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Autism and Autistic Disorder
Eleanor J. Rutherford, MD
Autistic disorder is the best known of the pervasive developmental disorders. It is characterized by sustained impairments in reciprocal social interactions, communication deviance, and restricted, stereotypical behavioral patterns. According to DSM-IV, abnormal functioning in the above areas must be present by age 3 years. More than two thirds of autistic persons function on a retarded level.
Most of the epidemiological surveys have found rates of 4 to 5 out of 10,000. However, recent studies have found higher rates, which may be attributed to more thorough case ascertainment, more uniform (or perhaps broader) diagnostic criteria, and, in some studies, earlier age at assessment.
The higher incidence of autism in boys than in girls has been well documented, with ratios of 2.6 to 1 common and ratios up to 4 to 1 found in some studies. Girls are often more severely affected than boys, however, and on average score lower on intelligence tests.
Early clues to the biological basis of autism included the high rate of associated mental retardation, the 4 to 1 male-female ratio, the increased incidence of seizure disorders, and the recognition that medical and genetic conditions such as congenital rubella and untreated phenylketonuria could be associated with the syndrome. It is now believed that autistic disorder is a behavioral syndrome that can be caused or influenced by diverse conditions that adversely affect the central nervous system (CNS). The biological abnormalities underlying the disorder are currently unknown, and most cases do not show an association with a known genetic or medical disorder or with obvious CNS damage.
Results of family and twin studies have established the likelihood that genetic factors may influence or contribute to the development of autism. Three twin studies comparing concordance rates for autism in monozygotic and same-sex dizygotic twin pairs found concordance rates for autism in monozygotic pairs of 36, 50, and 89 percent, respectively, and a concordance of zero in dizygotic pairs. The finding of a high rate of cognitive deficits in the nonautistic monozygotic twins and an association with perinatal complications in their autistic cotwins led some investigators to hypothesize an inherited cognitive liability that, when accompanied by a perinatal insult, results in autism. Other researchers, however, believe that studies would show higher concordance rates if the nonautistic monozygotic cotwins with cognitive-linguistic and social deficits were considered part of an autistic spectrum; they suggest that it is autism, not a cognitive disorder, that is inherited.
The fragile X syndrome is the second most important chromosomal etiology of mental retardation (after Down's syndrome) and the most important known cause of inherited mental retardation, with a prevalence rate possibly as high as 1 in 1,000. Although variable in expression, the syndrome is often characterized by mild to severe mental retardation, with the majority of affected persons being moderately retarded; less severely affected persons may present with learning disabilities. A cognitive profile indicating weakness in nonverbal spatial processing tasks and short-term memory and relative strength in skills requiring verbal reasoning has been proposed. Physical abnormalities include macroorchidism, prognathism, and big ears in 80 percent of affected postpubertal males and hyperextensible joints, which may be indicative of a connective tissue dysplasia. Clumsiness, grand mal seizures, and hyperreflexia are among the neurological findings that may be present. Frequently seen behavioral problems include hyperactivity, attention deficits, impulsivity, and anxiety. Autistic features such as gaze aversion, stereotypies, echolalic speech, and narrow and perseverative interests are frequently observed.
Since the association of autism and fragile X syndrome was first reported in 1982, estimates of the prevalence of fragile X syndrome in autistic populations have ranged from zero to 20 percent, with a pooled prevalence of 8 percent. Some investigators, finding low rates of the fragile X marker, believe the fragile X syndrome is associated with mental retardation, not with autism; others believe it is the most common known cause of autism. Differences in prevalence rates may have resulted from the manner in which autism was diagnosed and from ascertainment bias, for the use of institutionalized mentally retarded populations favored finding individuals with the fragile X syndrome. Differences among laboratories in the preparation of cell cultures, in the number of cells counted, and in the percentage of positive cells needed to make a diagnosis of fragile X syndrome may also account for the differences in prevalence rates. Although the association of fragile X syndrome with autism may be debated, there is a strong association of fragile X syndrome with social avoidance, irrespective of a diagnosis of autism. Research into that association may help elucidate the pathogenesis of autism.
A number of studies have shown an increased frequency of prenatal, perinatal, and neonatal complications in autistic children. The most frequently reported complications include bleeding after the first trimester and meconium staining of the amniotic fluid, an indication of fetal distress. One study found that maternal use of medication during pregnancy significantly differentiated autistic children from their normal siblings. Most studies finding an increased incidence of obstetrical complications in autistic children did not include a control group matched for I.Q., making it difficult to determine whether the complications were associated with autism or with mental retardation. One recent study comparing autistic children with their normal siblings, with normal children, and with I.Q.-matched controls found that delayed cry, respiratory distress syndrome, and neonatal anemia differentiated the autistic group from the control groups. Total obstetrical optimality scores (a rating based on a 61-item scale of prenatal, perinatal, and neonatal risk factors) were significantly lower for the autistic children than for all control groups.
The diagnosis of autistic disorder requires that a certain number of criteria in three symptom areas of social interaction, verbal and nonverbal communication and play, and repertoire of activities and interests be met. However, children meeting criteria for autistic disorder may appear very different from one another owing to differences in intellectual and language ability: Both the mute, aloof child and the one who asks grammatically perfect but inappropriately personal questions of strangers may be diagnosed with autistic disorder. The variability in phenomenology may lead to diagnostic errors, especially when children are at the extremes of intellectual functioning. In addition, certain behaviors characteristic of autism diminish with age, so that diagnoses made after childhood are not as reliable as those made in the preschool period, when many behaviors characteristic of autistic disorder are seen. The evaluation of autistic children requires a detailed prenatal and perinatal developmental, psychiatric, and medical history and a comprehensive medical examination that includes hearing, speech, and neurological evaluations. Neuropsychological testing, including I.Q. testing, should be performed. Because autism is believed to be a syndrome with multiple etiologies, it is important to rule out medical-genetic conditions that may underlie the disorder in a particular child.
Onset characteristically occurs before age 3 years and is marked by failure to develop language and failure to develop relatedness to parents--the most frequent reasons parents of autistic children contact health professionals. In addition, some parents fear that their child may be deaf, as the child may not respond when spoken to. Rarely, parents report that their child had normal social and language development but subsequently lost language and withdrew from social interaction.
| Physical examination (include measurement of head circumference, examination for minor physical anomalies and inspection of skin for adenoma sebaceum and hypo- and hyperpigmented areas) |
| Neurological examination |
| Neuropsychological testing |
| Hearing test |
| Test of visual acuity |
| Magnetic resonance imaging (MRI) |
| Electroencephalogram (EEG) |
| Cytogenetic study for chromosomal abnormalities, including fragile X screen |
| Blood lead level |
| Blood tests for inborn errors of metabolism, including phenylalanine and uric acid levels |
| 24-hour urine collection for mucopolysaccharidoses, uric acid, calcium |
The social impairment in autistic disorder was viewed by Kanner as the core deficit in a syndrome manifesting with myriad features. However, research in the past few decades was directed toward elucidating the cognitive and language impairments, thought by many to be primary deficits leading to a secondary disturbance in social interaction.
The nature of the social impairment in autism varies with the child's developmental level, and its severity often decreases as the child gets older. From the first year of life, autistic children may show an impairment in reciprocal social interaction, as seen in a failure to cuddle, failure to raise their arms in anticipation of being picked up, lack of imitation of speech and gestures, failure to point to or show objects to others, and abnormality of eye gaze behavior. For example, although autistic children may occasionally make eye contact when giving an object to an adult, they rarely make eye contact with an adult when both child and adult are watching something of interest. That last deficit, known as a deficit in joint attention--a concept well developed by 2 years of age--may be indicative of an inability to understand that a focus of attention or perspective may be shared. Reciprocal games such as patty cake and peek-a-boo may not appear. Although some autistic children may seem indifferent or unresponsive toward their parents' approaches or to separation from them, others may be anxious about separation and cling to their parents. Still others may be indiscriminately friendly and kiss strangers. Autistic children fail to develop social play with other children, often preferring solitary activities. The social aloofness seen in younger autistic children may decrease with age; nevertheless, although they may report an interest in making friendships, even the brightest children are hampered by an inability to understand many conventions of social interaction. That defect in social cognition may have its earliest roots in an inability to comprehend facial expressions or to express their own affective states vocally or by facial expression; those difficulties may underlie the autistic person's inability to relate empathically to others, which would preclude normal social interaction. Social interactions of autistic children have been divided into three groups: aloof, passive, and active but odd. Aloof interactions are seen in the most withdrawn individuals, who are usually indifferent to or upset by social approaches and show minimal attachment behavior and affection. Passive interactions are seen in those who accept social approaches and who may play with other children if the play is structured for them. Children with active but odd interactions spontaneously approach others, but the interaction is often inappropriate and one-sided. It appears that level of cognitive functioning distinguishes the groups, with the aloof-reaction group being the most impaired and the group exhibiting active but odd interactions being the least impaired.
Delays and abnormalities in language and speech are frequent presenting complaints of parents, and up to 50 percent of autistic children remain without spoken language. Babbling, which precedes words, may be absent. Autistic children often do not comprehend language spoken to them or have a selective disinterest. Autistic children without language often do not point or use gestures to communicate their needs but may grab their parents' hand and use it as a tool to get a desired object. Language, if acquired, is acquired slowly. Many autistic persons who acquire language have difficulty with semantics (the meaning of words and phrases), and all have difficulty with pragmatics (the use of language in context). Some children have difficulty understanding that a particular word represents a category of meaning, so that use of the word may be confined to the specific association and context in which it was learned; if categories are formed, they may be based on perceptual similarities rather than functional attributes. There may be difficulty in understanding that words can have multiple meanings. Words for which some understanding of context is required are particularly difficult to understand; examples are prepositions, directional verbs (give, take), and pronouns, which also require the child to shift perspective.
Autistic children often repeat words immediately heard (immediate echolalia) or heard in the past (delayed echolalia) without intent to communicate. When asked a question, they may repeat the question asked so that the pronoun is reversed or they are calling themselves by their own name; even when not repeating phrases, more able autistic children continue to reverse pronouns, calling themselves "you" long after normal children have learned to use pronouns correctly. They may talk to themselves, repeating jingles or snatches of dialogue heard on the television, or they may inappropriately repeat those phrases to another person in social situations where those phrases are irrelevant. Word use may be idiosyncratic or quasi-metaphorical; for example, a child may say the word "nine" each time he sees a train. One 5-year-old boy would sing "Mama little, little, is dressed that way" each time his mother wore a particular raincoat. Neologisms may be observed, as may close approximations to words and phrases, such as the boy who called teddy bears "stuffed-up animals."
Autistic children who do have communicative speech have difficulty having a conversation as they do not know how to take turns, maintain a topic, or look at their conversational partner. They may repeat questions over and over again even though they know the answer, or they may engage in lengthy monologues on subjects of interest only to themselves. Literal-mindedness, lack of flexibility, and concrete thinking preclude understanding humor, word puns, metaphor, and sarcasm in most autistic persons.
Autistic persons also show impairment in prosody, or the melody of speech. Their speech is often described as monotonous, wooden, or mechanical, or as having a singsong quality. There may be an overly pedantic, formal, uncolloquial quality to the speech of higher-functioning autistic persons. In addition, a person may have trouble modulating the voice volume and may be unaware of the need to lower the volume, depending on the social situation (for example, when in a restaurant or when discussing personal matters). Because prosody gives speech its affective coloring, the autistic person has difficulty expressing emotions through tone of voice.
Nonverbal communication is also impaired. Autistic children often do not use body gestures to communicate; they may not shake their head no or nod yes or wave good-bye. They are especially deficient in using expressive gestures to communicate their own emotional state or to acknowledge the emotional states of others such as by giving a pat on the back to give comfort, shrugging the shoulders to express resignation, or raising the eyebrows to convey suspicion.
Delays, deficits, and abnormalities in play are seen in autistic children. Play is stereotyped and repetitive and not creatively elaborated. Instead of building with blocks, autistic children may determinedly line them in rows. Instead of creating and elaborating imaginary roles, they may repetitively mimic a character from a television show. Autistic children show deficits in imaginative activity at different levels of symbolization. Some children never play appropriately with toys: Instead of pretending to dress or feed a doll, the child may bang it on a table; instead of rolling a toy truck along the ground, the autistic child may spin its wheels. Other autistic children are not as oblivious to the representational nature of toys and may play with them appropriately. More impaired is the ability to substitute one object for another, particularly if the substitute object bears no physical resemblance to the represented object (for example, using a stick to represent a horse).
Autistic children resist change in their environment and new routines. For example, the child may exhibit distress if the usual route to the supermarket is not taken or the bowl he or she is accustomed to eating from is not provided. New toys may be avoided for weeks. They may impose routines on others; one boy would cry if, when climbing up stairs, his mother did not start with her right foot. They may insist that parents repeat certain words or phrases. Interests are narrow, often idiosyncratic, and repetitive. For example, autistic children may spend hours flipping light switches, spinning bottles, watching sand flow through their fingers, collecting sticks, or memorizing the subway routes in the city. They may become attached to unusual objects and refuse to leave the house without them, as exemplified by the boy who carried around a dustpan. Children may not use objects correctly and instead may be preoccupied with parts of the object or with its sensory characteristics and may smell, mouth, or stroke the object.
Stereotypies are present in almost all autistic children and may include jumping up and down and hand flapping when excited, wiggling their fingers in front of their eyes, body rocking, or grimacing. They may enjoy spinning objects, twirling, and watching fans or washing machines rotate.
Approximately 75 to 80 percent are mentally retarded, with the majority functioning in the moderate range of retardation. The retardation is not a consequence of social isolation, lack of motivation, or negativity while taking intelligence tests. Autistic persons show a distinctive pattern on intelligence tests in that they perform worse on subtests that require verbal sequencing and abstraction abilities, such as the comprehension subtest, than on subtests that measure visual-spatial or rote memory skills, such as the information and block design subtests. Indeed, autistic children may perform better than matched controls on tests such as the embedded figures test, in which a smaller figure has to be discovered in a larger figure, paradoxically as a result of a cognitive deficit whereby context is ignored. Thus, performance scores are usually higher than verbal scores (although the reverse is often true in persons with Asperger's disorder).
Those findings and other findings from cognitive experiments have led to cognitive theories of autism. One hypothesis is that the lack of a central drive for coherence underlies the autistic disorder, creating both a fragmentary experience of the world and detachment from it. Another hypothesis is that autism is caused by the child's inability to attribute mental states to others, so that a theory of mind, whereby one person predicts another person's behavior by inferring his or her thoughts, beliefs, and feelings, is not developed. That theory would account for the lack of empathy and social cognition seen in autistic individuals. However, it does not account for the absence of basic social behaviors in autistic children before the age when a theory of mind develops. In addition, at least two studies have shown that people with Asperger's disorder are capable of solving problems requiring second-order thought attributions (predicting another person's behavior based on that person's belief about still another person's belief) but still show severe social impairment.
Intriguingly, some autistic persons exhibit so-called islets of abilities or splinter skills, such as perfect pitch or an excellent rote memory, or the ability to read material at a level far beyond that expected from intellectual performance (hyperlexia). Fifty percent of idiot savants--mentally retarded persons displaying extraordinary skills, such as calendar calculating, executing accurately detailed drawings of scenes from memory, or playing a piece of music after hearing it only once--are autistic.
Most autistic children display stereotypies, such as hand flapping and rocking, with the most severe stereotypies occurring in the most intellectually impaired. Motor mannerisms may be seen, such as odd posturing or "air writing," so named independently by two autistic boys who, for their own amusement, would spell words by tracing the letters with their index fingers in the air. Hyperactivity is common, especially in preschoolers. On the other hand, some children may be hypoactive, or hypoactivity may alternate with hyperactivity. Some children with pervasive developmental disorder exhibit inattention and impulsivity. There may be motor incoordination, tiptoe walking, and the assumption of odd postures. Some children are clumsy and may have trouble learning to tie shoelaces, brush their teeth, cut up food, or button shirts. There may be a delay in the disappearance of mirror movements.
Some children exhibit hypersensitivity to sound (hyperacusis) and cover their ears when they hear loud noises such as firecrackers exploding, dogs barking, or police sirens wailing. Other children may appear oblivious to loud noise but may be fascinated by the faint ticking of a wristwatch or the sound of crumpling paper. Bright light, including the examining light at the dentist's office, may be distressing, although some children are fascinated by lights. There may be extreme sensitivity to touch, and wearing certain clothes (of rough fabrics such as wool, or clothes with prickly labels) or even switching from short-sleeved to long-sleeved shirts when the weather changes may lead to tantrums. Some children, on the other hand, appear insensitive to pain and may not cry after a severe injury. Children may be fascinated by certain sensory stimuli, such as spinning objects, and many enjoy the stimulation of twirling, apparently not getting dizzy.
Sleep disturbances, such as reversal of sleep pattern and recurrent awakening at night, and eating disturbances, such as an aversion to certain foods because of their texture or smell, an insistence on eating a limited choice of foods (food faddism), a refusal to try new foods, or pica, can be very trying on parents.
Some autistic individuals show sudden mood changes and may laugh or cry for no apparent reason. It is not uncommon to see autistic children giggling to themselves. Some children are emotionally fragile. Excessive fears, sometimes of benign objects, and intense anxiety may characterize certain children. Separation anxiety may be intense. There are case reports of severe depression occurring in autistic adolescents.
Autistic children may bite their hands or fingers, which may lead to bleeding and callous formation. Head banging may result in welts and frontal bossing. They may pick their skin, pull their hair, bang on their chests, or hit themselves. The lack of a sense of danger commonly seen in autistic children may unintentionally lead to injuries. Temper tantrums are not uncommon, some children being easily frustrated or annoyed when demands are placed on them. Unprovoked aggressive outbursts may occur in some children.
Epileptic seizures occur in approximately 10 to 25 percent of autistic persons. The development of a seizure disorder is highly correlated with the severity of mental retardation and the level of CNS dysfunction. In most cases the seizures are grand mal seizures. It has been believed that autistic persons who develop seizures are more likely to develop them in adolescence, unlike mentally retarded persons, in whom seizures develop in early childhood. A recent study of 192 autistic children, however, found that the majority of the 41 who developed seizures did so in early childhood, with a second peak occurring in early adolescence. One longitudinal study reported the association of adolescent seizure development with deterioration in language, intellectual functioning, and inertia in a small number of cases.
Although most autistic children show improvement in social relatedness and language ability with increasing age, autistic disorder remains a lifelong disability, with the majority of persons so affected unable to live an independent existence and needing institutionalization or supervision.
| Criteria | Autistic Disorder | Mixed Receptive-Expressive Language Disorder |
|---|---|---|
| Incidence | 2-5 in 10,000 | 5 in 10,000 |
| Sex ratio (M:F) | 3-4:1 | Equal or almost equal sex ratio |
| Family history of speech delay or language problems | Present in about 25% of cases | Present in about 25% of cases |
| Associated deafness | Very infrequent | Not infrequent |
| Nonverbal communication (gestures, etc.) | Absent or rudimentary | Present |
| Language abnormalities (e.g., echolalia, stereotyped phrases out of context) | More common | Less common |
| Articulatory problems | Less frequent | More frequent |
| Level of intelligence | Often severely impaired | Though may be impaired, less frequently severe |
| Patterns of I.Q. tests | Uneven; lower on verbal scores than dysphasic patients, lower on comprehension subtest than dysphasic patients | More even, though verbal I.Q. lower than performance I.Q. |
| Autistic behaviors, impaired social life, stereotypies, ritualistic activities | More common and more severe | Absent or, if present, less severe |
| Imaginative play | Absent or rudimentary | Usually present |
Behavior therapy, which uses specific behavior modification procedures, may be helpful in establishing desired behaviors and eliminating problem behaviors in autistic children. After a behavioral analysis is performed, techniques such as shaping or prompting are used to develop desired responses, which are then reinforced by increasingly mature rewards. However, autistic children may fail to generalize the learned responses to other situations. In one study, very young autistic children who took part in an intensive behavioral program during which they received 40 or more hours of one-to-one behavioral treatment for two or more years showed significant improvement in I.Q. and higher levels of adaptive functioning than a control group of autistic children that did not receive the intensive treatment. By the end of the treatment period the experimental group included a subgroup of eight (42 percent) normal-functioning children who were able to be enrolled in regular classes. By contrast, no child in the control group achieved a favorable outcome.
With the recognition of the biological basis of autistic disorder came the realization that psychodynamic psychotherapy in young autistic children, including unstructured play therapy, was not appropriate. Individual psychotherapy, with or without medication, may be appropriate for higher-functioning persons who, as they get older, may become anxious or depressed as they become aware of their differences and difficulties in relating to others.
In a subgroup of autistic children with target symptoms, such as temper tantrums, aggressiveness, self-injury, hyperactivity, and stereotypies, appropriate psychoactive agents may be an important part of a comprehensive treatment program. Clinical and laboratory monitoring is recommended throughout pharmacotherapy. Periodic drug withdrawal (every six months) is recommended to assess whether there is continued need for treatment.
It was hypothesized that the stereotypies and hyperactivity seen in many autistic children were a function of increased dopaminergic activity. That was the rationale for the use of antipsychotics, which block dopamine receptors, in autistic children. In individually regulated doses of 0.25 to 4.0 mg a day, or from 0.016 to 0.217 mg/kg a day, the high-potency antipsychotic haloperidol proved more effective than placebo in reducing target symptoms. Side effects of sedation and neuroleptic-induced dystonia were seen at doses above therapeutic doses. No negative effect on learning or cognition was found, and in two studies haloperidol was shown to facilitate language development and learning in the laboratory. In one study that assessed the interaction of haloperidol and behavior therapy, the combination of the two treatments was superior to either treatment alone in facilitating speech acquisition. The efficacy of haloperidol is maintained over time, and the drug is especially effective in children who are angry, irritable, and emotionally labile. Tardive dyskinesia remains a significant untoward effect of antipsychotic treatment, with 29.27 percent of children who participated in a prospective study of haloperidol developing dyskinesias; 79.2 percent developed dyskinesia during drug withdrawal and 20.8 percent developed dyskinesia while taking the drug. Because stereotypies and dyskinesias often occur in the same body areas, particularly in the orofacial area, differentiating the two may be difficult, especially when stereotypies that had been suppressed by antipsychotic treatment reemerge on drug withdrawal. Therefore, it is important to make baseline ratings of abnormal movements in autistic children before commencing treatment with antipsychotics or any psychoactive agent.
In a double-blind, placebo-controlled study pimozide (Orap) (1.0 to 9.0 mg a day), another high-potency antipsychotic, was shown to be as effective as haloperidol in decreasing maladaptive behaviors. Pimozide may be more effective than haloperidol in treating hypoactive or normoactive autistic children, who frequently experience sedation on low doses of haloperidol without showing a decrease in maladaptive behaviors. The daily dosage should not exceed 0.3 mg/kg because of potential cardiotoxicity.
The finding of hyperserotonemia in one third of autistic children led to the hypothesis that autistic symptoms may be due to increased brain serotonin levels. That hypothesis in turn led to the study of fenfluramine, a serotonin depleter, in autistic children. In several studies fenfluramine was reported to decrease stereotypies and hyperactivity, increase intellectual functioning, foster language development, and improve social relatedness. However, those studies had serious methodological flaws. One well-designed double-blind, placebo-controlled study with random assignment of children having a narrow age range and which assessed cognition in a learning laboratory failed to show a difference for fenfluramine (optimal daily dosage range, 1.250 to 2.068 mg/kg) over placebo in reducing problem behaviors; learning was adversely affected by fenfluramine.
Similarities between the behaviors of autistic children and the behaviors of opiate addicts while intoxicated and during withdrawal led to the theory of opioid dysregulation in autism. Case reports and open trials involving a small number of children suggested that naltrexone, an opioid antagonist, reduced stereotypies, withdrawal, and hyperactivity and increased language production. In a recently completed double-blind, placebo-controlled study of naltrexone, the only significant finding in 41 autistic children, aged 2.9 to 7.8 years, who received dosages of 0.5 to 1.0 mg/kg a day of naltrexone was a decrease in hyperactivity; naltrexone had no adverse effect on learning in the laboratory, and the side effects of drowsiness, nausea, and vomiting were mild and transient. There was a suggestion that naltrexone might decrease self-injurious behavior.
The efficacy of amphetamines was investigated in autistic children because hyperactivity and inattention, frequently seen in such children, are ameliorated by amphetamines in nonautistic children with attention-deficit/hyperactivity disorder. Early studies of a large number of autistic children reported decreases in hyperactivity and increases in attention span, although severe behavioral toxicity and worsening of stereotypies were also observed. More recently, an open trial of methylphenidate (Ritalin) (optimal daily dose range, 10.0 to 50.0 mg) in nine autistic children resulted in a marked decrease in hyperactivity without major side effects.
Clomipramine (Anafranil), an antidepressant, inhibits the reuptake of serotonin, which has been implicated in the pathogenesis of autistic disorder. A recent double-blind, placebo-controlled crossover study found clomipramine to be superior to both desipramine (Norpramin) and placebo in decreasing obsessive-compulsive symptoms, anger, and core autistic symptoms, including withdrawal and abnormal object relations. The sample consisted of 7 autistic individuals aged 6 to 18 years. The mean dosage of clomipramine was 129 mg a day (4.3 mg/kg a day). However, in a recent pilot study conducted on eight hospitalized children, aged 3.5 to 8.7 years, clomipramine yielded therapeutic changes in only one child. Untoward effects were numerous and included acute urine retention, constipation, and behavioral effects indicating toxicity; the daily dosage ranged from 2.50 to 4.64 mg/kg (mean, 3.14 mg/kg a day).
The possibility that some symptoms of autism reflect hyperarousal and dysregulation of the adrenergic system led to the study of clonidine (Catapres), an alpha2 -adrenergic agonist that reduces noradrenergic activity. In one recent double-blind, placebo-controlled study, clonidine was found to be superior to placebo in decreasing certain problem behaviors. The transdermal administration of clonidine at a mean dosage of 0.005 mg/kg a day was associated with a decrease in stereotypies, withdrawal, hyperactivity, and temper outbursts in nine autistic male patients aged 5 to 33 years. A second double-blind, placebo-controlled study on eight autistic boys aged 5 to 13 years who were hyperactive and impulsive found modest decreases in teacher and parent ratings of hyperactivity and irritability; clinicians' ratings, however, failed to support an effect for clonidine.
The efficacy of various other psychopharmacological agents, including buspirone (BuSpar), propranolol (Inderal), and fluoxetine, in a few autistic persons has been reported.