Medical Interventions for Autism

Autism spectrum disorder is a prominent mental disorder that follows children until the end of their lives, and much research is needed in order to ensure that patients and families are able to cope with its effects. 

According to Hodges et al., ASD is a developmental disability that describes a range of social, communication, and behavioral challenges that generally appear in the first two years of life (2020). Children affected by ASD may become disabled for the rest of their lives, perhaps never being able to communicate properly with others or live independently, or they may go off to live normally. As a spectrum, ASD poses a unique issue on how to specifically diagnose and treat it. According to the DSM-5, ASD is characterized by a combination of impairment in communication, social behaviors, and repetitive behaviors (American Psychiatric Association, 2013): 

1. Social Interactions 

   1. Nonverbal behaviors (eye contact, facial expression, body postures, etc.)

   2. Developing peer relationships 

   3. Lack of sharing interest with others 

   4. Lack of social or emotional reciprocity (sympathy) 

1. Communication 

   1. Delay in development of spoken or sign language 

   2. Impairment in ability to sustain a conversation 

   3. Repetitive use of language 

   4. Lack of social imitation (natural in reciprocating to others) 

1. Repetition 

   1. Preoccupation with objects or interests with abnormal intensity 

   2. Inflexible to changes in routines 

   3. Repetitive motor movements 

However, because ASD is diagnosed so generally, patients have diverse combinations of social and neurological impairments of varying severity. For example, those with Asperger’s syndrome have little to no trouble learning while others may have difficulty learning how to speak. Currently, there is no medication that can cure ASD, but there are some medications and behavioral therapy that can treat certain behavioral symptoms associated with ASD, such as tantrums, self injury, and aggression. 

Medications - Risperidone 

For example, some medications target the mesolimbic pathway, or the “dopaminergic pathway,” which regulates the reward and motivation system in our brains. In one clinical trial, children were given risperidone, an antipsychotic drug used to treat mood disorders (Aman et al., 2009). Risperidone is an antagonist of dopamine receptors, meaning it blocks the receptors from connecting with dopamine which regulates the mesolimbic pathway. It also blocks the serotonin receptors, meaning it blocks excess serotonin stimulation that leads to aggression, alpha a1 and a2 adrenergic receptors, meaning it blocks excess adrenaline stimulation, and histamine H1 receptors, which may help in calming a patient.

Risperidone was discovered by the Janssen Pharmaceutical Research company for the Johnson & Johnson pharmaceutical company. During the 1970s and 1980s, the company had seen many discoveries with neuropsychiatric drugs, including fentanyl and haloperidol, which would be used as analgesic (preventing pain) and antipsychotic agents (Colpaert, 2003). 

Dr. Paul Janssen was a pioneer of a new technique called Drug Discrimination (DD) where rats were conditioned a certain behavior when they were given a certain drug (e.g. fentanyl) and to do a different behavior when they were given something else (e.g. saline injection). Experiments conducted using DD were interesting because the rats seemed to not develop tolerance for the opioid, a major problem which researchers had been struggling with for decades. Afterwards, researchers decided to try DD on rats to treat hallucinations and schizophrenia. 

Researchers used lysergic acid diethylamide (LSD) to induce hallucinations in rats, but they struggled to find another drug that could possibly counteract its effects. Their current research indicated that LSD might excite the dopaminergic (DA) and serotonergic (5-HT) systems in the brain, so they wanted a drug that could block both. Unfortunately, none of the discovered drugs did this, so they decided to discover a new drug, to what became risperidone. 

As a result, risperidone was one of the test drugs that were synthesized in the experimental phase of the research. To make it, the scientists added fluorine atoms to benzisoxazole, a basic chemical known to be synthesized into antidepressants, anti-inflammatory agents, antimalarial drugs, antipsychotics, antiviral agents, steroids, and anesthetics (Rakesh et al., 2017). Since benzisoxazole is a heterocyclic compound, it contains a ring of atoms of at least two elements, meaning it is aromatic and has increased stability. As a result, benzisoxazole’s chemical properties allowed researchers to change its structure to target specific receptors, such as the 1,2-benzisoxazole ring in risperidone to target dopamine and serotonin receptors. 

In other words, risperidone was discovered in order to complete a different experiment with LSD and Drug Discrimination. Moreover, the need for further experimentation led to the discovery of a drug that could be used to treat schizophrenia, a mental disorder that affects approximately 2.6 million adults in the United States (Wu et al., 2009).

The use of medicine to treat only downstream behaviors of ASD shows how broad the disorder is. In the clinical trial, children receiving risperidone and parental training seemed to be more relaxed and engaged in less serious maladaptive behavior. However, these only fix the symptoms, not the causes. Instead of specifying the causes of ASD, researchers struggle to define the different symptoms associated with it, including delayed communication development, repetitive behavior, and impaired social interaction. These three main symptoms are connected, but observably distinct. Moreover, when patients are diagnosed with only a select few of these symptoms, they are simply diagnosed with “pervasive developmental disorder” or PDD. This makes the problem very general and hard to treat for individualized cases. As a result, doctors, therapists, and psychiatrists have no choice but to only treat the surface-level symptoms, such as tantrums and self destructive behavior. 

Limitations with Preventative Treatments 

Some techniques are already being used in order to diagnose ASD, but they come with an even more worrisome problem. Microarray testing is used to detect insertions or deletions in large chromosomal segments, called copy number variants (CNVs), but not point mutations (smaller mutations). These tests compare the results with databases on autism spectrum disorder and try to match a percentage on how likely a child may develop ASD. However, since ASD can range in severity, a prenatal genetic test for the current “autism spectrum disorder” would be too general to be able to make an informed decision -- why would a mother choose to abort her child when they may only have minor symptoms? In a survey conducted with Taiwanese mothers of autistic children, the majority of mothers answered that they would do prenatal genetic testing (PGT) for autism, but abortion would be a different topic (Chen et al., 2021). Similarly, in the United States, another survey showed that mothers would only be concerned, not informed, if given an uncertain microarray testing that urged them to abort their child (Bernhardt et al., 2013). Current tests for ASD are simply not specific enough to make life-changing decisions. 

Moreover, since ASD also includes behavioral mechanisms, their brains change as they age, so it is hard to predict how autism can be tested before a child is born (van Rooij et al., 2018). Perhaps this means that autism is affected not just by one simple genetic mutation but a multitude of them affecting each other. One key area of study on ASD is how patients learn; according to a brain imaging study by the Johns Hopkins’ Center for Imaging Science, the thalamus and basal ganglia may provide clues on how different children learn (Di Martino et al., 2017). As a result, some adults are still able to adapt and learn differently to live out happy lives, as one study shows (Coderre et al., 2017). As a result, more research should be discussed in the fundamentals of language development in early stages of life as well as genes/chromosomal segments (such as mutations in SCN2A or 17q12 genes) associated with it. 

Citations

Aman, M. G., McDougle, C. J., Scahill, L., Handen, B., Arnold, L. E., Johnson, C., Stigler, K. A., Bearss, K., Butter, E., Swiezy, N. B., Sukhodolsky, D. D., Ramadan, Y., Pozdol, S. L., Nikolov, R., Lecavalier, L., Kohn, A. E., Koenig, K., Hollway, J. A., Korzekwa, P., Gavaletz, A., … Research Units on Pediatric Psychopharmacology Autism Network (2009). Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 48(12), 1143–1154. https://doi.org/10.1097/CHI.0b013e3181bfd669

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (7th ed.). https://doi.org/10.1176/appi.books.9780890425596

Bernhardt, B. A., Soucier, D., Hanson, K., Savage, M. S., Jackson, L., & Wapner, R. J. (2013). Women's experiences receiving abnormal prenatal chromosomal microarray testing results. Genetics in medicine : official journal of the American College of Medical Genetics, 15(2), 139–145. https://doi.org/10.1038/gim.2012.113

Chen, W. J., Zhao, S., Huang, T. Y., Kwok, O. M., & Chen, L. S. (2020). Autism Spectrum Disorders: Prenatal Genetic Testing and Abortion Decision-Making among Taiwanese Mothers of Affected Children. International journal of environmental research and public health, 17(2), 476. https://doi.org/10.3390/ijerph17020476

Coderre, E.L., Chernenok, M., Gordon, B. et al. Linguistic and Non-Linguistic Semantic Processing in Individuals with Autism Spectrum Disorders: An ERP Study. J Autism Dev Disord 47, 795–812 (2017). https://doi.org/10.1007/s10803-016-2985-0

Colpaert, F. C. (2003). Discovering risperidone: the LSD model of psychopathology. Nature Reviews Drug Discovery, 2(4), 315–320. doi:10.1038/nrd1062 

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Hodges, H., Fealko, C., & Soares, N. (2020). Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Translational pediatrics, 9(Suppl 1), S55–S65. https://doi.org/10.21037/tp.2019.09.09

Rakesh, K. P., Shantharam, C. S., Sridhara, M. B., Manukumar, H. M., & Qin, H. L. (2017). Benzisoxazole: a privileged scaffold for medicinal chemistry. MedChemComm, 8(11), 2023–2039. https://doi.org/10.1039/c7md00449d

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