This study provides an overview of the pharmacological management of ASD in children and adolescents through a retrospective review of patient medical files at a public hospital in KwaZulu-Natal, South Africa. A comprehensive list and description of pharmacological agents prescribed were analysed and reviewed.
While a number of pharmacological agents were found to be used in children with ASD, risperidone was the drug used most often. Risperidone is an FDA-approved agent for use in targeting the irritability and aggression associated with ASD in children (9). In this study, risperidone was prescribed to assist in the management of several comorbidities (irritability, aggression, disruptive behaviour, hyperactivity, and insomnia) as well as the core symptoms of ASD. Though its precise mechanism of action is not fully understood, the current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain (15). These dopamine and serotonin receptor antagonisms achieved by risperidone are believed to be responsible for the beneficial effects on ASD. The effects of risperidone on aggression, irritability stereotypes, tantrums, and restlessness can be attributed to dopamine antagonism. The effects on communication skills, restricted activity patterns and the ability to respond emotionally and socially can be considered a result of serotonin antagonism (16).
Although both risperidone and aripiprazole are FDA-approved agents for use in ASD (17), aripiprazole was only prescribed after consultation with a psychiatrist for a single patient with severe ASD who did not respond to risperidone. The limited use of aripiprazole would be an indication of adherence to standard treatment guidelines in South Africa, which lists risperidone as the only drug for the management of irritability, aggression, or self-injurious behaviour in children diagnosed with ASD (18). The switch from risperidone to aripiprazole in this study is in line with an international prospective study which concluded that aripiprazole might be generally well tolerated and may constitute an alternative treatment for individuals with ASD who experience poor efficacy or tolerability issues with risperidone treatment (19).
In addition to risperidone, methylphenidate was also frequently prescribed to children in the study. This could be due to 57% of children presenting with ADHD or hyperactivity symptoms. Methylphenidate is pharmacologically classified as a stimulant and is widely used as the first-line treatment in children with ADHD. The mechanism of action of methylphenidate is related to the release of dopamine and norepinephrine in the central nervous system (20). Various international studies (21–23) also support the use of methylphenidate to manage hyperactivity and ADHD symptoms in children diagnosed with ASD.
Sodium valproate was also a frequently prescribed drug (16%) and indicated for the management of epilepsy or seizures in this study. A variety of other drugs were also prescribed to manage epilepsy symptoms and included lamotrigine, clonazepam, levetiracetam, and topiramate. Epilepsy is reported to co-occur in individuals with ASD and studies across the world have found prevalence estimates ranging from 4 to 38% (24). Additionally, several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable anti-epileptic drugs for individuals with ASD (25). Although there are limited studies on the pharmacological management of epilepsy in children diagnosed with ASD, there is no evidence that seizures in children with ASD respond any differently to anti-epileptic drugs than seizures in children without ASD (26).
Cognitive impairment appeared in 16% of study subjects with ASD; however, it was unclear if any medication was prescribed to directly influence the management of this impairment. Additionally, neurodevelopmental regression appeared in 4% of children in this study. This condition is characterised by an initial normal social, emotional, and language development followed by loss of speech and social skills for no discernible reason (27). All children that presented with this condition were prescribed risperidone, either to treat additional comorbidities that the child presented with, and/or positively influence the symptoms of this condition. An interesting yet distressing observation was that a large number of children (48%) presented with two or more medical comorbidities simultaneously. According to the DSM-5, 70% of the time a diagnosis of ASD is accompanied by an additional comorbidity, and 40% of the time by two or more additional comorbidities of diagnosis (28). Additionally, an international study conducted to investigate the possibility of predictive patterns of ASD comorbidities in children, found there was an increased risk for seizures and sleep problems to co-occur with gastric disturbances, and behavioural impairments were also more severe as the number of co-occurring medical symptoms increased (29).
Common psychiatric comorbidities presented by children in this study included ADHD, aggression, disruptive behaviour, irritability, sleep dysregulation, anxiety, self-injurious behaviour, cognitive impairment, and neuro regression. Psychotropic medications are frequently used to target psychiatric symptoms in children with developmental conditions, despite limited evidence for their efficacy therefore clinicians should always use these drugs with caution, carefully weighing risks and benefits, and as a part of a comprehensive personalized approach (30). In this study, the likelihood of psychotropic drug combinations among children with ASD was highest among the 7–9-year-old age group (p = 0.03) and it was also evident that males across all age groups required a combination of psychotropic drugs more often than females. This is in line with a recent study that concluded that during early childhood, girls with ASD tend to show a greater reduction and less rise in their ASD symptom severity than boys with ASD (31).
The core symptoms of ASD recorded in this study included restricted, repetitive behaviours and social communication challenges. Despite the limited treatment options for ASD core symptoms, 20% of children displayed significant improvements in social communication impairments and/or restricted repetitive behaviours and the majority (83%) of them were prescribed risperidone either to target the core symptoms of ASD and/or manage a comorbidity. Various international studies also support the use of risperidone for the management of the core symptoms either as monotherapy (32) or with the addition of other therapeutic agents (33, 34). Targeting the core symptoms of ASD is of vital importance as these symptoms define ASD. A suggestion would be for prescribers to research current literature available regarding additional effective pharmacological management options for ASD core symptoms. As an example, recent clinical trials that utilise therapeutic agents like bumetanide (35), intranasal oxytocin (36), guanfacine (37), intranasal vasopressin (38), vitamin D (39), and omega fatty acids (40) have all demonstrated promising results on the core symptoms of ASD. It’s important to note that these therapeutic agents are still under study and evaluation and their usage to manage the core symptoms of ASD also depends on the availability of a drug in a particular country.
It is important to highlight the use of non – pharmacological therapies in conjunction with pharmacotherapy in the management of ASD in children. Non-pharmaceutical therapy can effectively relieve the core symptoms of ASD, has fewer side effects than drugs, and is easily accepted by patients (41). In this study, 44% of patients were receiving speech and/or occupational therapy and in 23% of patients, these types of therapies were recommended by the prescriber. Currently, no medication can cure ASD or manage all of its symptoms, however, research shows that medication is most effective when used in combination with behavioural therapies (42).
Previous international studies on the pharmacological management of ASD focus mainly on psychotropic drug use (43–45) while other studies involve reviews on drug treatment for a single type of ASD comorbidity (46–48) or an additional study focused on the prevalence of co-occurring conditions and medication use in the management of comorbidities among individuals with ASD (49). This study provides a review of the pharmacological management of comorbidities and core symptoms of ASD, therapeutic outcomes, and psychotropic drug usage in children diagnosed with ASD. Additionally, the results from the study were compared to various international trends. Interestingly, this is also the first known type of study to be conducted in a clinical setting in South Africa. This is taking into consideration, the study in the Western Cape related to the pharmacological management of ASD, conducted almost a decade ago in a school with a sample size of 65 pupils (13). As a recommendation, additional studies could be conducted in other provinces and could also include the private sector to obtain a more generalised summary of the role of pharmacotherapy in the management of ASD in South Africa.
Limitations
The results of this study are from a single hospital based in one district of the province of Kwa-Zulu Natal, however, this was a referral hospital and included patients from different locations throughout the province. The study was conducted in a public hospital setting therefore the therapeutic agents prescribed may differ from a private hospital setting as public hospitals in South Africa are required to adhere to standard treatment guidelines (18) and essential drug lists (18) when prescribing medication.
The study included a review of patient files with initial hospital visits from January 2019 to January 2022 only, therefore it does not reflect the total number of ASD patients that have visited the hospital. Additionally, the hospital utilises a manual filing system and this presented the challenging task of searching through the medical records of every patient that visited the hospital to locate patients that met the study inclusion criteria. Furthermore, medical records were filed according to the child's date of birth, and ASD patients were not filed separately from patients with other types of neurological disorders. Due to these challenges with locating patients, it is difficult to interpret the 181 patients included in the study as an exact numerical representation of patients that met the inclusion criteria for this study.