Correspondence

Autism

N Engl J Med 1997; 337:1555-1557November 20, 1997

Article

To the Editor:

In her comprehensive review, Dr. Rapin discussed many aspects of autism (July 10 issue).1 However, we believe certain recent findings deserve greater attention than they received in the article. Evidence that abnormalities in central nervous system serotonin function have a major role in the pathophysiology of autism is compelling. It has long been known that many persons with autism have increased levels of whole-blood and platelet serotonin, accompanied by increased rates of platelet serotonin transport.2 In addition, a recent candidate-gene study revealed evidence of an association between autistic disorder and a variant of the promoter region of the serotonin transporter gene3; these findings are particularly intriguing in the light of the efficacy of inhibitors of the serotonin transporter in ameliorating autistic symptoms in some patients.

Also suggestive of a major role for serotonin is a recent double-blind, placebo-controlled study of short-term depletion of tryptophan in drug-free adults with autistic disorder, which found that 65 percent of patients had a significant worsening of behavior with active, but not sham, depletion.4 Since the symptoms of drug-free patients with major depression, obsessive–compulsive disorder, and panic disorder do not worsen after the depletion of tryptophan, these results suggest that serotonergic dysfunction may be more central to the pathophysiology of autism than to that of other psychiatric conditions, even disorders that generally respond to treatment with inhibitors of serotonin uptake.

The pharmacologic options for the management of autistic disorders has grown substantially in recent years. In a double-blind, placebo-controlled study of 30 adults with autism, fluvoxamine significantly reduced aggression, maladaptive behavior, and obsessive–compulsive symptoms and improved certain aspects of social relatedness, most notably language use.5 There may also be a role for atypical neuroleptic agents, particularly risperidone, a potent serotonin-2A–receptor antagonist. Preliminary analysis of data from a double-blind, placebo-controlled study of risperidone in adults with autism, performed at this institution, found that it produced significant reductions in aggression, repetitive behavior, and affective symptoms.

As our understanding of the etiology of autism advances, serotonergic dysfunction is clearly implicated.6 Such knowledge has immediate application in the form of new and superior pharmacotherapies for this often devastating disorder.

James G. Longhurst, M.D.
Marc N. Potenza, M.D., Ph.D.
Christopher J. McDougle, M.D.
Yale University School of Medicine, New Haven, CT 06519

6 References

1
Rapin I. Autism. N Engl J Med 1997;337:97-104
Full Text | Web of Science | Medline

2
Cook EH, Leventhal BL. The serotonin system in autism. Curr Opin Pediatr 1996;8:348-354
CrossRef | Medline

3
Cook EH Jr, Courchesne R, Lord C, et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997;2:247-250
CrossRef | Web of Science | Medline

4
McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53:993-1000
Web of Science | Medline

5
McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996;53:1001-1008
Web of Science | Medline

6
Potenza MN, McDougle CJ. The role of serotonin in autism-spectrum disorders. CNS Spectrums 1997;2:25-42

To the Editor:

In her review Dr. Rapin states that “children with autism may be affectionate, but . . . without the expected joy and reciprocity.” Furthermore, she suggests that the basic capacity for such emotions and activities as joy and intimacy, emotional reciprocity, pretend play, creativity, and abstract thinking only very rarely improve to any significant degree. Recent reports, however, show that many children evidence happiness, joy, and intimacy, but nonetheless meet the criteria for autistic-spectrum diagnoses because of the presence of perseveration and self-stimulation, language, cognitive, and peer-relationship dysfunctions. In addition, with an intervention program that factors in each child's individual differences in sensory processing, modulation, and motor planning and focuses on affective reciprocity, a number of children are capable of becoming joyful, loving, and communicative as well as empathetic and abstract in their thinking capacities.1,2

The review also ignores controversies regarding current diagnostic criteria (as in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders), which many believe are not sufficiently precise or prioritized. For example, current criteria do not give special weight to children's difficulties in forming and maintaining relationships (included by Kanner in his original description of autism3) over symptoms such as perseveration and self-stimulation, which are seen in many nonautistic motor-processing and sensory dysfunctions.4 . . .

Stanley I. Greenspan, M.D.
George Washington University Medical School, Bethesda, MD 20814

4 References

1
Greenspan SI, Wieder S. Developmental patterns and outcomes in infants and children with disorders in relating and communication: a chart review of 200 cases of children with autistic spectrum diagnoses. J Dev Learn Disord 1997;1:80-122

2
Greenspan SI. Infancy and early childhood: the practice of clinical assessments and intervention with emotional and developmental challenges. Madison, Conn.: International Universities Press, 1992.

3
Kanner L. Autistic disturbances of affective contact. Nerv Child 1943;2:217-250

4
Diagnostic Classification Task Force. Diagnostic classification of mental health and developmental disorders of infancy and early childhood. Washington, D.C.: Zero to Three, 1994.

Author/Editor Response

Dr. Rapin replies:

To the Editor: Longhurst and colleagues stress the important role of serotonin in the pathophysiology of autism, pointing out that depletion of the serotonin precursor tryptophan aggravated symptoms in 20 adults with autism1 and that the serotonin transporter gene appears to be linked to autism.2 However, in the study by McDougle et al.3 only half of the 15 adults with autism who were treated for three months with the specific serotonin-uptake inhibitor fluvoxamine responded. The specific serotonin-uptake inhibitors ameliorate obsessive–compulsive behavior and may improve language use in autism. Awareness of the potential usefulness of serotonin-uptake inhibitors in autism has already spurred the widespread clinical use of this class of drug, even before the publication of formal studies of safety, efficacy, and specific indications, especially in young children.

I hope that Longhurst et al. would agree with me that their provocative studies are preliminary, that it is much too early to recommend these drugs as a panacea for autism, and that they are certainly not curative. That there are other classes of drugs with beneficial effects on some of the symptoms of autism suggests that networks other than the serotonin network may be important. There is much more to learn about the complex interactions of the neurotransmitters and neuromodulators in the brain and their effects on human behavior. All of us who care for persons with autism want better pharmacologic agents, but at this point rejoicing may be premature and needs to be tempered so as not to inflate expectations beyond what is clearly established.

Dr. Greenspan indicates that mildly affected persons with autism do not necessarily have a gloomy prognosis.4 My experience coincides with his. One can teach less severely affected children with autism many skills if they are young and if the program is individually tailored to each child's particular needs. For example, in one study of play in preschool children, my colleagues and I found that high-functioning children learned to play with representational toys, but once they showed they knew how, there was no further elaboration of play — an indication of stunted creativity.5 What persons with autism lack is the ability to learn social skills on their own and to experience the full richness of deepening interpersonal interactions. It is not that children with autism are incapable of love or affection, but as described by Temple Grandin, “personal relationships are something I don't really understand.” 5 Children with autism do laugh and may feel happy, but they are unlikely to grasp what another person finds funny or pleasurable. Gifted persons with autism may reason at the highest level of abstraction, yet lack the most elementary common sense in everyday social situations. Certainly, some children with autism have a great deal of improvement and do well, but improvement is not synonymous with recovery. Autism is a lifelong condition, even in mild cases.

My review was not an appropriate forum for a discussion of the virtues and inadequacies of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and its subtypes of pervasive developmental disorder — or what I prefer to refer to as the autistic spectrum. The tails of behavioral classifications that rest on quantitative rather than categorical criteria overlap both those of other disorders and the extremes of what is considered normal.6 The most recent genetic studies7 suggest that behaviorally based subtypes of the autistic spectrum, despite their usefulness for prognosis and intervention, may not have the support of genetic criteria. Very mild or borderline cases coexist with classic autism within families.

Isabelle Rapin, M.D.
Albert Einstein College of Medicine, Bronx, NY 10461

7 References

1
McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53:993-1000
Web of Science | Medline

2
Cook EH Jr, Courchesne R, Lord C, et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997;2:247-250
CrossRef | Web of Science | Medline

3
McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996;53:1001-1008
Web of Science | Medline

4
Greenspan SI, Wieder S. Developmental patterns and outcomes in infants and children with disorders in relating and communication: a chart review of 200 cases of children with autistic spectrum diagnoses. J Dev Learn Disord 1997;1:80-122

5
Wainwright L, Fein D. Play. In: Rapin I, ed. Preschool children with inadequate communication: developmental language disorder, autism, low IQ. No. 139 of Clinics in developmental medicine. London: Mac Keith Press, 1996:173-89.

6
Plomin R, Owen MJ, McGuffin P. The genetic basis of complex human behaviors. Science 1994;264:1733-1739
CrossRef | Web of Science | Medline

7
Rutter M, Bailey A, Simonoff E, Pickles A. Genetic influences and autism. In: Cohen DJ, Volkmar FR, eds. Handbook of autism and pervasive developmental disorders. 2nd ed. New York: John Wiley, 1997:370-87.

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