IJCRR - 9(18), September, 2017
Download XML Download PDF
Pharmacobiological Treatments in Autism Spectrum Disorders
Author: Anusha Jayaraman, Nandini Mundkur
Abstract:Autism spectrum disorders (ASD) refer to a group of neuro-developmental disorders affecting young children and adults. Currently, the treatment options for ASD are mostly restricted to treating its symptoms. Among the various approaches for treating ASD, pharmacobiology-based treatments are numerous. Our objective is to review the up-to-date information on different types of medications and briefly discuss the evidence-based potential of these treatments in ASD therapy. PubMed searches for reports and reviews on clinical data from the last 15 years, between 2002-2017, using search terms of each category of treatment along with the terms “autism”, “mechanism”, and/or “side effects” were conducted. Several pharmacobiological interventions have been prescribed for ASD, including antipsychotics, stimulants, antidepressants, supplements, and special diets. However, none of these methods is an effective ASD treatment, and only few show much promise. We provide a brief overview of the current pharmacobiological treatments for ASD, their mechanisms of action, and clinical research-based evidence on their effectiveness. Based on our review, we recommend that caution should be exercised when choosing a pharmacobiological treatment method for ASD as majority of existing evidence is not from large-scale long-term high quality studies.Future research should focus on rigorous investigative design, long-term implementation, and meaningful uniform outcome measurements.
Keywords: Antidepressants, Antipsychotics, Special diet, Vitamins
Autism spectrum disorders (ASD) in young children and adults are characterized by impaired 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]. According to recent statistics by Centers of Disease Control and Prevention (CDC), 1 in every 68 children in the US is affected by ASD . This could be due to true increase in prevalence or increased awareness and diagnosis. ASD also shows higher prevalence in boys, familial patterns and sibling learning issues [4, 5], and high monozygotic twin concordance . Numerous underlying causes for ASD have been indicated such as genetic mutations, neurotoxicity and inflammation, impaired immune response, dysbiosis, nutrient imbalance, and oxidative stress .
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, and special diets[7, 8]. Very limited data are currently available regarding the long-term effectiveness and side-effects of these treatments for ASD. So far, no medication has shown a consistent positive effect on patients with ASD.
Apart from the above mentioned treatments, therapeutic approaches such as stem cell therapy, hyperbaric oxygen therapy, transcranial magnetic stimulation, and early intervention therapies involving speech and language therapy, music therapy, and sensory therapy are also undertaken for patients with ASD[9, 10].Among all the different approaches for ASD treatment, the early intervention method has been shown to be most effective till date [11, 12]. However, a review of these targeted approaches are beyond the objective of this review.
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 .
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 . 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 [16, 17]. In addition, SSRIs such as olanzapine, and fluvoxamine, have been shown to have undesirable side effects including irritability and weight gain [16, 18]. A large multi-center, double-blinded, randomized controlled trial has been recently started known as Fluoxetine for Autistic Behaviors (FAB trial) to determine the efficacy of low-dose fluoxetine for treating ASD symptoms in children and adolescents .
On the other hand, prenatal exposure to SSRIs have been linked to ASD risk in epidemiological studies [20, 21]. 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 [22, 23].
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 . Low-dose amitriptyline has also shown promise in youth with ASD for hyperactivity and impulsivity . However, no large randomized clinical trials have been conducted till date with TCAs for treatment of ASD.
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[27, 28]. 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 [29, 30]. Another atypical antipsychotic drug, clozapine, has been shown to be effective against hyperactivity and aggression in children with ASD .Therefore, based on limited evidence with small sample sizes and short follow-ups, atypical antipsychotics may be more effective as short-term interventions for certain behavioral symptoms in patients with ASD.
Stimulants and Non-stimulants
Stimulants such as methylphenidate are shown to improve the hyperactivity-impulsive symptoms in children with ASD that are regulated by multiple monoaminergic gene variants and has been shown to be well-tolerated and efficacious in several studies [32, 33]. However, some studies have shown severe adverse effects with methylphenidate including social withdrawal, irritability, insomnia, and anorexia in children with ASD .
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 .
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. An insufficiency in omega-3-fatty acids has been linked to abnormal development of the nervous system and to various psychiatric disorders . In ASD studies, although omega-3-fatty acid supplementation had no significant beneficial effects in adult patients , another study on children have shown significant improvements in social and communication responses. Among vitamins, vitamin B6 and magnesium , and vitamin D , have shown beneficial effects in few studies, while others such as vitamin A, and vitamin B12 and folic acid have been proposed as potential treatment options for ASD. Minerals such as magnesium , iron, and zinc , 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.
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 [43, 44]. 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 .
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 .
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 from the last 15 years shows no large-scale, high-quality studies for any ASD treatments that have investigated 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. Based on the existing quality of evidence, we recommend caution before choosing these modes of treatment for ASD. Currently, early intervention-based approaches that integrates both developmental and behavioral models seem to be the most effective treatment paradigm for ASD.
Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.
Conflict of Interest
The authors have no conflict of interest to declare
- Ivanov HY, Stoyanova VK, Popov NT, Vachev TI. Autism Spectrum Disorder - A Complex Genetic Disorder.Folia Med (Plovdiv). 2015;57:19-28.
- Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. Autism: cause factors, early diagnosis and therapies.Rev Neurosci. 2014;25:841-50.
- Christensen DL, Baio J, Van Naarden Braun K, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years--Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012.MMWR Surveill Summ. 2016;65:1-23.
- Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311:1770-7.
- Risch N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions.Am J Psychiatry. 2014;171:1206-13.
- Rosenberg RE, Law JK, Yenokyan G, McGready J, Kaufmann WE, Law PA. Characteristics and concordance of autism spectrum disorders among 277 twin pairs.Arch Pediatr Adolesc Med. 2009;163:907-14.
- Accordino RE, Kidd C, Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Expert Opin Pharmacother. 2016; 17: 937-52.
- Sathe N, Andrews JC, McPheeters ML, Warren ZE. Nutritional and dietary interventions for autism spectrum disorder: A systematic review. Pediatrics. 2017; 139: pii. E20170346.
- Whitehouse AJ. Complementary and alternative medicine for autism spectrum disorders: rationale, safety and efficacy. J Paediatr Child Health. 2013; 49: E438-42.
- Poustka L, Kamp-Becker I. Current practice and future avenues in autism therapy. Curr Top Behav Neurosci. 2017; 30: 357-78.
- Zwaigenbaum L, Bauman ML, Choueiri R, et al. Early intervention for children with autism spectrum disorder under 3 years of age: Recommendations for practice and research. Pediatrics. 2015; 136 Suppl 1: S60-81.
- Sacrey LA, Bennett JA, Zwaigenbaum L. Early infant development and intervention for autism spectrum disorder. J Child Neurol. 2015;30:1921-9.
- Fidalgo S, Ivanov DK, Wood SH. Serotonin: from top to bottom. Biogerontology. 2013;14:21-45.
- Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014;24:919-29.
- Williams K, Brignell A, Randall M, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD).Cochrane Database Syst Rev. 2013;(8):CD004677.
- Hollander E, Wasserman S, Swanson EN, et al. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder.J Child Adolesc Psychopharmacol. 2006;16:541-8.
- Hollander E, Soorya L, Chaplin W, et al. A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am J Psychiatry. 2012;169:292-9.
- Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors.J Clin Psychiatry. 2004;65:1365-71.
- Mouti A, Reddihough D, Marraffa C, et al. Fluoxetine for Autistic Behaviors (FAB trial): study protocol for a randomized controlled trial in children and adolescents with autism.Trials. 2014;15:230.
- Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC. Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies. Neurosci Biobehav Rev. 2015;49:82-9.
- Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr. 2016;170:117-24.
- Sujan AC, Rickert ME, Öberg AS, et al. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA. 2017;317:1553-62.
- Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children. JAMA. 2017;317:1544-52.
- Nijenhuis CM, Horst PG, Berg LT, Wilffert B. Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1: Literature review. Br J Clin Pharmacol. 2012;73:16-26.
- Niederhofer H, Staffen W, Mair A. Tianeptine: a novel strategy of psychopharmacological treatment of children with autistic disorder. Hum Psychopharmacol. 2003;18:389-93.
- Bhatti I, Thome A, Smith PO, et al. A retrospective study of amitriptyline in youth with autism spectrum disorders. J Autism Dev Disord. 2013;43:1017-27.
- Dinnissen M, Dietrich A, van den Hoofdakker BJ, Hoekstra PJ. Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin Drug Metab Toxicol. 2015;11:111-24.
- Ghanizadeh A, Tordjman S, Jaafari N. Aripiprazole for treating irritability in children and adolescents with autism: A systematic review. Indian J Med Res. 2015;142:269-75.
- McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347:314-21.
- Findling RL, Mankoski R, Timko K, et al. A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder. J Clin Psychiatry. 2014;75:22-30.
- Frogley C, Taylor D, Dickens G, Picchioni M. A systematic review of the evidence of clozapine's anti-aggressive effects. Int J Neuropsychopharmacol. 2012;15:1351-71.
- McCracken JT, Badashova KK, Posey DJ, et al. Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders. Pharmacogenomics J. 2014;14:295-302.
- Pearson DA, Santos CW, Aman MG, et al. Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms. J Child Adolesc Psychopharmacol. 2013;23:337-51.
- Simonoff E, Taylor E, Baird G, et al. Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. J Child Psychol Psychiatry. 2013;54:527-35.
- Tumuluru RV, Corbett-Dick P, Aman MG, et al. Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism. J Child Adolesc Psychopharmacol. 2017; doi: 10.1089/cap.2016.0187.
- Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. J Clin Med. 2016;5. pii: E67.
- Politi P, Cena H, Comelli M, et al. Behavioral effects of omega-3 fatty acid supplementation in young adults with severe autism: an open label study. Arch Med Res. 2008;39:682-5.
- Amminger GP, Berger GE, Schäfer MR, Klier C, Friedrich MH, Feucht M. Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study. Biol Psychiatry. 2007;61:551-3.
- Murza KA, Pavelko SL, Malani MD, Nye C. Vitamin B6-magnesium treatment for autism: the current status of the research. Magnes Res. 2010;23:115-7.
- Mazahery H, Camargo CA Jr, Conlon C, Beck KL, Kruger MC, von Hurst PR. Vitamin D and Autism Spectrum Disorder: A Literature Review. Nutrients. 2016;8:236.
- Dosman CF, Drmic IE, Brian JA, et al. Ferritin as an indicator of suspected iron deficiency in children with autism spectrum disorder: prevalence of low serum ferritin concentration. Dev Med Child Neurol. 2006;48:1008-9.
- Babaknejad N, Sayehmiri F, Sayehmiri K, Mohamadkhani A, Bahrami S. The Relationship between Zinc Levels and Autism: A Systematic Review and Meta-analysis. Iran J Child Neurol. 2016;10:1-9.
- Piwowarczyk A, Horvath A, ?ukasik J, Pisula E, Szajewska H. Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. Eur J Nutr. 2017; doi: 10.1007/s00394-017-1483-2.
- Elder JH, Kreider CM, Schaefer NM, de Laosa MB. A review of gluten- and casein-free diets for treatment of autism: 2005-2015. Nutr Diet Suppl. 2015;7:87-101.
- Evangeliou A, Vlachonikolis I, Mihailidou H, Spilioti M, Skarpalezou A, Makaronas N, et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003;18:113-8.
- Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, et al. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012;16:485-91.