Pharmacological treatment in Autism Spectrum Disorder. Update

Pharmacological treatment in Autism Spectrum Disorder is not etiological, but focused on certain symptoms

Joaquín Díaz Atienza

INTRODUCTION

With the new DSM-5 classification, all pervasive developmental disorders (autistic disorder, Asperger's syndrome, Rett syndrome, etc.) are grouped into a single category called Disorder of the Autism Spectrum (299.00; F84.0).

Ultimately, the aim of this new classification is to include under this category all those patients who present a series of nuclear symptomsSpecifying in each case the presence or absence of other disorders, as well as their severity. For example, if an Autism Spectrum Disorder (ASD) presents with the typical symptoms of Rett syndrome, this should be explicitly stated in the diagnosis (ASD associated with Rett syndrome). Similarly, any other medical or genetic condition or factor associated with ASD must be included.

Regarding severity, three levels are included: Level 1: needs help; Level 2: needs significant help; Level 3: needs very significant help.

The nuclear symptoms These are the following: 1) Persistent deficits in communication and social interaction; 2) Restricted, repetitive patterns of interests or activities; 3) Symptoms must have been present since early developmental stages; 4) They must cause clinically significant impairment in social, occupational, or other important areas of functioning; 5) These impairments are not better explained by other causes (intellectual disability or global developmental delay). Each of these core symptoms must be accompanied by its degree of severity.

This update follows the same structure as that of Nash and Carter (2016), which we supplemented with publications appearing after theirs during 2016. I consider its structure interesting because it presents current knowledge based on the target symptoms to be addressed, as well as the criteria to consider for their therapeutic indication. Irritability and aggressive behaviors, self-harm and hyperactivity – attention deficit.

These are not the only drugs used, although they are currently the ones with the strongest scientific evidence and the fewest side effects. First-generation neuroleptics, haloperidol, periciazine, etc., They have been relegated to the "reserve" due to side effects, although we must remember that they can be useful as a last resort.

REVISION

Irritability and aggressive behavior

These symptoms are quite common in ASD. When their level of interference with individual, school, work, and/or family life is significant and does not respond to behavioral interventions, pharmacological treatment may be indicated. Currently, the medications used are primarily the second generation neuroleptics due to the lower incidence of extrapyramidal effects. Specifically, risperidone and aripiprazole are commonly used.

a) Risperidone. It is approved in Spain and by the FDA for the treatment of ASD. A wide variety of clinical trials support its beneficial effects compared to placebo. Typically, improvements in irritability are seen in 56,7–64% of patients taking risperidone versus 14,1–30,7% taking placebo, depending on the specific clinical trials.

Regarding the use of risperidone, not only for irritability but also for other target symptoms, research is being conducted on pharmacogenetics To specify individual indicators of response and tolerability, some genetic variants have been highlighted regarding the enzymes involved in the metabolism and achievement of stable plasma levels of the drug, which could be useful to optimize the individual prescription of risperidone (Medhasi et al., 2016)

b) Aripiprazole. It can act pharmacodynamically as both an antagonist and a partial agonist at dopamine receptors. In the US, it is FDA-approved for the treatment of irritability in children with autism spectrum disorder (ASD) aged 6-17 years. Several clinical trials have demonstrated its beneficial effect on irritability, with significant reductions in the corresponding subscale of the [unclear - possibly "Autism Spectrum Disorder"]. Aberrant Behavior Checklist (ABA) The average difference was -13 points in patients treated with aripiprazole compared to -5 points with placebo. According to the latest update by Hirsch and Pringsheim (2016) for Cochrane, aripiprazole produces significant improvements compared to placebo in the short term. They therefore recommend that treatment be discontinued periodically, as its differences compared to placebo are not significant over time.

Self-harm/self-aggression

Self-harm is quite common in ASD and is usually related to irritability and frustration. It typically responds to non-pharmacological interventions, such as developing parental skills for managing irritability and frustration, extinction programs, response anticipation programs, and reinforcement and punishment programs. The presence of neurocognitive deficits has been considered a potential risk factor. The recommended approach is the simultaneous use of behavioral therapy and medication when the situation causes significant interference, either for the patient or the family. The most commonly used medications are:

a) Risperidone. VSeveral clinical trials have shown that risperidone is more effective than placebo in treating irritability, self-harm, and hyperactivity.

b) Aripiprazole. It has shown a therapeutic effect similar to risperidone in the treatment of self-harm/self-injury.

c) Naltrexone. This drug is based on the hypothesis that endorphins are elevated in patients who self-harm. Its aim is to block opioid receptors in order to lower the pain threshold. However, there is insufficient scientific evidence to recommend it as a standard treatment. Nevertheless, given that some cases have shown improvement in their self-harm, it remains recommended for cases that are refractory to other treatments with stronger evidence.

Hyperactivity/Attention Deficit

Hyperactivity and attention difficulties are very common symptoms in autism spectrum disorder (ASD). While a dual diagnosis of ASD/ADHD was not possible before the DSM-5, it is now, although it is not yet possible to do so in the ICD-10.

a) Methylphenidate. We cite two studies, one preliminary to a controlled clinical trial and the other a controlled trial. The study prior to inclusion in the double-blind, low-dose, immediate-release methylphenidate trial demonstrated that patients with ASD can improve their hyperactivity and attention deficit with lower doses than those prescribed for children with ADHD, and also showed poorer tolerability to psychostimulants in patients with ASD. They conclude that patients with ASD may exhibit greater sensitivity to psychostimulants, therefore rigorous follow-up measures must be taken (Posey et al., 2005). Regarding the controlled clinical trial (Pearson et al., 2013), it yielded very promising results, although no further trials have been conducted. I believe the results obtained are overly positive, possibly due to diagnostic biases. Indeed, my experience does not align with the findings of this research; in fact, an increase in stereotypies and obsessive or ritualized behaviors, so common in ASD, is frequently observed.

b) AtomoxetineIt is a norepinephrine reuptake inhibitor and has been proposed as an alternative to psychostimulants. Indeed, some uncontrolled studies have shown improvements in hyperactivity greater than those observed with placebo.

It appears that standard treatments (psychostimulants and atomoxetine) for ADHD do not produce the same good results in ASD patients with hyperactivity symptoms, which would probably indicate that the etiopathogenesis is not the same in both disorders.

c) Clonidine. It is an alpha-2 agonist that has been widely used in ADHD. Regarding its prescription for ASD, while it does produce improvements in hyperactivity, there is a high rate of discontinuation due to its side effects, especially hypotension and drowsiness. Therefore, guanfacine, another alpha-agonist, is being investigated because it is believed to produce fewer side effects.

d) Guanfacine. I wanted to do a more detailed review of guanfacine since it is a drug that has just been marketed in Spain for the treatment of ADHD.

In 2004, Posey et al. conducted an open-label study concluding that guanfacine is effective in treating hyperactivity and attention deficit in patients with ASD, although patients without intellectual disability responded better (17,9% vs. 37,3%, respectively). Handen et al. (2008) corroborated these improvements in their research and proposed it as an alternative to psychostimulants, although they highlighted that in 27% of cases, the dose had to be adjusted due to drowsiness and lethargy. The only randomized, double-blind clinical trial we found in the literature, which evaluated the therapeutic outcomes and side effects in 53 boys and 9 girls with ASD (mean age 8,5 years) using delayed-release guanfacine (Scahill L, 2015), concluded that it is indeed effective in improving both hyperactivity and attention deficits. The most frequent side effects were drowsiness, loss of appetite, and fatigue. Regarding blood pressure, it decreased during the first four weeks, returning to normal from the eighth week onward.

CONCLUSIONS

1. 1. Drug treatment is an option when other interventions have not been successful.

2. The most researched drugs are the risperidone and aripiprazole, demonstrating its effectiveness in both irritability and aggressive behavior, as well as hyperactivity and self-harm.

3. 3. The psychostimulants They are not a first option for treating hyperactivity, due to their side effects.

3. 3. Naltrexone It lacks sufficient scientific evidence to prescribe it routinely.

3. 3. Although they have been used clonidine and guanfacineIts scientific evidence is very limited. Perhaps guanfacine in its delayed pharmacokinetic form could yield better therapeutic results, although more research is needed.

3. 3. Although generally well tolerated, with risperidone and aripiprazole Special care must be taken with patients who gain weight rapidly, and in general, due to the possibility of generating insulin resistance and metabolic syndrome. Therefore, it is imperative to control in BMI and increase in fat tissue at the waist. With aripiprazole, It is recommended to perform treatment-free intervals in order to assess whether the therapeutic effect is maintained.

REFERENCES

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