by James O’Hanlon, Ph.D., Psychopharmacologist

Most individuals with ASD suffer some degree of expressive and/or receptive language impairment. For the higher functioning it may only be a relative inability to comprehend the nuances of verbal or nonverbal communication implying the attitude, emotional state or wishes of another person. For others on the spectrum, it may delay or even prevent the acquisition of spoken language. Those who do speak may do so in an abnormal way, sometimes limited to single words or short phrases, sometimes idiosyncratic and sometimes simply echoing what is said to them. Prosody, the normal intonation, tone, stress and rhythm of expressed language, may be replaced by monotonic speech. Receptive language may be similarly affected. The afflicted individual may be unable to comprehend the meaning of the same verbal cues in the speech of others.

The question addressed here is whether pharmacotherapy by itself or adjunctive to speech therapy can reduce the language deficits of this disorder. Discovery of abnormalities in brain cholinergic systems in deceased adults with ASD, and subsequent trials with medication to compensate for these supposed abnormalities in children with ASD, suggests that targeted pharmacotherapy might be effective. Different cholinergic systems arise from major neuron clusters, located in the basal forebrain and the brain stem. Different clusters project axons to the cortex, hippocampus and thalamus where axons release the transmitter, acetylcholine (ACh). ACh acts on two types of receptors, each comprising multiple subtypes. Projections to the cortex mediate cognitive functions including working memory and learning. Those to the hippocampus mediate the exchange of information between working memory and long-term memory. The exchange is critical because information in working memory in constantly changing and would be lost if it were not consolidated in long term memory; i.e., learned. The same is true in reverse. Learned information in long-term memory would be useless if it could not be transferred to working memory; i.e. recalled. It is noteworthy that the cholinergic system projecting to the hippocampus is the first to degenerate in Alzheimer’s disease. This is held responsible for its earliest symptoms; i.e., the progressive deficits in both learning and recall. The deficits can be slowed but not reversed by drugs that inhibit acetylcholinesterase, the enzyme that inactivates ACh after release. Though the drugs cannot prevent steady attrition of cholinergic neurons, they at least increase the effectiveness of ACh released by the survivors.       

Discovery of cholinergic deficits in ASD occurred in the United Kingdom where Elaine Perry and associates undertook four postmortem studies of brains from a total of 24 adults with ASD, comparing them with the brains of age and IQ matched control subjects. Their work revealed that several ACh receptor subtypes were expressed at lower levels in ASD than control brains. One in particular was expressed in the cortex at levels of only 27% to 35% of the average control level. The relevance of these results was recognized by independent investigators in Germany, Iran and USA who sought drugs to improve cognitive functions in children with ASD. They turned to acetylcholinesterase inhibitors approved for the treatment of mild Alzheimer’s disease: donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon). Some but not all the investigators chose to measure drug effects on expressive and receptive language. Those who did were handicapped by the lack of validated tests for measuring drug-induced improvement in language. In all, 8 trials involving 197 children and adolescents with ASD were undertaken before 2019. Doses as well as drugs varied between trials. All were small with as few as 8 and no more than 43 participants. Only 3 were placebo-controlled. As might be expected, results were equivocal and sometimes contradictory. But in 3 of the 4 trials where expressive and receptive language skills were measured, drug effects were positive.

The latest and most rigorously controlled trial was undertaken in Israel.1  It included 60 children with ASD, aged 5-16, who were randomly assigned to receive treatment for 3 months, double-blind, with either placebo or the combination of donepezil and choline, an ACh precursor and widely available nutritional supplement. Various clinical, intellectual and behavioral tests were applied before and after the treatment period, including those for expressive and receptive language skills. In a departure from the way drug trials are usually conducted, this one did not end with the conclusion of the treatment period. Rather, the children were brought back after a 6-month ‘washout’ period for another round of testing. Children using up to two psychoactive drugs prior to the trial were allowed to continue using them but to remain in the trial, they were not allowed to change them in either the treatment or washout periods.

Results pertaining to treatment effects on language skills were surprising to me but perhaps not to the investigators. There were no significant differences between drug/supplement and placebo treatments for either expressive or receptive language over the 3-month treatment period. None of the other measures changed significantly either, except one of dubious importance; i.e., an indication of disturbed ‘health and physical behavior’ not corroborated by parents’ reports. Stunningly, a highly significant treatment effect emerged 6 months after treatment had ended. Receptive language skills of the group treated with donepezil plus choline had continued to improve over the ‘washout’ period, whereas those of the placebo group remained the same. However, expressive language skills remained at previous levels in both groups. The implication is that pharmacological treatment started a self-perpetuating process in the brain that eventually improved the children’s ability to at least understand verbal language if not to use it themselves. One wonders whether their improved receptive language will eventually lead to better expressive language.

1 Gabis LV, Ben-Hur R, Shefer S, et al (2019). Improvement of Language in Children with Autism with Combined Donepezil and Choline Treatment. J Mol  Neurosci; 9(2): 224-34