Drug Treatments for Autism: A Quick & Dirty History

A propos of this post at the New Republic, I've decided to do a timeline of all the different drug regimens that have been proposed --- and tested, usually on children --- as potential treatments for autism.

Autism, you were probably already aware, first came into existence as a diagnostic category in 1943, with Leo Kanner's paper "Autistic Disturbances of Affective Contact" in the journal Nervous Child*.

Kanner himself was convinced that his subjects' shared pattern of atypical development was a) a separate phenomenon from "childhood schizophrenia":

The combination of extreme autism ["autism" used here to refer only to that aloofness which makes up part of the developmental pattern being described, not --- yet --- as a name for the overall pattern itself], obsessiveness, stereotypy, and echolalia brings the total picture into relationship with some of the basic schizophrenic phenomena. ... But in spite of the remarkable similarities, the condition differs in many respects from all other known instances of childhood schizophrenia.

First of all, even in cases with the earliest recorded onset of schizophrenia, ... the histories specifically emphasize a more or less gradual change in the patients' behavior. The children in our group have all shown their extreme aloneness from the beginning of life, not responding to anything that comes to them from the outside world. ...

Second, our children are able to establish and maintain an excellent, purposeful, and "intelligent" relationship to objects that do not threaten to interfere with their aloneness, but are from the start anxiously and tensely impervious to people, with whom for a long time they do not have any kind of direct affective contact.

and b) inborn:

One other fact stands out prominently. In the whole group, there are very few really warmhearted fathers and mothers. For the most part, the parents, grandparents, and collaterals [???] are persons strongly preoccupied with abstractions of a scientific, literary, or artistic nature, and limited in genuine interest in people. ... The question arises whether or to what extent this fact has contributed to the condition of the children. The children's aloneness from the beginning of life makes it difficult to attribute the whole picture exclusively to the type of the early parental relations with our patients.

We must, then, assume that these children have come into the world with innate inability to form the usual, biologically provided affective contact with people, just as other children come into the world with innate physical or intellectual handicaps. ... [H]ere we seem to have pure-culture examples of inborn autistic disturbances of affective contact.

Disregarding Kanner's conclusions**, most psychiatrists of the time regarded autism (and schizophrenia, which was still seen as a closely related phenomenon) as a psychological response to family dynamics. Bruno Bettelheim, in particular, popularized the idea of the "refrigerator mother," which was to dominate both lay and professional understanding of autism through the 1950s, and into the '60s and '70s. By the '60s, however, some competing hypotheses had sprung up: There was Bernard Rimland's book Infantile Autism: The Syndrome and Its Implications for a Neural Theory of Behavior, which argued that autism, whether innate or not***, arose from biological rather than psychological causes, and there was Ole Ivar Lovaas, who pioneered the behavioral approach to autism --- i.e., it doesn't matter what causes it, as long as autistic children can be trained to emulate nonautistic ones.

At the same time, a number of drug therapies were being investigated, though with none too precise an idea of the mechanisms involved (see this 1942 article on the use of the powerful stimulant benzedrine in "neurotic" children displaying such eclectic symptoms as depression, "sexual tension," fear, anxiety, aggression, and "hyperkinesis"). The first drug treatment I'm aware of being proposed and tested specifically for autism is LSD (of all things!).

Here, from a 1962 study of the effects of LSD (and a similar compound, methysergide) on fourteen six- to ten-year-old children diagnosed with schizophrenia (but referred to in the article also as "autistic"), is the rationale:

[W]ith awareness of the current interest in LSD-25 as a therapeutic agent because of its psychotomimetic ["psychosis-mimicking," for you English speakers] properties, it occurred to us that LSD might be effective in breaking through the autistic defense, in chronically regressed, retarded, mute, and withdrawn children.
The theoretical interest in LSD as a serotonin inhibitor, with consideration of the possibility that serotonin is in some way related to schizophrenia, further justified this endeavor. Also, since LSD is an autonomic nervous system stimulant, it could be of particular value in treating schizophrenic children, in whom general tissue tone, especially the tone of the vascular system, and the pattern of the autonomic nervous system functions are impaired.

Since this first experiment with LSD was deemed a success, this avenue of research was pursued farther: another 1962 study of LSD in twelve "autistic schizophrenic" children; a larger study of "disturbed" children --- some autistic, some not; some verbal, some not --- coauthored by one of the authors of the study I quoted above; a pair of experiments on a set of very young autistic twin boys combining LSD dosage with a behavioral regime; and two reviews detailing a dozen or so other smallish studies were all published during the mid-1960s.

What was next? Well, in 1979 the Estonian-born neuroscientist Jaak Panksepp published "A Neurochemical Theory of Autism," in which he suggested that --- due to behavioral similarities between autistic children and animals dosed with morphine --- autism may be the external manifestation of an overactive endogenous-opioid system, and thus treatable with opiate antagonists like naltrexone or naloxone.

We recognized that much of the behaviour induced by low doses of narcotics was similar to the major symptoms of those autistic children who suffered disturbances of affective contact, as described by Kanner. Specifically, opiate-elicited symptoms corresponding to those observed in autistic children are as follows: (1) the opiate-treated animal does not appear to appreciate fully physical pain; (2) it does not cry as readily and spontaneously as normal animals; (3) it clings poorly; (4) it does not have a strong desire for social companionship; (5) it can show unusual learning effects characterized by extreme persistence of behaviour in the absence of external rewards (akin to the insistence on sameness by autistic children). The list of similarities suggests that the underlying neurochemical imbalance in autistic children may be excessive, or unusual, activity in their own endogenous brain opiate systems. Such a brain disturbance may block psychosocial development at its earliest stages - leading to failures in language acquisition and other idiosyncrasies in learning.

The opioid-excess theory, particularly its prediction that opiate antagonists would lead to more prosocial behavior in autistic patients, was tested in many, many small clinical trials throughout the 1980s and 1990s. Results of these have been uneven --- some found improvement, some found only modest, patchy improvement (particularly for decreasing self-injurious behaviors), some found no differences, and some actually found that patients taking naltrexone fared significantly worse than those on placebo. Overall, I'd call it a wash.

From the 1990s on, two trends have emerged as the dominant ones in pharmaceutical treatment of autism: antidepressants (specifically, SSRIs) and atypical antipsychotics. Here, too, effectiveness has been spotty, and the antipsychotics particularly can give rise to some truly nasty side effects. The rationale has shifted from seeking to correct any perceived underlying cause of autism (researchers are pretty sure they don't yet know what that would be) to trying to ameliorate some of the less pleasant things often associated with autism: anxiety, depression, obsessive-compulsive behaviors, self-injury, social withdrawal, hyperactivity, aggression and mood lability, among others.

(I also like how the thinking on serotonin's involvement in autism seems to have come full circle --- since the 1960s, higher levels of blood serotonin have been observed off and on in autistic people, and during the era of LSD experimentation, it was supposed that one of the ways LSD might act in a beneficial way for people with autism might be to tamp down this apparent overactivity of serotonin. Now, the approach toward serotonin is to make it more available for use in the brain, not less).

... Well, I guess I lied about the "quick" part of this Quick & Dirty History. Oh well. You win some, you lose some.

*Yes, I think that's a hilarious title for a medical journal.

**It must be pointed out that, even though he clearly states his belief that autism is probably innate, and biological, in origin, and though he often pooh-poohed Freudian notions of psychosexual development, Kanner was pretty ambiguous about this in his public pronouncements. He must have thought the interpersonal style of the autistic children's parents had some relevance, for he saw fit to emphasize it in this 1960 interview in Time magazine:

[T]here is one type of child to whom even Dr. Kanner cannot get close. All too often this child is the offspring of highly organized, professional parents, cold and rational --- the type that Dr. Kanner describes as "just happening to defrost enough to produce a child." The youngster is unable, because of regression or a failure in emotional development, to establish normal relations with his parents or other people.

Kanner then went on to write a second paper in 1949, "Problems of nosology and psychodynamics in early childhood autism," which did posit a role for "a genuine lack of maternal warmth" in causing autism. He seems to have been very much on the fence about the whole refrigerator-mother thing, evolving from believing autism to be innate, to suspecting maybe a chilly mother-child relationship might also be in play, to reiterating that autism is innate and hotly denying he ever suggested mothers might be to blame.

***Rimland later espoused the belief that vaccines could cause autism, so he clearly did not believe strongly that autism had to be genetic and inborn.