REVIEW ARTICLE

Paediatr Drugs 2000 Jan-Feb; 2 (1): 67-81 1174-5878/00/0001-0067/$20.00/0 Adis International Limited. All rights reserved.

Autism
Current Theories Regarding its Pathogenesis and Implications for Rational Pharmacotherapy
Jan K. Buitelaar and Sophie H.N. Willemsen-Swinkels
Department of Child Psychiatry, University Medical Centre Utrecht, Utrecht, The Netherlands

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Aetiology: Genes and Environment . . . . . . . . . . . 2. Neurobiology . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Postmortem Studies . . . . . . . . . . . . . . . . . 2.2 Brain Morphology . . . . . . . . . . . . . . . . . . . 2.3 Brain Function . . . . . . . . . . . . . . . . . . . . . 2.4 Neurochemistry . . . . . . . . . . . . . . . . . . . . 3. Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . 3.1 Drugs Affecting Serotonergic Neurotransmission . 3.2 Drugs Affecting Dopaminergic Neurotransmission 3.3 Drugs Affecting Peptidergic Systems . . . . . . . . 3.4 Drugs Affecting Noradrenergic Transmission . . . 3.5 Miscellaneous Agents . . . . . . . . . . . . . . . . 4. Clinical Recommendations . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 68 70 70 71 71 72 73 73 74 76 76 76 76 77

Abstract

Autism is a pervasive developmental disorder that is aetiologically and clinically heterogeneous. Twin and family-genetic studies provide evidence for strong genetic components. An international consortium using an affected sib pair strategy has found a promising linkage to a region on chromosome 7. In 10 to 15% of cases autism is due to associated medical conditions that affect normal brain functioning. Postmortem studies on small case series report cellular abnormalities in the limbic system and cerebellum. Between 10 and 20% of individuals with autism have macrocephalia, which is in accordance with magnetic resonance imaging (MRI) findings of an increased total brain tissue volume and enlargement most prominent in the occipital and parietal lobes. The most robust and well replicated neurobiological abnormality in autism is an elevation of whole blood serotonin (5-hydroxytryptamine; 5-HT) found in over 30% of patients. Pharmacological interventions with serotonin reuptake inhibitors or with atypical neuroleptics that block both dopamine (D2) and serotonin (5-HT2) receptors seem to offer clinical benefit and merit further study.

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This review presents the current theories regarding the pathogenesis of autism and draws implications for pharmacotherapy. Autistic disorder (autism) is the prototype of a pervasive developmental disorder (PDD) and is characterised by (1) qualitative impairments in reciprocal social interactions, (2) qualitative impairments in verbal and nonverbal communication, (3) restricted repetitive and stereotyped patterns of behaviour, interests and activities, and (4) onset prior to age 3 years.[1,2] The prevalence of autism is estimated at 2 to 5 per 10 000, with numbers expanding to 10 to 20 per 10 000 if broader definitions are used.[3] The manifestations of autism vary greatly, depending on developmental level and chronological age of the individual. The majority of persons with autism exhibit serious social and communicative handicaps throughout life, but some improve enough to be able to live relatively independently as adults. About 75% of individuals with autism have associated mental retardation. The category of PDD [Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV)[1] includes, along with autism, a number of related conditions, such as Retts disorder, childhood disintegrative disorder, Aspergers disorder and pervasive developmental disorder not otherwise specified (PDD-NOS). Both Retts disorder and childhood disintegrative disorder are rare conditions. Retts disorder has been reported only in females and is characterised by an apparently normal development till age 5 months, followed by deceleration of head growth and by loss of purposeful hand skills and social and communication skills. Childhood disintegrative disorder is marked by significant regression in multiple areas of functioning following a period of at least 2 years of apparently normal development. While this condition is occasionally attributed to a paediatric neurological disease (e.g. metachromatic leucodystrophy), most cases remain of unknown cause. The essential features of Aspergers disorder are impairments in reciprocal social interactions and restricted stereotyped patterns of interest (as in autism), along with relatively
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intact language skills at age 2 and 3 years (in contrast to autism). Additional features may be motor clumsiness and motor delays, and recognition at a somewhat later age than autism, i.e. during the school age period. PDD-NOS is a residual category for individuals who present with severe developmental problems typical of PDD but who fail to meet the criteria of any of the specific PDDs mentioned above. Recent work regarding diagnostic algorithms for PDD-NOS has described the condition as a subthreshold category of autism with at least 4 of the 12 criteria for autism present, including one of the social interaction criteria.[4,5] Although both Aspergers disorder and PDD-NOS appear to be more common than typical autism, precise prevalence estimates are lacking. Since research on the pathogenesis and treatment of PDD has been focused almost exclusively on autism, the remainder of this paper is limited to a discussion of autism. Pathogenesis refers to both the constellation of aetiological factors to which the disorder may be ascribed and the neurobiological processes and abnormalities which may underlie aetiological mechanisms. 1. Aetiology: Genes and Environment There is substantial evidence from twin and family-genetic studies that autism has strong genetic components. The recurrence risk for autism following the birth of an autistic child is 60 to 150 times the population base rate.[6] Epidemiologically based same-gender twin studies have reported much higher concordance rates for autism among identical than among nonidentical twins.[7-9] For example, in one study the pair-wise concordance rate for autism was 69% for identical twins and 0% for nonidentical twins.[9] Furthermore, both family-genetic[10]and twin studies[9] found that the autism phenotype extends well beyond the traditional diagnosis and involves more subtle social, cognitive and communicative handicap that are similar to autism in quality, but differ markedly in degree. The difference in pair-wise concordance rate between identical and nonidentical twins is
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even larger when the broader phenotype rather than a narrow definition of autism is applied, and this results in heritability estimates of about 90%.[9] The mode of genetic transmission is unclear and the marked fall-off in rate of autism which occurs from identical to nonidentical twins or siblings suggests that a small number of interacting genes rather than one single gene is involved.[11] A recent full genome search for susceptibility loci in autism using affected sib pairs has resulted in linkage to a region on chromosome 7q.[12] Replication studies and further fine mapping of this region, including tests for linkage disequilibrium and analysis of candidate genes, are under way. In 10 to 15% of cases, autism is associated with known medical causes that affect normal brain functioning.[13] The level of associated medical conditions is as high as 35% for atypical cases which satisfy the criteria of PDD-NOS and is further a function of the severity of comorbid mental retardation. In part, these medical conditions associated with autism are also (mono-)genetic disorders such as fragile X, tuberous sclerosis, neurofibromatosis and phenylketonuria. Environmental causes such as infections resulting from congenital rubella, cytomegalovirus or herpesvirus have been described occasionally, but are quite infrequent causes of autism in current practice and, if operative, are most likely to give rise to atypical symptomatology. An interesting question, of course, is by which mechanisms these associated medical conditions lead to autistic symptoms. Is autism a nonspecific sequela of mental retardation or is it the result of disruptions in brain circuits which are specifically involved in social and communicative behaviours? Work on tuberous sclerosis suggests that the latter explanation is most likely, and that the extent and localisation of brain lesions is the key variable. Autism is significantly more common in tuberous sclerosis when, in addition to mental retardation, epilepsy is present and lesions are found in the temporal lobes and the limbic areas of the brain.[14] Obstetric complications have for some time been considered as an important environmental cause.
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This view was based on the finding that in discordant identical twin pairs the autistic twin was more affected by obstetric hazards.[7,8] Later findings, however, have strongly modified this view, identifying that obstetric hazards are consequences of genetically influenced abnormal prenatal development rather than independent aetiological factors.[15] These interpretations stress that: (i) the obstetric complications in the twin studies were mostly very minor; (ii) the association between obstetric hazards and autism in singletons is quite weak; (iii) postmortem studies of autism have not detected lesions typical of perinatal brain damage, and (iv) 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.[16] Recently, attention has been drawn to a report on a consecutive series of 12 children with a history of PDD who were reported to exhibit loss of acquired skills and intestinal symptoms, such as diarrhoea, abdominal pain and food intolerance. Extensive clinical investigations revealed chronic inflammatory bowel disease, associated autism (in 9 children) or related conditions (in 3) and an absence of focal neurological abnormalities.[17] According to the parents, the onset of behavioural symptoms was associated with recent measles, mumps, rubella vaccination in 8 children, with measles infection in 1 child and with otitis media in another child. It was suggested that a dysfunctional intestine played a part in the behavioural changes of these children, possibly as a result of increased permeability to gut-derived peptides from food which in turn may exert central effects and interfere with neuroregulatory processes. Treatment of the intestinal pathology, by prevention of constipation and administration of aminosalicylates, led to behavioural improvements in several children. The idea that some cases of PDD may be linked to a form of inflammatory bowel disease merits further research and confirmation.
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Among other issues, the following should be clarified: what percentage of children with inflammatory bowel disease present neuropsychiatric symptoms, in order to control for selection bias; and to what extent these children exhibit typical rather than atypical autistic symptoms. Conversely, studies indicate that a significant proportion of individuals with PDD have gastrointestinal symptoms, such as abdominal distension, constipation and chronic diarrhoea, which may be due to altered intestinal permeability.[18] A key question to be answered, of course, is whether children with PDD without intestinal complaints should be referred to paediatric gastroenterologists for further investigations. The second idea of this report, the suggestion of a relationship between bowel disease/autism and vaccinations or viral infections is much more problematic and unsubstantiated, since the relationship may well be merely coincidental and not causal.[19] The potential importance of a brain-gastrointestinal axis in autism has been further emphasised by case reports on dramatic improvements of social and language skills of children with autism following administration of secretin.[20] Secretin is a polypeptide that is present in the so-called S cells in the mucosa of the upper small intestine in an inactive form, prosecretin. When acid chyme with pH <4.5 to 5.0 enters the duodenum, secretin is released into the blood. Secretin causes the pancreas to secrete large quantities of fluid that contains a high concentration of bicarbonate ions. This provides an appropriate pH in the duodenum for the digestive action of the pancreatic enzymes. Although inflated by media claims and reports on the Internet (http://secretin.com and http://autism.com/ari), the available evidence of the effects of secretin in autism is rather limited and preliminary. Limitations include small sample sizes, inadequately characterised patients, poorly defined outcome measures and the absence of placebo-controlled and double-blind designs. Furthermore, in addition to reports of dramatic improvements, it should be appreciated that other cases do not show positive responses and some
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cases even show behavioural regression. Moreover, the risks of secretin administration are unknown. However, this does not detract from the merit of thinking about biological mechanisms which may be involved in the effects of secretin and which may underlie autism. For example, secretin receptors are present in the hippocampus, and secretin has also been found to bind to receptors of another peptide (vasoactive intestinal peptide) in the hypothalamus, cortex and hippocampus. In addition to a direct neuropeptidergic action of secretin, indirect influences may be involved as well, such as on the activity of brain neurotransmitter systems, brain circulation, or gastrointestinal permeability.[20] 2. Neurobiology There is overwhelming evidence that abnormalities of brain structure and function underlie the autistic syndrome. However, the following points are also clear: reported abnormalities are rather heterogeneous and based on studies of small samples; most reported abnormalities have not been replicated; findings specific to the core social and communicative deficits have not yet been demarcated from nonspecific findings; and neurobiological abnormalities have not been examined in a genetic perspective, leaving it open whether, where and to what extent genetic influences on autism produce aberrant brain morphology or brain function. In this section the focus is on recent findings from postmortem and brain imaging studies and on neurochemical evaluations. Neuropsychological, neurophysiological and cognitive studies fall outside the scope of this paper, and interested readers may consult other recent reviews.[9,21]
2.1 Postmortem Studies

To date, there have been only a few autopsy studies in autism. Reduced cell size and increased cell packing density have been observed bilaterally in the hippocampus, amygdala, entorhinal cortex, mammillary body, medial septal nucleus and anterior cingulate gyrus.[22,23] These structures are known to be connected to each other by interrelated circuits and constitute a major portion of the limbic
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system of the brain. In the cerebellum, a marked reduction in the number of Purkinje cells has been found, along with a preservation of olivary neurons. This suggests that these brain lesions are of prenatal origin. Since it is now recognised that the cerebellum is involved in a variety of cognitive and affective processes, abnormalities of the limbic system and cerebellum may be linked to the core social and communicative deficits in autism. Another report, however, while replicating the reduction in Purkinje cells, did not substantiate the elevated neuronal density in the hippocampus and found more widespread abnormalities in the cortex and brainstem.[24]
2.2 Brain Morphology

Recent evidence using different samples has shown that macrocephaly occurs in 10 to 20% of autistic individuals.[9,10,25] This is an important finding, since the mean head circumference of mentally retarded individuals in general is 2 or more standard deviations below the mean of normal children and adults. The age at which macrocephaly develops in autistic children is not yet known. An explorative study found abnormal rates of head growth in early and middle childhood in some (37%) children with autism, with only a few children being macrocephalic at birth.[26] Important questions for further research are at what age macrocephaly develops, and whether rates of head growth in autism are related to clinical course and/or distinguish subtypes of autism. It should further be clarified to what extent macrocephaly is familial and to what extent it occurs in family members who do not themselves have autism. Qualitative magnetic resonance imaging (MRI) has revealed, in some individuals with autism, cortical malformations that might indicate possible neuronal migration defects.[27] Furthermore, consistent with head circumference findings, a number of MRI studies of persons with autism have found an increased total brain tissue volume (excluding CSF), which was regional and not generalised, with the greatest enlargement in the posterior regions of the brain, i.e. the occipital and parietal lobes.[28-30]
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An area of controversy over the past several years has involved quantitative MRI of the size of the cerebellum and brainstem. Earlier claims of neocerebellar hypoplasia[31,32] have not been replicated. On the contrary, total cerebellar volume was recently found to be greater in individuals with autism than in controls, with the increase being proportionate to the increase in total brain volume.[33] Findings that the pons, midbrain and medulla are significantly smaller in autistic individuals[34-36] are not in accordance with reports from other groups[37,38] and are probably due to concomitant mental retardation rather than to autism. The size of the body and posterior subregions, but not of the anterior subregions, of the corpus callosum was noted to be smaller in individuals with autism than in controls.[39] Although the posterior localisation of the abnormal size of the corpus callosum is consistent with the reports of volume abnormalities cited above, the direction of the size differences is opposite to what might have been predicted. All in all, the presence of brain enlargement may provide important clues to underlying abnormalities in brain development, and further clarification of the timing of brain enlargement through longitudinal studies is called for. Three possible mechanisms have been proposed to explain brain enlargement: increased neurogenesis, decreased neuronal death and increased production of nonneuronal brain tissue. The finding of head circumference at birth being within the normal range and accelerated brain growth in the early postnatal period would be most consistent with the mechanism of decreased programmed cell death, since neurogenesis occurs foremost in the prenatal period.
2.3 Brain Function

A number of recent functional brain imaging studies in autism point to the frontal lobes as an area of the brain potentially involved in the pathophysiology of the disorder. A Single Photo Emission Computer Tomography (SPECT) study of regional cerebral blood flow reported frontal hypoperfusion in children with autism at the age of 3 to 4 years, which was found to be no longer presPaediatr Drugs 2000 Jan-Feb; 2 (1)

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ent at re-examination 3 years later.[40] A 31P MRI spectroscopy study in adolescents and adults with autism provided evidence for an abnormal pattern of phospholipid metabolism in the dorsolateral prefrontal cortex.[41] The severity of metabolic abnormality was found to be significantly correlated with executive function and language deficits.
2.4 Neurochemistry

Current interest in the neurochemistry of autism is focused predominantly on serotonin (5-hydroxytryptamine: 5-HT) and peptidergic systems. Studies of the dopaminergic and noradrenergic systems in autism have failed to reveal consistent abnormalities. The potential relevance of the dopaminergic system for understanding the pathophysiology of autism comes from observations in animal studies in which the dopaminergic system was found to be involved in hyperactivity and stereotyped behaviours. Neurochemical research in autism has included the measurement of the major metabolite of dopamine, homovanillic acid (HVA), in body fluids. The HVA levels in CSF[42-46] and in urine[47-51] of individuals with autism have been found to be equal as well as increased, when compared with those of control and contrast groups. The excretion of dopamine in urine has been reported to be lowered, whereas higher levels of dopamine were measured in whole blood of individuals with autism.[50] A recent positron emission tomography (PET) scan study suggested low activity of the frontal dopamine system in autism.[52] Elevation of the level of serotonin in whole blood of individuals with autism compared with normal controls is one of the most robust and well replicated findings in the neurobiology of autism.[53-55] The elevation is commonly observed in >30% of all individuals with autism, and the magnitude of the difference in mean level is about 25%. The importance of hyperserotonaemia in autism, however, had remained unclear for at least 2 reasons. First, the CSF levels of 5-hydroxyindoleacetic acid (5-HIAA), the breakdown product of serotonin, were not found to differ between individuals with autism and controls.[43-46] Second,
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hyperserotonaemia has also been reported in nonautistic individuals with mental handicaps.[56] Arecent attempt to resolve these inconsistencies regarding hyperserotonaemia in autism pointed to the importance of pubertal and racial factors when interpreting serotonin levels.[57] Hyperserotonaemia appears to be a function of pubertal status (measured in prepubertal but not in postpubertal autistic individuals) and was not found to be present in mentally retarded or cognitively impaired control individuals without autism.[57] Although the mechanisms underlying hyperserotonaemia have not been fully clarified, increased activity of the serotonin transporter of platelets and decreased binding to the serotonin 5-HT2 receptor have been observed.[58] Preliminary findings from candidate-gene studies indicate that the short variant of the promoter of the serotonin transporter gene in one report,[59] the long variant in another report[60] but not a polymorphism of the serotonin 5-HT2 receptor gene have been significantly associated with autism.[61] The clinical relevance of hyperserotonaemia for autism is further strengthened by reports of positive correlations of whole blood serotonin levels with clinical severity[61] and negative correlations with verbal-expressive abilities in autistic probands and their first degree relatives.[62] Findings concerning the central activity of serotonin metabolism are mixed. Measurements of serotonin metabolites in the CSF of autistic individuals have failed to demonstrate consistent abnormalities,[46] but neuroendocrine responses to pharmacological probes of the serotonin system were found to be blunted,[63,64] suggesting a low central tonus of the serotonin system. Using radioactive tryptophan as a tracer for serotonin synthesis with PET, unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys were observed.[65] Furthermore, acute dietary depletion of tryptophan, a precursor of serotonin, was associated with an exacerbation of stereotyped behaviours rather than with changes of social unrelatedness in drug-free adults with autism.[66] Any implication of serotonin in the pathogenesis of autism would be
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of great interest, given the critical role of serotonin during embryogenesis and maturation of the brain and its modulatory effects on a variety of important processes, such as sensory perception, motor function, learning and memory, and sleep, which are all often perturbed in autism. Since opioids have been found to be involved in maternal-infant attachment in animal studies by influencing feelings of social comfort and blocking separation distress reactions, it has been hypothesised that excessive activity of opioid systems in the brain would prevent the formation of normal social bonding in humans and contribute to the genesis and maintenance of autistic symptoms.[67] However, research on -endorphin levels in CSF and plasma of individuals with autism has yielded inconsistent results.[68,69] The finding that the levels of both -endorphin and corticotropin were increased in the plasma of individuals with severe autism in the absence of changes in plasma levels of cortisol most likely indicates that there is a heightened response to acute stressors rather than a chronic alteration of the basal level of functioning of these systems.[69] Another peptide that has been implicated in maternal-infant bonding and affiliative behaviour is oxytocin.[70,71] The potential relevance of oxytocin for the pathophysiology of autism is reflected in recent findings that plasma levels of oxytocin were significantly lower in individuals with autism than in normal controls, and that the pattern of associations with clinical measures was different for the autistic and the normal sample.[72] It should be appreciated, however, that attachment behaviour and social bonding per se are not abnormal in individuals with autism and that any neurobiological account of autism should explain why some social and communicative behaviours are impaired whereas others are relatively intact.[73] 3. Drug Treatment Given that the neurochemical basis of autism is unknown, there is as yet no place for pharmacotherapy based on defined pathogenesis of the core social and communicative deficits. The exception,
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perhaps, is intervention in the serotonin neurotransmitter system, which may be based on evidence for abnormalities in serotonin metabolism in a subgroup of individuals with autism. Other interventions of clinical utility have been developed more from a pragmatic perspective. This is not to play down the importance of medications for individuals with autism in the treatment of distressing or maladaptive target symptoms, such as hyperactivity, aggression, excitement, negativism and ritualised, stereotyped or self-injurious behaviours. Furthermore, clinicians should not hesitate to treat comorbid disorders, such as major depressive disorder or bipolar disorder, appropriately with medications. Drug treatment, however, should never be considered as a single intervention, and should always be part of a comprehensive, multidisciplinary treatment approach. When starting with medication, it is important to select appropriate targets of treatment and to monitor efficacy and adverse effects on a regular basis. A comprehensive approach to the treatment of individuals with autism usually includes a combination of structured and special educational techniques, individual behaviour modification, home training, family counselling, and placement in special schools or daycare centres. Detailed information about the principles, indications and effectiveness of behavioural and psychological treatment interventions may be found elsewhere.[74,75]
3.1 Drugs Affecting Serotonergic Neurotransmission

Early studies with fenfluramine, a halogenated amphetamine which promotes the release and inhibits the reuptake of serotonin and blocks dopamine receptors, reported dramatic improvements.[76,77] The results of a subsequent large-scale multicentre trial and a number of independent controlled trials, however, were mixed and initial claims could not be supported. In combination with the potential neurotoxity of fenfluramine[78] and reports of serious adverse effects,[79] this is sufficient reason not to recommend fenfluramine for clinical use.[80] Moreover, in many countries fenfluramine has
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now been withdrawn from the market because of these concerns over its tolerability. Clomipramine is a tricyclic antidepressant and a potent nonselective serotonin reuptake inhibitor. Treatment with clomipramine led to improvements of social relatedness, obsessive-compulsive symptoms and aggressive and impulsive behaviour in 4 out of 5 autistic patients aged 13 to 33 years in an open-label study.[81] These findings have been extended in another open-label study with clomipramine in 35 adults with PDD.[82] About 55% of these patients showed a significant treatment response and improvement in repetitive thoughts and rituals, aggression and social behaviour. In a controlled study in autistic children and adolescents aged between 6 and 18 years the response to clomipramine was compared with that of desipramine, a tricyclic noradrenergic uptake inhibitor.[83] Clomipramine was found to be superior to desipramine in improving social relatedness and anger/uncooperativeness, and both drugs were superior to placebo in decreasing symptoms of hyperactivity. Since treatment with clomipramine may result in troublesome and potentially serious adverse effects (such as a grand mal seizure because of the lowered seizure threshold), anticholinergic and cardiovascular adverse effects and behavioural toxicity,[84] our recommendation is to use this medication judiciously in children with autism. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), proved significantly more effective than placebo in a recent 12-week double-blind, placebo-controlled trial with 30 autistic adults.[85] Of the 15 patients who received fluvoxamine, 8 were categorised as responders. Apart from mild sedation and nausea, fluvoxamine was well tolerated. A similar study with fluvoxamine in autistic individuals younger than 18 years, however, could not establish a significant treatment response but documented a high rate of adverse effects and adverse behavioural activation.[86] Since fluvoxamine given in similar dosages to youngsters with obsessivecompulsive disorder (OCD) was found to be devoid of distressing behavioural activation,[87] children with PDD may be particularly sensitive to
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SSRIs. This suggests that the serotonergic system is differentially involved in PDD compared with OCD. Two other SSRIs, fluoxetine and sertraline, have been studied in autism. Fluoxetine was reported to improve 15 of 23 adolescents and adults with autism in an open-label study.[88] In a placebocontrolled study of 5 autistic individuals aged 10 to 30 years, only one improved moderately in compulsive symptoms on 20mg fluoxetine per day. Results from open-label studies of sertraline in autism have also been promising, with 24 of 42 adults rated as markedly improved following treatment with 50 to 200mg sertraline for 12 weeks.[89] The results with the SSRIs are encouraging in adults with autism who are characterised by strong behavioural rigidity and OCD-like symptoms. In contrast, children and adolescents seem to be very sensitive to the stimulating adverse effects of SSRIs and have a much lower response rate. Buspirone, an agonist of the serotonin 5-HT1A receptor with anxiolytic and mildly antidepressant effects, has been reported only in open studies. Buspirone 5mg 3 times daily for 4 weeks was given to 4 autistic children aged 9 to 10 years.[90] Two children showed clinical improvements, and no significant adverse effects were reported. Developmentally disabled adults with autism were treated in an open-label study with buspirone in dosages of 15 to 45 mg/day and showed a decrease of anxiety, temper tantrums, aggression and self-injurious behaviour.[91,92] We have successfully used buspirone 15 to 30 mg/day as an adjuvant in the residential treatment of disorganised and hyperaroused children with autism. Positive drug responses consisted of a reduction in affective lability and a decrease in anxieties and sleeping problems.[93]
3.2 Drugs Affecting Dopaminergic Neurotransmission

Of the classic neuroleptic drugs, haloperidol has been studied intensively for its effects and tolerability in autism. In a series of controlled investigations, haloperidol in dosages of 0.25 to 4.0 mg/day for 4 weeks was significantly effective in
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decreasing motor stereotypies, hyperactivity, withdrawal and negativism in a group of 2- to 8-yearold autistic children.[94,95] After 6 months of continuation treatment, haloperidol remained effective with 71.5% of the children, but left 20% unchanged and 8.5% worsened.[96] Short term adverse effects include dystonic reactions, acute dyskinesias, parkinsonism, akathisia, and autonomous and cardiovascular signs and symptoms. The long term efficacy of haloperidol is not well documented, however, and the risk for serious long term adverse effects such as tardive dyskinesias, induction of anxiety and depression, and weight gain is of great concern. In a prospective study of 82 autistic children treated with haloperidol, 24 children were found to develop dyskinesias.[97] The design of the study included a 6-month period of haloperidol treatment, followed by a 4-week period of placebo. In 5 cases tardive dyskinesias occurred, and in 19 cases withdrawal dyskinesias. All the dyskinesia symptoms disappeared spontaneously or after discontinuation of haloperidol. Pimozide, in dosages ranging from 0.25 to 4 mg/day, proved to be as effective as haloperidol in a multicentre controlled trial[98] and was found to decrease hypoactivity in autistic children.[99] The newer or atypical neuroleptics have received much interest over recent years, given their lower propensity to induce extrapyramidal adverse effects at therapeutic doses. In addition, the positive effects of the atypical neuroleptics on the negative symptoms of schizophrenic patients seem promising as a potential strategy to improve the core social deficits of individuals with autism. Pharmacologically, these newer neuroleptics block both dopamine (D2) and serotonin (5-HT2) receptor systems. To the best of our knowledge, clozapine has not been investigated in autism. A series of open-label studies in children, adolescents and adults have documented promising clinical improvements following treatment with risperidone.[100-105] For example, 20 children and adolescents with a developmental disorder refractory to other psychotropic treatments were successfully treated with
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risperidone in dosages ranging from 1.5 to 10 mg/day.[100] Common adverse effects of risperidone are weight gain and sedation. However, the risk of extrapyramidal adverse effects and tardive dyskinesias with risperidone is not totally absent and necessitates low dosage treatment, preferably in the range of 0.5 to 4.0 mg/day. In our clinical practice we recently treated 2 boys with autism who developed tardive dyskinesia when on risperidone. Both boys had symptoms in the oro-buccal region which disappeared over a period of some weeks after risperidone had been discontinued. It is further recommended to monitor weight gain carefully. Occasionally, an increase of hepatic enzymes and fatty infiltration has been reported following risperidone treatment.[106,107] National Institutes of Health (NIH)-sponsored placebo-controlled multicentre studies regarding the efficacy and tolerability of risperidone in children with autism are ongoing. A placebo-controlled parallel study in adults with autism and PDDNOS indicated that risperidone in dosages of 1.0 to 6.0 mg/day for 12 weeks was superior to placebo in improving irritability, aggression, and repetitive and affective symptoms.[108] Objective changes in social and communicative behaviour were not observed. The drug was well tolerated, the most prominent adverse effect being mild transient sedation. Psychostimulants are the first-line treatment of symptoms of hyperactivity, inattentiveness and impulsivity. Since individuals with autism are often hyperactive and highly distractible, treatment with stimulants would appear an obvious strategy. Earlier studies found that methylphenidate worsened symptoms such as stereotypies when used in hyperactive children with autism.[109,110] A recent double-blind crossover study in 10 autistic children aged 7 to 11 years, using placebo and 2 doses of methylphenidate (10mg and 20mg twice daily), showed that both doses of methylphenidate resulted in a significant decrease in hyperactivity. Troublesome adverse effects were found to be absent, particularly the worsening of stereotypic
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movements.[111] Negative effects of stimulants are thought to occur mostly with mentally retarded children with IQ below 45 or mental age below 4.5 years.[112]
3.3 Drugs Affecting Peptidergic Systems

The results of placebo-controlled studies in children with autism treated with naltrexone, an opiate antagonist which can be orally administered, were overall disappointing.[113-118] Although treatment with naltrexone in a dosage of about 1.0 mg/kg/day was consistently associated with a significant but modest reduction of hyperactivity, the social and communicative deficits and the stereotyped behaviours at group level were not ameliorated. Openlabel continuation treatment for a period of 6 months of 5 autistic children, who showed a clear individual response to naltrexone in the 4-week trial, did not reveal therapeutic effects on social and communicative functioning.[119] Furthermore, in a double-blind, placebo-controlled, crossover study in mentally retarded adults with autism and/or selfinjurious behaviour, naltrexone failed to affect self-injurious and autistic behaviour in a positive way.[120] Naltrexone has a bitter taste which can give rise to compliance problems. Adverse effects of naltrexone are mild and transient. On balance, we would not advocate naltrexone for the treatment of autism on a routine basis. The use of secretin for individuals with autism (see section 1) should at this stage be restricted to approved research protocols.
3.4 Drugs Affecting Noradrenergic Transmission

In open trials propranolol, a lipophilic blocker, was used to treat aggression, self-injury and impulsivity in developmental disorders.[122,123] It is necessary to perform an ECG before starting treatment to check for pre-existing cardiac conduction anomalies, and to monitor heart rate and blood pressure regularly because of the risk of bradycardia and hypotension. Contraindications to the use of -blockers are, among others, comorbid diabetes mellitus, obstructive pulmonary diseases and cardiovascular diseases.
3.5 Miscellaneous Agents

When the symptoms of a child show a cyclic pattern, or when for instance a bipolar mood disorder is suspected, treatment with lithium can be helpful. Successful treatments in autistic patients with periodic increases in symptomatology have been described.[124,125] Lithium can also be used in the treatment of aggressive and self-injurious behaviour in autistic patients.[126] Some 20 to 30% of children with autistic disorder also have epilepsy. Therefore anticonvulsants can play a role in the management of the disease. Carbamazepine is reported to have, as well as an anticonvulsive effect, positive effects on mood disorders and on aggressive, irritative or explosive behaviour in autistic children.[127] Open-label treatment with valproate also produced an improvement in behavioural symptoms associated with autism.[128] 4. Clinical Recommendations Medication may be considered for individuals with autism when target symptoms such as hyperactivity, aggression and self-injury, stereotypies and rigidity, and anxieties interfere with psychosocial adaptation or negatively influence the effectiveness of psychological and behavioural treatment approaches. For a number of these target behaviours, environmental manipulations and focused behavioural interventions may be as effective as medication.[74,75,129] Furthermore, incidental or episodic comorbid disorders such as depressive conditions may be a focus of pharmacotherapy. The
Paediatr Drugs 2000 Jan-Feb; 2 (1)

Two controlled studies[121] reported on the use of clonidine, a presynaptic 2-adrenergic receptor agonist. Clonidine was able to reduce hyperactivity, impulsivity and irritability on a short term basis. Clinical experience, however, indicates that many patients develop tolerance to the therapeutic effects of clonidine, which seems to limit its applicability in clinical practice. Reported adverse effects are an increase in drowsiness, decreased activity and hypotension.
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Table I. Clinical guidelines for pharmacotherapy in autism Target Hyperactivity, impulsiveness Medications Methylphenidate or other stimulants Atypical antipsychotics Clonidine Naltrexone Rigidity, rituals Selective serotonin reuptake inhibitors Atypical antipsychotics Aggression, self-injury Atypical antipsychotics Lithium

-Blockers
Anticonvulsants Clonidine Anxiety, affective symptoms Buspirone Atypical antipsychotics Clonidine

guidelines and dosages for the pharmacotherapy of autism are summarised in tables I and II. Hyperactivity and inattentiveness in a task-related context similar to that observed in attention-deficit hyperactivity disorder may be responsive to stimulant treatment, and should be differentiated from a lack of social attention associated with joint attention deficits and from being absorbed in preoccupations and interests. Clinical experience suggests that SSRIs are particularly effective in treating rigidity, rituals and stereotyped patterns of behaviour when interruption of these behaviours is accompanied by aggression or increased anxiety. 5. Conclusions Autism is a an aetiologically and clinically heterogeneous disorder, for which, as yet, no consistent neuroanatomical, neurophysiological or neurochemical abnormality has been found. Internationally concerted efforts are being made to unravel the genetic mechanisms of autism and to localise and ultimately identify genes involved. This has the prospect of potentially documenting new biochemical pathways to normal and abnormal social and

clinician should make a careful assessment of the risks and benefits of medications, since the database of well performed and controlled medication studies in autism is limited and our knowledge of, particularly, long term effectiveness and tolerability of drug treatment is incomplete. This should be communicated to the patient and/or their family in the process of obtaining informed consent. Clinical
Table II. Medication regimens for treatment of autism Medications Stimulants methylphenidate dexamfetamine Clonidine Naltrexone Atypical antipsychotics risperidone olanzapine Lithium 0.25-3 mg/day in 1-2 doses 2.5-15 mg/day in 1-2 doses Dosages

Comments Low dose regimen; be aware of induction of stereotypies and of psychotic decompensation

0.3-0.7 mg/kg/day (5-60 mg/day) in 2-4 doses 0.15-0.35 mg/kg/day (2.5-40 mg/day) in 2-4 doses Approximately 4 g/kg/day in 2-3 doses 0.5-2.0 mg/kg/day in 2-3 doses

Bitter taste Low dose regimen; be aware of weight gain, behavioural activation and extrapyramidal symptoms

To a serum concentration of 0.8-1.2 mEq/L 20-300 mg/day in 3-4 doses 25-300 mg/day in 1-2 doses 5-80 mg/day in 1-2 doses 25-200 mg/day in 1-2 doses 15-60 mg/day in 3 doses To a blood concentration of 4-12 mg/L To a blood concentration of 50-100 mg/L Low dose regimen; be aware of behavioural activation

-Blocking agents
propranolol SSRIs fluvoxamine fluoxetine sertraline Buspirone Anticonvulsants carbamazepine valproate

SSRIs = selective serotonin reuptake inhibitors.

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Correspondence and reprints: Prof. Jan K. Buitelaar, Dept. of Child Psychiatry, B.01.324, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: J.K.Buitelaar@psych.azu.nl

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