRS in a sample of children and adolescents at genetic high risk for schizophrenia. These findings suggest that abnormal synaptic structure and function in the prefrontal cortex is a marker of schizophrenia risk. Further follow-up is required to determine if these findings have predictive value. Implications for Neurodevelopmental Models of Schizophrenia Taken together, the neuropathological and brain imaging findings provide considerable support for the idea of progressive neurodevelopmental changes in schizophrenia including excessive synaptic elimination resulting in aberrant neural connectivity. The progressive nature of brain volume reductions in adolescence, and the fact that reduced brain volume is not accompanied by reduced intracranial volume, suggests that a static pre- or perinatal brain insult is insufficient to account for this process. While early random events in fetal neurodevelopment (e.g., hypoxia, viruses) may affect baseline synaptic density, genetically determined excessive synaptic elimination as proposed by the “late” neurodevelopmental model may be the neurobiological process underlying disorders in the schizophrenia spectrum (McGlashan & Hoffman, 2000). What is unclear is whether excessive synaptic elimination in the prefrontal cortex (and possibly other brain regions) is a sufficient cause for psychosis to occur, or whether it provides a vulnerable neurocognitive substrate that must interact with environmental stressors (e.g., cannabis exposure or cognitive or social stressors) to produce psychotic symptoms. Genetics of Schizophrenia Multigene Models of Risk Twin studies have suggested the heritability of schizophrenia to be as high as 83% (Cannon, Kaprio, Lonnqvist, Huttunen, & Koskenvuo, 1998). However, one of the most significant implications of twin, adoption and family studies in schizophrenia has been the challenge the results pose to traditional qualitatively distinct categories of disorder (Rutter & Plomin, 1997). Quantitative genetic studies have shown that the genetic liability to schizophrenia extends to schizoptypal personality disorders and other conditions viewed as lying on the broader schizophrenia spectrum (Erlenmeyer-Kimling, Squires-Wheeler, Adamo et al., 1995; Kendler, Neale, & Walsh, 1995). These results suggest that what is inherited in schizophrenia is likely to be quantitative traits that determine liability to disorder. While the mode of inheritance in schizophrenia remains unknown, most evidence supports a multilocus or multifactorial threshold model. This model proposes that schizophrenia results from the combined action of multiple genes of small effect that confer susceptibility to the schizophrenic phenotype, with the disorder being expressed above a particular liability threshold. Susceptibility to the disorder is expressed as a dimension in the population (i.e., the risk of schizophrenia in the population is distributed normally, not bimodally). Because there are likely to be multiple genes involved, the genetics of schizophrenia is moving away from the rather simplistic notion of finding a single major gene for the disorder, towards a search for genes that confer susceptibility traits. Susceptibility alleles may be quite common in the population and hence the predictive value of any individual allele alone will be low. It is commonly assumed that genes affecting brain development in schizophrenia are only expressed during fetal neurodevelopment. However, it is quite possible that while some susceptibility genes for schizophrenia may affect fetal brain development, other genes do not exert their effect until adolescence, possibly causing excessive or aberrant synaptic pruning with reduction in temporal and frontal lobe volume (Feinberg, 1997). CHAPTER 45 744 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 744

premorbid social and academic adjustment (Rapoport, Addington, & Frangou, 2005). Finally, a polymorphism of the GAD1 (glutamic acid decarboxylase) gene has been associated with both childhood-onset schizophrenia and abnormal frontal gray matter loss (Addington, Gornick, Duckworth et al., 2005). Cytogenetic Abnormalities The association between schizophrenia and chromosomal deletions offers another possible route to locating candidate genes (Hennah, Thompson, Peltonen, & Porteous, 2006). The velocardiofacial syndrome (VCFS) microdeletion on chromosome 22q11 (which includes the COMT gene plus two candidates, PRODH and ZDHHC8) is associated with adult schizophrenia, occurring at a rate of 2% compared to 0.02% in the normal population (see chapter 24; Karayiogou, Morris, Morrow et al., 1995). The association with schizophrenia is not specific, as the VCFS microdeletion is also linked with higher rates of other psychiatric disorders (e.g., affective disorder, ADHD). In the NIMH COS study, a high rate of previously undetected cytogenetic abnormalities was found, including 4 of 80 (5%) with VCFS (Sporn, Addington, Reiss et al., 2004b). The 22q11DS is associated with progressive cortical gray matter loss in children and adolescents who are not yet psychotic, suggesting that a gene or genes mapping to 22q11 is responsible for a high-risk phenotype (Sporn, Addington, Reiss et al., 2004b). Another major finding based on a chromosomal abnormality comes from an extended Scottish pedigree where a balanced translocation (1:11)(q42;q14.3) showed linkage with a phenotype including schizophrenia, bipolar disorder and depression (Hennah, Thompson, Peltonen et al., 2006). The translocation disrupts two genes on chromosome 1: DISC1 and DISC2. There is some evidence that DISC1 is linked to the regulation of neural migration, which may have a role in the pathogenesis of schizophrenia. Two studies found mutations or polymorphisms of DISC1 associated with schizophrenia, while two other studies have failed to find an association (Owen, Craddock, & O’Donovan, 2005). Overlap with Bipolar Disorder Several genes influence susceptibility to both schizophrenia and bipolar disorder, including NRG1, DISC1 and G72 (DAOA; Owen, Craddock, & O’Donovan, 2005). These findings suggest that the two disorders share pathogenic mechanisms and challenge the long-held Kraepelinian dichotomy that views schizophrenia and bipolar disorder as separate diagnostic entities. Prototypic schizophrenia and bipolar disorder can be seen as lying at the extreme ends of a spectrum of psychosis with mixed or intermediate phenotypes lying in between. Within this spectrum of psychosis, dysbindin (DTNBP1) predisposes predominantly to schizophrenia with negative symptoms, DAOA and BDNF predispose predominantly to mood disorder, and NRG1 and DISC1 predispose to both prototypic forms of disorder (Craddock, O’Donovan, & Owen, 2005). SCHIZOPHRENIA AND ALLIED DISORDERS 745 Linkage Studies Two meta-analyses of schizophrenia linkage studies have supported a multilocus model with several chromosomal regions implicated. Lewis, Levinson, Wise et al. (2003) found the strongest evidence for linkage on 2q, with weaker support obtained for regions on chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q and 14p. Meanwhile, Badner and Gershon (2002) found evidence supporting susceptibility genes on chromosomes 8p, 13q and 22q. Hence, both studies converged on two regions: 8p and 22q, with nine other regions being supported by only one metaanalysis. While failure to replicate genetic findings has plagued schizophrenia research, this is to be expected if schizophrenia is an etiologically (and genetically) heterogeneous disorder. Positional Candidate Genes and Neurobiology Convergent findings from linkage studies have led to mapping of implicated regions and identification of putative susceptibility genes. A number of replicated associations have recently been reported between DNA polymorphisms of various positional candidate genes and schizophrenia. The positional candidate genes most clearly implicated impact on either synaptogenesis or glutamate neurotransmission (Harrison & Owen, 2003). The strongest evidence favors dysbindin (DTNBP1) (6p22.3) and neuroregulin (NRG1) (8p21–p22). There is also promising but less compelling evidence for catecholamine-Omethyltransferase (COMT), d-amino-acid oxidase (DAO), its activator DAOA (previously known as G72) and regulator G protein signaling 4 (RGS4). The high-risk COMT val allele associated with schizophrenia is hypothesized to have its effect by reducing dopaminergic transmission in the prefrontal cortex. Dysbindin may affect the uptake of glutamate into synaptic vesicles, NRG1 is released from glutamate terminals and regulates N-methyl-d-aspartate (NMDA) glutamate receptors and DAO, activated by DAOA, is an indirect modulator of NMDA receptors. The actions of many of these genes converge on a shared pathophysiological process that suggests that abnormalities of synaptic signaling, in particular at the glutamatergic synapse, may be a primary abnormality in schizophrenia (Harrison & Weinberger, 2005; Mirnics, Middleton, Lewis, & Levitt, 2001). At a simple conceptual level, these genes are all thought to influence information processing (via synaptic signaling) in cortical circuits. The clinical correlates of these candidate genes are more likely to be neurodevelopmental and cognitive impairments than fluctuating positive symptoms of schizophrenia. Candidate Genes in Childhood-Onset Schizophrenia The DAOA polymorphism (13q33.2) was associated with childhood-onset schizophrenia (COS) in the NIMH sample (Addington, Gornick, Sporn et al., 2004). Interestingly, in the same NIMH sample DAOA was associated with later age of onset and lower scores for premorbid autism symptoms. Another intriguing finding in the NIMH COS sample is an association between dysbindin (DTNBP1) (6p22.3) and poor 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 745

schizophrenia (Kumra, Sporn, Hommer et al., 2001). Similar ETD has been reported in adult schizophrenia (Iacono & Koenig, 1983). ETD is also a potential genetic endophenotype trait marker for schizophrenia that has been detected in healthy siblings of COS and parents of adult-onset schizophrenia patients (Sporn, Greenstein, Gogtay et al., 2005). Non-psychotic relatives of schizophrenic patients also show eye-tracking deficits that correlate with subtle frontal lobe dysfunction (O’Driscoll, Benkelfat, Florencio et al., 1999). Finally, children with schizophrenia also show similar impairments to adult patients on tests of frontal lobe executive function such as the Wisconsin Card Sorting Test (WCST; Asarnow, Thompson, Hamilton et al., 1994). Hence, reduced prefrontal activation may be one expression of a genetic susceptibility to schizophrenia. In summary, while basic sensorimotor skills, associative memory and simple language abilities tend to be preserved in children with schizophrenia, deficits are most marked on tasks that require focused and sustained attention, flexible switching of cognitive set, high information processing speed and suppression of prepotent responses (Asarnow, Brown, & Stranberg, 1995). The diverse cognitive processes described here have been integrated under the cognitive domain of “executive functions”, which are presumed to be mediated by the prefrontal cortical system. Executive function skills are necessary to generate and execute goal-directed behavior, especially in novel situations. Goalorientated actions require that information in the form of plans and expectations are held “online” in working memory, and flexibly changed in response to feedback. Similar deficits have also been found in children genetically at “high risk” for schizophrenia (Erlenmeyer-Kimling & Cornblatt, 1978) and non-psychotic relatives of schizophrenic probands (Park, Holzman, & Goldman-Rakic, 1995). This strengthens the argument that cognitive deficits cannot be simply dismissed as non-specific consequences of schizophrenic symptoms, but rather are likely to be indicators of underlying genetic and neurobiological risk. Several candidate susceptibility genes (dysbindin-1 and COMT) have been linked to impaired working memory and may provide molecular mechanisms underlying this intermediate (endo)phenotype of schizophrenia (Egan, Goldberg, Kolachana et al., 2001). However, executive functions deficits are probably not a primary or sufficient cause of schizophrenia given that they also occur in other neurodevelopmental disorders including autism and ADHD (Pennington, 1997). Course of Cognitive Deficits Kraepelin’s term “dementia praecox” implied a progressive cognitive decline as part of the disease process. Jones, Rogers, Murray et al. (1994) described how academic performance becomes progressively more deviant during adolescence in those individuals destined to developed schizophrenia in adult life. A similar finding of IQ decline from childhood through adolescence which precedes the onset of schizophrenia in adult life has been reported from a large Israeli population-based cohort (Reichenberg, Weiser, Rapp et al., 2005). There is some CHAPTER 45 746 Neuropsychology of Schizophrenia Pattern of Cognitive Deficits There is growing awareness that cognitive deficits in schizophrenia are a core feature of the disorder and cannot simply be dismissed as secondary consequences of psychotic symptoms (Breier, 1999). The degree of cognitive impairment is greater in child- and adolescent-onset than in adult-onset patients. These findings raise several important questions. 1 Are the cognitive deficits specific or general (i.e., are some aspects of cognitive functioning affected more than others?)? 2 Which deficits precede the onset of psychosis and could be causal, and which are consequences of psychosis? 3 Is the pattern of deficits specific to schizophrenia or shared with other developmental and psychotic disorders? 4 Are cognitive impairments progressive or static after the onset of psychosis? Children with schizophrenia have specific difficulties with cognitive tasks that make demands on short-term working memory and selective and sustained attention and speed of processing (Asarnow, Brown, & Stranberg, 1995). These deficits are similar to the deficits reported in adult schizophrenia (Saykin, Shtasel, Gur et al., 1994). Deficits of attention, shortterm and recent long-term memory have also been reported in adolescents with schizophrenia (Friedman, Findling, Buch et al., 1996). In contrast, well-established “over learned” rote language and simple perceptual skills are unimpaired in child- and adolescent-onset schizophrenia. Asarnow, Granholm, & Sherman (1991), Asarnow, Brown, & Stranberg (1995) have shown that children with schizophrenia have impairments on the span of apprehension task (a target stimulus has to be identified from an array of other figures when displayed for 50 ms). Performance on the task deteriorates markedly when increasing demands are made on information processing capacity (e.g., increasing the number of letters in the display from 3 to 10). Furthermore, event-related potential (ERP) studies using the span of apprehension task in both children and adults with schizophrenia, when compared with age-matched controls, show less negative endogenous activity measured 100–300 ms after the stimulus. Similar findings of reduced ERPs (processing negativity Np, and P2 components) have been found during the CPT in both childhood- and adult-onset schizophrenia (Strandburg, Marsh, & Brown, 1999). These findings indicate a deficit in the allocation of attentional resources to a stimulus (Asarnow, Brown, & Stranberg, 1995). As with adults, children and adolescents with schizophrenia show high basal autonomic activity and less autonomic responsivity than controls (Gordon, Frazier, McKenna et al., 1994), with attenuated increases in skin conductance following the presentation of neutral sounds (Zahn, Jacobsen, Gordon et al., 1997). Childhood-onset patients, like adults, show increased reaction times with a loss of ipsimodal advantage compared to healthy controls (Zahn, Jacobsen, Gordon et al., 1998). Eye tracking dysfunction (ETD) – a proxy of frontal lobe dysfunction – as indexed by abnorm-alities in smooth pursuit eye movements (SPEM) has also been found in childhood-onset 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 746

SCHIZOPHRENIA AND ALLIED DISORDERS 747 tentative evidence for a small decline in IQ following the onset of psychosis in childhood-onset schizophrenia (Alaghband-Rad, McKenna, Gordon et al., 1995), followed by a stabilization of cognitive function despite progressive cortical gray matter loss during adolescence (Gochman, Greenstein, Sporn et al., 2005). However, without longitudinal control data this is difficult to evaluate, given that, in typically developing samples, most IQ tests will show improved scores with repeated administration. Furthermore, the small drop in IQ after the onset of psychosis could possibly be caused by the effect of psychotic symptoms on performance. In so far as there is an effect, it looks like premature arrest, or slowing, of normal cognitive development in child- and adolescent-onset schizophrenia, rather than a progressive dementia. Assessment The assessment of a child or adolescent with possible schizophrenia should include a detailed history, mental state and physical examination. In addition, a baseline psychometric assessment is desirable. A detailed understanding of specific cognitive deficits in individual cases of adolescent schizophrenia can be particularly helpful in guiding education and rehabilitation. In the physical examination, particular attention should be given to detecting dysmorphic features that may betray an underlying genetic syndrome. The neurological examination should focus on abnormal involuntary movements and other signs of extrapyramidal dysfunction. Spontaneous abnormal involuntary movements have been detected in a proportion of drug-naïve first-episode schizophrenic or schizophreniform patients as well as in those receiving typical antipsychotics (Gervin, Browne, Lane et al., 1998). Developmental Issues The cognitive level of the child will influence their ability to understand and express complex psychotic symptoms such as passivity phenomena, thought alienation and hallucinations. In younger children, careful distinctions have to be made between developmental immaturity and psychopathology. For example, distinguishing true hallucinations from normal subjective phenomena such as dreams and communication with imaginary friends may be difficult for young children. Developmental maturation can also affect the localization of hallucinations in space. Internal localization of hallucinations is more common in younger children and makes these experiences more difficult to differentiate subjectively from inner speech or thoughts (Garralda, 1984). Formal thought disorder may also appear very similar to the pattern of illogical thinking and loose associations seen in children with immature language development. Negative symptoms can appear very similar to non-psychotic language and social impairments and can also be easily confused with anhedonia and depression. Differential Diagnosis Psychotic symptoms in children and adolescents are diagnostically non-specific, occurring in a wide range of functional psychiatric and organic brain disorders. A summary of physical investigations in children and adolescents with suspected schizophrenia is listed in Table 45.1. Referral for a neurological opinion is recommended if neurodegenerative disorder is suspected (see chapter 30). Affective, Schizoaffective and “Atypical” Psychoses The high rate of positive psychotic symptoms found in adolescent-onset major depression and mania can lead to diagnostic confusion (Joyce, 1984). Affective psychoses are most likely to be misdiagnosed as schizophrenia if a Schneiderian concept of schizophrenia is applied with its emphasis on firstrank symptoms. Because significant affective symptoms also occur in about one-third of first-episode patients with schizophrenia, it may be impossible to make a definitive diagnosis on the basis of a single cross-sectional assessment. In DSM-IV the distinction between schizophrenia, schizoaffective disorder Investigation Target disorder Urine drug screen Drug-related psychosis (amphetamines, ecstasy, cocaine, LSD and other psychoactive compounds) EEG Complex partial seizures/TLE MRI brain scan Ventricular enlargement, structural brain anomalies (e.g. cavum septum pellucidum) Enlarged caudate (typical antipsychotics) Demyelination (metachromatic leukodystrophy) Hypodense basal ganglia (Wilson’s disease) Serum copper and ceruloplasmin Wilson’s disease Urinary copper Arylsulfatase A (white blood cell) Metachromatic leukodystrophy Karyotype/cytogentics (FISH) Sex chromosome aneuploidies, velocardiofacial syndrome (22q11 microdeletion) EEG, electroencephalogram; FISH, fluorescent in situ hybridization; LSD, lysergic acid diethylamide; MRI, magnetic resonance imaging; TLE, temporal lobe epilepsy. Table 45.1 Physical investigations in childand adolescent-onset psychoses. 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 747

and affective psychoses is determined by the relative predominance and temporal overlap of psychotic symptoms (hallucinations and delusions) and affective symptoms (elevated or depressed mood). Given the difficulty in applying these rules with any precision, there is a need to identify other features to distinguish between schizophrenia and affective psychoses. Irrespective of the presence of affective symptoms, the most discriminating symptoms of schizophrenia are an insidious onset and the presence of negative symptoms (Hollis, 1999). Similarly, complete remission from a first psychotic episode within 6 months of onset is the best predictor of a diagnosis of affective psychosis (Hollis, 1999). Schizoaffective and atypical psychoses are diagnostic categories with low predictive validity and little longitudinal stability (Hollis, 2000). Autistic Spectrum and Developmental Language Disorders Some children on the autistic spectrum or with Asperger syndrome have social and cognitive impairments that overlap closely with the premorbid phenotype described in schizophrenia. Furthermore, children on the autistic spectrum can also develop psychotic symptoms in adolescence (Volkmar & Cohen, 1991). Towbin, Dykens, Pearson, and Cohen (1993) have labeled another group of children who seem to belong within the autistic spectrum as having “multiplex developmental disorder.” An increased risk for psychosis has also been noted in the adult follow-up of childhood developmental receptive language disorders (Clegg, Hollis, & Rutter, 2005). In the NIMH COS sample, 19 cases (25%) had a lifetime diagnosis of autism spectrum disorder (ASD), one had autism, two had Asperger syndrome and 16 had pervasive develomental disorder not otherwise specified (PDD-NOS; Sporn, Addington, Gogtay et al., 2004a). The COS-ASD subgroup did not differ from the rest of the COS sample on a range of measures including age of onset, IQ, response to medications and familial schizotypy. However, the rate of cortical gray matter loss was greater in the ASD group. While the authors concluded that ASD was more likely to be a severe form of premorbid social impairment rather than true comorbidity, an unexplained finding was the occurrence of two cases of autism in the siblings of the COS-ASD subgroup. While some children on the autistic spectrum can show a clear progression into classic schizophrenia, others show a more episodic pattern of psychotic symptoms without the progressive decline in social functioning and negative symptoms characteristic of child- and adolescent-onset schizophrenia. Often it is only possible to distinguish between schizophrenia and disorders on the autistic spectrum by taking a careful developmental history that details the age of onset and pattern of autistic impairments in communication, social reciprocity and interests/behaviors. According to DSM-IV, schizophrenia cannot be diagnosed in a child with autism/PDD unless hallucinations/delusions are present for at least 1 month. DSM-IV does not rank the active phase symptoms of thought disorder, disorganization or negative symptoms as sufficient to make a diagnosis of schizophrenia in the presence of autism. In contrast, ICD-10 does not include autism/PDD as exclusion criteria for diagnosing schizophrenia. “Multidimensionally Impaired Syndrome” and Schizotypal Personality Disorder Multidimensionally impaired syndrome (MDI) is a label applied to children who have brief transient psychotic symptoms, emotional lability, poor interpersonal skills, normal social skills and multiple deficits in information processing (Kumra, Jacobsen, Lenane et al., 1998c). The diagnostic status of this group remains to be fully resolved. Short-term follow-up suggests that they do not develop full-blown schizophrenic psychosis. However, they have an increased risk of schizophrenia spectrum disorders among first-degree relatives and the neurobiological findings (e.g., brain morphology) are similar to those in childhood onset schizophrenia (Kumra, Jacobsen, Lenane et al., 1998c). At 11 year follow-up, 38% (12 of 32) of patients met criteria for bipolar 1 disorder, 12% (4 of 32) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free (“good outcome,” n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy (“poor outcome,” n = 10; Stayer, Sporn, Gogtay et al., 2005). Children with schizotypal personality disorder (SPD) lie on a phenotypic continuum with schizophrenia and have similar cognitive and social impairments and are prone to magical thinking, mood disturbances and non-psychotic perceptual disturbances. Distinction from the prodromal phase of schizophrenia is particularly difficult when there is a history of social and academic decline without clear-cut, or persisting, psychotic symptoms. A follow-up of children with SPD found that 25% developed schizophrenia spectrum disorders (schizophrenia and schizoaffective disorder), suggesting that SPD may be a precursor of schizophrenia (Asarnow, 2005). It has been reported that negative symptoms and attention in SPD improve with a low dose of risperidone (0.25–2.0 mg; Rossi, Mancini, Stratta et al., 1997). Epilepsy Psychotic symptoms can occur in temporal and frontal lobe partial seizures (for a description of these seizures see chapter 30). A careful history is usually sufficient to reveal an aura followed by clouding of consciousness and the sudden onset of brief ictal psychotic phenomena accompanied often by anxiety, fear, derealization or depersonalization. However, longer-lasting psychoses associated with epilepsy can occur in clear consciousness during postictal or interictal periods (Sachdev, 1998). In epileptic psychoses, hallucinations, disorganized behavior and persecutory delusions predominate, while negative symptoms are rare. Children with complex partial seizures also have increased illogical thinking and use fewer linguistic-cohesive devices which can resemble formal thought disorder (Caplan, Guthrie, Shields, & Mori, 1992). A PET study showed hypoperfusion in the frontal, temporal CHAPTER 45 748 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 748

and basal ganglia in psychotic patients with epilepsy compared with non-psychotic epileptic patients (Gallhofer, Trimble, Frackowiak, Gibbs, & Jones, 1985). Epilepsy and schizophrenia may co-occur in the same individual, so that the diagnoses are not mutually exclusive. The onset of epilepsy almost always precedes psychosis unless seizures are secondary to antipsychotic medication. In a longterm follow-up of 100 children with temporal lobe epilepsy, 10% developed schizophrenia in adult life (Lindsay, Ounstead, & Richards, 1979). An electroencephalogram (EEG) should be performed if a seizure disorder is considered in the differential diagnosis or arises as a side effect of antipsychotic treatment. Ambulatory EEG monitoring and telemetry with event recording may be required if the diagnosis remains in doubt. Neurodegenerative Disorders Rare neurodegenerative disorders with onset in late childhood and adolescence (see chapter 30) can mimic schizophrenia. The most important examples are Wilson’s disease (hepatolenticular degeneration), and metachromatic leukodystrophy. These disorders usually involve significant extrapyramidal symptoms (e.g., tremor, dystonia and bradykinesia) or other motor abnormalities (e.g., unsteady gait) and a progressive loss of skills (dementia), which can aid the distinction from schizophrenia. Suspicion of a neurodegenerative disorder is one of the clearest indications for brain MRI in adolescent psychoses. Adolescents with schizophrenia show relative gray matter reduction with white matter sparing. In contrast, metachromatic leukodystrophy is characterized by frontal and occipital white matter destruction and demyelination. In Wilson’s disease, hypodense areas are seen in the basal ganglia, together with cortical atrophy and ventricular dilatation. The pathognomonic Kayser–Fleisher ring in Wilson’s disease begins as a greenish-brown crescent-shaped deposit in the cornea above the pupil (this is most easily seen during slit lamp examination). In Wilson’s disease there is increased urinary copper excretion, and reduced serum copper and serum ceruloplasmin levels. The biochemical marker for metachromatic leukodystrophy is reduced arylsulfatase-A (ASA) activity in white blood cells. This enzyme deficiency results in a deposition of excess sulfatides in many tissues including the CNS. Drug Psychoses Illicit drug use is increasingly common among young people (see chapter 36), so the frequent co-occurrence of drug use and psychosis is to be expected. Psychotic symptoms can occur as a direct pharmacological effect of intoxication with stimulants (amphetamine, ecstasy and cocaine), hallucinogens (lysergic acid diethylamide “LSD,” phencyclidine, psilocybin “magic mushrooms” and mescaline), cannabis (Poole & Brabbins, 1996) and ketamine, an NMDA receptor antagonist and anesthetic (Krystal, Perry, Gueorguieva et al., 2006). The psychotic symptoms associated with drug intoxication are usually short-lived and resolve within a few days of abstinence from the drug. These drugs can have surprisingly long half-lives, with cannabinoids still measurable up to 6 weeks after a single dose. Psychotic symptoms in the form of “flashbacks” can also occur after cessation from chronic cannabis and LSD abuse. These phenomena are similar to alcoholic hallucinosis and typically involve transient vivid auditory hallucinations occurring in clear consciousness. It is often assumed that there is a simple causal relationship between drug use and psychosis, with any evidence of drug use excluding the diagnosis of a functional psychosis. However, this is a naïve approach, as drug use can be either a consequence of psychosis with patients using drugs to “treat” their symptoms in the early stages of a psychotic relapse or, with cannabis, a cause of schizophrenia in susceptible individuals (Arseneault, Cannon, Witton et al., 2004). Overall, there is very little evidence to invoke a separate entity of “druginduced” psychosis in cases where psychotic symptoms arise during intoxication but then persist after the drug is withdrawn (Poole & Brabbins, 1996). Patients whose so-called “druginduced” psychoses last for more than 6 months appear to have more clear-cut schizophrenic symptoms, a greater familial risk for psychosis and greater premorbid dysfunction (Tsuang, Simpson, & Kronfold, 1982). DSM-IV takes the sensible position that a functional psychosis should not be excluded unless there is compelling evidence that symptoms are uniquely associated with drug use. Other Investigations Whether any physical investigations should be viewed as routine is debatable (see chapter 22). However, it is usual to obtain a full blood count and biochemistry including liver and thyroid function and a drug screen (urine or hair analysis). The high yield of cytogenetic abnormalities reported in childhoodonset schizophrenia (Nicolson, Giedd, Lenane et al., 1999) suggests the value of cytogenetic testing including karyotypying for sex chromosome aneuploidies and fluorescent in situ hybridization (FISH) for 22q11DS (velocardiofacial syndrome). The evidence of progressive structural brain changes (Rapoport, Giedd, Blumenthal et al., 1999) indicates the value of obtaining a baseline and annual follow-up brain MRI scans, although this is not a diagnostic test. Assessment Interviews and Rating Scales Structured diagnostic investigator-based interviews that cover child and adolescent psychotic disorders include the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS; Ambrosini, 2000), the Child and Adolescent Psychiatric Assessment (CAPA; Angold & Costello, 2000) and the Diagnostic Interview for Children and Adolescents (DICA; Reich, 2000). The DSM and ICD definitions of schizophrenia do not provide symptom definitions so the detailed glossaries that accompany these interviews are particularly useful. Rating scales give quantitative measures of psychopathology and functional impairment. Scales to assess psychotic symptoms include the Scale for Assessment of Positive Symptoms (SAPS; SCHIZOPHRENIA AND ALLIED DISORDERS 749 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 749

Andreasen, 1984), the Scale for Assessment of Negative Symptoms (SANS; Andreasen, 1983) and the Positive and Negative Syndrome Scale (PANSS; Kay, Opler, & Lindenmayer, 1987). The 30-item Kiddie-PANSS has been developed for use in children and adolescents, and contains three subscales: positive syndrome, negative syndrome and general psychopathology (Fields, Grochowski, Lindenmayer et al., 1994). The Children’s Global Assessment Scale (C-GAS) provides a rating of functional impairment on a 0–100 scale (Shaffer, Gould, Brasic et al., 1983). These scales can be used to record the longitudinal course of illness and treatment response. The Kiddie Formal Thought Disorder Story Game and Kiddie Formal Thought Disorder Scale (Caplan, Guthrie, Tanguay, Fish, & David-Lando, 1989) are research instruments produced for the assessment of thought disorder in children. Assessments of extrapyramidal symptoms and involuntary movements can be made using the Abnormal Involuntary Movements Scale (AIMS; Rapoport, Conners, & Reatig, 1985) and the Simpson– Angus Neurological Rating Scale (Simpson & Angus, 1970). Treatment Approaches General Principles While antipsychotic drugs remain the cornerstone of treatment in child and adolescent schizophrenia, all young patients with schizophrenia require a multimodal treatment package that includes pharmacotherapy, family and individual counseling, education about the illness, and provision to meet social and educational needs (AACAP, 2001; Clark & Lewis, 1998). Prevention and Early Detection In theory at least, the onset of schizophrenia could be prevented if an intervention reduced the premorbid “risk” status or exposure to causative risk factors. The difficulty with the premorbid phenotype as currently conceived (i.e., subtle social and developmental impairments) is its extremely low specificity and positive predictive value for schizophrenia in the general population. The premorbid psychopathology in childhood-onset schizophrenia is equally non-specific with a range of diagnoses (e.g., conduct disorder, ADHD, anxiety states, depression and ASD preceding schizophrenia; Schaeffer & Ross, 2002). Future refinement of the premorbid phenotype is likely to move from the traditional phenomenological approach to include genetic and neurocognitive markers in order to achieve greater sensitivity and specificity. An alternative approach is to target putative environmental risk factors such as cannabis exposure. If a direct causal relationship between cannabis and schizophrenia is assumed, then the population attributable fraction for the Dunedin cohort is 8% (Arseneault, Cannon, Witton et al., 2004). Put another way, removal of cannabis use from 15-year-olds in the Dunedin cohort would have resulted in an 8% reduction in the incidence of schizophrenia. Given the rising prevalence of cannabis use in younger adolescents – a group who may be particularly sensitive to its effects – an important public policy intervention would be to delay the onset of cannabis use in young people. In contrast to primary prevention, the aim of early detection is to identify the onset of deterioration in vulnerable individuals with a high predictive validity. Follow-up of the Australian Early Psychosis Prevention and Intervention Centre (EPPIC) “ultra high risk” sample over 12 months found 40.8% developed a psychotic disorder. Significant predictors of transition to psychosis included long duration of prodromal symptoms, poor functioning at intake, low-grade psychotic symptoms, depression and disorganization (Yung, Phillips, Yuen et al., 2003). A key question is whether early intervention in an “ultra high risk” or prodromal group can prevent the transition to psychosis. The EPPIC group conducted a randomized controlled trial of combined low-dose risperidone (mean 1.3 mg.day−1 ) and cognitive–behavioral therapy (CBT) compared to standard needs-based intervention in the “ultra high risk” group (McGorry, Yung, Phillips et al., 2002). The risperidone/CBT intervention significantly reduced transition to psychosis at 6 months (3 of 31 vs. 10 of 28 developed psychosis) but there was no significant difference by 12 months. These findings suggest that aggressive early intervention in a population presenting with high-risk mental states and attenuated psychotic symptoms may delay the onset of frank psychosis (prevalence reduction) but may not necessarily reduce the incidence of psychosis. A pragmatic stance would be to monitor children and adolescents with a strong family history and/or suggestive prodromal symptoms to ensure prompt treatment of psychosis. A key argument used to support early intervention in psychosis has been the finding that a long duration of untreated psychosis is associated with poor long-term outcome in schizophrenia (Loebel, Lieberman, Alvir et al., 1992; Wyatt, 1995). A similar association has been found in child- and adolescent-onset psychoses (Hollis, 1999). While the association between duration of untreated psychosis and poor outcome seems secure, the causal connection is far less certain. A long duration of untreated psychosis is also associated with insidious onset and negative symptoms, which could confound links with poor outcome. While there are good a priori clinical reasons for the early treatment of symptoms to relieve distress and prevent secondary impairments, as yet it remains unproven whether early intervention actually alters the longterm course of schizophrenia. Pharmacological Treatments Because of the very small number of trials of antipsychotics conducted with child and adolescent patients, it is necessary to extrapolate most evidence on drug efficacy from studies in adults. This seems a reasonable approach given that schizophrenia is essentially the same disorder whether it has onset in childhood or adult life. However, it should be noted that children and adolescents show a greater sensitivity to a range of antipsychotic-related adverse events including extrapyramidal side effects (EPS) and treatment resistance with traditional antipsychotics (Kumra, Jacobsen, Lenane et al., 1998b) and CHAPTER 45 750 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 750

weight gain, obesity and metabolic syndrome with the newer atypical antipsychotics (Ratzoni, Gothelf, Brand-Gothelf et al., 2002). Antipsychotics can be broadly divided into the traditional “typical” and newer “atypical” drugs. The typical drugs include haloperidol, chlorpromazine and trifluoperazine, which block D2 receptors, produce catalepsy in rats, raise plasma prolactin and induce EPS. The newer atypical drugs are effective antipsychotics that are “atypical” in the sense that they do not produce catalepsy, do not raise prolactin levels and produce significantly fewer EPS. Not all atypicals neatly fit this definition; for example, risperidone raises prolactin levels and may cause EPS at higher doses (>4 mg·day−1 ) with “atypicality” resulting from antagonism of 5HT receptors rather than reduced D2 receptor blockade. The atypicals were introduced during the 1990s and currently include clozapine, risperidone, olanzapine, quetiapine, zotepine and amisulpride. More recently, aripiprazole, a partial dopamine agonist, has been introduced. The pharmacological profile of the atypicals is diverse, involving various combinations of 5HT and dopamine receptor blockade. Aripiprazole acts as a dopamine antagonist at hyperdopaminergic sites (e.g., mesolimibic system in schizophrenia) and as a dopamine agonist at hypodopaminergic sites (e.g., prefrontal cortex in schizophrenia). Interestingly, the therapeutic effects of clozapine (potent affinity for D4 and 5HT1,2,3 receptors) is independent of D2 receptor occupancy, previously thought to be essential for antipsychotic action. The typical antipsychotic haloperidol has been shown to be superior to placebo in two double-blind controlled trials of children and adolescents with schizophrenia (Pool, Bloom, Miekle, Roniger, & Gallant, 1976; Spencer & Campbell, 1994). It is estimated that about 70% of patients show good or partial response to antipsychotic treatment although this may take 6–8 weeks to become apparent (AACAP, 2001; Clark & Lewis, 1998). The main drawbacks concerning the use of high-potency typicals such as haloperidol in children and adolescents is the high risk of EPS (produced by D2 blockade of the nigrostriatal pathway), tardive dyskinesia and the lack of effect against negative symptoms and cognitive impairment. Clozapine (the prototypic atypical) has been shown to be superior to haloperidol in a double-blind trial of 21 cases of childhood-onset schizophrenia (Kumra, Frazier, Jacobsen et al., 1996). Larger open clinical trials of clozapine confirm its effectiveness in child- and adolescent-onset schizophrenia (Remschmidt, Schultz, & Martin, 1994). Similar, although less marked, benefits of olanzapine over typical antipsychotics in childhood-onset schizophrenia have been reported (Kumra, Jacobsen, Lenane et al., 1998a). Recent head-to-head comparisons of atypicals (risperidone and olanzapine) vs. typicals (haloperidol) in adolescents with schizophrenia have reported broadly similar efficacy against psychotic symptoms (with a non-significant trend in favor of atypicals) but a differing profile of adverse effects (Gothelf, Apter, Reidman et al., 2003; Sikich, Hamer, Bashford, Sheitman, & Lieberman, 2004). These finding broadly replicate results from the large NIMH-CATIE pragmatic trial that found no overall difference in effectiveness between typical and atypical antipsychotics in adults, whereas there were differences in tolerability and side effect profiles (Lieberman, Stroup, McEvoy et al., 2005). The UK CUtLASS study compared effects after randomization to either typical or atypical antipsychotics following a clinical decision to change medication in adults with chronic schizophrenia (Jones, Barnes, Davies et al., 2006). There were no differences in outcome (quality of life, symptoms and adverse events) measured at 1 year when comparing the broad classes of typical and atypical antipsychotic. While similar pragmatic clinical effectiveness studies are needed in children and adolescents with schizophrenia, we know that younger and first-episode patients are more sensitive to both therapeutic and adverse effects of antipsychotics. Furthermore, individual drugs within both classes differ importantly in terms of tolerability and side effect profiles when prescribed to children and adolescents. In younger patients (children and adolescents), EPS are more common with haloperidol and high-dose risperidone than olanzapine. Weight gain and obesity are more common with olanzapine (most), then risperidone and least with haloperidol. Sedation is greater with olanzapine and haloperiol than risperidone (Toren, Ratner, Laor, & Weizman, 2004). Further evidence is emerging that children and adolescents experience more rapid and serious weight gain on olanzapine and risperidone than do adults (Ratzoni, Gothelf, Brand-Gothelf et al., 2002). Morbid obesity (body mass index [BMI] >90th percentile) is found in up to 50% of adolescents and young people chronically treated with atypical antipsychotics (Theisen, Linden, Geller et al., 2001). Complications of obesity include hyperglycemia (type 2 diabetes), hyperlipidemia and hypercholesterolemia. It is recommended that dietary advice (reducing carbohydrate intake) combined with regular exercise should be prescribed before initiating atypicals in children and adolescents. Drawing this evidence together, a strong case can be made for the first-line use of atypicals in child and adolescent schizophrenia (clozapine is licensed in the UK only for treatmentresistant schizophrenia). Treatment resistance in child and adolescent patients should be defined as follows: 1 Non-response with at least two antipsychotics (drawn from different classes and at least one being an atypical), each used for at least 4–6 weeks; and/or 2 Significant adverse effects with conventional antipsychotics. The recommended order of treatment for first-episode schizophrenia in children and adolescents is as follows: atypical as first line, if inadequate response change to a different atypical or conventional antispyschotic, if response is still inadequate or side effects are intolerable then initiate clozapine. While atypicals reduce the risk of EPS, they can produce other troublesome side effects (usually dose-related) including weight gain (olanzapine, clozapine, risperidone), hyperlipidemia (olanzapine), sedation, hypersalivation and seizures (clozapine, olanzapine, quetiapine) and hyperprolactinemia (risperidone, amisulpride). The risk of blood dyscrasias on clozapine is effectively managed by mandatory routine blood monitoring. SCHIZOPHRENIA AND ALLIED DISORDERS 751 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 751

However, knowledge about potential adverse reactions with the newest atypicals is still limited in child and adolescent patients. Baseline investigations and follow-up monitoring every 6 months are recommended when prescribing antipsychotics. Baseline monitoring should include height, weight, blood pressure, full blood count, liver function and creatine kinase, fasting glucose, prolactin (risperidone, amisulpride), lipids (olanzapine, clozapine) and electrocardiogram (ECG) (zotapine). A further consideration is the greater cost of newer atypicals compared to traditional antipsychotics. Although economic studies of cost-effectiveness have suggested that the costs of the atypicals are recouped in reduced in-patient stays and indirect social costs (Aitcheson & Kerwin, 1997), the high cost of these drugs may limit availability, particularly in developing countries. The UK National Institute for Health and Clinical Excellence (NICE, 2002) has recommended the use of atypicals (risperidone, olanzapine, quetiapine, amisulpride and zotapine) in all first-episode, newly diagnosed patients with schizophrenia and those on established therapy showing resistance to typical antipsychotics. Clinical trial evidence suggests that clozapine is the most effective antipsychotic in child- and adolescent-onset schizophrenia, although its use is restricted to treatment-resistant cases. In summary, atypicals such as olanzapine or risperidone should be used as a first-line treatment given that child- and adolescent-onset schizophrenia is characterized by negative symptoms, cognitive impairments, sensitivity to EPS and relative resistance to traditional antipsychotics. However, a growing awareness of adverse effect profiles of different drugs and greater sensitivity to these effects in children and adolescents means drug choice should be a collaborative exercise, tailored to the needs and preferences of the young person and their family. Psychosocial Interventions Psychosocial interventions range from CBT targeted at symptoms, problem-solving skills and stress reduction, to patient and family psychoeducation, family therapy, counseling and support, social skills training and remedial education. Psychoeducation and Family Interventions The rationale for psychosocial family interventions follows from the association between high EE and the risk of relapse in schizophrenia (Dixon & Lehman, 1995). The overall aim is to prevent relapse (secondary prevention) and improve the patient’s level of functioning by modifying the family atmosphere. Psychosocial family interventions have a number of principles in common (Lam, 1991). First, it is assumed that it is useful to regard schizophrenia as an illness as patients are less likely to be seen as responsible for their symptoms and behavior. Second, the family is not implicated in the etiology of the illness. Instead, the burden borne by the family in caring for a disturbed or severely impaired young person is acknowledged. Third, the intervention is offered as part of a broader multimodal package including drug treatment and out-patient clinical management. An important issue when working with parents of children and adolescents with schizophrenia is to recognize that the illness typically results in a bereavement process for the loss of their “normal” child. Parents will often value a clear diagnosis of schizophrenia as it can provide an explanation for previously unexplained perplexing and disturbed behavior. Understanding schizophrenia as a disorder of the developing brain can also relieve commonly expressed feelings of guilt among parents and carers. Lam (1991) conducted a systematic review of published trials of psychoeducation and more intensive family interventions in schizophrenia and drew the following conclusions. First, education packages on their own increase knowledge about the illness but do not reduce the risk of relapse. Second, more intensive family intervention studies with high EE relatives have shown a reduction in relapse rates linked to a lowering of EE. Third, family interventions tend to be costly and timeconsuming with most clinical trials employing highly skilled research teams. Whether these interventions can be transferred into routine clinical practice is uncertain. Fourth, interventions have focused on the reduction of EE in “high-risk” families. Whether low EE families would also benefit from these interventions is less clear. This is particularly relevant to the families of children and adolescents with schizophrenia as, on average, these parents express lower levels of criticism and hostility than parents of adult-onset patients (Asarnow, Thompson, Hamilton et al., 1994). Cognitive–Behavioral Therapy In adult patients, cognitive-behavioral therapy (CBT) has been used to reduce the impact of treatment-resistant positive symptoms (Tarrier, Beckett, Harwood et al., 1993). CBT has been shown to improve the shortterm (6 month) outcome of adult schizophrenic patients with neuroleptic-resistant positive symptoms (Turkington & Kingdon, 2000). Whether CBT is equally effective with younger patients, or those with predominantly negative symptoms, remains to be established. Cognitive Remediation Cognitive remediation is a relatively new psychological treatment that aims to arrest or reverse the cognitive impairments in attention, concentration and working memory associated with negative symptoms and poor functional outcome in schizophrenia (Greenwood, Landau, & Wykes, 2005). The results of an early controlled trial in adults are promising, with gains found in the areas of memory and social functioning (Wykes, Reeder, Williams et al., 2000). The severity of cognitive executive impairments in child and adolescent patients suggests that early remediation strategies may be a particularly important intervention in younger patients. Helpful advice can also be offered to parents, teachers and professionals such as breaking down information and tasks into small manageable parts to reduce demands on working memory and speed of processing. Organization of Treatment Services It is a paradox that patients with very early-onset schizophrenia CHAPTER 45 752 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 752

have the most severe form of the disorder yet they often receive inadequate and poorly co-ordinated services. Possibly, this is because the responsibility for schizophrenia is seen to lie with adult psychiatric services with a remit that typically does not extend to patients under age 18. In the UK, community-based child and adolescent mental health services (CAMHS) provide the first-line assessment and care for child and young adolescent psychoses, with only about half of these cases referred to in-patient units (Slaveska, Hollis, & Bramble, 1998). Whereas adolescent in-patient admission is often inappropriate, generic CAMHS services are usually unable to provide the mix of assertive outreach, early intervention and crisis resolution services that have developed over the last decade in UK adult mental health services for psychoses and severe mental illness. Young people with schizophrenia are not generally well served by a separation of services and professional responsibilities at age 16 or 18 (see chapter 13). An alternative model is a community-based young person’s psychosis service spanning ages 14–25 with access to dedicated adolescent and young adult beds. Such a service would provide early intervention, assertive outreach, intensive home treatment and crisis resolution. It would integrate professional expertise from CAMHS (in particular, addressing family, developmental and educational issues) and adult mental health services. Conclusions The last decade has seen a dramatic growth in our understanding of the clinical course and neurobiological underpinnings of schizophrenia presenting in childhood and adolescence. It is now clear that adult-based diagnostic criteria have validity in this age group and the disorder has clinical and neurobiological continuity with schizophrenia in adults. Childhood-onset schizophrenia is a severe variant of the adult disorder associated with greater premorbid impairment, a higher familial risk, more severe clinical course and poorer outcome. The poor outcome of children and adolescents with schizophrenia has highlighted the need to target early and effective treatments and develop specialist services for this high-risk group. Unraveling neurocognitive and clinical heterogeneity should lead to improvements in our ability to deliver individually targeted treatments, as well as the ability to identify those “at risk” in order to prevent the onset of psychosis. Further Reading Harrison, P. J., & Owen, M. J. (2003). Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet, 361, 417–419. Hirsch, S. R., & Weinberger, D. (Eds.). (2003). Schizophrenia (2nd edn.). Oxford: Blackwell. Rapoport, J. L., Addington, A. M., & Frangou, S. (2005). The neurodevelopmental model of schizophrenia: update, 2005. Molecular Psychiatry, 10, 434–449. References Addington, A. M., Gornick, M., Duckworth, J. Sporn, A., Gogtay, N., Bobb, A., et al. (2005). GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter loss. Molecular Psychiatry, 10, 581–588. Addington, A. M., Gornick, M., Sporn, A. L. Gogtay, N., Greenstein, D., Lenane, M. C., et al. (2004). Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified. Biological Psychiatry, 55, 976–980. Aitchison, K. J., & Kerwin, R. W. (1997). The cost effectiveness of clozapine. British Journal of Psychiatry, 171, 125–130. Alaghband-Rad, J., McKenna, K., Gordon, C. T., Albus, K. E., Hamburger, S. D., Rumsey, J. M., et al. (1995). Childhood-onset schizophrenia: The severity of premorbid course. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1273– 1283. Alaghband-Rad, J., Hamburger, S. D., Giedd, J., Frazier, J. A., & Rapoport, J. L. (1997). Childhood-onset schizophrenia: Biological markers in relation to clinical characteristics. American Journal of Psychiatry, 154, 64–68. Ambrosini, P. J. (2000). Historical development and present status of the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Journal of the American Academy of Child and Adolescent Psychiatry, 39, 49–58. American Academy of Child and Adolescent Psychiatry (AACAP). (2001). Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 4S–23S. Andreasen, N. C. (1983). Scale for the Assessment of Negative Symptoms (SANS). University of Iowa: Iowa City. Andreasen, N. C. (1984). Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa: Iowa City. Angold, A., & Costello, J. E. (2000). The Child and Adolescent Psychiatric Assessment (CAPA). Journal of the American Academy of Child and Adolescent Psychiatry, 39, 39–48. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (4th en.). Text revision. Washington, DC: American Psychiatric Association. Arendt, M., Rosenberg, R., Foldager, L., Perto, G., & MunkJorgensen, P. (2005). Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. British Journal of Psychiatry, 187, 510–515. Arseneault, L., Cannon, M., Poulton, R., Murray, R., Caspi, A., & Moffitt, T. E. (2002). Cannabis use in adolescence and risk for adult psychosis: Longitudinal prospective study. British Medical Journal, 325, 1212–1213. Arseneault, L., Cannon, M., Witton, J., & Murray, R. (2004). Causal association between cannabis and psychosis: Examination of the evidence. British Journal of Psychiatry, 184, 110–117. Asarnow, J. R. (2005). Childhood-onset schizotypal disorder: A follow-up study and comparison with childhood-onset schizophrenia. Journal of Child and Adolescent Psychopharmacology, 15, 395–402. Asarnow, R., Granholm, E., & Sherman, T. (1991). Span of apprehension in schizophrenia. In: S. R. Steinhauer, J. H. Gruzelier, & J. Zubin (Eds.), Handbook of Schizophrenia, Vol. 5. Neuropsychology, Psychophysiology and Information Processing (pp. 335–370). Amsterdam: Elsevier. Asarnow, J. R., Thompson, M. C., Hamilton, E. B., Goldstein, M. J., & Guthrie, D. (1994). Family-expressed emotion, childhood-onset depression, and childhood-onset schizophrenia spectrum disorders: Is expressed emotion a nonspecific correlate of child psychopathology or a specific risk factor for depression? Journal of Abnormal Child Psychology, 22, 129–146. Asarnow, R., Brown, W., & Stranberg, R. (1995). Children with schizophrenic disorder: Neurobehavioural studies. Neuroscience European Archives of Psychiatry and Clinical Neuroscience, 245, 70–79. SCHIZOPHRENIA AND ALLIED DISORDERS 753 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 753

Badner, J. A., & Gershon, E. S. (2002). Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Molecular Psychiatry, 7, 405–411. Bertolino, A., Kumra, S., Callicott, J. H., Muttay, V. S., Lestz, R. M., Jacobsen, L., et al. (1998). Common pattern of cortical pathology in childhood-onset and adult-onset schizophrenia as identified by proton magnetic resonance spectroscopic imaging. American Journal of Psychiatry, 155, 1376–1383. Breier, A. (1999). Cognitive deficit in schizophrenia and its neurochemical basis. British Journal of Psychiatry, 174, 16–18. Broome, M. R., Woolley, J. B., Tabraham, P., Johns, L. C., Bramon E., Murray, G. K., et al. (2005). What causes the onset of psychosis? Schizophrenia Research, 79, 23–34. Bullmore, E. T., O’Connell, P., Frangou, S., & Murray, R. M. (1997). Schizophrenia as a developmental disorder or neural network integrity: The dysplastic net hypothesis. In M. S. Keshavan, & R. M. Murray (Eds.), Neuorodevelopment and adult psychopathology (pp. 253–266). Cambridge: Cambridge University Press. Cannon, M., Caspi, A., Moffitt, T. E., Harrington, H., Taylor, A., Murray, R. M., et al. (2002). Evidence for early childhood, pandevelopmental impairment specific to schizophreniform disorder: Results from a longitudinal birth cohort. Archives of General Psychiatry, 59, 449–456. Cannon, T. D., Kaprio, J., Lonnqvist, J., Huttunen, M., & Koskenvuo, M. (1998). The genetic epidemiology of schizophrenia in a Finnish twin cohort: A population-based modeling study. Archives of General Psychiatry, 55, 67–74. Cantor-Graae, E., & Selten, J. P. (2005). Schizophrenia and migration: A meta-analysis and review. American Journal of Psychiatry, 162, 12–24. Caplan, R., Guthrie, D., Tanguay, P. E., Fish, B., & David-Lando, G. (1989). The Kiddie Formal Thought Disorder Scale (K-FTDS): Clinical assessment reliability and validity. Journal of the American Academy of Child and Adolescent Psychiatry, 28, 408–416. Caplan, R., Guthrie, D., Shields, W. D., & Mori, L. (1992). Formal thought disorder in pediatric complex partial seizure disorder. Journal of Child Psychology and Psychiatry, 33, 1399–1412. Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., et al. (2005). Moderation of the effect of adolescentonset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: Longitudinal evidence of a gene × environment interaction. Biological Psychiatry, 57, 1117– 1127. Castle, D., & Murray, R. (1991). The neurodevelopmental basis of sex differences in schizophrenia. Psychological Medicine, 21, 565–575. Clark, A., & Lewis, S. (1998). Treatment of schizophrenia in childhood and adolescence. Journal of Child Psychology and Psychiatry, 39, 1071–1081. Clegg, J., Hollis, C., & Rutter, M. (2005). Developmental language disorders: A follow-up in later adult life. Cognitive, language and psychosocial outcomes. Journal of Child Psychology and Psychiatry, 46, 128–149. Craddock, N., O’Donovan, M. C., & Owen, M. J. (2005). Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophrenia Bulletin, 32, 9–16. Dasari, M., Friedman, L., Jesberger, J., Stuve, T. A., Findling, R. L., Swales, T. P., et al. (1999). A magnetic resonance study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls. Psychiatry Research, 91, 155–162. Dean, B., Bradbury, R., & Copolov, D. L. (2003). Cannabis-sensitive dopaminergic markers in postmortem central nervous system: changes in schizophrenia. Biological Psychiatry, 53, 585–592. Dixon, L. B., & Lehman, A. F. (1995). Family interventions for schizophrenia. Schizophrenia Bulletin, 21, 631–643. Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., et al. (2001). Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences of the USA, 98, 6917–6922. Eggers, C., & Bunk, D. (1997). The long-term course of childhoodonset schizophrenia: A 42-year follow-up. Schizophrenia Bulletin, 23, 105–117. Erlenmeyer-Kimling, L., & Cornblatt, B. (1978). Attentional measures in a study of children at high risk for schizophrenia. In L. C. Wynne, R. L. Cromwell, & S. Matthysse (Eds.), The Nature of Schizophrenia: New approaches to research and treatment (pp. 359–365). New York: Wiley. Erlenmeyer-Kimling, L., Squires-Wheeler, E., Adamo, U. H., Rock, D., Roberts, S. A., Bassett, A. S., et al. (1995). The New York High Risk Project: Psychoses and Cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Archives of General Psychiatry, 52, 857–865. Feinberg, I. (1983). Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence. Journal of Psychiatric Research, 17, 319–344. Fields, J. H., Grochowski, S., Lindenmayer, J. P., Kay, S. R., Grosz, D., Hyman, R. B., et al. (1994). Assessing positive and negative symptoms in children and adolescents. American Journal of Psychiatry, 151, 249–253. Fleischhacker, C., Schulz, R., Tepper, K., Martin, M., Hennighausen, K., & Remschmidt, H. (2005). Long-term course of adolescent schizophrenia. Schizophrenia Bulletin, 31, 769–780. Frazier, J. A., Giedd, J. N., Kaysen, D., Albus, K., Hamburger, S., Alaghband-Rad, J., et al. (1996). Childhood-onset schizophrenia: Brain magnetic resonance imaging rescan after two years of clozapine maintenance. American Journal of Psychiatry, 153, 564– 566. Friedman, L., Findling, R. L., Buch, J., Cola, D. M., Swales, T. P., Kenny, J. T., et al. (1996). Structural MRI and neuropsychological assesments in adolescent patients with either schizophrenia or affective disorders. Schizophrenia Research, 18, 189–190. Feinberg, I. (1997). Schizophrenia as an emergent disorder of late brain maturation. In: M. S. Keshervan, & R. M. Murray (Eds), Neurodevelopment and Adult Psychopathology. Cambridge University Press: Cambridge (pp. 237–252). Frith, C. D. (1994). Theory of mind in schizophrenia. In A. David, & J. S. Cutting (Eds.), The Neuropsychology of Schizophrenia (pp. 147–161). Hove: Lawrence Erlbaum. Galdos, P. M., van Os, J., & Murray, R. (1993). Puberty and the onset of psychosis. Schizophrenia Research, 10, 7–14. Gallhofer, B., Trimble, M. R., Frackowiak, R., Gibbs, J., & Jones, T. (1985). A study of cerebral blood flow and metabolism in epileptic psychosis using positron emission tomography and oxygen. Journal of Neurology Neurosurgery and Psychiatry, 48, 201–206. Garralda, M. E. (1984). Hallucinations in children with conduct and emotional disorders. I. The clinical phenomena. Psychological Medicine, 14, 589–596. Geddes, J. R., & Lawrie, S. M. (1995). Obstetric complications and schizophrenia: A meta-analysis. British Journal of Psychiatry, 167, 786–793. Gervin, M., Browne, S., Lane, A., Clarke, M., Waddington, J. L., Larkin, C., et al. (1998). Spontaneous abnormal involuntary movements in first-episode schizophrenia and schizophreniform disorder: Baseline rate in a group of patients from an Irish catchment area. American Journal of Psychiatry, 155, 1202–1206. Giedd, J. N., Castellanos, F. X., Rajapakse, J. C., Vaituzis, A. C., & Rapoport, J. L. (1996). Quantitative analysis of grey matter volumes in childhood-onset schizophrenia and attention deficit/hyperactivity disorder. Society for Neuroscience Abstracts, 22, 1166. Giedd, J. N., Jeffries, N. O., Blumenthal, J., Castellanos, F. X., Vaituzis, A. C., Fernandez, T., et al. (1999). Childhood-onset schizophrenia: Progressive brain changes during adolescence. Biological Psychiatry, 46, 892–898. CHAPTER 45 754 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 754

Gillberg, C., Wahlstrom, J., Forsman, A., Hellgren, L., & Gillberg, J. C. (1986). Teenage psychoses: Epidemiology, classification and reduced optimality in the pre-, peri- and neonatal periods. Journal of Child Psychology and Psychiatry, 27, 87–98. Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of General Psychiatry, 57, 65–73. Gochman, P. A., Greenstein, D., Sporn, A., Gogtay, N., Keller, B., Shaw, P., et al. (2005). IQ stabilization in childhood-onset schizophrenia. Schizophrenia Research, 77, 271–277. Goldstein, M. J. (1987). The UCLA High-Risk Project. Schizophrenia Bulletin, 13, 505–514. Goodman, R. (1988). Are complications of pregnancy and birth causes of schizophrenia? Developmental Medicine and Child Neurology, 30, 391–406. Gogtay, N., Sporn, A., Clasen, L. S., Nugent, T. F. 3rd., Greenstein, D., Nicholson, R., et al. (2004). Comparison of progressive cortical gray matter loss in childhood-onset schizophrenia and that in childhoodonset atypical psychoses. Archives of General Psychiatry, 61, 17–22. Gordon, C. T., Frazier, J. A., McKenna, K., Giedd, J., Zametkin, A., Zahn, T., et al. (1994). Childhood-onset schizophrenia: A NIMH study in progress. Schizophrenia Bulletin, 20, 697–712. Gothelf, D., Apter, A., Reidman, J., Brand-Gothelf, A., Bloch, Y., Gal, G., et al. (2003). Olanzapine, risperidone and haloperidol in the treatment of adolescent patients with schizophrenia. Journal of Neural Transmission, 110, 545–560. Green, W., Padron-Gayol, M., Hardesty, A., & Bassiri, M. (1992). Schizophrenia with childhood onset: a phenomenological study of 38 cases. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 968–976. Greenwood, K. E., Landau, S., & Wykes, T. (2005). Negative symptoms and specific cognitive impairments as combined targets for improved functional outcome within cognitive remediation therapy. Schizophrenia Bulletin, 31, 910–921. Gualtieri, C. T., Adams, A., & Chen, C. D. (1982). Minor physical abnormalities in alcoholic and schizophrenic adults and hyperactive and autistic children. American Journal of Psychiatry, 139, 640–643. Gur, R. E., Cowell, P., Turetsky, B. I., Gallacher, F., Cannon, T., Bilker, W., et al. (1998). A follow-up magnetic resonance imaging study of schizophrenia: Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Archives of General Psychiatry, 55, 145–152. Gur, R. E., Cowell, P., Latshaw, A., Turetsky, B. I., Grossmand, R. I., Arnold, S. E., et al. (2000a). Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Archives of General Psychiatry, 57, 761–768. Gur, R. E., Turetsky, B. I., Cowell, P., Finkelman, C., Maany, V., Grossman, R. I., et al. (2000b). Temporolimbic volume reductions in schizophrenia. Archives of General Psychiatry, 57, 769–775. Hafner, H., & Nowotny, B. (1995). Epidemiology of early-onset schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 245, 80–92. Harrison, P. J., & Owen, M. J. (2003). Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet, 361, 417–419. Harrison, P. J., & Weinberger, D. R. (2005). Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Molecular Psychiatry, 10, 40–68. Hennah, W., Thompson, P., Peltonen, L., & Porteous, D. (2006). Genes and schizoprenia: Beyond schizophrenia: The role of DISC1 in major mental illness. Schizophrenia Bulletin, 32, 409–416. Hollis, C. (1995). Child and adolescent (juvenile onset) schizophrenia: A case–control study of premorbid developmental impairments. British Journal of Psychiatry, 166, 489–495. Hollis, C. (1999). A study of the course and adult outcomes of child and adolescent-onset psychoses. PhD Thesis, University of London. Hollis, C. (2000). The adult outcomes of child and adolescent-onset schizophrenia: Diagnostic stability and predictive validity. American Journal of Psychiatry, 157, 1652–1659. Hollis, C. (2003). Developmental precursors of child- and adolescentonset schizophrenia and affective psychoses: Diagnostic specificity and continuity with symptom dimensions. British Journal of Psychiatry, 182, 37–44. Hollis, C., & Taylor, E. (1997). Schizophrenia: A critique from the developmental psychopathology perspective. In M. S. Keshavan, & R. M. Murray (Eds.), Neuorodevelopment and adult psychopathology (pp. 213–233). Cambridge: Cambridge University Press. Hooley, J. M. (1987). The nature and origins of expressed emotion. In K. Hahlweg, & M. J. Goldstein (Eds.), Understanding major mental disorder: The contribution of family interaction research (pp. 176–194). New York: Family Process. Iacono, W. G., & Koenig, W. G. R. (1983). Features that distinguish smooth the pursuit eye-tracking performance of schizophrenic, affective-disorder, and normal individuals. Journal of Abnormal Psychology, 92, 29–41. Jacobsen, L., Giedd, J. N., Berquin, P. C., Krain, A. L., Hamburger, S. D., Kumra, S., et al. (1997a). Quantitative morphology of the cerebellum and fourth ventricle in childhood-onset schizophrenia. American Journal of Psychiatry, 154, 1663–1669. Jacobsen, L., Hamburger, S. D., Van Horn, J. D., Vaituzis, A. C., McKenna, K., Frazier, J. A., et al. (1997b). Cerebral glucose metabolism in childhood-onset schizophrenia. Psychiatry Research, 75, 131–144. Jacobsen, L., & Rapoport, J. (1998). Research update: Childhoodonset schizophrenia: Implications for clinical and neurobiological research. Journal of Child Psychology and Psychiatry, 39, 101– 113. James, A. C. D., Javaloyes, A., James, S., & Smith, D. M. (2002). Evidence for non-progressive changes in adolescent-onset schizophrenia: Follow-up magnetic resonance imaging study. British Journal of Psychiatry, 180, 339–344. James, A. C. D., Smith, D. M., & Jayaloes, J. S. (2004). Cerebellar, prefrontal cortex, and thalamic volumes over two time points in adolescent-onset schizophrenia. American Journal of Psychiatry, 161, 1023–1029. Jarbin, H., Ott, Y., & Von Knorring, A. L. (2003). Adult outcome of social function in adolescent-onset schizophrenia and affective psychosis. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 176–183. Jones, P., Rogers, B., Murray, R., & Marmot, M. (1994). Child development risk factors for adult schizophrenia in the British, 1946 birth cohort. Lancet, 344, 1398–1402. Jones, P. B., Barnes, T. R., Davies, L., Dunn, G., Lloyd, H., Hayhurst, K. P., et al. (2006). Randomized controlled trial of the effect on Quality of Life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUTLASS 1). Archives of General Psychiatry, 63, 1079–1087. Joyce, P. R. (1984). Age of onset in bipolar affective disorder and misdiagnosis of schizophrenia. Psychological Medicine, 14, 145– 149. Karayiorgou, M., Morris, M. A., Morrow, B., Shprintzen, R. J., Goldberg, R., Borrow, J., et al. (1995). Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences of the USA, 92, 7612–7616. Kay, S. R., Opler, L. A., & Lindenmayer, J. P. (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261–276. Keller, A., Castellanos, F., Vaituzis, C. A., Jefferies, N. O., Giedd, J. N., & Rapoport, J. L. (2003). Progressive loss of cerebellar volume in childhood-onset schizophrenia. American Journal of Psychiatry, 160, 128–133. SCHIZOPHRENIA AND ALLIED DISORDERS 755 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 755

Kendall, R. E., McInneny, K., Juszczak, E., & Bain, M. (2000). Obstetric complications and schizophrenia: Two case–control studies based on structured obstetric records. British Journal of Psychiatry, 176, 516–522. Kendler, K. C., Neale, M. C., & Walsh, D. (1995). Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study. American Journal of Psychiatry, 152, 749–754. Kerns, J. G., Cohen, J. D., MacDonald, A. W., Johnson, M. K., Stenger, V. A., Aizenstein, H., et al. (2005). Decreased conflict- and errorrelated activity in the anterior cingulate cortex in subjects with schizophrenia. American Journal of Psychiatry, 162, 1833–1839. Keshavan, M. S., Stanley, J. A., Montrose, D. M., Minshew, N. J., & Pettegrew, J. W. (2003). Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: An in vivo 31p MRS study. Molecular Psychiatry, 8, 316–323, 251. Kim-Cohen, J., Caspi, A., Moffitt, T. E., Harrington, H., Milne, B. J., & Poulton, R. (2003). Prior juvenile diagnosis in adults with mental disorder: Developmental follow-back of a prospective longitudinal cohort. Archives of General Psychiatry, 60, 709–717. Krystal, J. H., Perry, E. B., Gueorguieva, R., Belger, A., Madonick, S. H., Abi-Dargham, A., et al. (2006). Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: Implications for glutamatergic and dopaminergic model psychoses and cognitive function. Archives of General Psychiatry, 62, 985– 995. Kumra, S., Frazier, J. A., Jacobsen, L. K., McKenna, K., Gordon, C. T., Lenane, M. C., et al. (1996). Childhood-onset schizophrenia: A double blind clozapine–haloperidol comparison. Archives of General Psychiatry, 53, 1090–1097. Kumra, S., Jacobsen, L. K., Lenane, M., Karp, B. I., Frazier, J. A., Smith, A. K., et al. (1998a). Childhood-onset schizophrenia: An openlabel study of olanzapine in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 360–363. Kumra, S., Jacobsen, L. K., Lenane, M., Smith, A., Lee, P., Malanga, C. J., et al. (1998b). Case series: Spectrum of neuroleptic-induced movement disorders and extrapyramidal side-effects in childhoodonset schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 221–227. Kumra, S., Jacobsen, L. K., Lenane, M., Zahn, T. P., Wiggs, E., Alaghband-Rad, J., et al. (1998c). “Multidimensionally impaired disorder”: Is it a variant of very early-onset schizophrenia? Journal of the American Academy of Child and Adolescent Psychiatry, 37, 91–99. Kumra, S., Sporn, A., Hommer, D. W., Nicholson, R., Thaker, G., Israel, E., et al. (2001). Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders. American Journal of Psychiatry, 158, 1291–1298. Lam, D. H. (1991). Psychosocial family intervention in schizophrenia: A review of empirical studies. Psychological Medicine, 21, 423–441. Lawrie, S. M., & Abukmeil, S. S. (1998). Brain abnormalities in schizophrenia: A systematic and quantitative review of volumetric magnetic resonance imaging studies. British Journal of Psychiatry, 172, 110–120. Lay, B., Blanz, B., Hartmann, M., & Schmidt, M. H. (2000). The psychosocial outcome of adolescent-onset schizophrenia: A 12-year follow-up. Schizophrenia Bulletin, 26, 801–816. Leff, J., & Vaughn, C. (1985). Expressed emotion in families: Its significance for mental illness. Guilford Press: London. Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, L. E., Straub, R. E., Hovatta, I., et al. (2003). Genome scan meta-analysis of schizophrenia and bipolar disorder. II. Schizophrenia. American Journal of Human Genetics, 73, 34–48. Lewis, S. W., & Murray, R. M. (1987). Obstetric complications, neurodevelopmental deviance and risk of schizophrenia. Journal of Psychiatric Research, 21, 414–421. Liddle, P. (1987). The symptoms of chronic schizophrenia: A reexamination of the positive–negative dichotomy. British Journal of Psychiatry, 151, 145–151. Liddle, P., & Pantelis, C. (2003). Brain imaging in schizophrenia. In S. R. Hirsch, & D. R. Weinberger (Eds.), Schizophrenia (2nd edn.). Oxford: Blackwell. Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., et al. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine, 353, 1209–1223. Lindsay, J., Ounsted, C., & Richards, P. (1979). Long-term outcome of children with temporal lobe seizures. II. Marriage, parenthood and sexual indifference. Developmental Medicine and Child Neurology, 21, 433–440. Loebel, A. D., Lieberman, J. A., Alvir, J. M., Mayerhoff, D. I., Geisler, S. H., & Szymanski, S. R. (1992). Duration of psychosis and outcome in first-episode schizophrenia. American Journal of Psychiatry, 149, 1183–1188. Maj, M. (1998). Critique of the DSM-IV operational diagnostic criteria for schizophrenia. British Journal of Psychiatry, 172, 458– 460. Marquardt, R. K., Levitt, J. G., Blanton, R. E., Caplan, R., Asarnow, R., Siddarth, P., et al. (2005). Abnormal development of the anterior cingulate in childhood-onset schizophrenia: A preliminary quantitative MRI study. Psychiatry Research, 138, 221–233. Mason, P., Harrison, G., Croudace, T., Glazebrook, C., & Medley, I. (1997). The predictive validity of a diagnosis of schizophrenia. British Journal of Psychiatry, 170, 321–327. Matsumoto, H., Takei, N., Saito, H., Kachi, K., & Mori, N. (1999). Childhood-onset schizophrenia and obstretic complications: A case– control study. Schizophrenia Research, 38, 93–99. Matsumoto, H., Takei, N., Saito, H., Kachi, K., & Mori, N. (2001). The association between obstretric complications and childhoodonset schizophrenia: A replication study. Psychological Medicine, 31, 907–914. McGlashan, T. H., & Hoffman, R. E. (2000). Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Archives of General Psychiatry, 57, 637–648. McGrath, J., & Murray, R. (1995). Risk factors for schizophrenia: from conception to birth. In S. R. Hirsch, & D. R. Weinberger (Eds.), Schizophrenia (pp. 187–205). Oxford: Blackwell Science. McGorry, P. D., Yung, A. R., Phillips, L. J., Yuen, H. P., Francey, S., Cosgrave, E. M., et al. (2002). Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Archives of General Psychiatry, 59, 921–928. Mirnics, K., Middleton, F. A., Lewis, D. A., & Levitt, P. (2001). Analysis of complex brain disorders with gene expression microarrays: Schizophrenia as a disease of the synapse. Trends in Neuroscience, 24, 479–486. Morgan, C., & Fisher, H. (2007). Environmental factors in schizophrenia: Childhood trauma. Schizophrenia Bulletin, 33, 3–10. National Institute for Clinical Excellence (NICE). (2002). Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia. NICE Technology Appraisal Guidance No. 43. London: NICE. Nelson, M. D., Saykin, A. J., Flashman, L. A., & Riodan, H. J. (1998). Hippocampal volume reduction in schizophrenia assessed by magnetic resonance imaging: A meta-analytic study. Archives of General Psychiatry, 55, 433–440. Nicolson, R. M., Giedd, J. N., Lenane, M., Hamburger, S., Singaracharlu, S., Bedwell, J., et al. (1999). Clinical and neurobiological correlates of cytogenetic abnormalities in childhood-onset schizophrenia. American Journal of Psychiatry, 156, 1575–1579. Nopoulos, P., Torres, I., Flaum, M., Andreasen, N. C., Ehrhaerdt, J. C., & Yuh, W. T. C. (1995). Brain morphology in first-episode schizophrenia. American Journal of Psychiatry, 152, 1721–1723. CHAPTER 45 756 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 756

Nopoulos, P. C., Giedd, J. N., Andreasen, N. C., & Rapoport, J. L. (1998). Frequency and severity of enlarged septi pellucidi in childhood-onset schizophrenia. American Journal of Psychiatry, 155, 1074–1079. O’Driscoll, G. A., Benkelfat, C., Florencio, P. S., Wolff, A. L., Joober, R., Lal, S., et al. (1999). Neural correlates of eye tracking deficits in first-degree relatives of schizophrenic patients: A positron emission tomography study. Archives of General Psychiatry, 56, 1127–1134. Owen, M. J, Craddock, N., & O’Donovan, M. C. (2005). Schizophrenia: Genes at last? Trends in Genetics, 21, 518–525. Pantelis, C., Velakoulis, D., McGorry, P. D., Wood, S. J., Suckling, J., Phillips, L. J., et al. (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet, 361, 281–288. Park, S., Holzman, P. S., & Goldman-Rakic, P. S. (1995). Spatial working memory deficits in the relatives of schizophrenic patients. Archives of General Psychiatry, 52, 821–828. Perlstein, W. M., Carter, C. S., Noll, D. C., & Cohen, J. D. (2001). Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. American Journal of Psychiatry, 158, 1105–1113. Pennington, B. F. (1997). Dimensions of executive functions in normal and abnormal velopment. In N. Krasnegor, G. R. Lyon, & P. S. Goldman-Rakic (Eds.), Prefrontal cortex: Evolution, development, and behavioral neuroscience (pp. 265–281). Baltimore: Brooke Publishing. Pettegrew, J. W., Keshavan, M. S., Panchalingam, K., Strychor, S., Kaplan, D. B., Tretta, M. G., et al. (1991). Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Archives of General Psychiatry, 48, 563– 568. Pistis, M., Perra, S., Pillolla, G., Melia, M., Muntoni, A. L., & Gessa, G. L. (2004). Adolescent exposure to cannabinoids induces longlasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biological Psychiatry, 56, 86–94. Pool, D., Bloom, W., Miekle, D. H., Roniger, J. J., & Gallant, D. M. (1976). A controlled trial of loxapine in 75 adolescent schizophrenic patients. Current Therapeutic Research, 19, 99–104. Poole, R., & Brabbins, C. (1996). Drug induced psychosis. British Journal of Psychiatry, 168, 135–138. Poulton, R., Caspi, A., Moffitt, T. E., Cannon, M., Murray, R., & Harrington, H. (2000). Children’s self-reported psychotic symptoms and adult schizophreniform disorder: A 15-year longitudinal study. Archives of General Psychiatry, 57, 1053–1058. Purves, D. L., & Lichtmen, J. W. (1980). Elimination of synapses in the developing nervous system. Science, 210, 153–157. Rapoport, J. L., Addington, A. M., & Frangou, S. (2005). The neurodevelopmental model of schizophrenia: Update, 2005. Molecular Psychiatry, 10, 434–449. Rapoport, J. L., Conners, C., & Reatig, N. (1985). Rating scales and assessment instruments for use in paediatric psychopharmacology research. Psychopharmacology Bulletin, 21, 1077–1080. Rapoport, J. L., Giedd, J., Blumenthal, J., Hamburger, S., Jeffries, N., Fernandez, T., et al. (1999). Progressive cortical change during adolescence in childhood-onset schizophrenia: A longitudinal magnetic resonance imaging study. Archives of General Psychiatry, 56, 649–654. Ratzoni, G., Gothelf, D., Brand-Gothelf, A., Reidman, J., Kikinzon, L., Gal, G., et al. (2002). Weight gain associated with olanzapine and risperidone in adolescent patients: A comparative prospective study. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 337–343. Read, J., van Os, J., Morrison, A. P., & Ross, C. A. (2005). Childhood trauma, psychosis and schizophrenia: A literature review with theoretical implications. Acta Psychiatrica Scandinavica, 112, 330–350. Reich, W. (2000). Diagnostic Interview for Children and Adolescents (DICA). Journal of the American Academy of Child and Adolescent Psychiatry, 39, 59–66. Reichenberg, A., Weiser, M., Rapp, M. A., Rabinowitz, J., Caspi, A., Schmeidler, J., et al. (2005). Elaboration on Premorbid Intellectual Performance in Schizophrenia: Premorbid Intellectual Decline and Risk for Schizophrenia. Arch Gren Psychiatry, 62, 1297–1304. Remschmidt, H., Schultz, E., & Martin, M. (1994). An open trial of clozapine with thirty-six adolescents with schizophrenia. Journal of Child and Adolescent Psychopharmacology, 4, 31–41. Roberts, G. W., Colter, N., Lofthouse, R., Bogerts, B., Zech, M., & Crow, T. J. (1986). Gliosis in schizophrenia: A survey. Biological Psychiatry, 21, 1043–1050. Robinson, D., Woerner, M. G., Alvir, J. M., Bilder, R., Goldman, R., Geisler, S., et al. (1999). Predictors of relapse following a first episode of schizophrenia or schizoaffective disorder. Archives of General Psychiatry, 56, 241–247. Rossi, A., Mancini, F., Stratta, P., Mattei, P., Gismondi, R., Pozzi, F., et al. (1997). Risperidone, negative symptoms and cognitive deficit in schizophrenia: An open study. Acta Psychiatrica Scandinavica, 95, 40–43. Russell, A. T., Bott, L., & Sammons, C. (1989). The phenomena of schizophrenia occurring in childhood. Journal of the American Academy of Child and Adolescent Psychiatry, 28, 399–407. Rutter, M., & Plomin, R. (1997). Opportunities for psychiatry from genetic findings. British Journal of Psychiatry, 171, 209–219. Sachdev, P. (1998). Schizophrenia-like psychosis and epilepsy: The status of the association. American Journal of Psychiatry, 155, 325–336. Saykin, A. J., Shtasel, D. L., Gur, R. E., Kester, D. B., Mozley, L. H., Stafiniak, P., et al. (1994). Neuropsychological deficits in neurolepticnaive patients with first-episode schizophrenia. Archives of General Psychiatry, 51, 124–131. Schaeffer, J. L., & Ross, R. G. (2002). Childhood-onset schizophrenia: Premorbid and prodromal diagnostic and treatment histories. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 538–545. Schmidt, M., Blanz, B., Dippe, A., Koppe, T., & Lay, B. (1995). Course of patients diagnosed as having schizophrenia during first episode occurring under age 18 years. European Archives of Psychiatry and Clinical Neuroscience, 245, 93–100. Selemon, L. D., Rajkowska, G., & Goldman-Rakic, P. S. (1995). Abnormally high neuronal density in the schizophrenic cortex: A morphometric analysis of prefrontal area 9 and occipital area 17. Archives of General Psychiatry, 52, 805–818. Shaffer, D., Gould, M. S., Brasic, J., Ambrosini, P., Fisher, P., Bird, H., et al. (1983). The Children’s Global Assessment Scale (CGAS). Archives of General Psychiatry, 40, 1228–1231. Sikich, L., Hamer, R. M., Bashford, R. A., Sheitman, B. B., & Lieberman, J. A. (2004). A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: A double-blind, randomized, 8-week trial. Neuropsychopharmacology, 29, 133–145. Simpson, G., & Angus, J. S. W. (1970). A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica, 212, 9–11. Slaveska, K., Hollis, C. P., & Bramble, D. (1998). The use of antipsychotics by the child and adolescent psychiatrists of Trent region. Psychiatric Bulletin, 22, 685–687. Spencer, E. K., & Campbell, M. (1994). Children with schizophrenia: Diagnosis, phenomenology and pharmacotherapy. Schizophrenia Bulletin, 20, 713–725. Sporn, A. L., Addington, A. M., Gogtay, N., Ordonez, A. E., Gornick, M., Clasen, L., et al. (2004a). Pervasive developmental disorder and childhood-onset schizophrenia: Co-morbid disorder or phenotypic variant of a very early onset illness? Biological Psychiatry, 55, 989–994. SCHIZOPHRENIA AND ALLIED DISORDERS 757 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 757

Tsuang, M. T., Simpson, J. C., & Kronfold, Z. (1982). Subtypes of drug abuse with psychosis. Archives of General Psychiatry, 39, 141–147. Turkington, D., & Kingdon, D. (2000). Cognitive–behavioural techniques for general psychiatrists in the management of patients with psychoses. British Journal of Psychiatry, 177, 101–106. Vita, A., Dieci, M., Giobbio, G. M., Azzone, P., Garbarini, M., Sacchetti, E., et al. (1991). CT scan abnormalities and outcome of chronic schizophrenia. American Journal of Psychiatry, 148, 1577– 1579. Volkmar, F. R., & Cohen, D. J. (1991). Comorbid association of autism and schizophrenia. American Journal of Psychiatry, 148, 1705– 1707. Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44, 660–669. Werry, J. S., McClellan, J. M., & Chard, L. (1991). Childhood and adolescent schizophrenia, bipolar and schizoaffective disorders: A clinical and outcome study. Journal of the American Academy of Child and Adolescent Psychiatry, 30, 457–465. Werry, J. S., McClellan, J. M., Andrews, L., & Ham, M. (1994). Clinical features and outcome of child and adolescent schizophrenia. Schizophrenia Bulletin, 20, 619–630. White, T., Andreasen, N. C., Nopoulos, P., & Magnotta, V. (2003). Gyrification abnormalities in childhood-onset schizophrenia. Biological Psychiatry, 54, 418–426. Woods, B. T. (1998). Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. American Journal of Psychiatry, 155, 1661–1670. World Health Organization. (1996). Multiaxial classification of child and adolescent psychiatric disorders: The ICD-10 classification of mental and behavioural disorders in children and adolescents. Cambridge, UK: Cambridge University Press. Wyatt, R. J. (1995). Early intervention in schizophrenia: can the course be altered? Biological Psychiatry, 38, 1–3. Wykes, T., Reeder, C., Williams, C., Corner, J., Rice, C., & Everitt, B. (2000). Cognitive remediation: Predictors of success and durability of improvements (Abstract). Schizophrenia Research, 41, 221. Yung, A. R., Phillips, L. J., Yuen, H. P., Francey, S. M., McFarlane, C. A., Hallgren, M., et al. (2003). Psychosis prediction: 12-month follow up of a high-risk (“prodromal”) group. Schizophrenia Research, 60, 21–32. Zahn, T. P., Jacobsen, L. K., Gordon, C. T., McKenna, K., Frazier, K., & Rapoport, J. L. (1997). Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia. Archives of General Psychiatry, 54, 904–912. Zahn, T. P., Jacobsen, L. K., Gordon, C. T., McKenna, K., Frazier, K., & Rapoport, J. L. (1998). Attention deficits in childhood-onset schizophrenia: Reaction time studies. Journal of Abnormal Psychology, 107, 97–108. CHAPTER 45 758 Sporn, A. L., Addington, A. M., Reiss, A. L., Dean, M., Gogtay, N., Potocnik, U., et al. (2004b). 22q11 deletion syndrome in childhoodonset schizophrenia: An update. Molecular Psychiatry, 9, 225– 226. Sporn, A. L., Greenstein, D., Gogtay, N., Jeffries, N. O., Lenane, M., Gochman, P., et al. (2003). Progressive brain volume loss during adolescence in childhood-onset schizophrenia. American Journal of Psychiatry, 160, 1281–1289. Sporn, A. L., Greenstein, D., Gogtay, N., Sailer, F., Hommer, D. W., Rawlings, R., et al. (2005). Childhood-onset schizophrenia: Smooth pursuit eye-tracking dysfunction in family members. Schizophrenia Research, 73, 243–252. St. Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., et al. (2005). Rates of adult schizophrenia following prenatal exposure to the Chinese Famine of 1959–1961. Journal of the American Medical Association, 294, 557–562. Stayer, C., Sporn, A., Gogtay, N., Tossell, J. W., Lenane, M., Gochman, P., et al. (2005). Multidimensionally impaired: The good news. Journal of Child and Adolescent Psychopharmacology, 15, 510–519. Strandburg, R. J., Marsh, J. T., Brown, W. S., et al. (1999). Continuous-processing ERPS in adult schizophrenia: Continuity with childhood-onset schizophrenia. Biological Psychiatry, 45, 1356– 1369. Susser, E., & Lin, S. P. (1992). Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944–1945. Archives of General Psychiatry, 49, 983–988. Tarrier, N., Beckett, R., Harwood, S., Baker, A., Yusupoff, L., & Ugarteburu, I. (1993). A trial of two cognitive–behavioural methods of treating drug-resistant residual psychotic symptoms in schizophrenic patients. I. Outcome. British Journal of Psychiatry, 162, 524–532. Thomas, M. A., Ke, Y., Levitt, J., Caplan, R., Curran, J., Asarnow, R., et al. (1998). Preliminary study of frontal lobe 1 H MR spectroscopy in childhood-onset schizophrenia. Journal of Magnetic Resonance Imaging, 8, 841–846. Theisen, F. M., Linden, A., Geller, F., Schafer, H., Martin, M., Remschmidt, H., et al. (2001). Prevalence of obesity in adolescent and young adult patients with and without schizophrenia and in relationship to antipsychotic medication. Journal of Psychiatric Research, 35, 339–345. Toren, P., Ratner, S., Laor, N., & Weizman, A. (2004). Benefit–risk assessment of atypical antipsychotics in the treatment of schizophrenia and comorbid disorders in children and adolescents. Drug Safety, 27, 1135–1156. Towbin, K. R., Dykens, E. M., Pearson, G. S., & Cohen, D. J. (1993). Conceptualizing “borderline syndrome of childhood” and “childhood schizophrenia” as a developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 775– 782. 9781405145497_4_045.qxd 29/03/2008 02:54 PM Page 758

759 Autism spectrum disorders (ASD; or Pervasive Developmental Disorders, PDD) are a group of conditions characterized by three cardinal clinical features: qualitative impairments in social interactions; qualitatively impaired verbal and non-verbal communication; and restricted range of interests. Additional characteristics include onset early in life, delay and/or deviance of development of key psychological functions, multifactorial etiology in which several as yet unknown genetic risk factors interact with each other and with environmental factors, change and mitigation of symptomatic expression by age and, despite this, a chronic course with strong persistence of handicaps over time. However, it is equally true that ASD are clinically very heterogeneous conditions. A main factor that determines diversity is variation in level of cognitive functioning and language skills. There is a large difference between a severely intellectually impaired person with autism who is unable to speak and who engages in motor stereotypies and self-injury, and a highly skilled computer engineer with Asperger disorder or with high functioning autism who is fluent in his one-sided exchange of excessive and obsessive preoccupations about, for example, the constellation of the planets and stars. Other aspects of diversity concern age, severity of cardinal features, coexisting somatic conditions including epilepsy, and coexisting psychiatric conditions. Over the past decades, clinical and research interest has moved from a focus on a more narrowly defined group of subjects with severe manifestations of the three cardinal features (i.e., “typical autism”) to a broader and more prevalent category with more subtle and less severe symptoms, usually classified as atypical autism or pervasive developmental disorder not otherwise specified (PDD-NOS). Although most of our knowledge about ASD is still derived from research in typical autism, this chapter takes a perspective on the whole range of severity of ASD. Recent findings indicate that ASD can be conceptualized as disorders of early brain development. Functional and morphological abnormalities of the brain, induced by both static persistent processes that started in utero and dynamic processes that change over time and continue to change in postnatal life, underlie the complex behavioral and cognitive manifestations of ASD. History Kanner (1943) first described a syndrome of “autistic disturbances” with case histories of 11 children who presented between the ages of 2 and 8 years and who shared unique and previously unreported patterns of behavior including social remoteness, obsessiveness, stereotypy and echolalia. After its initial description, autism was poorly ascertained during the middle decades of the 20th century. In DSM-I, autism was classified as a childhood type of schizophrenia. Despite this early view of autism as a psychosis, several prominent research groups had formulated the first set of diagnostic criteria for this disorder by the 1970s (Ritvo & Freeman, 1978; Rutter & Hersov, 1977). With DSM-III, the term Pervasive Developmental Disorders (PDD) was first used to describe disorders characterized by distortions in the development of multiple basic psychological functions that are involved in the development of social skills and language, such as attention, perception, reality testing and motor movement. The term PDD was selected because it described most accurately that many basic areas of psychological development are severely affected at the same time. This new PDD umbrella included, for the first time, the term Infantile Autism (with onset prior to age 30 months) as well as Childhood Onset Pervasive Developmental Disorder (with onset after age 30 months). In DSM-III, autism was also clearly differentiated from childhood schizophrenia and other psychoses for the first time, and the absence of psychotic symptoms, such as delusions and hallucinations, became one of the six diagnostic criteria. In 1944, Asperger wrote the first paper (in German), on what has come to be known as his disorder (translated into English in Frith, 1991). He outlined the clinical picture of four children with normal IQ who were socially odd, naïve and inappropriate, had good grammar and extensive vocabularies, poor non-verbal communication, circumscribed interests and poor motor coordination. However, this paper was virtually unnoticed until it was extensively discussed in an English publication (Wing, 1981). Asperger syndrome was first included as a diagnostic category in DSM-IV (American Psychiatric Association, 2000) and ICD-10 (World Health Organization, 1996). Clinical Characteristics The diagnostic frameworks currently used, DSM-IV and ICD10, include a very similar list of disorders under ASD or PDD. Autism Spectrum Disorders 46 Herman van Engeland and Jan K. Buitelaar 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 759 Rutter’s Child and Adolescent Psychiatry, 5th Edition, Edited by M. Rutter, D. V. M. Bishop D. S. Pine, S. Scott, J. Stevenson, E. Taylor and A. Thapar © 2008 Blackwell Publishing Limited. ISBN: 978-1-405-14549-7

Speech tends to be in a monotone without the usual emphasis to support meaning of phrases. The autistic child may also use neologisms, echoing or pronoun reversal. Remember that immediate echolalia is a crucial aspect of normal language development under the age of 2 years. It becomes pathological when it is still present as the sole and predominant expressive language after the age of about 24 months, and can often be present throughout the preschool or school-age years in children with autism. ASD are also associated with deficits in nonverbal communication, including the use of gestures such as pointing, showing and nodding. Some children with autism do not use miniature objects, animals or dolls appropriately in pretend play. Others use the materials in a repetitive mechanical fashion without evidence of flexible representational play. Some highly verbal children may invent a fantasy world which becomes the sole focus of repetitive play. Imitation skills are weak or absent, as is the ability to engage in social play, such as peek-a-boo or hide and seek. Restricted, Repetitive and Stereotypic Patterns of Behaviors, Interests and Activities Some children show an unusual and intense preoccupation with a topic of private interest such as washing machines, trains or railway schedules. Other children are absorbed in fixed daily routines and rituals. Many children with autism are so preoccupied with “sameness” in their home and school environments, or with routines, that little can be changed without prompting a tantrum or other emotional disturbance. For example, some insist on taking only a certain route to school, entering the supermarket only by one specific door, or never stopping or turning around once the car starts moving. Repetitive behaviors commonly observed in children with autism may include motor mannerisms such as hand-flapping, rocking, flipping objects or lining up toys in a fixed fashion. Some display sensory abnormalities, and are preoccupied by auditory, visual, tactile, haptic or kinesthetic stimuli and apparently are hypo- or hyper-responsive to these. These repetitive and sensory abnormalities can be a source of pleasure or selfstimulation, which differentiates these behaviors from those seen in obsessive-compulsive disorder. Classification The prototype of ASD, autistic disorder, is defined by the presence of marked symptoms in all three of the key domains of qualitative impairments in social interactions, qualitatively impaired communication and restricted range of interests. In addition, at least some of these features must have been manifest by the age of 3 years (APA, 2000; WHO, 1996). Asperger syndrome is defined by the presence of social impairment and repetitive behaviors and restricted interests, as in autism. However, in contrast to autism, there is no overall delay in language development, as indexed from the use of single words by age 2 and communicative phrases by age 3 years. Normal or near-normal IQ is also the rule. The lack CHAPTER 46 760 Qualitative Impairment in Social Interactions The emphasis is on the qualitative impairment in reciprocal social interactions and not on the absolute lack of social behaviors. There is wide variation in social symptoms, which range from a total lack of awareness of another person to intrusive social approaches that are inappropriate to context. In the first year of life, some children with autism do not lift up their arms or change posture in anticipation of being held. Some children do make eye contact, often only in brief glances, but the eye contact is usually not used to direct attention to objects or events of interest. Other children make inappropriate eye contact, by turning someone else’s head to gaze into their eyes, or tend to stare at other people’s faces. Some children make indiscriminate approaches to strangers (e.g., may climb into the examiner’s lap before the parent has even entered the room). The capacity to make social connections and engage in relationships appropriate to age level is limited. Young children may demonstrate lack of interestin, or even lack of awareness of other children. Older children with autism have no ageappropriate friends, are socially isolated and may be teased or bullied. Nonetheless, they may express social interest by saying they want “friends.” Tragically, they do not understand the principles of the reciprocity and sharing of interests inherent in friendship and they lack the pragmatics of “how socially to do what, when and where.” More verbally able children may have one “friend” but the relationship is usually very limited and based on a similar circumscribed interest, such as dinosaurs or a particular computer game. They often do not point things out or use eye contact to share the pleasure of seeing something with another person, which is called joint attention. There are often deficits in reading social cues in body language and facial expressions of others. Some children tend to have a more passive type of social interaction characterized by a lack of social initiative and an observing and compliant style of simply following the directions of others. Qualitative Impairment in Communication In a similar way, the communication impairments seen in ASD are diverse, and vary from simple speech delay to muteness, to fluency with subtle peculiarities of intonation and inability to adjust vocabulary and conversational style to social context. As a result, fluency is often accompanied by many semantic (word meaning) and verbal pragmatic errors. Young autistic children, even if verbal, almost universally have comprehension deficits, in particular deficits in understanding higher order complex questions. Some children with autism do not respond to their names when called by a parent or other favored caretaker, and often they are initially presumed to be severely hearing-impaired. A characteristic behavior of many children with autism is mechanically to use another person’s hand to indicate the desired object, often called “hand over hand pointing.” Other “independent” children make no demands or requests of the parents, but rather learn to climb at a young age and acquire the desired object for themselves. When language is present, children with autism seem unable or unwilling to initiate or sustain conversation in a give-and-take fashion. 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 760

of clear language deviance usually leads to later clinical recognition than with other ASD, which is presumably a result of the normal or near-normal adaptive behavior early in life (Volkmar & Cohen, 1991). Yet the language in Asperger disorder is clearly not typical or normal. Individuals usually have pedantic and poorly modulated speech, poor non-verbal pragmatic or communication skills, and intense preoccupations with circumscribed topics such as the weather or railway timetables. They often have both fine and gross motor deficits, including clumsy and uncoordinated movements and odd postures. In spite of the consensus definition of Asperger disorder in DSM-IV and ICD-10, the validity of Asperger disorder as a discrete diagnostic entity distinct from high-functioning (verbal) autism has remained controversial (Klin, McPartland, & Volkmar, 2005a; Schopler, Mesibov, & Kunce, 1998). Researchers have adopted various diagnostic schemes which differ by whether the focus was on onset of any concerns before age 3, on the presence of speech delay by age 2–3 or by the application of unique investigator-based criteria (Klin, Pauls, Schultz et al., 2005b). The diagnosis of PDD-NOS (or atypical autism) is appropriate when a subject exhibits impairments in social interactions, impaired communication or restricted range of interests, but does not meet the full criteria for autistic disorder or Asperger disorder. This would apply when the number of criteria met is subthreshold, age of onset is after age 3 years, atypical symptoms are present or more than one of these are present. Balancing sensitivity and specificity in differentiating PDD-NOS from both autism and non-ASD conditions, diagnostic algorithms have been proposed that describe PDD-NOS as a lesser variant of autism, requiring that at least 4 of the 12 DSMIV criteria of autism are met, including at least one of the social interaction criteria (Buitelaar & van der Gaag, 1998; Buitelaar, van der Gaag, Klin, & Volkmar, 1999a). Epidemiology Whereas the first epidemiological studies of autism reported the population prevalence at around 4 per 10,000 (Lotter, 1966), recent large systematic surveys indicate a much higher rate. The current estimates are 30–100 per 10,000 for all ASD, including 13–30 per 10,000 for autism and 3 per 10,000 for Asperger disorder (Baird, Simonoff, Pickles et al., 2006; Fombonne, 1999, 2003). Estimates from single studies vary widely, because of differences in screening and ascertainment procedures, sample size, publication year and geographic location. The increase in reported rates of ASD is largely a consequence of two factors (Rutter, 2005). First, recent studies used systematic standardized and often multiple screenings of total populations or birth cohorts, and by consequence have missed fewer children with ASD than older studies that were more focused on special populations or case registries. Second, over the years the diagnostic concept of ASD has broadened considerably and has included a much better recognition of the expression of autistic symptoms in individuals with near-normal or normal non-verbal intelligence, along with insights from family genetic and twin studies that the genetic liability of autism extends well beyond the traditional categories into more subtle social and communicative abnormalities (Bolton, Macdonald, Pickles et al., 1994; Le Couteur, Bailey, Goode et al., 1996). However, it is unclear whether there is also a rise in the true incidence of ASD, and whether – if so – this is a result of some as yet unknown environmental factor. The increase, particularly since the early 1980s, has led to claims that specific environmental factors such as the use of mumps–measles– rubella (MMR) triple vaccine are a major factor (Roger, 2000; Wakefield, Murch, Anthony et al., 1998). However, empirical evidence for these claims is absent (Rutter, 2005). For example, a total population study in the Yokohama district, Japan, was able to examine the cumulative incidence of ASD before the introduction of the MMR vaccination and after its withdrawal (Honda, Shimizu, & Rutter, 2005). The findings indicated a continuing rise in incidence of ASD even after the withdrawal of the vaccination. Further, the incidence pattern of ASD associated with regression was similar to that of ASD as a whole. It is also relevant that an independent study of Wakefield’s claims on finding the measles virus in body tissues has not confirmed the findings (D’Souza, Fombonne, & Ward, 2006). Finally, in particular the incidence of ASD with high IQ showed a significant increase. The use of thimerosal, a vaccine preservative that contains ethyl mercury, has in a somewhat similar way been linked to a rise in incidence of ASD. Because mercury, in high dosage, can cause neurodevelopmental sequelae, there is greater biological plausibility in this argument. However, discontinuation of the thimerosal-containing vaccines in Denmark was followed by an increase in the incidence of ASD and not by the predicted decrease (Atladóttir, Parner, Schendel et al., 2007; Madsen, Lauritsen, Pedersen et al., 2003). Recent surveys continue to indicate associations of ASD with gender, IQ and other medical disorders (Fombonne, 2003). Males are about four times more often affected than females, with gender differences even more pronounced in the normal range of intellectual functioning, up to a male : female ratio of 6:1. The gender difference in ASD is poorly understood. Although Baron-Cohen, Knickmeyer, and Belmonte (2005) have speculated that autism may represent an extreme male brain, there is a paucity of supporting evidence and the suggestion side-steps the important finding that most early-onset neurodevelopmental disorders (such as attention deficit/hyperactivity disorder [ADHD] and dyslexia) show a marked male preponderance (see chapter 3; Rutter, Caspi, & Moffitt, 2003a). It may be more profitable to ask why males are more vulnerable to this range of disorders, rather than to view autism as a special case. The rate of coexisting severe to profound intellectual impairment is about 40%, mild to moderate cognitive impairments are found in 30% and normal intellectual functioning in another 30%. Potentially causal medical associations are found in about 5–10% of the cases. The strongest connection is found for tuberous sclerosis (Smalley, 1998); approximately 20% of AUTISM SPECTRUM DISORDERS 761 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 761

patients with tuberous sclerosis also have autism, although, in contrast, tuberous sclerosis is found only in a small percentage of cases with autism. Other medical conditions that may be associated with autism are cerebral palsy, fragile X, phenylketonuria, neurofibromatosis, congenital rubella and Down’s syndrome (Fombonne, 2003). These associations with intellectual impairment and known medical conditions are much stronger for typical autism than more broadly defined ASD. Course of Autism Most children with autism are identified by their parents as showing abnormalities or delays in the second year of life, and many parents suspect problems long before this (Zwaigenbaum, Bryson, Rogers et al., 2005). Parents who have already had a child tend to recognize social deficits earlier than parents of firstborns, and social deficits are often less recognizable in very young children than when they are older (De Giacomo & Fombonne, 1998). Often, the problems noticed are not specific autistic features, but rather concerns that the child is less socially responsive and has difficulties in settling, eating and sleeping (Dahlgren & Gillberg, 1989). Home videos similarly show that by the age of 12–18 months (or even earlier) there may be manifestations of abnormal development, but often the indications are quite subtle (Rutter, 2005). Many autistic children under the age of 3 years do not yet show clear examples of restricted or repetitive behaviors (Cox, Klein, Charman et al., 1999). It has long been noted that about one-quarter to one-third of all children with ASD appear to lose previously acquired language skills (usually between 18 and 24 months; Rogers & DiLalla, 1990; Rutter, 2005). Surprisingly, the phenomenon has been subject to remarkably little systematic study. Some of these apparent developmental regressions are minor and probably of little significance but there is no doubt that a marked loss of skills does occur in a substantial minority of children with ASD. In one well-documented study (Pickles, Simonoff, Conti-Ramsden et al., submitted), the phenomenon was shown to be common in children with ASD but did not occur in those with specific language impairment (SLI). If confirmed, this would suggest that developmental regression is of some diagnostic significance. However, its meaning remains obscure. Despite claims to the contrary (in relation to MMR), it does not imply any environmental cause and there is no evidence that ASD with regression is becoming more frequent (Rutter, 2005). When children with ASD enter school, many of them are described as more flexible and socially directed. Data from 13 follow-up studies extending into adult life show a general pattern of modest improvement over time (Howlin, 2005). Some adults with ASD experience real behavioral and social improvements in their late 20s and early 30s (Mesibov, 1984). However, autism is a lifelong disorder, and the likelihood of complete independence is low. Individuals with both autism and intellectual disability require supervised living and working situations throughout their lives. Opportunities within communities, rather than in institutions, have increased in the last decades. Most adults with ASD, even those with average or greater intelligence, require some help in finding and keeping jobs and coping with responsibilities and social demands. Comparisons of outcome studies over the last 30 years suggest that among those of intelligence within the normal range, there has been some increase in the proportion obtaining employment. Admissions with institutional care have also fallen. Nevertheless, even in individuals with an IQ above 70, only about one-quarter show good social functioning. Early reports commented on apparent cognitive deterioration in adolescence in some individuals, but true cognitive decline seems uncommon. In a recent large follow-up study with a low attrition rate and using systematic interviews to obtain clinical information, Hutton, Goode, Murphy et al. (in press) found that 16% of the autistic participants developed a definite new psychiatric disorder that was not just a worsening of pre-existing autistic features. Five out of 135 developed an obsessivecompulsive disorder and/or catatonia; a further eight developed affective disorders with marked obsessional features; and seven developed complex or straightforward affective disorders. There was no case of schizophrenia in this study, indicating a lack of continuity between autism and schizophrenia (Volkmar & Cohen, 1991). However, there are reports of autistic individuals who show isolated psychotic symptoms, including hallucinations and delusional thoughts (Clarke, Littlejohns, Corbett, & Joseph, 1989; Szatmari, Bartolucci, & Bremmer, 1989; Vorstman, Staal, van Daalen et al., 2006; Wing & Shah, 2000). Hutton, Goode, Murphy et al. (in press) found that one-fifth of individuals with ASD followed into adult life experience one or more epileptic attacks and that about twothirds of these had their onset in adolescence or adult life. There are a number of largely anecdotal reports of offending by people with autism or Asperger syndrome. Inappropriate social responses, especially to strangers, may result in police involvement and crimes may also be linked to obsessional interests. Because of this, offending may well be of an unusual or even bizarre nature (Baron-Cohen, 1988; Chesterman & Rutter, 1994). Scragg and Shah (1994) assessed the entire male population of Broadmoor Special Hospital and identified three cases of autism and six with Asperger syndrome out of a total of 392 (just over 2%), clearly a much higher figure than the rates for autism or Asperger syndrome in the general population. In their review of offending by people with Asperger syndrome, Ghaziuddin, Tsai, and Ghaziuddin (1991) found that only 3 out of a total of 132 cases had a clear history of violent behavior. Estimates on the prevalence of violence in people with ASD can only be made on the basis of community studies; these are lacking so far. Predictors of Outcome Predictors of outcome from preschool to later childhood and adolescence have included joint attention (Sigman, Ruskin, CHAPTER 46 762 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 762

Arbeile et al., 1999), verbal imitation (Smith & Bryson, 1994) and social communicative aspects of adaptive skills (Lord & Schopler, 1989). However, non-verbal IQ and language are the most powerful predictors. A non-verbal IQ below 50 in preschool years is associated with a reduced likelihood that the child will acquire a useful level of spoken language and a very low probability of good social functioning in adolescence or adulthood (Lockyer & Rutter, 1969). Variations in nonverbal IQ in the range of 50–70 have a somewhat similar effect, but those within the normal range do not. In children with autism but without severe intellectual disability, language skills (and verbal IQ) are the strongest predictors of social outcome. A child who does not have fluent speech by the age of 5 years will make significant gains, but the later these gains come, the less likely the child’s language will be flexible and complex, and the more likely language delays of some sort will reduce his or her level of independence (Szatmari, Bryson, Streiner et al., 2000). Although intrinsic factors such as high IQ and good language abilities are important for outcome, these alone are not enough to ensure a positive outcome. External factors, including appropriate junior and secondary school provision, improved transitional programs for entry into college and supported employment schemes, are also crucial (Howlin, Alcock, & Burkin, 2005; Keel, Mesibov, & Woods, 1997; Smith, Belcher, & Juhrs, 1995). It is clear that a considerable minority of individuals with ASD, although continuing to be affected by their condition, can find work, live independently and maintain relationships with others. However, such achievements do not come easily. While some individuals have access to specialist support systems, in many cases jobs are found only with the support of families, and opportunities to live independently depend heavily on local provision – and often too on parental determination and persistence. Differential Diagnosis In daily practice it is often not simple to distinguish autistic syndrome from other pervasive developmental disorders, developmental language disorder, intellectual impairment, sensory defects and severe emotional neglect. Each of these syndromes is briefly described below, and possible differential diagnostic characteristics mentioned. Atypical Autism/Pervasive Developmental Disorder Not Otherwise Specified These terms refer to non-specific patterns that seem to involve the same deficits as those associated with autism, although they do not fulfill all the accepted diagnostic criteria (Buitelaar, van der Gaag, Klin et al., 1999a). The atypicality may lie in the symptom pattern, its severity or age of first manifestation. Epidemiological analyses (Wing & Gould, 1979) and clinical investigations indicate the frequency of these atypical patterns but they have been subject to little systematic research. It is likely that they reflect variations in the ways in which ASD may present, rather than a separate category (Rapin, 1997; Wing, 1997). The service needs are similar to those for autism, and it remains unknown whether the apparent atypicality has any implications for etiology. Asperger Syndrome In the last two decades, the concept of Asperger syndrome as used by researchers (Frith, 1991; Gillberg, 1989; Klin, Volkmar, & Sparrow, 2000) and clinicians (Attwood, 1997; Wing, 1981) has served to highlight the occurrence of ASD in individuals who are intellectually able and verbally fluent (Grandin & Sciarino, 1986). It has not proved easy to produce satisfactory diagnostic criteria, and differences in both definition and sampling have led to conflicting findings (Green, Gilchrist, Burton, & Cox, 2000; Klin, Volkmar, & Sparrow, 2000; Szatmari, Bryson, Streiner et al., 2000). In keeping with the lack of language delay, the diagnosis tends to be made substantially later than in autism as such, and the diagnosis of Asperger syndrome tends to be associated with a higher verbal than non-verbal IQ (Klin, Volkmar, Sparrow, Cicchetti, & Rourke, 1995). It remains uncertain whether Asperger syndrome and autism differ in pattern of neuropsychological deficits (Ozonoff, Pennington, & Rogers, 1991a,b) and outcome (Howlin, 2003). Rett Syndrome Rett syndrome is a progressive developmental disorder that affects 1 in 10,000–15,000 girls (Kozinetz, Skender, MacNaughton et al., 1993) and is the only pervasive developmental disorder with a known genetic cause (see chapter 24). Rett syndrome is brought about by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2; Moretti & Zoghbi, 2006). It is characterized by a relatively normal general and psychomotor development through the first 6– 18 months of life, followed by stagnation of developmental acquisitions and a rapid deterioration of behavior and mental status, resulting in dementia with apparently autistic-like features within less than 18 months; loss of purposeful use of the hands following the earlier acquisition of normal grasp function; jerky ataxia of the trunk and limbs, awkward, unsteady gait and acquired microcephaly; followed by a protracted period with a relatively stable mental status, marked by the emergence over years of other neurological abnormalities – especially spasticity of the lower limbs and epilepsy (Hagberg, Aicardi, Dias, & Ramos, 1983). Because of its crucial prognostic significance, its diagnosis is most important. The acquired microcephaly (after a normal head circumference at birth), associated with the loss of purposive hand movement and often a midline “handwashing” stereotypy, may be most crucial. There are no specific treatments currently available, although recent animal studies suggest that, potentially, the neural degeneration might ultimately prove to be reversible (Guy, Gan, Selfridge, Cobb, & Bird, 2007). Childhood Disintegrative Disorder Childhood disintegrative disorder (previously termed Heller AUTISM SPECTRUM DISORDERS 763 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 763

syndrome) is a very rare disorder (prevalence rate 0.2 per 10,000; Fombonne, 2002) that manifests after an apparently normal development for the first 2 years of life. Receptive and expressive language functions are lost, and there is often a loss of coordination and the development of fecal and urine incontinence (Volkmar & Rutter, 1995). The child withdraws from social engagement and develops hand and finger stereotypies and simple rituals similar to those seen in autism. The deterioration continues for several months before reaching a plateau that is often difficult to distinguish from autism combined with intellectual impairment (Mouridsen, Rich, & Isager, 1999). In some cases the deterioration progresses and motor dysfunction, epileptic attacks and localized neurological deficits can occur (Corbett, Harris, Taylor, & Trible, 1977). While a very few cases of childhood disintegrative disorder are caused by cerebral lipoidosis or leukodystrophy, in most cases a cause cannot be established (see chapter 30). It remains quite unknown whether it constitutes an atypical variant of ASD or some meaningfully different syndrome. Receptive-Expressive Language Disorders Language delay is a common reason for initial referral of children with autistic disorder (Siegel, Pliner, Eschler, & Elliot, 1988); autistic spectrum disorders differ from the more common varieties of developmental language disorder in the severity of receptive language impairment (Fischel, Whitehurst, Caulfield, & DeBaryshe, 1989; Kjelgaard & Tager-Flusberg, 2001). There are non-autistic children of normal non-verbal intelligence who have a severe receptive-expressive language disorder (see chapter 47). Many have some symptoms that overlap with ASD, and some may fit descriptions of “semantic-pragmatic disorder” (Bishop, 1989; Boucher, 1998), meaning problems with the social communicative aspects of conversational interchange. These children with receptive-expressive language disorder may have immediate echolalia, substantial social impairment and limited imaginative play; in contrast to children with autism they seldom show stereotyped behavior or preoccupations and their non-verbal behavior (looking at people; facial expressions and gestures) is not really impaired. Landau–Kleffner Syndrome Landau–Kleffner syndrome or acquired aphasia with epilepsy (Miller, Campbell, Chapman, & Weismer, 1984; Mouridsen, 1995) may mimic autism, although the differentiation is usually straightforward. Children with this disorder have normal development and then lose receptive and expressive language in conjunction with epileptic seizures or transient electroencephalogram (EEG) abnormalities. The regression may be associated with some social withdrawal and behavioral abnormalities, while non-verbal cognitive and motor functioning remain intact. Sometimes language is regained. Intellectual Disability More than two-thirds of children with autism are also intellectually impaired. Wing and Gould (1979), studying children with an intellectual disability, found that half of all children with an IQ lower than 50 also had disturbances of social communication, stereotyped behavior and/or disorders of language development. These three symptoms are similar to the diagnostic core criteria of autism, and these children are usually classified as having PDD-NOS. In daily practice it is not always easy to determine whether a child has a “pure” intellectual disability or intellectual impairment that is part of ASD (see chapter 49). Sensory Deficits The parents of a child with autism often approach their general practitioner with the suspicion that their child is deaf, because the child does not react to his or her name or to doors slamming shut, etc. A careful history should clarify the situation, but this does not obviate the need to carry out auditory testing, if necessary supplemented with monitoring of brainstem-evoked responses. As babies, children with autism are often noticeable for not making eye contact – they stare into space or fixedly gaze at something, such as a lamp. This sometimes makes parents think that their child is blind. Extensive ophthalmological investigations may provide information regarding the differential diagnosis. Emotional Neglect Children who have experienced very severe institutional deprivation can show language delay, abnormal social behavior and marked circumscribed interests and preoccupations (Rutter, Anderson-Wood, Beckett et al., 1999). In early childhood the clinical picture is rather like autism, although there is usually more social reciprocity than typical with autism, and the course is different, so that by middle childhood it is social disinhibition and circumscribed interests that tend to predominate. Assessment Because no single symptom is pathognomonic for ASD, the essence of the diagnostic process is to recognize a particular pattern of social and communicative symptoms and of rigidity that was first manifest early in life, is rather stable over development and cannot better be attributed to other conditions. Assessment requires sufficient expertise with the wide range of expression of the symptoms of ASD by age and level of cognitive and language skills, and is best performed systematically and in a stepwise fashion. Extensive information about assessment of ASD can be found in recent practice parameters (American Academy of Pediatrics, 2000; Volkmar, Cook, Pomeroy, Realmuto, & Tanguay, 1999). The interview with the parents or caregivers should cover both the core features of ASD as well as comorbid symptoms such as aggression, tantrums, hyperactivity, inattention, impulsivity, sleep problems and self-injury. In older children and adolescents, it is often helpful to focus on age 4–5 years, when the expression of symptoms of ASD is most typical. Necessary components of the interview are a family history CHAPTER 46 764 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 764

with probes for ASD, intellectual disability, fragile X syndrome, tuberous sclerosis, and more subtle language, learning and communication problems (see chapter 22). The child’s medical history-taking should explore signs of deterioration, seizure activity, brain injury, gastrointestinal disease, pica and other medical conditions. The observation or interview of the child is best conducted in conditions of both high-structure and low-structure, and by using several strategies varying from direct and intrusive approach and probes for engagement to passive observation while the child wanders around or is with others. It allows the clinician to document behaviors reported in the interview and explore the responses of the child to intrusiveness and structure. Diagnostic Instruments Several standardized diagnostic instruments are available to facilitate the assessment of ASD. These instruments are commonly used in research and also increasingly in clinical practice. The Autism Diagnostic Interview–Revised (ADI-R) is a comprehensive diagnostic interview conducted by a trained clinical interviewer (Le Couteur, Lord, & Rutter, 2003; Rutter, Le Couteur, & Lord, 2003b). It focuses both on the period between 4 and 5 years of age and on current symptoms, encompasses 92 questions and takes about 120 min to administer. The ADI-R is reliable and valid, and has a scoring algorithm for DSM-IV and ICD-10 diagnoses of autism, but not for PDD-NOS or Asperger disorder. Less often used is the Diagnostic Interview for Social and Communicative Disorders (DISCO) which also provides a broad base of information on developmental and behavioral issues (Leekam, Libby, Wing, Gould, & Taylor, 2002; Wing, Leekam, Libby, Gould, & Larcombe, 2002). The Vineland Adaptive Behavior Scale is a semi-structured interview with parents or caregivers to measure functional ability in everyday life on three domains: communication, daily living and socialization (Sparrow, Balla, & Cicchetti, 1984). The interview has US norms for age and gender. Individuals with autism often have Vineland scores that are 2 standard deviations below their measured IQ. Rating scales that can be used to assess a broader spectrum of behavioral problems in ASD are the Aberrant Behavior Checklist (ABC; Aman, Singh, Stewart, & Field, 1985) and the Developmental Behavior Checklist (DBC; Einfeld & Tonge, 1995). Rating scales that have been developed to measure the core symptoms of autism but also more subtle manifestations that characterize subjects with the broad autism phenotype are the Social Responsiveness Scale (SRS; Constantino, Gruber, Davis et al., 2004) and the Child Social Behavior Questionnaire (CSBQ; Hartman, Luteijn, Serra, & Minderaa, 2006). A rating scale to be completed by parents, based on items from the ADI-R and developed to be used as a screening instrument, is the Social Communication Questionnaire (SCQ; Berument, Rutter, Lord, Pickles, & Bailey, 1999). The scale has good validity in differentiating ASD from non-ASD in children of 4 years and older, relatively independently from IQ, but has not been studied sufficiently below age 4 years. The most often used standardized observation schedule is the Autism Diagnostic Observation Schedule (ADOS; Lord, Rutter, DiLavore, & Risi, 2001). It is built on a series of structured and semi-structured scenarios for interaction with the child by a well-trained interviewer. The presentation of the modules varies according to the child’s verbal skills and the modules have been developed to optimally elicit the core symptoms of ASD. The ADOS takes about 40 min to administer, after which the scoring sheet should be completed. The selection of specific IQ tests depends on the chronological age, mental age, verbal skills and level of cooperation, and should be carried out by an experienced psychologist. The same applies to the selection of language tests. A summary of available tests can be found elsewhere (Howlin, 1998). A comprehensive physical examination is an indispensable component of the assessment. Particular attention should be paid to the presence of identifiable clinical syndromes, such as tuberous sclerosis (including the use of Wood’s light to assess any skin lesions) or neurofibromatosis, dysmorphic features and any localizing neurological impairments (see chapter 22). Most experts agree that there is no indication in the clinical setting for routine magnetic resonance imaging (MRI) of the brain or lumbar punctures or metabolic screens, except when neurological abnormalities or clear major regression are present (Filipek, Accardo, Ashwal et al., 2000). Given the increased rate of chromosomal anomalies in ASD, there is a need for routine DNA testing, including high-resolution chromosome testing, fluorescent in situ hybridization testing for Williams syndrome and subtelomeric deletions, and testing for the fragile X anomaly. There is a possibility that the premutation status (with an increase in trinucleotide repeats compared to the general population but below the full mutation expansion) has an increased risk for either ASD or other cognitive or behavioral problems (Hagerman, 2006). Lead levels should be obtained for children with developmental delays, even in the absence of a clear history of pica. About 30% of subjects with autism develop seizures, with a first manifestation either before age 5 years or in adolescence (Volkmar & Nelson, 1990). Sudden unexplained behavioral changes that are outside of the context of autistic symptoms should alert the clinician to this possibility. Assessment procedures that cannot be recommended as a routine are allergy testing, hair analysis, chelation challenge testing, gut permeability studies and stool analysis (Filipek, 2005). Early Detection Early identification of ASD is now considered to be clinical best practice, because it enables avoidance of unnecessary medical shopping for parents with clinical concerns, provides for early guidance and genetic counseling and starting early interventions (Charman & Baird, 2002; Rutter, 2006). A large proportion of subjects with ASD will nowadays be diagnosed around age 3–4 years, but somewhat later when early cognitive and language development are intact (Howlin & Moore, 1997). Systematic analysis of video home movies of children in the first 2 years of their life and later diagnosed with ASD has AUTISM SPECTRUM DISORDERS 765 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 765

shown that manifestation of ASD as early as 9–12 months may include difficulties orienting to social stimuli (e.g., less looking at people or faces and less responsiveness to name). This tends to be accompanied by less babbling, a limited understanding of spoken language and a paucity of gestures to express social interest or to draw attention to some object of interest in the environment (as distinct from gestures pointing to an object that the child wants). These difficulties tend to become more obvious in the second year of life, and extend to differences in joint attention and verbal communication. Prospective studies in high-risk siblings report consistent results (Zwaigenbaum, Bryson, Rogers et al., 2005). The frequent association with intellectual impairment makes the early differentiation between ASD and intellectual disability problematic, and only a reduced frequency of looking at people and responding to name appears to differentiate ASD. The discriminative value of other behaviors is less clear, such as increased frequency of unusual visual inspection of objects, abnormal sensory reactions, and decreased flexibility and variety of play (Swinkels, Dietz, van Daalen et al., 2006). In contrast to this early-onset type of autism, 20–40% of children with ASD manifest an early regression of language and behavior, most often between 18 and 24 months (Werner & Dawson, 2005). Although there is no accepted definition of regression, parents report loss of using words or phrases, together with the loss of sociability and loss of interest in playing with toys, and in some cases the appearance of stereotypies and rigid behavior patterns. Home movies have confirmed the reality of developmental regression and shown that children who regress in the second year of life nonetheless tend to show subtle pre-existent social and regulatory problems (Werner & Dawson, 2005). It is unknown whether early regression represents a specific genetic or neurobiological subtype of ASD. The clinical and prognostic meaning of early regression is also unclear. At this stage, the wide range of individual differences in both typical and atypical development in the first years of life makes effective screening for ASD below 18 months in normal populations not useful when parents have no clinical concerns (Dietz, Swinkels, van Daalen, van Engeland, & Buitelaar, 2006). Screening is possible and worthwhile after 18 months, particularly in cases of high-risk status or clinical concerns by parents or health care professionals, and is recommended as part of more comprehensive surveillance programs to identify children in need of further assessment. In addition to parental concerns about poor communication, socialization or other behavioral problems, absolute indications for further specialist referral are the absence of babbling by 12 months, the absence of gesturing (pointing, waving bye-bye, etc.) by 12 months, no single words by 16 months, no two-word spontaneous (not just echolalic) phrases by 24 months, and any loss of any language or social skills at any age (Filipek, Accardo, Baranek et al., 1999). A number of instruments are available to be used around 18–30 months such as the Checklist for Autism in Toddlers (CHAT; Baron-Cohen, Allen, & Gillberg, 1992, Baron-Cohen, Wheelwright, Cox et al., 2000), Modified Checklist for Autism in Toddlers (M-CHAT; Robins, Fein, Barton, & Green, 2001) and Early Screening for Autistic Traits (ESAT; Swinkels, Dietz, van Daalen et al., 2006). Cognitive Theories Cognitive models have been developed in an attempt to explain the heterogeneous clinical manifestations of ASD by a so-called core deficit (i.e., a basic impairment that is primary and underived from other cognitive factors in development, and underlies the clinical social symptoms). Mentalizing Ability The theory of mind hypothesis proposes that individuals with ASD have a fundamental problem in attributing mental states such as feelings, desires, intentions, fantasies, dreams and beliefs to others and oneself. This leads to “mind-blindness,” a failure to perceive others as social agents, and therefore results in deficient social, emotional and communicative actions and responses, and a failure of imagination. This hypothesis has stimulated a body of experimental psychological work in individuals with ASD that has revealed widespread problems in mentalizing and empathizing ability (Baron-Cohen, 1995; Baron-Cohen, Tager-Flusberg, & Cohen, 1993; Frith, 2003). The spin-off has also been studies into the neural substrate of mentalizing skills in normal subjects and in ASD (BaronCohen, Ring, Wheelwright et al., 1999; Castelli, Frith, Happe, & Frith, 2002). Important components of the so-called “social brain” are the amygdala, the orbitrofrontal and medial frontal cortex, and the superior temporal sulcus and gyrus in these regions have shown abnormalities in autism. However, there are several arguments against a core deficit in theory of mind in autism. Social dysfunction in autism is typically present prior to the time at which even the earliest precursors of a theory of mind emerge (Klin, Volkmar, & Sparrow, 1992). The theory of mind hypothesis is less able to explain the lack of spontaneous and original activity of persons with autism, their repetitive behavior, their impairment in understanding conversation (Yirmiya, Sigman, Kasari, & Mundy, 1992) and their executive dysfunctioning (Hughes, Russell, & Robbins, 1994). Impairments in theory of mind do not seem to be specific, nor are they universally present in ASD (Buitelaar, van der Wees, Swaab Barneveld, & van der Gaag, 1999b). Relatively able individuals with ASD, such as those with Asperger disorder, can solve theory of mind problems, albeit often by idiosyncratic and alternative strategies, and still present with major social handicaps in everyday life (Bowler, 1992; Ozonoff & McEvoy, 1994; Ziatas, Durkin, & Pratt, 1998). The mentalizing account of ASD was later extended to the empathizing–systemizing (E-S) theory (Baron-Cohen, 2002). In addition to weak mentalizing–empathizing skills, systemizing is either intact or superior. Systemizing is the drive to analyze systems in terms of their underlying rules and regularities. Good systemizing skills would explain islets of abilities, the content CHAPTER 46 766 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 766

of obsessional symptoms and repetitive behavior. Such predictions have yet to be adequately tested. Central Coherence Theory The central coherence theory originally suggested that a core deficit in processing information for meaning and for global (gestalt) form would explain the social symptoms in ASD (Frith, 1991). Weak central coherence, with an undue focus on details, would lead to a disregard to contextual issues, and to fragmented perceptions of the external world. This was illustrated remarkably well by performances on the Block Design test of the Wechler’s Intelligence Scales and on the Embedded Figures test. Both tests require “field independence,” that is, the ability to disregard context (Frith & Happé, 1994). However, later work has challenged this view in the following ways (for review see Happé & Frith, 2006). Weak global extraction of information may be the result of a superior performance in local processing of details, rather than vice versa. Further, many individuals with ASD seem able to pay sufficient attention to global information when specifically directed to do so. This means that the strong preference for local detailed information is a cognitive style or processing bias rather than a cognitive deficit. Weak central coherence characterizes a subsample of the ASD population and seems to be an aspect of their cognitive set-up of ASD, but does not serve as the all-explaining core deficit. Executive Functioning Executive functions (EFs) are mental control processes that enable the self-control necessary for the attainment of a future goal (Pennington & Ozonoff, 1996). EF refers to cognitive functions mediated by the prefrontal cortex (Fuster, 1997), such as inhibition, working memory, cognitive flexibility or set-shifting, planning and verbal fluency (Pennington & Ozonoff, 1996). The EF account of ASD assumes that the weak performance of one or more of these cognitive functions (poor attentional regulation, inability to shift attention) on the basis of some form of neurological abnormality of the prefrontal cortex, leads to the perseverative inflexible problem-solving strategies commonly observed in ASD and ultimately to the other social and communicative symptoms. Multiple studies have identified EF deficits in preschoolers, children and adolescents as well as adults with autism (Geurts, Verte, Oosterlaan, Roeyers, & Sergeant, 2004; Williams, Goldstein, Carpenter, & Minshew, 2005), although inconsistent findings have also been reported (Griffith, Pennington, Wehner, & Rogers, 1999; Ozonoff & Strayer, 1997; Russell, Jarrold, & Hood, 1999). However, it would be simplistic to assume that autism can be explained by poor EF, because: 1 Poor EF is also found in other disorders such as ADHD, although EF deficits were much more widespread in ASD than in ADHD in a direct comparison (Geurts, Verte, Oosterlaan et al., 2004); 2 EF deficits are not always seen in ASD; 3 Children with early frontal lesions do not all appear to be autistic (Ozonoff, Pennington, & Rogers, 1991a,b); and 4 The correlation between EF deficits and social impairment is not very strong (Dawson & Osterling, 1997). Treatment The main aims of the treatment of ASD are (Rutter, 1985): 1 As much as possible to facilitate and stimulate the normal development of cognition, language and socialization; 2 To decrease autism-bound maladaptive behaviors such as rigidity, stereotypy, and inflexibility; 3 To reduce or even eliminate non-specific maladaptive behaviors such as hyperactivity, irritability and impulsivity; and 4 To alleviate stress and burden for the family. Further information about treatment of ASD is available in recent US practice parameters (American Academy of Pediatrics, 2000; Volkmar, Cook, Pomeroy et al., 1999). The treatment of individuals with ASD should be multimodal, with a combination of family counseling, structured and special educational techniques, individual behavior modification, home training, and placement in special schools or daycare centers. So far, ASD are chronically disabling conditions for which no effective evidence-based cure exists. This does not detract from the great benefits that can be brought by a comprehensive and intensive treatment plan to patients and their families in terms of improvement in quality of life. Recent research suggests that the most effective results stem from early intensive behavioral interventions. Medication treatment has not been shown to influence the core symptoms of ASD, but may be considered when troublesome target and comorbid symptoms such as aggression, temper tantrums, irritability, hyperactivity, self-injurious behavior, rigidity, anxiety and sleeping problems do not respond to behavioral interventions or seriously interfere with the application of these interventions. There are some general principles of treatment of ASD that are important. Individuals with ASD reach a higher level of social functioning in highly structured than in unstructured situations. For example, the daily routines of a classroom provide structure, whereas anxiety, social isolation and rigidities may emerge rapidly during free time and lunch breaks. In relation to this, the social functioning of those with ASD is usually better in an environment with moderate levels of expression of emotions and symbolic meanings. For example, the difficulty for individuals with ASD to grasp the symbolic meaning of special events and ceremonies such as a birthday party or Christmas can easily make them anxious or lead to aggressive reactions when pushed too much. The intensity of social stimulation offered should be adjusted to the level that can be handled. When a child has reached an equilibrium in interacting with one or two other children as buddies at school, this should first be consolidated before other classmates are to be involved. Every treatment plan should accommodate for the often profound limitations in communication of individuals with ASD. This could be addressed by some form of speech and language therapy, and for very young or nonverbal subjects by the Picture Exchange Communication System AUTISM SPECTRUM DISORDERS 767 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 767

(Bondy & Frost, 1998, 2001), Social Stories, which is the use of cartoon-type illustrations to help children understand how to respond in social situations, or peer-mediated intervention (Roeyers, 1996). Training and interventions should be performed as much as possible in daily-life situations, in an attempt to overcome the problems of the transfer of skills mastered in one setting to another. Counseling for Parents and Family Support It is very important to inform parents about the diagnosis and implications for the future of the child. Parents may have difficulty in accepting the diagnosis. Once a family has a child with ASD, the risk of recurrence of ASD in subsequent children rises to 3–7%. Therefore, parents need appropriate counseling on genetic issues. During the different stages of development, the child and parents have different needs. For example, placement in a school that provides a specialized education can be enough for the first years, but when behavior management problems occur, more intensive counseling, behavioral therapy and/or medication may be an option. In some countries, patients and their families are organized into National Autistic Societies which hold information evenings where parents can meet each other and where “non-professional” support is given. Most parents benefit from training courses aimed at skills building and reduction of problematic behavior. In adolescence, attention should be paid to sexuality issues that may be relevant to ASD – such as masturbation, inappropriate touching, privacy issues and public exposure. Early Intervention There are great expectations in the field from the benefits of intensive early interventions for children with ASD (Butter, Wynn, & Mulick, 2003). Typically, these interventions would be started shortly after diagnosis and continued up to kindergarten or primary school, depending on the child’s progress and areas of handicap. Work on early intensive treatment has started with claims about significant gains in IQ and outcome in a sample of 19 young autistic children (Lovaas, 1987). However, this promising result and that of a related study (McEachin, Smith, & Lovaas, 1993) have been questioned because of methodological problems (Campbell, Schopler, Cueva, & Hallin, 1996). There are now a number of positive studies of intensive early intervention which indicate that a subsample of children with ASD make considerable progress and nearly all children show some benefits (Medical Research Council, 2001; National Research Council, 2001). However, observations also indicate that some young children with ASD improve rapidly with relatively little intervention, and others show very little progress despite very intensive and comprehensive multimodal treatments. It is claimed that effective early interventions include the following important components (Kabot, Masi, & Segal, 2003): 1 Provision at the earliest possible age; 2 High intensity, with the suggestion of a threshold of at least 20 h per week spent one-to-one with the child; 3 Strongly based on parent involvement, training and support; 4 Various modules and training schemes to stimulate social and communicative functioning of the child in a developmentally oriented way; 5 Systematic instruction with individual goals, based on applied-behavioral analysis (ABA) and stepwise approach; and 6 Investment in attempts to generalize acquired skills to other settings of daily life. Further research is needed to test these claims. Education Opportunities for adequate education are essential, as followup studies have indicated that children who complete some form of education have a better outcome (van der Gaag, 1993). It is necessary for the teacher to be informed about the nature of autism and the child’s needs. An autistic child at school needs extra individual attention, a very structured approach and special education programs, such as the Treatment and Education of Autistic and related Communication-handicapped CHildren program (TEACCH; Mesibov, Shea, & Schopler, 2004). This program emphasizes extensive collaboration with and training of the parents, so that they become knowledgeable about their child’s disorder and needs. This program provides a highly structured approach for autistic children at school. Based on principles from cognitive–behavioral theory, a system is developed with stepwise visualization of the actions needed to fulfill a task. Through this system the life-environment can be structured, and parents can act as co-therapists and continue with the principles of TEACCH at home. Skills Training and Behavioral Therapy Depending on clinical needs, a number of specific treatment modalities may be helpful. In cases of clumsiness or delays in motor development, there is an indication for sensorimotor training. Language and communication skills can be facilitated by means of language training. Occupational therapy and play therapy may be of use in some cases. For high-functioning autistic children, individual therapy can be an option, for instance when the child is suffering from the awareness of being different. Social skills training programs, delivered on an individual or on a group basis, are being offered to children and adolescents with ASD at an increasing rate (Bauminger, 2002; Koegel & Frea, 1993). Recently, social skills training programs have been nurtured with ideas from research on theory of mind and emotion recognition deficits in autism (Howlin, BaronCohen, & Hadwin, 1999). Although the benefits may be an improvement of social awareness and the acquisition of routine social skills, the merits on a long-term basis are often disappointing because of a lack of generalization of skills. Behavioral treatment based on classic and operant conditioning is the most studied and publicized form of non-medical treatment. There is a clear indication for specific behavioral interventions in cases of severely interfering and maladaptive behaviors such as stereotypies, self-injury and negativism. Also, the acquisition of normal behaviors, such as toileting, may benefit from behavioral interventions. These interventions should be based on a detailed analysis of the functional CHAPTER 46 768 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 768

relationship between the child and the environment (Campbell, Schopler, Cueva et al., 1996), which can then give rise to an individual treatment plan designed for the child. Vocational Training ASD are lifelong disorders that impact on the ability of individuals to obtain employment, care for themselves and live independently. As a result, many individuals with autism require some form of community support. Projects have been established that involve autistic people living with more or less intensive supervision by a professional. Specialist-supported employment services have been designed for high-ability adults with autism; approximately 68% of clients found employment (Howlin, Alcock, & Burkin, 2005; Mawhood & Howlin, 1999). Medication There is no drug that has been shown to have a consistent and worthwhile effect on the core symptoms of autism. Accordingly, treatment plans should not involve any presupposition that medication should be used. Nevertheless, drugs can be useful in modifying some specific behaviors and hence we review the findings accordingly. When using medication, it is important to select appropriate targets of treatment and to monitor efficacy and side effects on a regular basis. Potential benefits of any medication should be weighed against side effects and risks. Concern over side effects such as tardive dyskinesia and extrapyramidal symptoms (EPS) of conventional antipsychotics has led to increased use of the newer atypical antipsychotics. Risperidone, the best studied and most often used atypical antipsychotic, has shown superiority to placebo in short-term randomized controlled trials in children and adolescents with ASD (McCracken, McGough, Shah et al., 2002; Shea, Turgay, Carroll et al., 2004) and in adults (McDougle, Holmes, Carlson et al., 1998). Maintenance of effect of risperidone over a period of 6 months has been established in placebo-controlled discontinuation studies (RUPP, 2005b; Troost, Lahuis, Steenhuis et al., 2005). Risperidone in low daily doses (0.5–1.5 mg for most subjects) appears to be effective in decreasing irritability, temper tantrums, hyperactivity, aggression and self-injurious behavior in ASD, but without convincing positive effects on the core symptoms. Although risperidone is usually well tolerated, except for mild initial sedation, and the risk of EPS is low, a serious limitation of the use of risperidone is the risk of significant weight gain. Weight gain should be monitored each week, and an increase of 3 kg or more in the first month of treatment should lead to discontinuation. Less well studied in ASD are other atypical antipsychotics such as olanzapine, quetiapine, ziprasidone and aripiprazole. Fluoxetine treatment has been studied in children and adults with ASD and was shown to be effective in reducing compulsive and repetitive behaviors, stereotypies and rituals (DeLong, Teague, & McSwain, 1998; Hollander, Phillips, Chaplin et al., 2005). Fluoxetine was generally well tolerated; adverse effects included agitation, hyperactivity, hypomania and disinhibition. Similar treatment effects were obtained with fluvoxamine in a controlled trial in adults with autism (McDougle, Naylor, Cohen et al., 1996b). However, a trial with fluvoxamine in children and adolescents with autism was unable to establish a significant treatment response but documented a high rate of side effects and adverse behavioral activation (McDougle, personal communication). A recent large controlled trial with methylphenidate in children with ASD and symptoms of ADHD found that the clinical response was lower and that the risk for adverse effects such as irritability was increased, compared to that in children with typical ADHD. When using low dosages (0.125–0.5 mg·kg−1 per day) and careful clinical monitoring, treatment with stimulants none the less may be of substantial clinical value in individuals with ASD and symptoms of ADHD (RUPP, 2005a). Mood stabilizers such as lithium and valproic acid have been used to treat affective instability, impulsivity and aggression in individuals with ASD (Hollander, Dolgoff-Kaspar, Cartwright, Rawitt, & Novotny, 2001; Kerbeshian, Burd, & Fisher, 1987; Plioplys, 1994). Anticonvulsants are important in the management of the seizure disorders in ASD. Buspirone, an agonist of the serotonin 5T1a receptor, may be useful in improving anxiety, temper tantrums, and aggression associated with ASD in regimens of 10–45 mg·day−1 (Buitelaar, van der Gaag, & van der Hoeven, 1998). Propranolol, a lipophilic beta-blocker, may be used to treat aggression, self-injury and impulsivity in developmental disorders (Ratey, Bemporad, Sorgi et al., 1987a; Ratey, Mikkelsen, Sorgi et al., 1987b). It is necessary to obtain an electrocardiogram (ECG) before treatment starts and to monitor pulse rate and blood pressure regularly because of the risk of bradycardia and hypotension. Ineffective or Unproven Treatments Probably more often than in any other psychiatric condition of childhood and adolescence, parents of children with ASD tend to seek out complementary and alternative medical (CAM) treatments both for the core symptoms and for comorbid symptoms (Levy & Hyman, 2003). It is important to respect parents’ views, critically discuss the merits and risk–benefit ratio of these treatments and advise the family on treatments with and without supporting evidence, and for families choosing CAM treatments, assisting to determine if the treatment is helpful by gathering clinical outcome data (Aman, 2005). Among the ineffective or unproven treatments are facilitated communication, administration of secretin (a gastrointestinal peptide hormone with putative effects on the brain), auditory integration training, treatment with vitamin B6 and magnesium, gluten- and casein-free diets, essential fatty acid treatment, Son-Rise Program and cranial osteopathy (Aman, 2005; Howlin, 2005). Etiology Environmental Risk Factors Although the high heritability of ASD might seem to imply that environmental risk factors will be unimportant, this does AUTISM SPECTRUM DISORDERS 769 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 769

not necessarily follow (Rutter, 2006; Rutter, Moffitt, & Caspi, 2006). If the rise in the rate of diagnosed ASD represents a true rise in incidence (which remains quite uncertain), there would be the implication that some new (or increased) environmental risk factor was operative. If so, it is likely that the risks would stem from some prenatal or early postnatal factor, most likely of a physical nature. The large-scale Norwegian prospective longitudinal study of a cohort of some 100,000 being followed from pregnancy provides the possibility of identifying any such risks (Magnus, Irgens, Haug et al., 2006; Rønningen, Paltiel, Meltzer et al., 2006). They could be in toxins, pollutants, diet or immunological abnormalities. An area of uncertainty includes the possibility of abnormalities in the immune system in ASD. Studies of immunological function reveal a wide range of abnormalities, including decreased cellular immune capacity, decreased plasma complement component C4b, and increased humoral immune and autoantibody responses (Hornig & Lipkin, 2001). These abnormalities of the peripheral immune system have been linked to the hypothesis that children with ASD are predisposed to abnormal responses to viral infections either through the establishment of persistent infections or a virally triggered autoimmune diathesis. However, immune dysfunction in ASD has not been established or corroborated by measures more directly related to the brain, such as by studies of cerebrospinal fluid (CSF) or at autopsy. Thus, it is unclear whether systemic immune dysfunction is truly common in ASD (Murch, 2005). With respect to possible environmental risk factors, it will also be necessary to consider the possible role of gene–environment interaction (Hornig, Chian, & Lipkin, 2004; Rutter, 2006; Rutter, Moffitt, & Caspi, 2006). There is a long-standing interest in obstetric risk factors, and recent studies have confirmed that individuals with autism have more obstetric risk factors than controls, as evidenced, for example, by the presence of fetal distress, being delivered by elective or emergency Cesarean section, more frequent breech presentations, and lower Apgar scores at 1 or 5 min (Glasson, Bower, Petterson et al., 2004; Larsson, Eaton, Madsen et al., 2005). Cases with PDD-NOS or Asperger disorder had lower risk scores than subjects with typical autism, and higher than controls (Glasson, Bower, Petterson et al., 2004). However, because unaffected siblings of cases were more similar to cases than to control subjects in their profile of complications, the higher rate of obstetric complications may reflect underlying genetic vulnerability or an interaction between genetic factors and the environment. Other data support the view that obstetric hazards are, at least in part, consequences of genetically influenced abnormal prenatal development rather than independent etiological factors (Bolton, Murphy, Macdonald et al., 1997). For example, postmortem studies of autism have not detected lesions typical of perinatal brain damage, and studies of autistic singletons have found that the number of minor congenital anomalies is higher in probands than in siblings or normal controls, which suggests that the early in utero development of autistic individuals may be suboptimal (Bailey, Phillips, & Rutter, 1996). CHAPTER 46 770 Developmental Perturbations Traditionally, studies of non-genetic influences on causal pathways for disorders have focused on specific environmental hazards of some kind. However, as Molenaar, Boomsma, and Dolan (1993) pointed out, it is also necessary to consider the possibility of chance causing developmental perturbations that increase the risk of some maladaptive outcomes. Three sets of findings suggest that such perturbations may contribute to the liability to autism. First, surveys indicate that 5–10% of individuals with ASD have some form of chromosomal anomaly (Autism Genome Project Consortium, 2007). However, apart from duplications of 15q11–q13, typically of maternal origin (which occur in 1–3% of cases), the anomalies span virtually all chromosomes and offer no good leads for the location of susceptibility genes. Nevertheless, the raised rate of anomalies relative to the general population does suggest some type of developmental perturbation. Perhaps the significant feature lies in the suggestion that development has gone awry, rather than the specific form of the anomaly. The parallel would be in the increased rate of minor congenital anomalies associated with an increased risk for many types of psychopathology. Second, the large-scale Autism Genome Project Consortium (2007) study found an increased rate of copy number abnormalities (CNAs) – such as exemplified by the chromosome 15 duplication. For a variety of conceptual and technical reasons, it is difficult to provide a confident quantitative estimate of their frequency, but a figure of about 10% seems likely for families in which all affected individuals share the same possibly detrimental abnormality. Third, a recent large-scale study of Israeli army conscripts found an association between autism and raised paternal age (Reichenberg, Gross, Weiser et al., 2006). The finding has yet to be replicated, but it too suggests that a focus on developmental perturbations might prove profitable. Neural Basis of Autism The last decade has seen an enormous proliferation of studies seeking to identify the neural basis of autism (for reviews see DiCicco-Bloom, Lord, Zwaigenbaum et al., 2006; Moldin & Rubenstein, 2006; Moldin, Rubenstein, & Hyman, 2006). Attention has been drawn to the possible role of mirror neuron dysfunction because these neurons respond to perceived mental states (Dapretto, Davies, Pfeifer et al., 2006). A range of animal models has been proposed but, at least so far, their relevance to autism seems quite uncertain. Thus, there was excitement over the social differences between montane and prairie moles, with findings pointing to the role of oxytocin and vasopressin (Young & Wang, 2004) but knockout mice display social amnesia, which is not what is found in autism. Numerous leads are worth following up but they have yet to deliver; accordingly, we focus primarily on human studies. Head Circumference One of the most consistent anatomical findings in autism research is an enlarged head circumference (Bailey, Phillips, & Rutter, 1996; DiCicco-Bloom, Lord, Zwaigenbaum et al., 2006; 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 770

Fombonne, Rogé, Claverie, Courty, & Frémolle, 1999). Brain size is approximately normal at birth but increases in the preschool years so that by 3–4 years of age, the average brain size in individuals with autism in increased by about 10%. The evidence with respect to older ages is more limited but it seems that brain size remains increased to some extent (Palmen, Hulshoff Pol, Kemner et al., 2005) but probably to a lesser degree. The available evidence suggests that the increased brain growth affects both gray and white matter, but the findings are inconsistent and inconclusive (Palmen, Hulshoff Pol, Kemner et al., 2005). Whether or not it reflects an excess of neurons, and/or reduced synaptic pruning, remains uncertain (Keller & Persico, 2003). It also remains uncertain how far the macrocephaly is proportionate or disproportionate to overall body growth (Torrey, Dhavale, Lawlor, & Yolken, 2004). Accordingly, it remains unclear what role the increased rate of brain growth in early life plays in the pathogenesis of autism. Neuroimaging Structural neuroimaging studies in individuals with autism converge to show that the brain is abnormally large in some, but not all children with autism (Lainhart, 2006; Palmen & van Engeland, 2004). Advances in structural brain mapping have been used to investigate morphological connectivity. Structures in the brain whose functions are tightly coupled grow and develop in unison. Children with autism show evidence of marked disruption in relationships between cortical–subcortical and cortical–cortical gray matter volumes (McAlonan, Cheung, Cheung et al., 2005). Correlations between frontal lobe gray matter volume and temporal lobe, parietal lobe and subcortical gray matter have been found to be aberrant in autistic children. Functional MRI (fMRI) studies examine functional connectivity in the brain by measuring the correlation between the amount of activation of two brain areas during task performance measuring social attribution, sentence comprehension and working memory (Castelli, Frith, Happe et al., 2002; Just, Cherkassky, Keller, & Minshew, 2004; Koshino, Carpenter, Minshew et al., 2005). Aberrant or reduced connectivity patterns have been found. Other fMRI studies of brain function during tasks or in response to visual and auditory stimuli show evidence that individuals with autism appear to be using different cognitive strategies and some different brain areas to process information (Gervais, Belin, Boddaert et al., 2004; Hadjiklani, Joseph, Snyder et al., 2004; Muller, Kleinhans, Kemnotsu, Pierce, & Courchesne, 2003; Pierce, Haist, Sedaghar, & Courchesne, 2004; Piggot, Kwon, Mobbs et al., 2004; Schultz, Gauthier, Klein et al., 2000; Wang, Ting, Dapretto et al., 2004; Williams, Goldstein, Carpenter et al., 2005). Neuropathology A review of postmortem studies in autism revealed that approximately 40 brains have been studied (Palmen & van Engeland, 2004) with an emerging pattern of increased cell packing in the limbic system, reduced numbers of Purkinje cells in the cerebellum, age-related changes in cerebellar nuclei and inferior olives, cortical dysgenesis and increased brain weight. However, all reported studies had to contend with the problem of small sample sizes, the use of quantification techniques not free of bias and assumptions, and high percentages of autistic subjects with co-occurring intellectual impairment and epilepsy (at least 70% and 40%, respectively). Cortical minicolumns have been measured in postmortem brains of autistic persons and compared with non-affected controls. Minicolumns consist of approximately 80–100 neurons arranged radially like beads on a string and are believed to comprise the smallest level of functional organization in the cortex cerebri (Mountcastle, 1997). Minicolumnar width, interneuronal distance, peripheral neuropil space and compactness were evaluated and it was found that minicolumns in the brains of autistic persons were more numerous, “narrower” with less peripheral neuropil space and increased spacing among the constituent cells (Casanova, 2004; Casanova, Buxhoeveden, Switala et al., 2002; Casanova, van Kooten, Switala et al., 2006). The authors conjecture that these micro-architectural abnormalities originate during prenatal development and reflect progressive encephalization, defined as a disproportionate increase in white matter relative to gray matter. Neurophysiology Along with epilepsy (Rutter, 1970), one of the first indications of abnormal brain function in autism came from EEG studies. With repeated or extensive testing, EEG abnormalities are found in about 50% of individuals with autism (Minshew, 1991). Although regional differences in EEG power have been reported, there is no evidence of regional localization of abnormalities (Dawson & Osterling, 1997). For many years event-related potentials (ERPs) were the only means available to investigate brain function during specific cognitive tasks (Burack, Enns, Stauder, Mottron, & Randolphe, 1997). Event-related evoked potentials and magnetoelectro-encephalography provide information about temporal and spatial aspects of brain functioning in autism. Studies using these methods show that individuals with autism have slowed face processing, decreased sensitivity to whether a face is upright or inverted, less effect to repeated presentation of a face, abnormal brain response to eye-gaze detection, abnormal hemispheric lateralization and different localization of processing within the cortex (Bailey, Braeutigam, Jousmäki, & Swithenby, 2005; Grice, Halit, Farroni et al., 2005; McPartland, Dawson, Webb, Panagiotides, & Carver, 2004). Behavioral studies have shown subjects with ASD to have a variety of abnormalities in attentional processing (Allen & Courchesne, 2001). Several ERP studies focused on attentional and perceptual processing of visual stimuli in persons with autism. Although some studies reported that subjects with ASD show less long-latency activity (mostly reflected in P3 peak) in response to infrequently occurring stimuli within an oddball paradigm, these findings are not consistent (Kemner & van Engeland, 2006). A serious problem in the interpretation of these studies is that subjects were not matched for IQ and age, and there is evidence that the P3 peak is sensitive to these AUTISM SPECTRUM DISORDERS 771 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 771

variables (Polich & Herbst, 2000; Wahlovd & Fjell, 2003). The only study in which subjects were age and IQ matched (Kemner, Verbaten, Cuperus, Camfferman, & van Engeland, 2004) did not find differences between persons with autism and control groups in this respect. Additionally, there are no indications that individuals with autism have a decreased processing capacity (Hoeksma, Kenemans, Kemner, & van Engeland, 2005). ERP studies of the ability to focus attention on a specific channel of information (selective attention) failed to find consistent evidence of abnormal attentional processing in subjects with autism (Ciesielski, Courchesne, & Elmasian, 1990; Hoeksma, Kenemans, Kemner et al., 2005). Recently, several studies have indicated that the atypical processing of visual stimuli in autistic children and adolescents might occur at a perceptual level, because ERP studies have provided evidence that activity over the modality-specific cortex is already abnormal at an early stage of processing (Boeschoten, Kemner, Kenemans, & van Engeland, 2007; Hoeksma, Kenemans, Kemner et al., 2005; Kemner, Verbaten, Cuperus et al., 2004; Verbaten, Roelofs, van Engeland, Kenemans, & Slangen, 1991). The authors conjecture that this abnormal brain activation might be related to the spatial frequency content of the visual stimuli and a decreased specialization of the visual brain pathways for spatial frequency processing (Kemner & van Engeland, 2006). Other studies have examined the processing of auditory stimuli in autism. These studies found evidence that children with autism have neural-based impairments in automatically orienting to speech-like sounds but not to non-speech sounds (Ceponiene, Lepistö, Shestakova et al., 2003). Adults with autism may have impairments in one of the earliest levels of cortical speech processing, automatic detection of change in speech (Kasai, Hashimoto, Kawakubo et al., 2005). In noisy environments, individuals with autism appear to have neuralbased deficits in recognizing and understanding speech and attending to socially relevant sounds (Alcantara, Weisblatt, Moore, & Bolton, 2004; Teder-Salajarri, Pierce, Courchesne, & Hillyard, 2005). Involuntary orienting to sound depends on neural communication in a widely distributed network, involving auditory cortex, multimodal sensory areas in the parietal lobe, and dorsolateral prefrontal cortex. Neurochemistry The most robust and well-replicated biological finding is the 25–50% increase in levels of serotonin in blood platelets in subjects with autism (for reviews see Lam, Aman, & Arnold, 2006; McDougle, Erickson, Stigler, & Posey, 2005) and the broader phenotype (Mulder, Anderson, Kema et al., 2004). The mechanism of the alteration remains unknown. Additional factors that may determine serotonin levels in blood are pubertal status, race and use of medication (McBride, Anderson, Hertzig et al., 1998). Abnormalities of central rather than peripheral serotonin systems matter when considering the pathophysiology of ASD. Acute depletion of dietary tryptophan (the dietary precursor of serotonin) leads to a forced lowering of serotonin in the brain and worsening of autistic symptomatology (McDougle, Naylor, Cohen et al., 1996a; McDougle, Naylor, Cohen et al., 1996b), underlining the role of central serotonin in the expression of the syndrome. Further, positron emission tomography (PET) using a tracer for the synthesis of serotonin in the brain found indications for an abnormal serotonin synthesis capacity over time in autism (Chugani, Muzik, Rothermel et al., 1997). Because serotonin acts as a growth factor and regulator of early neuronal development before assuming its role as a neurotransmitter in the mature brain, this suggests that developmental dysregulation of serotonin synthesis may be involved in the pathogenesis of ASD (Whitaker-Azimitia, 2001). Research into the dopamine neurotransmitter system by measuring levels of dopamine’s major metabolite homovanillic acid (HVA) in blood, urine and CSF did not reveal significant differences (McDougle , Erickson, Stigler et al., 2005). A PET scan study showed reduced accumulation of dopamine in the prefrontal cortex of subjects with autism (Ernst, Zametkin, Matochik, Pascualvaca, & Cohen, 1997). There are no notable abnormalities in neurochemical indices of the norepinephrine transmitter system in ASD. Little research has been performed examining the role of glutamate and gamma-aminobutyric acid (GABA) in ASD. Glutamate is the primary excitatory transmitter and is crucially involved in neuronal plasticity and higher cognitive functions (Purcell, Jeon, Zimmerman, Blue, & Pevsner, 2001), whereas GABA is the primary inhibitory transmitter in the brain. Measuring peripheral levels of these transmitters has produced conflicting findings, but postmortem studies found indirect evidence for altered status of glutamate and GABA receptors in the hippocampus (Fatemi, Halt, Stary et al., 2002). Animal work has led to interest in the role of neuropeptides such as endogenous opioids, oxytocin and vasopressin in regulating social behavior. Nevertheless, neither evaluations of levels of opioids in body fluids nor clinical trials investigating the effects of opioid receptor antagonists lend support for a key role of opioids in the pathophysiology of ASD (Tordjman, Anderson, McBride et al., 1997; WillemsenSwinkels, Buitelaar, Nijhof, & van Engeland, 1995). Children with autism were shown to have lower plasma levels of oxytocin (Green, Fein, Modahl et al., 2001) but intravenous administration of oxytocin did not lead to changes in the core symptoms of ASD (Hollander, Novotny, Hanratty et al., 2003). Research on melatonin and secretin does not support a role of these neuropeptides in the pathophysiology of ASD (Esch & Carr, 2004; Nir, Meir, Zilber et al., 1995). Findings of early abnormalities in the development of the brain in ASD, and a potential contribution therein of neuropeptides and/or neurotrophins, led to an analysis of peptide concentrations in frozen blood samples of neonates subsequently diagnosed with ASD and contrast and control samples (Nelson, Grether, Croen et al., 2001; Nelson, Kuddo, Song et al., 2006). Concentrations of some neurotrophic factors were higher in subjects with ASD and with intellectual disability but they did not differentiate these two groups; these results await replication and extension. CHAPTER 46 772 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 772

Genetics Data from several epidemiological twin and family studies provide substantial evidence that ASD are amongst the most heritable complex disorders (Rutter, 2000). The concordance rate in monozygotic (MZ) twins is 60–90% and the autism rate in siblings is about 5% (Bailey, Palferman, Heavey et al., 1998b; Szatmari, Jones, Zwaigenbaum, & MacLean, 1998). Folstein and Rutter’s (1977) twin study was remarkable for indicating that the phenotype associated with a genetic predisposition to autistic disorder included cognitive and social difficulties extending beyond autism as traditionally diagnosed. In a follow-up into adulthood of this original sample, the majority of non-autistic MZ cotwins showed social and/or cognitive abnormalities, with the most severely affected individuals having more well-defined ASD (Bailey, Le Couteur, Gottesman et al., 1995). A parallel family history study found similar social and/or cognitive abnormalities at a higher rate in relatives of probands with autism compared to relatives of probands with Down syndrome (Bolton, Macdonald, Pickles et al., 1994). In fact, individuals with autism represented only a small proportion of all the individuals showing phenotypic expression. Since then numerous family studies have reported mild autism-related behavioral phenotypes manifesting as social, communicative and repetitive impairments, either alone or in combination in first-, second- or third-degree family members of autistic probands (for a review Bailey, Palferman, Heavey et al., 1998b). Some relatives of autistic individuals show a lack of interest in others, or a lack of socioemotional responsiveness, whereas others may show socially odd behavior, a history of language delay, circumscribed interests, rigidity, obsessive-compulsive and repetitive behavior and a lack of seeking change (Bailey, Palferman, Heavey et al., 1998b; Lainhart, 1999; Piven, Palmer, Jacobi, Childress, & Arndt, 1997; Starr, Berument, Pickles et al., 2001). It is estimated that this “broader phenotype” or “milder variant” can be found in 20–30% of the relatives of autistic individuals (de Jonge, 2006; Fombonne, Bolton, Prior, Jordan, & Rutter, 1997). The highest rates of “broader phenotype” characteristics were found in multi-incidence families (Lainhart, 1999; Piven, Palmer, Jacobi et al., 1997; Szatmari, Bryson, Streiner et al., 2000). Clearly, genetic risk ASD is not conferred in a simple Mendelian fashion. Statistical modeling of the data derived from twin and family studies has implicated the involvement of several genes interacting with one another to produce the clinical phenotype that is a multilocal model with epistasis. Latent class analysis of twin and family data has suggested that as few as 3–4 predisposing genes may be involved (Pickles, Bolton, Macdonald et al., 1995), although the presence of as many as 15 loci has been proposed (Risch, 1999). The clinical complexity and heterogeneity of the autism phenotype are also likely to reflect the presence of genetic heterogeneity (different genes or combination of genes may be involved in different families). Other factors, such as sex and environmental influences, may also affect phenotypic expression. Moreover, epigenetic mechanisms such as DNA methylation defects or abnormal imprinting have also been proposed as possible factors in the etiology of autism (Abdolmaleky, Smith, Faraone et al., 2004; Lamb, Barnby, Bonora et al., 2005). Although autism and ASD exhibit high heritability, the identification of susceptibility genes has so far been elusive. The major challenges are represented by the complex inheritance pattern, the likely involvement of multiple genes each having a moderate effect on disease risk, the high degree of heterogeneity and the lack of clear pathophysiological clues that could suggest particularly strong candidate genes. Therefore, the typical approach adopted by many research groups has been to perform genome-wide scans for linkage. This entails screening large samples of affected sib pair (ASP) or affected relative pair (ARP) families using microsatellite markers, in order to identify chromosomal regions that co-segregate with the phenotype within families. During the last decade at least a dozen genome scan studies of ASD have been published (for reviews see Autism Genome Project Consortium, 2007; Bachelli & Maestrini, 2006; Coon, 2006; Trikalinos, Karvouni, Zintzaras et al., 2006), each identifying several chromosomal regions of suggestive linkage. Although no region of strong evidence of linkage has been consistently replicated, the overlap in linkage findings from these international family collections points to a few regions that are likely to harbor autism susceptibility genes. A region on chromosome 7q, designated as AUTs 1, stands out as the region with the greatest concordance of findings (Bachelli & Maestrini, 2006; IMGSAC, 1998; Lamb, Barnby, Bonora et al., 2005). Another region of interest is on chromosome 2q, representing the strongest linkage finding obtained in the expanded IMGSAC data set of 219 ASP (IMGSAC, 2001; Lamb, Barnby, Bonora et al., 2005), which overlaps with linkage results reported by three additional studies (Buxbaum, Silverman, Smith et al., 2001; Philippe, Martinez, Guilloud-Bataille et al., 1999; Shao, Raiford, Wolpert et al., 2002). Similarly, overlapping linkage findings have been reported for a region on chromosome 17q, although these were not confirmed in the large-scale consortium study. However, it did produce suggestive evidence of linkage in the vicinity of 11q12–13 (Autism Genome Project Consortium, 2007). The overlaps in findings of these scans are somewhat encouraging, providing a first step towards the identification of autism susceptibility loci. However, there are some limitations in the interpretation of these results. Each genome scan has shown little evidence for strong linkage signals, the loci found so far are rather broad, containing many genes, and most of the linkage results do not converge on the same linkage peaks (Bachelli & Maestrini, 2006). The lack of reproducibility between linkage studies suggests that autism may involve extensive genetic heterogeneity and/or many interacting genes of weak effect. The identification of many potential susceptibility loci and the failure to narrow down the chromosomal intervals using linkage or cytogenetic approaches have prompted many groups to undertake association studies of candidate genes. AUTISM SPECTRUM DISORDERS 773 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 773

Candidate genes are genes thought to be involved in relevant pathophysiological processes (functional candidates), or genes within the chromosomal interval identified by linkage analysis or close to cytogenetic rearrangements associated with autism (positional candidates). In the last decade, over 100 positional and functional candidate genes have been studied, such as the neuroligin genes, the serotonin transporter gene, the Reelin gene and several GABA-ergic genes (for a review see Bachelli & Maestrini, 2006). Up until now the candidate gene studies are characterized by a lack of reproducibility because of similar problems to those encountered in linkage analysis. A clear involvement of any gene in autism has not yet been conclusively identified (Bachelli & Maestrini, 2006). Future Directions Autism is a disorder with a strong genetic basis. It is unclear whether the 10% variance that is not genetic is due to stochastic factors, measurement error, environmental influence, mitochondrial genomic variation or other non-Mendelian genetic influences. There is no doubt that a feeling of disappointment in the field of autism genetics because definitive answers have not come more easily. However, there are several reasons to put this aside and push forward: 1 Autism remains strongly genetic, and even – if possible – more complex than originally estimated. 2 The development of novel, and more accurate highthroughput approaches, together with access to data from large international patient samples and bioinformatics resources is now providing the opportunity to generate an unprecedented amount of information. 3 Identification of susceptibility genes will lead directly to studies of protein function in single cell systems, and might possibly lead to the development of animal models of autism. 4 These cell systems seen in animal models may provide an opportunity to study the neuropathological and neurophysiological consequences of gene activity in the developing organism and to develop novel psychopharmacological strategies. There have been significant advances in our understanding of some central aspects of developmental psychopathology in ASD. Nevertheless, there is still a need to identify more accurately those abnormalities that are potentially specific as well as to understand the possible interactions among different processes early in development. Functional imaging and evoked electrocortical response techniques provide a means to move beyond localization of abnormal brain activity to an understanding of underlying mechanisms such as functional coherence in neuronal networks and connectivity. There is growing evidence that early detection of ASD at 2 years of age is feasible and there are great expectations from the benefits of intensive early interventions for children with ASD. The available evidence on the effectiveness of early intervention approaches is not conclusive, and further randomized and large-scale studies and follow-up measurements are required. Questions to be answered are about intensity and dosage (is there really a threshold at 20 h per week one-toone contact with the child?; does this apply to all children, or is there a subgroup for which lower-intensity treatment is sufficient?), timing, cost-effectiveness, feasibility and availability of high-intensity treatment, the specific behavioral domains improved, and the magnitude and persistence of change induced. In clinical work, difficulties in dissemination and availability of services and facilities are often more limiting than the absence of knowledge. Continued parent and professional advocacy for clinical, educational and vocational services remains necessary, and service models should be modified to address the needs of individuals, from younger children to older adults and their families. The importance of multifaceted individual treatment plans, specific to a particular child and family and supported by knowledgeable clinicians and educators, must continue to be recognized, as models for evidencebased and manualized interventions are disseminated. Further Reading Moldin, S. O., & Rubenstein, J. L. R. (Eds.). (2006). Understanding autism: From basic neuroscience to treatment. Boca Raton, FL: CRC Press, Taylor & Francis Group. Volkmar, F. R., Paul, R., Klin, A., & Cohen, D. (Eds.). (2005). Handbook of autism and pervasive developmental disorders. (3rd edn., Vols 1 & 2). New Jersey: John Wiley & Sons. References Abdolmaleky, H. M., Smith, C. L., Faraone, S. W., Shafe, R., Stone, W., Glatt, S. S., et al. (2004). Methylomics in psychiatry: Modulation of gene–environment interactions may be through DNA methylation. American Journal of Medical Genetics. B. Neuropsychiatric Genetics, 127, 51–59. Alcantara, J. I., Weisblatt, E., Moore, B., & Bolton, P. (2004). Speech-in-noise perception in high-functioning individuals with autism or Asperger syndrome. Journal of Child Psychology and Psychiatry, 45, 1107–1114. Allen, G., & Courchesne, E. (2001). Attention function and dysfunction in autism. Frontiers in Bioscence, 6, D105–D119. Aman, M. G. (2005). Treatment planning for patients with autism spectrum disorders. Journal of Clinical Psychiatry, 66, 38–45. Aman, M. G., Singh, N. N., Stewart A. W., & Field C. J. (1985). Psychometric characteristics of the Aberrant Behavior Checklist. American Journal of Mental Deficiency, 89, 492–502. American Academy of Pediatrics. (2000). Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics, 105, 1158–1170. American Psychiatric Association (APA). (2000). Diagnostic and statistical manual of mental disorders (4th edn.). Text revision. Washington, DC: American Psychiatric Association. Atladóttir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders: A Danish cohort study. Archives of Pediatrics and Adolescent Medicine, 161, 193–198. Attwood, T. (1997). Asperger syndrome: A guide for parents and professionals. London: Jessica Kingsley. Autism Genome Project Consortium. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328. Bacchelli, E., & Maestrini, E. (2006). Autism spectrum disorders: Molecular genetic advances. American Journal of Medical Genetics. C. Seminars in Medical Genetics, 142, 13–23. CHAPTER 46 774 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 774

Bailey, A. J., Braeutigam, S., Jousmäki, V., & Swithenby, S. J. (2005). Abnormal activation of face processing systems at early and intermediate latency in individuals with autism spectrum disorder: A magnetoencephalographic study. European Journal of Neuroscience, 21, 2575–2585. Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., et al. (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63–77. Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., et al. (1998a). A clinicopathological study of autism. Brain, 121, 889–905. Bailey, A., Palferman, S., Heavey, L., & Le Couteur, A. (1998b). Autism: The phenotype in relatives. Journal of Autism and Developmental Disorders, 28, 369–392. Bailey, A., Phillips, W., & Rutter, M. (1996). Autism: Towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. Journal of Child Psychology and Psychiatry and Allied Disciplines, 37, 89–126. Baird, G., Simonoff, E., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., et al. (2006). Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: The Special Needs and Autism Project (SNAP). Lancet, 368, 210– 215. Baron-Cohen, S. (1988). An assessment of violence in a young man with Asperger syndrome. Journal of Child Psychology and Psychiatry, 29, 351–360. Baron-Cohen, S. (1995). Mindblindness: An essay on autism and theory of mind. Boston, MA: MIT Press/Bradford Books. Baron-Cohen, S. (2002). The extreme male brain theory of autism. Trends in Cognitive Sciences, 6, 248–254. Baron-Cohen, S., Allen, J., & Gillberg, C. (1992). Can autism be detected at 18 months? The needle, the haystack, and the CHAT. British Journal of Psychiatry, 161, 839–843. Baron-Cohen, S., Knickmeyer, R. C., & Belmonte, M. K. (2005). Sex differences in the brain: Implications for explaining autism. Science, 310, 819–823. Baron-Cohen, S., Ring, H. A., Wheelwright, S., Bullmore, E. T., Brammer, M. J., Simmons, A., et al. (1999). Social intelligence in the normal and autistic brain: An fMRI study. European Journal of Neuroscience, 11, 1891–1898. Baron-Cohen, S., Tager-Flusberg, H., & Cohen, D. (1993). Understanding other minds: Perspectives from autism. Oxford: Oxford University Press. Baron-Cohen, S., Wheelwright, S., Cox, A., Baird, G., Charman, T., Swettenham, J., et al. (2000). Early identification of autism by the Checklist for Autism in Toddlers (CHAT). Journal of the Royal Society of Medicine, 93, 521–525. Bauminger, N. (2002). The facilitation of social-emotional understanding and social interaction in high-functioning children with autism: Intervention outcomes. Journal of Autism and Developmental Disorders, 32, 283–298. Berument, S. K., Rutter, M., Lord, C., Pickles, A., & Bailey, A. (1999). Autism screening questionnaire: Diagnostic validity. British Journal of Psychiatry, 175, 444–451. Bishop, D. V. (1989). Autism, Asperger syndrome and semanticpragmatic disorder: Where are the boundaries? British Journal of Disorders of Communication, 24, 107–121. Boeschoten, M. A., Kemner, C., Kenemans, J. L., & van Engeland, H. (2007). Abnormal spatial frequency processing in children with Pervasive Developmental Disorder (PDD). Clinical Neurophysiology, 118, 2076–2088. Bolton, P., Macdonald, H., Pickles, A., Rios, P., Goode, S., Crowson, M., et al. (1994). A case–control family history study of autism. Journal of Child Psychology and Psychiatry, 35, 877–900. Bolton, P. F., Murphy, M., Macdonald, H., Whitlock, B., Pickles, A., & Rutter, M. (1997). Obstetric complications in autism: Consequences or causes of the condition? Journal of the American Academy of Child and Adolescent Psychiatry, 36, 272–281. Bondy, A. S., & Frost, L. A. (1998). The picture exchange communication system. Seminars in Speech and Language, 19, 373–388. Bondy, A., & Frost, L. (2001). The Picture Exchange Communication System. Behavior Modification, 25, 725–744. Boucher, J. (1998). SPD as a distinct diagnostic entity: Logical considerations and directions for future research. International Journal of Language and Communication Disorders, 33, 71–108. Bowler, D. M. (1992). Theory of mind in Asperger syndrome. Journal of Child Psychology and Psychiatry, 33, 877–893. Buitelaar, J. K., & van der Gaag, R. J. (1998). Diagnostic rules for children with PDD-NOS and multiple complex developmental disorder. Journal of Child Psychology and Psychiatry, 39, 911–920. Buitelaar, J. K., van der Gaag, R. G., Klin, A., & Volkmar, F. (1999a). Exploring the boundaries of Pervasive Developmental Disorder Not Otherwise Specified: Analyses of data from the DSM-IV autistic disorder field trial. Journal of Autism and Developmental Disorders, 29, 33–43. Buitelaar, J. K., van der Gaag, R. J., & van der Hoeven, J. (1998). Buspirone in the management of anxiety and irritability in children with pervasive developmental disorders: results of an open-label study. Journal of Clinical Psychiatry, 59, 56–59. Buitelaar, J. K., van der Wees M., Swaab-Barneveld, H., & van der Gaag, R. J. (1999b). Theory of mind and emotion-recognition functioning in autistic spectrum disorders and in psychiatric control and normal children. Development and Psychopathology, 11, 39–58. Burack, J. A., Enns, J. T., Stauder, J. E., Mottron, L., & Randolph, B. (1997). Attention and autism: Behavioral and electrophysiological evidence. In D. J. Cohen, & F. R. Volkmar (Eds.), Handbook of autism and pervasive developmental disorder (2nd edn., pp. 226– 242). New York: John Wiley & Sons. Butter, E. M., Wynn, J., & Mulick, J. A. (2003). Early intervention critical to autism treatment. Pediatric Annals, 32, 677–684. Buxbaum, J. D., Silverman, J. M., Smith, J. C., Kilifarski, M., Reichert, J., Hollander, E., et al. (2001). Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. American Journal of Human Genetics, 68, 1514–1520. Campbell, M., Schopler, E., Cueva, J. E., & Hallin, A. (1996). Treatment of autistic disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 134–143. Casanova, M. F. (2004). White matter volume increase and minicolums in autism. Annals of Neurology, 56, 453. Casanova, M. F., Buxhoeveden, D. P., Switala, A. E., & Roy, E. (2002). Minicolumnar pathology in autism. Neurology, 58, 428–432. Casanova, M. F., van Kooten, I., Switala, A. E., van Engeland, H., Heinsen, H., Steinbusch, H. W., et al. (2006). Minicolumnar abnormalities in autism. Acta Neuropathologica (Berlin), 112, 287–303. Castelli, F., Frith, C., Happe, F., & Frith, U. (2002). Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain, 125, 1839–1849. Ceponiene, R., Lepistö, T., Shestakova, A., Vanhala, R., Alku, P., Näätänen, R., et al. (2003). Speech-sound-selective auditory impairment in children with autism: They can perceive but do not attend. Proceedings of the National Academy of Sciences of the USA, 100, 5567–5572. Charman, T., & Baird, G. (2002). Practitioner review: Diagnosis of autism spectrum disorder in 2- and 3-year-old children. Journal of Child Psychology and Psychiatry and Allied Disciplines, 43, 289–305. Chesterman, P., & Rutter, S. C. (1994). A case report: Asperger syndrome and sexual offending. Journal of Forensic Psychiatry, 4, 555–562. Chugani, D. C., Muzik, O., Rothermel, R., Behen, M., Chakraborty, P., Mangner, T., et al. (1997). Altered serotonin synthesis in the AUTISM SPECTRUM DISORDERS 775 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 775

dentatothalamocortical pathway in autistic boys. Annals of Neurology, 42, 666–669. Ciesielski, K. T., Courchesne, E., & Elmasian, R. (1990). Effects of focused selective attention tasks on event-related potentials in autistic and normal individuals. Electroencephalography and Clinical Neurophysiology, 75, 207–220. Clarke, D. J., Littlejohns, C. S., Corbett, J. A., & Joseph, S. (1989). Pervasive developmental disorders and psychoses in adult life. British Journal of Psychiatry, 155, 692–699. Constantino, J. N., Gruber, C. P., Davis, S., Hayes, S., Passanante, N., & Przybeck, T. (2004). The factor structure of autistic traits. Journal of Child Psychology and Psychiatry and Allied Disciplines, 45, 719–726. Coon, H. (2006). Current perspectives on the genetic analysis of autism. American Journal of Medical Genetics. C. Seminars in Medical Genetics, 142, 24–32. Corbett, J., Harris, R., Taylor, E., & Trible, M. (1977). Progressive integrative psychosis of childhood. Journal of Child Psychology and Psychiatry, 18, 211–219. Cox, A., Klein, K., Charman, T., Baird, G., Baron-Cohen, S., Swettenham, J., et al. (1999). Autism spectrum disorders at 20 and 42 months of age: Stability of clinical and ADI-R diagnosis. Journal of Child Psychology and Psychiatry, 40, 719–732. Dahlgren, S. O., & Gillberg, C. (1989). Symptoms in the first two years of life: A preliminary population study of infantile autism. European Archives of Psychiatry and Neurological Science, 238, 169–174. Dapretto, M., Davies, M. S., Pfeifer, J. H., Scott, A. A., Sigman, M., Bookheimer, S. Y., et al. (2006). Understanding emotions in others: Mirror neuron dysfunction in children with autism spectrum disorder. Nature Neuroscience, 9, 28–30. Dawson, G., & Osterling, J. (1997). Early intervention in autism: Effectiveness and common elements of current approaches. In M. Guralnick (Ed.), The effectiveness of early intervention: Second generation research (pp. 307–326). Baltimore: Brookes. de Jonge, M. V. (2006). The search for endophenotypic markers of autism spectrum disorders. Unpublished dissertation, Utrecht University. De Giacomo, A., & Fombonne, E. (1998). Parental recognition of developmental abnormalities in autism. European Child and Adolescent Psychiatry, 7, 131–136. DeLong, G. R., Teague, L. A., & McSwain, K. M. (1998). Effects of fluoxetine treatment in young children with idiopathic autism. Developmental Medicine and Child Neurology, 40, 551–562. D’Souza, Y., Fombonne, E., & Ward, B. J. (2006). No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics, 118, 1664–1675. DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager, S. R., Schmitz, C., et al. (2006). The developmental neurobiology of autism spectrum disorder. Journal of Neuroscience, 26, 6897–6906. Dietz, C., Swinkels, S., van Daalen, E., van Engeland, H., & Buitelaar, J. K. (2006). Screening for Autistic Spectrum Disorder in children aged 14–15 months. II. Population screening with the Early Screening of Autistic Traits questionnaire (ESAT). Design and general findings. Journal of Autism and Developmental Disorders, 36, 713–722. Einfeld, S. L., & Tonge, B. J. (1995). The Developmental Behavior Checklist: The development and validation of an instrument to assess behavioral and emotional disturbance in children and adolescents with mental retardation. Journal of Autism and Developmental Disorders, 25, 81–104. Ernst, M., Zametkin, A. J., Matochik, J. A., Pascualvaca, D., & Cohen, R. M. (1997). Low medial prefrontal dopaminergic activity in autistic children [letter]. Lancet, 350, 638. Esch, B. E., & Carr, J. E. (2004). Secretin as a treatment for autism: A review of the evidence. Journal of Autism and Developmental Disorders, 34, 543–556. Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 52, 805–810. Filipek, P. A. (2005). Medical aspects of autism. In F. R. Volkmar, R. Paul, A. Klin, & D. Cohen (Eds.), Handbook of autism and pervasive developmental disorders (3rd edn., Vols 1 & 2, pp. 534– 581). Hoboken, NJ: John Wiley & Sons. Filipek, P. A., Accardo, P. J., Ashwal, S., Baranek, G. T., Cook, E. H. Jr., Dawson, G., et al. (2000). Practice parameter: Screening and diagnosis of autism. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology, 55, 468–479. Filipek, P. A., Accardo, P. J., Baranek, G. T., Cook, E. H. Jr., Dawson, G., Gordon, B., et al. (1999). The screening and diagnosis of autistic spectrum disorders. Journal of Autism and Developmental Disorders, 29, 439–484. Fischel, J. E., Whitehurst, G. J., Caulfield, M. B., & DeBaryshe, B. (1989). Language growth in children with expressive language delay. Pediatrics, 83, 218–227. Folstein, S., & Rutter, M. (1977). Infantile autism: A genetic study of 21 twin pairs. Journal of Child Psychology and Psychiatry, 18, 297–321. Fombonne, E. (1999). The epidemiology of autism: A review. Psychological Medicine, 29, 769–786. Fombonne, E. (2002). Epidemiological trends in rates of autism. Molecular Psychiatry, 7, S4–S6. Fombonne, E. (2003). The prevalence of autism. Journal of the American Medical Association, 289, 87–89. Fombonne, E., Bolton, P., Prior, J., Jordan, H., & Rutter, M. (1997). A family study of autism: Cognitive patterns and levels in parents and siblings. Journal of Child Psychology and Psychiatry, 38, 667–683. Fombonne, E., Rogé, B., Claverie, J., Courty, S., & Frémolle, J. (1999). Microcephaly and macrocephaly in autism. Journal of Autism and Developmental Disorders, 29, 113–119. Frith, U. (1991). Autism and Asperger Syndrome (pp. 37–92). Cambridge, UK: Cambridge University Press. [Translation of Asperger, H. (1944). Die autistischen Psychopathen im Kindesalter. Archiv fur Psychiatrie und Nervenkrankheitan, 117, 76–136.] Frith, U. (2003). Autism: Explaining the enigma (2nd edn.). Oxford, UK: Blackwell Publishing. Frith, U., & Happé, F. (1994). Autism: Beyond “theory of mind”. Cognition, 50, 115–132. Fuster, J. M. (1997). The prefrontal cortex: Anatomy, physiology, and neuropsychology of the frontal lobe (3rd edn.). Philadelphia: Lippincott-Raven. Gervais, H., Belin, P., Boddaert, N., Leboyer, M., Coez, A., Sfaello, I., et al. (2004). Abnormal cortical voice processing in autism. Nature Neuroscience, 7, 801–802. Geurts, H. M., Verte, S., Oosterlaan, J., Roeyers, H., & Sergeant, J. A. (2004). How specific are executive functioning deficits in attention deficit hyperactivity disorder and autism? Journal of Child Psychology and Psychiatry and Allied Disciplines, 45, 836–854. Ghaziuddin, M., Tsai, L., & Ghaziuddin, N. (1991). Brief report: Violence in Asperger syndrome: A critique. Journal of Autism and Developmental Disorders, 21, 349–354. Gillberg, C. (1989). Asperger syndrome in 23 Swedish children. Developmental Medicine and Child Neurology, 31, 520–531. Glasson, E. J., Bower, C., Petterson, B., de Klerk, N., Chaney, G., & Hallmayer, J. F. (2004). Perinatal factors and the development of autism: A population study. Archives of General Psychiatry, 61, 618–627. Grandin, T., & Scariano, M. (1986). Emergence: Labeled autistic. New York: Warner Books. Green, J., Gilchrist, A., Burton, D., & Cox, A. (2000). Social and psychiatric functioning in adolescents with Asperger syndrome CHAPTER 46 776 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 776

compared with conduct disorder. Journal of Autism and Developmental Disorders, 30, 279–293. Green, L., Fein, D., Modahl, C., Feinstein, C., Waterhouse, L., & Morris, M. (2001). Oxytocin and autistic disorder: Alterations in peptide forms. Biological Psychiatry, 50, 609–613. Grice, S. J., Halit, H., Farroni, T., Baron-Cohen, S., Bolton, P., & Johnson, M. H. (2005). Neural correlates of eye-gaze detection in young children with autism. Cortex, 41, 342–353. Griffith, E. M., Pennington, B. F., Wehner, E. A., & Rogers, S. J. (1999). Executive functions in young children with autism. Child Development, 70, 817–832. Guy, J., Gan, J., Selfridge, J., Cobb, S., & Bird, A. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science, 315, 1143–1147. Hadjikhani, N., Joseph, R. M., Snyder, J., Chabris, C. F., Clark, J., Steele, S., et al. (2004). Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces. Neuroimage, 22, 1141–1150. Hagberg, B., Aicardi, J., Dias, K., & Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett syndrome. Report of 35 cases. Annals of Neurology, 14, 471–479. Hagerman, R. J. (2006). Lessons from fragile X regarding neurobiology, autism and neurodegeneration. Journal of Developmental and Behavioral Pediatrics, 27, 63–74. Happé, F., & Frith, U. (2006). The weak coherence account: Detailfocused cognitive style in autism spectrum disorders. Journal of Autism and Developmental Disorders, 36, 5–25. Hartman, C. A., Luteijn, E., Serra, M., & Minderaa, R. (2006). Refinement of the Children’s Social Behavior Questionnaire (CSBQ): An instrument that describes the diverse problems seen in milder forms of PDD. Journal of Autism and Developmental Disorders, 36, 325–342. Hoeksma, M. R., Kenemans, J. L., Kemner, C., & van Engeland, H. (2005). Variability in spatial normalization of pediatric and adult brain images. Clinical Neurophysiology, 116, 1188–1194. Hollander, E., Dolgoff-Kaspar, R., Cartwright, C., Rawitt, R., & Novotny, S. (2001). An open trial of divalproex sodium in autism spectrum disorders. Journal of Clinical Psychiatry, 62, 530–534. Hollander, E., Novotny, S., Hanratty, M., Yaffe, R., DeCaria, C. M., Aronowitz, B. R., et al. (2003). Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger disorders. Neuropsychopharmacology, 28, 193–198. Hollander, E., Phillips, A., Chaplin, W., Zagursky, K., Novotny, S., Wasserman, S., et al. (2005). A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology, 30, 582–589. Honda, H., Shimizu, Y., & Rutter, M. (2005). No effect of MMR withdrawal on the incidence of autism: A total population study. Journal of Child Psychology and Psychiatry and Allied Disciplines, 46, 572–579. Hornig, M., & Lipkin, W. I. (2001). Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: Epidemiology, hypotheses, and animal models. Mental Retardation and Developmental Disabilities Research Reviews, 7, 200–210. Hornig, M., Chian, D., & Lipkin W. I. (2004). Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Molecular Psychiatry, 9, 833–845. Howlin, P. (1998). Practitioner review: Psychological and educational treatments for autism. Journal of Child Psychology and Psychiatry, 39, 307–322. Howlin, P. (2003). Outcome in high-functioning adults with autism with and without early language delays: Implications for the differentiation between autism and Asperger syndrome. Journal of Autism and Developmental Disorders, 33, 3–13. Howlin, P. (2005). Outcomes in autism spectrum disorders. In F. R. Volkmar, R. Paul, A. Klin, & D. Cohen (Eds.), Handbook of autism and pervasive developmental disorders (3rd edn), (pp. 201–220). Hoboken, NJ: John Wiley & Sons. Howlin, P. (2005). The effectiveness of interventions for children with autism. Journal of Neural Transmission Supplementum, 69, 101–119. Howlin, P., Alcock, J., & Burkin, C. (2005). An 8 year follow-up of a specialist supported employment service for high-ability adults with autism or Asperger syndrome. Autism: the International Journal of Research and Practice, 9, 533–549. Howlin, P., Baron-Cohen, S., & Hadwin, J. (1999). Teaching children with autism to mind-read: A practical guide for teachers and parents. New York/London: Wiley & Son. Howlin, P., & Moore, A. (1997). Diagnosis of autism: a survey of over 1200 patients in the UK. Autism, 1, 135–162. Hughes, C., Russell, J., & Robbins, T. W. (1994). Evidence for executive dysfunction in autism. Neuropsychologia, 32, 477–492. Hutton, J., Goode, S., Murphy, M., Le Couteur, A., & Rutter, M. (in press). New-onset psychiatric disorders in individuals with autism. Autism. International Molecular Genetic Study of Autism Consortium (IMGSAC). (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7, 571–578. International Molecular Genetic Study of Autism Consortium (IMGSAC). (2001). A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p. American Journal of Human Genetics, 69, 570–581. Just, M. A., Cherkassky, V. L., Keller, T. A., & Minshew, N. J. (2004). Cortical activation and synchronization during sentence comprehension in high-functioning autism: Evidence of underconnectivity. Brain, 127, 1811–1821. Kasai, K., Hashimoto, O., Kawakubo, Y., Yumoto, M., Kamio, S., Itoh, K., et al. (2005). Delayed automatic detection of change in speech sounds in adults with autism: A magnetoencephalographic study. Clinical Neurophysiology, 116, 1655–1664. Kabot, S., Masi, W., & Segal, M. (2003). Advances in the diagnosis and treatment of autism spectrum disorders. Professional Psychology, 34, 26–33. Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217–250. Keel, J. H., Mesibov, G. B., & Woods, A. V. (1997). TEACCHsupported employment program. Journal of Autism and Developmental Disorders, 27, 3–9. Keller, F., &. Persico, A. M. (2003). The neurobiological context of autism. Molecular Neurobiology, 28, 1–22. Kemner, C., & van Engeland, H. (2006). ERPs and eye movements reflect atypical visual perception in pervasive developmental disorder. Journal of Autism and Developmental Disorders, 36, 45–54. Kemner, C., Verbaten, M. N., Cuperus, J. M., Camfferman, G., & van Engeland, H. (2004). Visual and somatosensory event-related brain potentials in autistic children and three different control groups. Electroencephalography and Clinical Neurophysiology, 92, 225–237. Kerbeshian, J., Burd, L., & Fisher, W. (1987). Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. Journal of Clinical Psychopharmacology, 7, 401–405. Kjelgaard, M. M., & Tager-Flusberg, H. (2001). An investigation of language impairment in autism: Implications for genetic subgroups. Language and Cognitive Processes, 16, 287–308. Klin, A., McPartland, J., & Volkmar F. R. (2005a). Asperger syndrome. In F. R. Volkmar, R. Paul, A. Klin, & D. Cohen (Eds.), Handbook of autism and pervasive developmental disorders (3rd edn., pp. 88–125). Hoboken, NJ: John Wiley & Sons. Klin, A., Pauls, D., Schultz, R., & Volkmar, F. (2005b). Three diagnostic approaches to Asperger syndrome: Implications for research. Journal of Autism and Developmental Disorders, 35, 221–234. AUTISM SPECTRUM DISORDERS 777 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 777

Klin, A., Volkmar, F. R., & Sparrow, S. S. (1992). Autistic social dysfunction: Some limitations of the theory of mind hypothesis. Journal of Child Psychology and Psychiatry, 33, 861–876. Klin, A., Volkmar, F. R., & Sparrow, S. S. (Eds.). (2000). Asperger syndrome. New York: Guilford Press. Klin, A., Volkmar, F. R., Sparrow, S. S., Cicchetti, D. V., & Rourke, B. P. (1995). Validity and neuropsychological characterization of Asperger syndrome: Convergence with nonverbal learning disabilities syndrome. Journal of Child Psychology and Psychiatry, 36, 1127–1140. Koegel, R. L., & Frea, W. D. (1993). Treatment of social behavior in autism through the modification of pivotal social skills. Journal of Applied Behavior Analysis, 26, 369–377. Koshino, H., Carpenter, P. A., Minshew, N. J., Cherkassky, V. L., Keller, T. A., & Just, M. A. (2005). Functional connectivity in an fMRI working memory task in high-functioning autism. Neuroimage, 24, 810–821. Kozinetz, C. A., Skender, M. L., MacNaughton, N., Almes, M. J., Schultz, R. J., Percy, A. K., et al. (1993). Epidemiology of Rett syndrome: A population-based registry. Pediatrics, 91, 445–450. Lainhart, J. E. (1999). Psychiatric problems in individuals with autism, their parents and siblings. International Review of Psychiatry, 11, 278–298. Lainhart, J. E. (2006). Advances in autism neuroimaging research for the clinician and geneticist. American Journal of Medical Genetics. C. Seminars in Medical Genetics, 142, 33–39. Lam, K. S. L., Aman, M. G., & Arnold, L. E. (2006). Neurochemical correlates of autistic disorder: A review of the literature. Research in Developmental Disabilities, 27, 254–289. Lamb, J. A., Barnby, G., Bonora, E., Sykes, N., Bachelli, E., Blasi, F., et al. (2005). Analysis of IMGSAC autism susceptibility loci: Evidence for sex limited and parent of origin specific effects. Journal of Medical Genetics, 42, 132–137. Larsson, H. J., Eaton, W. W., Madsen, K. M., Vestergaard, M., Olesen, A. V., Agerbo, E., et al. (2005). Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status. American Journal of Epidemiology, 161, 916–925. Le Couteur, A. C., Bailey, A., Goode, S., Pickles, A., Robertson, S., Gottesman, I., et al. (1996). A broader phenotype of autism: The clinical spectrum in twins. Journal of Child Psychology and Psychiatry, 37, 785–801. Le Couteur, A., Lord, C., & Rutter, M. (2003). The Autism Diagnostic Interview: Revised (ADI-R). Los Angeles, CA: Western Psychological Services. Leekam, S. R., Libby, S. J., Wing, L., Gould, J., & Taylor, C. (2002). The Diagnostic Interview for Social and Communication Disorders: Algorithms for ICD-10 childhood autism and Wing and Gould autistic spectrum disorder. Journal of Child Psychology and Psychiatry and Allied Disciplines, 43, 327–342. Levy, S. E., & Hyman, S. L. (2003). Use of complementary and alternative treatments for children with autistic spectrum disorders is increasing. Pediatric Annals, 32, 685–691. Lockyer, L., & Rutter M. (1969). A five- to fifteen-year follow-up study of infantile psychosis. III. Psychological aspects. British Journal of Psychiatry, 115, 865–882. Lord, C., & Schopler, E. (1989). Stability of assessment results of autistic and non-autistic language-impaired children from preschool years to early school age. Journal of Child Psychology and Psychiatry, 30, 575–590. Lord, C., Rutter, M., DiLavore, P. C., & Risi, S. (2001). Autism Diagnostic Observation Schedule (ADOS manual). Los Angeles, CA: Western Psychological Services. Lotter, V. (1966). Epidemiology of autistic conditions in young children. I. Prevalence. Social Psychiatry, 1, 124–137. Lovaas, O. I. (1987). Behavioral treatment and normal educational and intellectual functioning in young autistic children. Journal of Consulting and Clinical Psychology, 55, 3–9. Madsen, K. M., Lauritsen, M. B., Pedersen, C. B., Thorsen, P., Plesner, A. M., Andersen, P. H., et al. (2003). Thimerosal and the occurrence of autism: Negative ecological evidence from Danish population-based data. Pediatrics, 112, 604–606. Magnus, P., Irgens, L. M., Haug, K., Nystad, W., Skjaerven, R., Stoltenberg, C., & the MoBa Study Group. (2006). Cohort profile: The Norwegian mother and child cohort study (MoBa). International Journal of Epidemiology, 35, 1146–1150. Mawhood, L. M., & Howlin, P. (1999). The outcome of a supported employment scheme for high functioning adults with autism of Asperger syndrome. Autism: International Journal of Research and Practice, 3, 229–253. McAlonan, G. M., Cheung, V., Cheung, C., Suckling, J., Lam, G. Y., Tai, K. S., et al. (2005). Mapping the brain in autism: A voxelbased MRI study of volumetric differences and intercorrelations in autism. Brain, 128, 268–276. McBride, P. A., Anderson, G. M., Hertzig, M. E., Snow, M. E., Thompson, S. M., Khait, V. D., et al. (1998). Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 767–776. McCracken J. T., McGough, J., Shah, B., Cronin, P., Hong, D., Aman, M. G., et al. (2002). Risperidone in children with autism and serious behavioral problems. New England Journal of Medicine, 5, 314–321. McDougle, C. J., Erickson, C. A., Stigler, K. A., & Posey, D. J. (2005). Neurochemistry in the pathophysiology of autism. Journal of Clinical Psychiatry, 66, 9–18. McDougle, C. J., Holmes, J. P., Carlson, D. C., Pelton, G. H., Cohen, D. J., & Price, L. H. (1998). A double-blind, placebocontrolled study of risperidone in adults with autistic disorder and other pervasive developmental disorders [see comments]. Archives of General Psychiatry, 55, 633–641. McDougle, C. J., Naylor, S. T., Cohen, D. J., Aghajanian, G. K., Heninger, G. R., & Price, L. H. (1996a). Effects of tryptophan depletion in drug-free adults with autistic disorder. Archives of General Psychiatry, 53, 993–1000. McDougle, C.J., Naylor, S.T., Cohen, D.J., Volkmar, F.R., Heninger, G.R., & Price L.H. (1996b). A double-blind placebo-controlled study of fluvoxamine in adults with autistic disorder. Archives of General Psychiatry, 53, 1001–1008. McEachin, J. J., Smith, T., & Lovaas, O. I. (1993). Long-term outcome for children with autism who received early intensive behavioral treatment. American Journal of Mental Retardation, 97, 359–372. McPartland, J., Dawson G., Webb, S. J., Panagiotides, H., & Carver, L. J. (2004). Event-related brain potentials reveal anomalies in temporal processing of faces in autism spectrum disorder. Journal of Child Psychology and Psychiatry, 45, 1235–1245. Medical Research Council. (2001). MRC review of autism research: Epidemiology and causes. London: Medical Research Council. Mesibov, G. B. (1984). Social skills training with verbal autistic adolescents and adults: A program model. Journal of Autism and Developmental Disorders, 14, 395–404. Mesibov, G., Shea, V., & Schopler, E. (2004). The TEACCH approach to autism spectrum disorders. New York: Plenum Press. Miller, J. F., Campbell, T. F., Chapman, R. S., & Weismer S. E. (1984). Language behaviour in acquired childhood aphasia. In A. Holland (Ed.), Language disorders in children (pp. 57–99). Cambridge: College-Hill. Minshew, N. J. (1991). Indices of neural function in autism: Clinical and biologic implications. Pediatrics, 87, 774–780. Moldin, S. O., & Rubenstein, J. L. R. (Eds.). (2006). Understanding autism: From basic neuroscience to treatment. Boca Raton, FL: CRC Press, Taylor & Francis Group. Moldin, S. O., Rubenstein, J. L., & Hyman, S. E. (2006). Can autism speak to neuroscience? Journal of Neuroscience, 26, 6893–6896. CHAPTER 46 778 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 778

Molenaar, P. C. M., Boomsma, D. I., & Dolan, C. V. (1993). A third source of developmental differences. Behavior Genetics, 23, 519– 524. Moretti, P., & Zoghbi, H. Y. (2006). MeCP2 dysfunction in Rett syndrome and related disorders. Current Opinion in Genetics and Development, 16, 276–281. Mountcastle, V. B. (1997). The columnar organization of the neocortex. Brain, 120, 701–722. Mouridsen, S. E. (1995). The Landau–Kleffner syndrome: A review. European Child and Adolescent Psychiatry, 4, 223–228. Mouridsen, S. E., Rich, B., & Isager, T. (1999). Psychiatric morbidity in disintegrative psychosis and infantile autism: A long-term followup study. Psychopathology, 32, 177–183. Mulder, E. J., Anderson, G. M., Kema, I. P., de Bildt, J. A., van Lang, N. D., Den Boer, J. A., et al. (2004). Platelet serotonin levels in pervasive developmental disorders and mental retardation: Diagnostic group differences, within-group distribution, and behavioral correlates. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 491–499. Müller, R. A., Kleinhans, N., Kemnotsu, N., Pierce, K., & Courchesne, E. (2003). Abnormal variability and distribution of functional maps in autism: An FMRI study of visuomotor learning. American Journal of Psychiatry, 160, 1847–1862. Murch, S. (2005). Diet, immunity, and autistic spectrum disorders. Journal of Pediatrics, 146, 582–584. National Research Council. (2001). Educating children with autism. Committee on Educational Interventions for Children with Autism. Washington, DC: National Academy Press. Nelson, K. B., Grether, J. K., Croen, L. A., Dambrosia, J. M., Dickens, B. F., Jelliffe, L. L., et al. (2001). Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Annals of Neurology, 49, 597–606. Nelson, P. G., Kuddo, T., Song, E. Y., Dambrosia, J. M., Kohler, S., Satyanarayana, G., et al. (2006). Selected neurotrophins, neuropeptides, and cytokines: Developmental trajectory and concentrations in neonatal blood of children with autism or Down syndrome. International Journal of Developmental Neuroscience, 24, 73– 80. Nir, I., Meir, D., Zilber, N., Knobler, H., Hadjez, J., & Lerner, Y. (1995). Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism. Journal of Autism and Developmental Disorders, 25, 641–654. Ozonoff, S., & McEvoy, R. E. (1994). A longitudinal study of executive function and theory of mind development in autism. Development and Psychopathology, 6, 415–431. Ozonoff, S., Pennington, B., & Rogers, S. (1991a). Executive function deficits in high-functioning autistic children: Relationship to theory of mind. Journal of Child Psychology and Psychiatry, 31, 1081–1105. Ozonoff, S., Rogers, S. J., & Pennington, B. F. (1991b). Asperger syndrome: Evidence of an empirical distinction from high-functioning autism. Journal of Child Psychology and Psychiatry, 32, 1107– 1122. Ozonoff, S., & Strayer, D. L. (1997). Inhibitory function in nonretarded children with autism. Journal of Autism and Developmental Disorders, 27, 59–77. Palmen, S. J., & van Engeland, H. (2004). Review on structural neuroimaging findings in autism. Journal of Neural Transmission, 111, 903–929. Palmen, S. J., Hulshoff Pol, H. E., Kemner, C., Schnack, H. G., Sitskoorn, M. M., Appels, M. C., et al. (2005). Brain anatomy in non-affected parents of autistic probands: An MRI study. Psychological Medicine, 35, 1411–1420. Pennington, B. F., & Ozonoff, S. (1996). Executive functions and developmental psychopathology. Journal of Child Psychology and Psychiatry, 37, 51–87. Philippe, A., Martinez, M., Guilloud-Bataille M., Gillberg, C., Rastam Sponheim E., Coleman, M., et al. (1999). Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Human Molecular Genetics, 8, 805–812. Pickles, A., Bolton, P., Macdonald, H., Bailey, A., Le Couteur, A., Sim, C. H., et al. (1995). Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: A twin and family history study of autism. American Journal of Human Genetics, 57, 717–726. Pickles, A., Simonoff, E., Conti-Ramsden, G., Falcaro, M., Simkin, Z., Charman, T., et al. (submitted). Loss of language in early development of autism and specific language impairment. Pierce, K., Haist, F., Sedaghar, F., & Courchesne, E. (2004). The brain response to personally familiar faces in autism: Findings of fusiform activity and beyond. Brain, 127, 2703–2716. Piggot, J., Kwon, H., Mobbs, D., Blasey, C., Lotspeich, L., Menon, V., et al. (2004). Emotional attribution in high-functioning individuals with autistic spectrum disorder: A functional imaging study. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 473–480. Piven, J., Palmer, P., Jacobi, D., Childress, D., & Arndt, S. (1997). Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. American Journal of Psychiatry, 154, 185–190. Plioplys, A. V. (1994). Autism: Electroencephalogram abnormalities and clinical improvement with valproic acid. Archives of Pediatric and Adolescent Medicine, 148, 220–222. Polich, J., & Herbst K. L. (2000). P300 as a clinical assay: Rationale, evaluation, and findings. International Journal of Psychophysiology, 38, 3–19. Purcell, A. E., Jeon, O. H., Zimmerman, A. W., Blue, M. E., & Pevsner, J. (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 57, 1618–1628. Rapin, I. (1997). Autism. New England Journal of Medicine, 337, 97–104. Ratey, J. J., Bemporad, J., Sorgi, P., Bick, P., Polakoff, S., O’Driscoll, G., et al. (1987a). Brief report: Open trial effects of beta-blockers on speech and social behaviors in 8 autistic adults. Journal of Autism and Developmental Disorders, 17, 439–446. Ratey, J. J., Mikkelsen, E., Sorgi, P., Zuckerman, S., Polakoff, S., Bemporad, J., et al. (1987b). Autism: The treatment of aggressive behaviors. Journal of Clinical Psychopharmacology, 7, 35–41. Reichenberg, A., Gross, R., Weiser, M., Bresnahan, M., Silverman, J., Harlap, S., et al. (2006). Advancing paternal age and autism. Archive of General Psychiatry, 63, 1026–1032. Research Units on Pediatric Psychopharmacology (RUPP). (2005a). Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Archives of General Psychiatry, 62, 1266–1274. Research Units on Pediatric Psychopharmacology (RUPP). (2005b). Risperidone treatment of autistic disorder: Longer-term benefits and blinded discontinuation after 6 months. American Journal of Psychiatry, 162, 1361–1369. Risch, N. (1999). Linkage strategies for genetically complex traits. American Journal of Human Genetics, 46, 222–253. Ritvo, E. R., & Freeman, B. J. (1978). Current research on the syndrome of autism: introduction. The National Society for Autistic Children’s definition of the syndrome of autism. Journal of the American Academy of Child Psychiatry, 17, 565–575. Robins, D. L., Fein, D., Barton, M. L., & Green, J. A. (2001). The Modified Checklist for Autism in Toddlers: An initial study investigating the early detection of autism and pervasive developmental disorders. Journal of Autism and Developmental Disorders, 31, 131–144. Roeyers, H. (1996). The influence of nonhandicapped peers on the social interactions of children with a pervasive development disorder. Journal of Autism and Developmental Disorders, 26, 303–320. AUTISM SPECTRUM DISORDERS 779 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 779

Roger, J. H. (2000). The MMR question. Lancet, 356, 160–161. Rogers, S. J., & DiLalla, D. L. (1990). Age of symptom onset in young children with pervasive developmental disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 863– 872. Rønningen, K. S., Paltiel, L., Meltzer, H. M., Nordhagen, R., Lie, K. K., Hovengen, R., et al. (2006). The biobank of the Norwegian Mother and Child Cohort Study: A resource for the next 100 years. European Journal of Epidemiology, 21, 619–625. Russell, J., Jarrold, C., & Hood, B. (1999). Two intact executive capacities in children with autism: Implications for the core executive dysfunctions in the disorder. Journal of Autism and Developmental Disorders, 29, 103–112. Rutter, M. (1970). Autistic children: Infancy to adulthood. Seminars in Psychiatry, 2, 435–450. Rutter, M. (1985). The treatment of autistic children. Journal of Child Psychology and Psychiatry, 26, 193–214. Rutter, M. (2000). Genetic studies of autism: From the 1970s into the millennium. Journal of Abnormal Child Psychology, 28, 3–14. Rutter, M. (2005). Incidence of autism spectrum disorders: Changes over time and their meaning. Acta Paediatrica, 94, 2–15. Rutter, M. (2006). Autism: Its recognition, early diagnosis, and service implications. Journal of Developmental and Behavioral Pediatrics, 27, S54–S58. Rutter, M., & Hersov, L. (1977). Child psychiatry: Modern approaches. Oxford: Blackwell Publishing. Rutter, M., Anderson-Wood L., Beckett, C., Bredenkamp, D., Castle, J., Groothues C., et al. (1999). Quasi-autistic patterns following severe early global privation. English and Romanian Adoptees (ERA) Study Team. Journal of Child Psychology and Psychiatry, 40, 537–549. Rutter, M., Caspi, A., & Moffitt, T. E. (2003a). Using sex differences in psychopathology to study causal mechanisms: Unifying issues and research strategies. Journal of Child Psychology and Psychiatry, 44, 1092–1115. Rutter, M., Le Couteur, A., & Lord, C. (2003b). Autism Diagnostic Interview revised (ADI-R). Los Angeles, CA: Western Psychological Services. Rutter, M., Moffitt, T. E., & Caspi, A. (2006). Gene–environment interplay and psychopathology: Multiple varieties but real effects. Journal of Child Psychology and Psychiatry, 47, 226–261. Schopler, E., Mesibov, G. B., & Kunce, L. J. (1998). Asperger syndrome or high-functioning autism? New York/London: Plenum Press. Schultz, R. T., Gauthier, I., Klein, A., Fulbright, R. K., Anderson A. W., Volkmar, F., et al. (2000). Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Archives of General Psychiatry, 57, 331– 340. Scragg, P., & Shah, A. (1994). Prevalence of Asperger syndrome in a secure hospital. British Journal of Psychiatry, 161, 679–682. Shao, Y., Raiford, K. L., Wolpert, C. M., Cope, H. A., Ravan, S. A., Ashley-Koch A. A., et al. (2002). Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. American Journal of Human Genetics, 70, 1058–1061. Shea, S., Turgay, A., Carroll, A., Schulz, M., Orlik, H., Smith, I., et al. (2004). Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics, 114, 634–641. Siegel, B., Pliner, C., Eschler, J., & Elliott, G. R. (1988). How children with autism are diagnosed: Difficulties in identification of children with multiple developmental delays. Journal of Developmental and Behavioral Pediatrics, 9, 199–204. Sigman, M., Ruskin, E., Arbeile, S., Corona, R., Dissanayake, C., Espinosa, M., et al. (1999). Continuity and change in the social competence of children with autism, Down syndrome, and developmental delays. Monographs of the Society for Research in Child Development, 64, 1–114. Smalley, S. L. (1998). Autism and tuberous sclerosis. Journal of Autism and Developmental Disorders, 28, 407–414. Smith, I. M., & Bryson, S. E. (1994). Imitation and action in autism: A critical review. Psychological Bulletin, 116, 259–273. Smith, M. D., Belcher, R. G., & Juhrs, P. D. (1995). A guide to successful employment for individuals with autism. Baltimore: Paul H. Brookes. Sparrow, S. S., Balla, D., & Cicchetti, D. V. (1984). Vineland Adaptive Behavior Scales: Manual. Circle Pines, MN: American Guidance Service. Starr, E., Berument, S. K., Pickles, A., Tomlins, M., Bailey, A., Papanikolaou, K., et al. (2001). A family genetic study of autism associated with profound mental retardation. Journal of Autism and Developmental Disorders, 31, 89–96. Swinkels, S. H. N., Dietz, C., van Daalen, E., Kerkhof, I. H., van Engeland, H., & Buitelaar, J. K. (2006). Screening for autistic spectrum in children aged 14 to 15 months. I. The development of the Early Screening of Autistic Traits Questionnaire (ESAT). Journal of Autism and Developmental Disorders, 36, 723–732. Szatmari, P., Bartolucci, G., & Bremner, R. (1989). Asperger syndrome and autism: comparison of early history and outcome. Developmental Medicine and Child Neurology, 31, 709–720. Szatmari, P., Bryson, S. E., Streiner D. L., Wilson, F. B. A., Archer, L., & Ryerse, C. (2000). Two-year outcome of preschool children with autism or Asperger syndrome. American Journal of Psychiatry, 157, 1980–1987. Szatmari, P., Jones, M. B., Zwaigenbaum, L., & MacLean, J. E. (1998). Genetics of autism: Overview and new directions. Journal of Autism and Developmental Disorders, 28, 351–368. Teder-Sälejärvi, W. A., Pierce, K. L., Courchesne, E., & Hillyard, S. A. (2005). Auditory spatial localization and attention deficits in autistic adults. Brain Research. Cognitive Brain Research, 23, 221–234. Tordjman, S., Anderson, G. M., McBride, P. A., Hertzig, M. E., Snow, M. E., Hall, L. M., et al. (1997). Plasma beta-endorphin, adrenocorticotropic hormone, and cortisol in autism. Journal of Child Psychology and Psychiatry, 38, 705–715. Torrey, E. F., Dhavale, D., Lawlor, J. P., & Yolken, R. H. (2004). Autism and head circumference in the first year of life. Biological Psychiatry, 56, 892–894. Trikalinos, T. A., Karvouni, A., Zintzaras, E., Ylisaukko-oja, T., Peltonen, L., Jarvela, I., et al. (2006). A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Molecular Psychiatry, 11, 29–36. Troost, P. W., Lahuis, B. E., Steenhuis, M. P., Ketelaars, C. E., Buitelaar, J. K., van Engeland, H., et al. (2005). Long-term effects of risperidone in children with autism spectrum disorders: A placebo discontinuation study. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 1137–1144. Van der Gaag, R. J. (1993). Multiplex developmental disorder: An exploration of borderlines on the autistic spectrum. Utrecht: Unpublished thesis, Utrecht University. Verbaten, M. N., Roelofs, J. W., van Engeland, H., Kenemans, J. K., & Slangen, J. L. (1991). Abnormal visual event-related potentials of autistic children. Journal of Autism and Developmental Disorders, 21, 449–470. Volkmar, F., Cook, E. H. Jr., Pomeroy, J., Realmuto, G., & Tanguay, P. (1999). Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 32S–54S. Volkmar, F. R., & Cohen, D. J. (1991). Comorbid association of autism and schizophrenia. American Journal of Psychiatry, 148, 1705–1707. Volkmar, F. R., & Nelson, D. S. (1990). Seizure disorders in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 127–129. CHAPTER 46 780 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 780

Wing, L. (1997). The autistic spectrum. Lancet, 350, 1761–1766. Wing, L. (1981). Asperger syndrome: A clinical account. Psychological Medicine, 11, 115–129. Wing, L., Leekam, S. R., Libby, S. J., Gould, J., & Larcombe, M. (2002). The Diagnostic Interview for Social and Communication Disorders: Background, inter-rater reliability and clinical use. Journal of Child Psychology and Psychiatry and Allied Disciplines, 43, 307–325. Wing, L., & Gould, J. (1979). Severe impairments of social interaction and associated abnormalities in children: Epidemiology and classification. Journal of Autism and Developmental Disorders, 9, 11–29. Wing, L., & Shah, A. (2000). Catatonia in autistic spectrum disorders. British Journal of Psychiatry, 176, 357–362. World Health Organization (WHO). (1996). Multiaxial classification of child and adolescent psychiatric disorders: The ICD-10 classification of mental and behavioural disorders in children and adolescents. Cambridge, UK: Cambridge University Press. Yirmiya, N., Sigman, M. D., Kasari, C., & Mundy, P. (1992). Empathy and cognition in high-functioning children with autism. Child Development, 63, 150–160. Young, L. J., & Wang, Z. (2004). The neurobiology of pair bonding. Nature Neuroscience, 7, 1048–1054. Ziatas, K., Durkin, K., & Pratt, C. (1998). Belief term development in children with autism, Asperger syndrome, specific language impairment, and normal development: Links to theory of mind development. Journal of Child Psychology and Psychiatry, 39, 755– 763. Zwaigenbaum, L., Bryson, S., Rogers, T., Roberts, W., Brian, J., & Szatmari, P. (2005). Behavioral manifestations of autism in the first year of life. International Journal of Developmental Neuroscience, 23, 143–152. AUTISM SPECTRUM DISORDERS 781 Volkmar, F. R., & Rutter, M. (1995). Childhood disintegrative disorder: Results of the DSM-IV autism field trial. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1092– 1095. Vorstman, J. A., Staal, W. G., van Daalen, E., van Engeland, H., Hochstenbach, P. F. R., & Franke, L. (2006). Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Molecular Psychiatry, 11, 18–28. Wakefield, A. J., Murch, S. H., Anthony, A., Linnell, J., Casson, D. M., Malik, M., et al. (1998). Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children [see comments]. Lancet, 351, 637–641. Walhovd, K. B., & Fjell, A. M. (2003). The relationship between P3 and neuropsychological function in an adult life span sample. Biological Psychology, 62, 65–87. Wang, A. T., Ting, M. A., Dapretto, M., Hariri, A. R., Sigman, M., & Bookheimer, S. Y. (2004). Neural correlates of facial affect processing in children and adolescents with autism spectrum disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 481–490. Werner, E., & Dawson, G. (2005). Validation of the phenomenon of autistic regression using home videotapes. Archives of General Psychiatry, 62, 889–895. Whitaker-Azmitia, P. M. (2001). Serotonin and brain development: Role in human developmental diseases. Brain Research Bulletin, 56, 479–485. Willemsen-Swinkels, S. H., Buitelaar, J. K., Nijhof, G. J., & van Engeland, H. (1995). Failure of naltrexone hydrochloride to reduce self-injurious and autistic behavior in mentally retarded adults: Double-blind placebo-controlled studies. Archives of General Psychiatry, 52, 766–773. Williams, D. L., Goldstein, G., Carpenter, P. A., & Minshew, N. J. (2005). Verbal and spatial working memory in autism. Journal of Autism and Developmental Disorders, 35, 747–756. 9781405145497_4_046.qxd 29/03/2008 02:54 PM Page 781

782 Speech, Language and Communication The distinction between speech, language and communication may be illustrated by three child cases. Emma is a lively and engaging 9-year-old who has difficulty making herself understood because her production of speech sounds is very unclear. However, she demonstrates normal language skills: she understands what others say to her, and can express herself in writing using long and complex sentences. Her ability to communicate is hampered by her speech difficulties, but she enjoys interacting with others, and when people fail to understand her, she supplements her utterances with gesture and facial expression to get her message across. Thomas is a 6-year-old who has no difficulty in producing speech sounds clearly, but his language skills are limited, as evidenced by his use of simple and immature sentence construction. Instead of saying “I’d like a drink” he says “Me want drink.” However, although his language is far more simple than that of other 6-year-olds, he does use it to communicate with other children and adults. In contrast, 4-yearold Jack produces a great deal of complex, fluent and clearly articulated language, but he does not use it to communicate effectively. Thus, his opening gambit to a stranger might be to say: “In Deep Space Nine you can’t get to level 6 until you have killed all the foot soldiers, but if you get to level 6, you have to first destroy the klingons before you can enter the palace of death.” One way of depicting the relationship between speech, language and communication is shown in Fig. 47.1, where language is a subset of communication and speech is a subset of language. Communication is defined by McArthur (1992, p. 238) as “the transmission of information (a message) between a source and a receiver, using a signaling system.” The primary means of communication between humans is through language, but communication also encompasses other means of signaling meaning, such as facial expression, bodily gesture and non-verbal sounds. Language differs from these other communicative modes; it is a complex formal system in which a small number of elements are combined in a rule-based manner to generate an infinite number of possible meanings. Most human language is expressed in speech (i.e., meanings are represented by words that are composed of a small set of speech sounds, or phonemes). Where learning of oral language is compromised because a child is deaf, manual (sign) languages have evolved, showing similar structural characteristics to spoken languages. In addition, oral language can be expressed in written form. Language involves more than speech, and communication involves more than language. However, it is possible for someone to speak without producing language (e.g., when a person utters meaningless gobbledegook), and it is possible for someone to produce utterances that obey the formal rules of language, yet communication is not achieved, as in the case of Jack. In evaluating children with impairments, it is important to keep these three levels in mind, and to recognize that a problem at one level does not necessarily entail a problem at another. In this chapter we make a broad division between disorders affecting speech, and those affecting language and communication. This distinction has some similarity with the distinction made in DSM-IV-TR (American Psychiatric Association, 2000) between phonological disorder (315.39) and language disorder (315.31), but the coverage is broader. Among speech disorders, we cover disorders affecting fluency, voice and prosody as well as problems of speech sound production that may have a neurological basis. For language and communication disorders, we focus heavily on specific language impairment (SLI), which is analogous to the DSM language disorder category, but we also consider other conditions required for a differential Speech and Language Disorders 47 Dorothy V. M. Bishop and Courtenay Frazier Norbury Fig. 47.1 Relationship between speech, language and communication. Communication Language Speech 9781405145497_4_047.qxd 29/03/2008 02:54 PM Page 782 Rutter’s Child and Adolescent Psychiatry, 5th Edition, Edited by M. Rutter, D. V. M. Bishop D. S. Pine, S. Scott, J. Stevenson, E. Taylor and A. Thapar © 2008 Blackwell Publishing Limited. ISBN: 978-1-405-14549-7

diagnosis, including acquired epileptic aphasia, autistic disorder and selective mutism. General Principles of Assessment In most instances, detailed assessment of the speech and language system will be carried out by a specialist speechlanguage therapist, who will have extensive knowledge of linguistics and language development, the anatomy and physiology that support the language system, and access to a variety of assessment and intervention techniques. With regard to communication, the primary decisions for the practitioner to make at initial assessment are: 1 Is the child’s communication development delayed or disordered? 2 What aspects of communication are causing the most concern? 3 Is referral to speech-language therapy warranted? The first port of call in the assessment process is the case history. This will give the practitioner an opportunity to explore with the child’s parents who is concerned about communication, and precisely what they are concerned about. Although many parents will be concerned about their child’s language development, others may not be aware of difficulties with communication. These parents may not see language as the central problem, but will voice concerns about behavior, social skills and learning that may be related to underlying language difficulties. As part of the case history, it is essential to obtain from parents clear examples of what motivates the child to communicate and how the child achieves communication. For example, does the child communicate only to get his or her basic needs met? Does the child communicate to show others things that interest him or her? Does the child use words or phrases? If not, does the child gesture, vocalize and/or point in an effort to get the message across? In addition to concrete examples of the types of communication the child produces, it is also important to ascertain the types of communication the child can understand. Does the child follow an adult’s point or eye gaze? Can he or she follow simple verbal instructions out of context? For more able children this may not pose a problem, but they may have difficulty following a story or getting the point of a joke. Once the practitioner has gained an impression of the child from the parents, it will be necessary to determine directly the child’s current level of functioning. Throughout the rest of this chapter, we give specific signposts to impairment in speech, language and broader communication, and suggest standardized assessments in each of these domains that can assist in the diagnostic process (Table 47.1). However, it is usually preferable to start by observing the child’s communication in a less structured setting. This can be achieved by videoing the child playing with his or her parents or siblings in the clinic. If the child has some verbal language, this play session can be supplemented by asking the child to recall a favorite story, computer game or television program. During these informal tasks, the practitioner can make a number of important observations. The first concerns the child’s expressive language output. How long and grammatically complex are the child’s utterances? How rich is the child’s vocabulary? Does he or she struggle to find the words for common objects? Does he or she use gestures and facial expression? Is the speech fluent, or is the child’s speech peppered with hesitations and repetitions? What is the child’s voice quality like? Is he or she shouting and hoarse, or whispering inappropriately? Is the child intelligible, or are there numerous speech errors that impede understanding? Does the child tell a story as a coherent sequence of events, or does he or she get muddled and leave important events out? The next set of observations concerns the child’s understanding, which may be more difficult to gauge in this setting. Nevertheless, it can be revealing to observe how the child responds to the questions and comments of others. Are the answers appropriate to the questions? Does the child follow adult directions? Does the child understand the premise of a story or does he or she misinterpret key events? Does the child appear to understand the gestures and facial expressions of others? Can the child listen while engaged with something else, or must the adult focus his or her attention before speaking? Finally, these informal interactions enable the practitioner to observe other important behaviors. How and why does the child engage with the other people in the room? Does he or she look up when called? Is the child’s play creative and imaginative, or destructive and repetitive? Can the child stick with an activity, or is his or her attention span unduly short? Is the child frustrated when he or she is not understood? Does he or she try again? Does the child recognize when he or she has not understood something and ask for clarification? Is the child anxious, or does he or she quickly adjust to the new situation? In combination with the case history, this set of observations should provide the practitioner with a working hypothesis of the child’s strengths and weaknesses, which will guide the assessment process (see chapters 19 and 21). Speech Disorders Speech refers to the production of oral language, which is achieved by modifications to the vocal tract while a stream of air is breathed out from the lungs. Speech difficulties in children are not difficult to detect, but accurate diagnosis requires specialist assessment by a speech and language therapist. The main types of difficulty that are encountered are those affecting the distinctive production of speech sounds, fluency of connected speech, voice, and prosody (i.e., speech melody and intonation). Differential Diagnosis of Speech Sound Disorders All spoken languages encode meaning in terms of a small set of vowels and consonants: in standard British English there are 24 consonants and 20 vowels that can be combined to yield thousands of words. When a child’s speech is difficult SPEECH AND LANGUAGE DISORDERS 783 9781405145497_4_047.qxd 29/03/2008 02:54 PM Page 783

784 Table 47.1 Language assessments in common use in the UK. Assessment Phonology Goldman–Fristoe Test of Articulation–2 (Goldman & Fristoe, 2000) Diagnostic Evaluation of Articulation and Phonology (DEAP) (Dodd et al., 2002) Phonological Assessment Battery (PhAB) (Frederickson et al., 1997) Children’s Test of Non-word Repetition (Gathercole & Baddeley, 1996) Semantics MacArthur–Bates Communicative Development Inventories (Fenson et al., 2003) British Picture Vocabulary Scales–2 (Dunn et al., 1998) Expressive/Receptive One Word Picture Vocabulary Tests (Gardner, 2000) Test of Word Knowledge (ToWK) (Wiig & Secord, 1992) Syntax Renfrew Action Picture Test (RAPT) (Renfrew, 1988) Test for Reception of Grammar–2 (TROG-2) (Bishop, 2003b) Narrative The Bus Story (Renfrew, 1988) Expression, Reception and Recall of Narrative Instrument (ERRNI) (Bishop, 2004) Pragmatics Children’s Communication Checklist–2 (CCC-2) (Bishop, 2003a) Omnibus tests Assessment of Comprehension and Expression (ACE) (Adams et al., 2001) Clinical Evaluation of Language Fundamentals– Preschool (Wiig et al., 1992) and Clinical Evaluation of Language Fundamentals (Semel et al., 2003) Pre-school Language Scales–3 (Zimmerman et al., 1997) Reynell Developmental Language Scales–3 (Edwards et al., 1997) Test of Language Competence (Wiig & Secord, 1989) Test of Language Development–3 (TOLD-3) (Newcomer & Hammill, 1997) Age range 2–21 years 3–6 years 6–14 years 4–8 years 8–30 months 3–15 years 2–12 years 5–17 years 3–8 years 4 years–adult 3–8 years 6 years–adult 4–16 years 6–11 years 3–6 years; 5 years–adult Birth–6 years 1–7 years 9–18 years 4–12 years Description Naming task which samples all consonants and clusters of English in initial, medial and final word positions. Assesses spontaneous and imitated speech Picture materials elicit speech with goal of differentiating between articulation problems, delayed phonology and consistent versus inconsistent phonological disorder Tests of phonological processing: alliteration, naming speed, rhyme, spoonerisms, fluency and non-word reading A measure of phonological short-term memory; the child listens to non-words and repeats them Parent reports of words child understands and produces early communicative gestures and early word combinations Understanding of single words. Child matches spoken word to one of four pictures Child either names a picture (expressive) or matches a spoken word to one of four pictures Expressive and receptive semantics including definitions, antonyms, synonyms, multiple meanings Sentence elicitation task in which children describe what is happening in 10 different pictures. Scored for information content and syntactic complexity Child matches spoken sentence to one of four pictures. Assesses range of grammatical structures Provides age equivalent scores for story information and sentence complexity Narrative assessment that provides standard scores for information content, complexity of grammatical structure, comprehension of pictured story, recall of narrative Parental report of language and pragmatic behaviors in everyday situations. Provides standard scores Assesses sentence comprehension, inferencing, naming, formulating sentences, semantics, non-literal language comprehension, narrative Assesses basic concepts, syntax, morphology, semantics, verbal memory. Provides receptive and expressive as well as total language score Assesses listening comprehension, expressive communication and provides a total language score Measures receptive language (verbal and non-verbal) and expressive language, including structure and vocabulary Assesses higher level language skills such as inferencing, multiple meanings, figurative language, sentence production in conversational contexts Subtests measure both semantic knowledge and grammar 9781405145497_4_047.qxd 29/03/2008 02:54 PM Page 784

to understand, analysis of the pattern of errors will be helpful in distinguishing whether the difficulty is the result of a structural or motor impairment affecting the articulatory apparatus (i.e., a dysarthria) or whether other explanations need to be sought (Dodd, 2005). Usually, dysarthria will be accompanied by other evidence of physical or neurological impairment, and the production of speech sounds will be distorted or labored. Phonological Disorder Contrary to popular belief, most childhood problems with speech production do not have a physical basis. For many years there was a belief that children’s speech difficulties could be caused by “tongue tie,” which could be cured by cutting the frenum. However, surgery is seldom effective in improving speech and it is now recognized that interventions that train children to perceive and produce sounds accurately are more effective. The key point to note is that speech production involves more than articulation: in learning a language, the child has to integrate speech perception with production, and work out which sounds in the language are used to signal contrasts in meaning (i.e., correspond to phonemes). To illustrate the difference between articulation and phonology, consider the following: many native English-speakers have great difficulty in correctly learning to produce the French words “rue” and “roux” distinctively. This is because the vowel contrast in these words does not match the phonemes in English, where there is just one “oo” sound. This has nothing to do with the structure of the articulatory apparatus, and everything to do with perceptual experience of a language, which leads English-speakers to treat all instances of “oo” as one phoneme, where French-speakers divide the vowel space into two phonemes. Most cases of childhood speech production difficulties appear analogous to the problems of the second language-learner: they arise because the child has not learned to categorize speech sounds appropriately, and so may fail to differentiate sounds that are important for signaling contrasts in meaning. Over the years, a variety of terminology has been used to describe such difficulties, including functional articulation disorder and phonological disorder/impairment. Developmental Verbal Dyspraxia Sitting somewhat uneasily between dysarthria on the one hand, and phonological disorder on the other is the category of developmental verbal dyspraxia, also known as developmental apraxia of speech. An early use of the term was by Morley (1957), who applied it to children in whom the neuromuscular control of the articulators seemed adequate for all purposes except the rapid integrated movements used in speech. Such children might be able to imitate accurately a simple syllable or word, but would make errors if asked to produce longer words or connected sentences. Stackhouse and Wells (1997) noted that production of longer words may be inconsistent as well as inaccurate, so that “caterpillar” could be produced as “capertillar,” “taperkiller” or “takerpillar.” The term “dyspraxia” is taken from adult neurology where it describes a disorder of planning movement sequences that is not accounted for in terms of lower-level difficulties in executing individual movements. However, it is unclear whether motor programing is at the root of the inconsistent speech difficulties seen in children. Individuals with the clinical picture of developmental verbal dyspraxia often have major problems in perception as well as production of speech sounds, doing poorly on tests that require them to discriminate or classify sounds (Stackhouse & Wells, 1997). Some experts argue that developmental verbal dyspraxia is simply an unusually severe kind of phonological disorder in children, reflecting an underlying difficulty learning the categorization of speech sounds, rather than having motor origins. The jury is still out on this question, not least because different experts use different diagnostic criteria (Forrest, 2003). One way of bypassing diagnostic difficulties has been to use the more general term “speech sound disorder” (SSD) to encompass all difficulties of speech sound production in children that do not have a physical basis, without needing to specify whether they are motor-based or phonological in origin. Although such “lumping” of disorders might seem likely to obscure important differences between phenotypes, Lewis, Freebairn, Hansen et al. (2004) argued in its favor. They compared family pedigrees of children with verbal dyspraxia and children with other forms of SSD. Verbal dyspraxia showed very high familiality, but the disorder did not “breed true,” and affected relatives were more likely to have other forms of SSD or language impairment than to have verbal dyspraxia themselves. Lewis, Freebairn, Hansen et al. (2004) concluded that the principal difference between children with verbal dyspraxia and those with other SSD was in the degree of genetic loading for disorder. Assessment of Speech Sound Disorders Coplan and Gleason (1988) provided guidelines to help health professionals decide when to refer a child for speech assessment, based on a parent’s response to the question, “How much of your child’s speech can a stranger understand?” By 2 years, it should be possible to understand at least 50% of what the child says, by 3 years, 75%, and by 4 years the child’s speech should be completely intelligible. Referral should be considered if these cut offs are not met (see p. 786). Assessment by the speech-language therapist will involve examination of the articulatory apparatus. A history of difficulty with sucking, chewing, dribbling, licking or blowing should alert the clinician to the possibility of physical impairment, such as submucous cleft palate, or neurological impairment. Where there is facial dysmorphology or evidence of neurological dysfunction, referral to specialist medical services (pediatric neurology, otolaryngology or clinical genetics) is warranted. The speech-language therapist will construct a phonemic inventory of sounds the child is able to produce and will look for inconsistency of word pronunciations and the presence of “phonological processes” (i.e., consistent error patterns), such as replacing /k/ with /t/ so that “cat” becomes “tat” and SPEECH AND LANGUAGE DISORDERS 785 9781405145497_4_047.qxd 29/03/2008 02:54 PM Page 785

“take” becomes “tate.” Many of these processes are seen in the course of normal phonological development; however, an SSD is diagnosed when such processes continue beyond the normal age, or when there are numerous inconsistencies and atypical phonological processes. “Phonological processing” is a general term used to cover more subtle difficulties in using phonological information. Phonological awareness in particular is nowadays often targeted in assessment as research has demonstrated links with later literacy difficulties (Snowling & Stackhouse, 2006). This refers to the ability to manipulate the sound segments in the language and includes tasks such as rhyming, segmenting syllables and phonemes in words, identifying initial and final word sounds, and deleting, adding or transposing phonemes in words. Such problems can been seen in children with normal speech sound production but are often also seen in children with SSD, suggesting their difficulties do not involve the physical act of articulating speech, but rather the ability to perceive and categorize different exemplars of the same phoneme (Bird, Bishop, & Freeman, 1995; Stackhouse & Wells, 1997). An important point to stress is that although speech and language difficulties are not the same thing, they do often cooccur. We therefore recommend that any child who presents with a speech difficulty should have a full assessment of both speech and language. Prevalence, Causes and Correlates of Speech Sound Disorders Estimates of prevalence of SSD are hampered by inconsistencies in diagnostic criteria. Gierut (1998) cited a 1994 report from the US National Institute on Deafness and Other Communication Disorders which estimated that phonological disorders affected approximately 10% of preschool and school-aged children, and that in 80% of cases the disorder was severe enough to merit clinical treatment. At 6 years of age, the prevalence of “speech delay” was estimated at 3.8% in a US epidemiological study (Shriberg, Tomblin, & McSweeny, 1999). Campbell, Dollaghan, Rockette et al. (2003) identified a number of factors that greatly increased the risk of speech sound disorders in preschool children. These included male gender, limited maternal education and a positive family history of speech and language disorder. These authors also suggested that an accumulation of risk factors exerted a greater threat to developmental outcome than individual risks. Children with only one risk factor were 1.7–2.6 times more likely than children who had none of these characteristics to have speech delay at 3 years; children with all three risk factors present were almost eight times more likely to have speech delay at 3 years. Both family (Lewis, Freebairn, Hansen et al., 2004) and twin studies (Bishop, 2002; DeThorne, Petrill, Deater-Deckard et al., 2006) suggest a strong genetic etiology for SSD. Although verbal dyspraxia can follow an autosomal dominant pattern of inheritance in some families (Hurst, Baraitser, Auger, Graham, & Norell, 1990), in most cases there are numerous genes that contribute to risk of poor speech and language skills, rather than a single genetic mutation. To date, progress in the search for a molecular basis has been limited to one report of linkage to a site on chromosome 3 (Stein, Schick, Taylor et al., 2004). Intervention and Prognosis for Speech Sound Disorders A variety of techniques may be employed to improve speech intelligibility, and research to date suggests that no single treatment approach is appropriate for all children with SSD (Dodd & Bradford, 2000). Techniques might include using tactile and visual cues to enable children to produce the target sound accurately. This will be combined with repeated practice at producing the target sound in words with corrective feedback. More meta-linguistic approaches involve games and exercises to develop the child’s awareness of meaningful phonemic contrasts (Gierut, 1998). In a recent meta-analysis of the literature, Law, Garrett, and Nye (2004) found that phonological interventions were generally effective when compared with no treatment. The most effective treatments were those carried out by speech-language therapists, rather than parent-administered treatments, and those that lasted for longer than 8 weeks. Therapist-led treatments may incorporate a variety of techniques, such as “articulation drills” in which the child learns and practices correct production of speech sounds with visual aids such as cued articulation (hand gestures that illustrate the place and manner of articulation) or symbols (pictures of place and manner of articulation). Other techniques (e.g., Metaphon) emphasize a meta-linguistic approach to improving speech production (Howell & Dean, 1994). This treatment teaches sound “concepts” so that children learn, for example, the differences between “short” sounds (/t/ and /d/) and “long” sounds (/s/ and /f/). The therapy also utilizes “meaningful minimal contrasts,” in which the child is required to alter speech production to avoid ambiguity. For instance, if the child is “fronting” (producing /k/ sounds as /t/ sounds), the therapist might construct a game in which the child has to ask for “key” or “tea.” If the child intends to ask for the “key” but the therapist responds with the “tea,” the child is forced to adapt his pronunciation to convey his or her intended meaning. Many therapists will use a combination of techniques depending on the needs of the child, as there is currently no evidence that one method of treatment is more effective than any other method. The longer-term prognosis for children with isolated phonological impairments is much better than that of language impairment, especially if the phonological difficulties resolve by the time the child starts school. However, the child who starts school with phonological difficulties is at increased risk of long-lasting literacy deficits (Stothard, Snowling, Bishop, Chipchase, & Kaplan, 1998). Other Types of Speech Disorder Fluency Disorders Stuttering and stammering are two popular terms for dysfluent speech. Developmental dysfluency is characterized by CHAPTER 47 786 9781405145497_4_047.qxd 29/03/2008 02:54 PM Page 786