Pharmacobiological t...

Pharmacobiological treatments for ASD

 

Autism spectrum disorders (ASD) in young children and adults are characterized by problems in socialization, communication, emotion processing, and stereotyped/repetitive behaviors, along with sensory processing dysfunction, speech and language impediments, seizures, gastrointestinal issues, irritability, aggression, hyperactivity, and sleep disorders [1, 2]. Numerous underlying causes for ASD have been indicated such as genetic mutations, neurotoxicity and inflammation, impaired immune response, dysbiosis, nutrient imbalance, and oxidative stress [2].

Several treatment strategies have been undertaken in patients with ASD including behavioral and physiological interventions. Here, we review some of the physiology- and pharmacology-based interventions for ASD along with recent-advances in ASD treatment and their effectiveness in treating ASD. These include selective serotonin receptor-uptake inhibitors (SSRIs), antidepressants, antipsychotic drugs, stimulants, dietary supplements, herbal medications, special diets, hyperbaric oxygen therapy, stem cell therapy, and transcranial magnetic stimulation. Very limited data are currently available regarding the long-term effectiveness and side-effects of these existing treatments for ASD. So far, no medication has shown a consistent positive effect on patients with ASD.

 

Selective serotonin-uptake inhibitors (SSRIs) and Tricyclic antidepressants

Serotonin (5-hydroxytryptamine) is a neurotransmitter derived from tryptophan, and mainly sourced from the raphe nuclei in the brain. The serotonergic system plays an important role in attention, arousal, and feeding. Studies have shown that children with autism have elevated levels of blood serotonin [3].

SSRIs used in the treatment of ASD in various randomized controlled trials (RCTs) include fluoxetine, fluvoxamine, fenfluramine, and citalopram. SSRIs block the re-uptake of serotonin at the synapse, thus increasing the availability of serotonin and the activation of serotonin receptors [4]. In children and adults, SSRIs have shown limited positive outcome, although all the studies have been with small sample sizes, with potential risk of bias. In addition, SSRIs such as olanzapine, and fluvoxamine, have been shown to have undesirable side effects including irritability and weight gain [5, 6]. On the other hand, prenatal exposure to SSRIs have been linked to ASD risk in epidemiological studies [7, 8]. However, two very recent studies have concluded that there is no significant relationship between prenatal exposure to SSRIs and ASD risk and suggest that the previously observed association may be due to other factors [9, 10].

Tricyclic antidepressants (TCAs) have the same effect as SSRIs in increasing the serotonin levels. A short-term treatment of tianeptine showed a modest effect on irritability in 12 children with ASD [11]. Low-dose amitriptyline has also shown promise in youth with ASD for hyperactivity and impulsivity [12]. However, no large randomized clinical trials have been conducted till date with TCAs for treatment of ASD.

Antipsychotics

Old antipsychotics or neuroleptics are D2 dopamine receptor antagonists, although they are also effective against acetylcholine receptors, serotonin receptors, and adrenergic receptors. The old antipsychotics are less preferable due to their tight, long-lasting binding with the receptors. On the other hand, the second generation or atypical antipsychotics such as risperidone and aripiprazole, dissociate more rapidly from the receptors due to hit-and-run binding properties. Risperidone and aripiprazole have shown positive effects in several different clinical trials especially for ASD-related irritability [13, 14]. However, the major drawback of atypical antipsychotics are side effects such as weight gain, metabolic changes, sleep disturbances, higher risk of sedation and tremor, drooling, increased appetite, fatigue, dizziness, and withdrawal dyskinesias. Another atypical antipsychotic drug, clozapine, has been shown to be effective against hyperactivity and aggression in children with ASD [15].   

Stimulants and Non-stimulants

Stimulants such as methylphenidate are shown to improve the hyperactivity-impulsive symptoms in children with ASD. However, some studies have shown severe adverse effects with methylphenidate including social withdrawal, irritability, insomnia, and anorexia in children with ASD [16].   

Among non-stimulants, atomoxetine has been commonly used for treating the hyperactivity-attention deficit symptoms of ASD. In a recent double-blind placebo-controlled trial in children with ASD, the atomoxetine group showed an improvement in hyperactivity symptoms, with side effects of only fatigue and reduced appetite [17].

Supplements

Based on the Pauling theory that suggests that deficiencies of vitamins and minerals may lead to mental disorders, many doctors have recommended the use of supplements in children with ASD, including omega-3-fatty acids, various vitamins, magnesium, iron, zinc and copper. In ASD studies, although omega-3-fatty acid supplementation had no significant beneficial effects in adult patients [18], another study on children have shown significant improvements in social and communication responses [19]. Among vitamins, vitamin B6 and magnesium [20], and vitamin D [21], have shown beneficial effects in few studies. Minerals such as magnesium [20], iron [22], and zinc [23], have also been recommended for nutritional therapies in ASD. However, large-scale high-quality randomized-controlled studies are required to conclusively determine if nutritional supplements are an effective therapeutic approach for ASD.

Special diets

Although special diets such as  gluten-free casein-free (GFCF) diet have been reported to have beneficial outcomes in children with ASD, most of these reports are anecdotal and do not have sufficient clinical evidence. The hypothesis behind the proposal of GFCF diet for ASD treatment is that the overload of high peptides such as gluten and casein may produce an opioid-like effect that could manifest as common behavioral symptoms of ASD. In addition, inflammation of the gastro-intestinal tract as well as unbalanced gut microbial, both of which are implicated in ASD, could get aggravated with casein and gluten, causing discomfort and pain in children with ASD leading to behavioral issues. However, intervention studies with GFCF diet show mixed results. Two of the most recent reviews on this topic suggest that there is very little evidence to suggest any beneficial outcome with GFCF diet on ASD symptoms [24, 25]. GFCF diet may be beneficial for ASD individuals with specific gut-related issues, or as a short-term relief.

The ketogenic diet, which is usually used for treating children with refractive epilepsy, is a high-fat, low-protein, low-carbohydrate diet. One study that investigated the effect of ketogenic diet on 30 children with ASD showed significant improvements in social and communication functions [26].

A low-oxalate diet has been recommended for children with ASD (40-50 mg per day) based on one study in patients with ASD showing higher plasma oxalate and urine oxalate levels [27].

Herbal medicines

A preliminary study using Panax ginseng, a commonly used herbal medicine, showed improvements of ASD symptoms, suggesting that it could be used as an add-on therapy for treating ASD [28].

Hyperbaric oxygen therapy

In hyperbaric oxygen therapy (HBOT), the patient is exposed to multiple sessions of pure oxygen in a sealed chamber, where the pressure is 1.5 to 3 times the normal atmospheric pressure. It is hypothesized that HBOT increases tissue oxygenation, decreased inflammation, and may have an anti-oxidation effect.  However, a randomized controlled trial with 60 children with ASD showed no improvements in any ASD symptoms compared to sham treatment, and more children in the hyperbaric oxygen group experienced adverse events compared to those in the sham treatment group [29].

Stem cell therapy

Since ASD has been linked to immune alterations and inflammatory cytokine overproduction, stem cells have been proposed as a treatment option due to their paracrine and immunomodulatory properties. A very recent study using human embryonic stem cell treatment in three pediatric patients showed improvements in various ASD symptoms including speech, cognition, eye coordination, and balance, and showed reduced hypersensitivity [30]. Another short study on bone marrow aspirate concentrate cell therapy in 10 patients with ASD also showed improvements in scores in autism scales after the therapy [31]. Combined transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in 37 subjects with ASD showed significantly improved scores in standard scales for ASD, with no safety issues and adverse events [32]. Similar improvements in scores were also observed in a pilot study using fetal stem cells in children with ASD [33]. However, given the controversial nature of using certain stem cells, and lack of solid evidence from a large-scale study, stem cell therapy for ASD should be considered with caution.

Transcranial magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure for altering the excitability of the brain. Alterations in the cortical excitatory/inhibitory balance and abnormal event-related potentials (ERPs) have been implicated in ASD (34). It has been hypothesized that low-frequency rTMS over dorsolateral prefrontal cortex (DLPFC) would help modulate this imbalance and help in the treatment of ASD symptoms, and preliminary study results have been obtained to this effect [35, 36]. Although promising, carefully designed controlled clinical trials are required to evaluate the use of rTMS as a therapeutic approach for ASD.

Apart from the various treatments reviewed here, other approaches such as acupuncture, music therapy, various early behavior interventions, and social skill groups have been implemented for treatment of ASD with varying results. The review of recent literature shows us that there are no large-scale, high-quality studies for any ASD treatments that have looked at their long-term effectiveness and/or side effects. Moreover, the evidence is contradictory between studies for several treatments. For treatments that show promise, for example, atypical antipsychotic drugs, the side effects are significant. Hence, well-designed long-term RCTs with sufficient sample size are required to conclusively link the potential efficacy and/or the side effects of these treatments with ASD.

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