Targeted Biomedical Treatment for Autism Spectrum Disorders

Iliyana       Pacheva; Ivan       Ivanov
doi:10.2174/1381612825666191205091312
Abstract

Background: A diagnosis of autism spectrum disorders (ASD) represents presentations with impairment in communication and behaviour that vary considerably in their clinical manifestations and etiology as well as in their likely pathophysiology. A growing body of data indicates that the deleterious effect of oxidative stress, mitochondrial dysfunction, immune dysregulation and neuroinflammation, as well as their interconnections are important aspects of the pathophysiology of ASD. Glutathione deficiency decreases the mitochondrial protection against oxidants and tumor necrosis factor (TNF)-α; immune dysregulation and inflammation inhibit mitochondrial function through TNF-α; autoantibodies against the folate receptors underpin cerebral folate deficiency, resulting in disturbed methylation, and mitochondrial dysfunction. Such pathophysiological processes can arise from environmental and epigenetic factors as well as their combined interactions, such as environmental toxicant exposures in individuals with (epi)genetically impaired detoxification. The emerging evidence on biochemical alterations in ASD is forming the basis for treatments aimed to target its biological underpinnings, which is of some importance, given the uncertain and slow effects of the various educational interventions most commonly used.
Methods: Literature-based review of the biomedical treatment options for ASD that are derived from established pathophysiological processes.
Results: Most proposed biomedical treatments show significant clinical utility only in ASD subgroups, with specified pre-treatment biomarkers that are ameliorated by the specified treatment. For example, folinic acid supplementation has positive effects in ASD patients with identified folate receptor autoantibodies, whilst the clinical utility of methylcobalamine is apparent in ASD patients with impaired methylation capacity. Mitochondrial modulating cofactors should be considered when mitochondrial dysfunction is evident, although further research is required to identify the most appropriate single or combined treatment. Multivitamins/multiminerals formulas, as well as biotin, seem appropriate following the identification of metabolic abnormalities, with doses tapered to individual requirements. A promising area, requiring further investigations, is the utilization of antipurinergic therapies, such as low dose suramin.
Conclusion: The assessment and identification of relevant physiological alterations and targeted intervention are more likely to produce positive treatment outcomes. As such, current evidence indicates the utility of an approach based on personalized and evidence-based medicine, rather than treatment targeted to all that may not always be beneficial (primum non nocere).
Keywords: Autism spectrum disorders, mitochondria, pathophysiological mechanisms, biomedical treatment, biomarkers, personalized medicine.
« Previous Next »
[1] 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.  5th ed. Arlington, VA: American Psychiatric Association 2013.
[2] 
Baron-Cohen S, Scott FJ, Allison C, et al. Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry  2009; 194(6): 500-9.
[http://dx.doi.org/10.1192/bjp.bp.108.059345] [PMID:  19478287] 
[3] 
Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu MC. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011-2012. Natl Health Stat Rep  2013; (65): 1-11.
[PMID:  24988818] 
[4] 
Xu G, Strathearn L, Liu B, et al. Prevalence and treatment patterns of autism spectrum disorder in the United States, 2016. JAMA Pediatr  2019; 173(2): 153-9.
[http://dx.doi.org/10.1001/jamapediatrics.2018.4208] [PMID:  30508021] 
[5] 
Inui T, Kumagaya S, Myowa-Yamakoshi M. Neurodevelopmental hypothesis about the etiology of autism spectrum disorders. Front Hum Neurosci  2017; 11: 354.
[http://dx.doi.org/10.3389/fnhum.2017.00354] [PMID:  28744208] 
[6] 
Gabis LV, Pomeroy J. An etiologic classification of autism spectrum disorders. Isr Med Assoc J  2014; 16(5): 295-8.
[PMID:  24979834] 
[7] 
Betancur C, Coleman M. Etiological heterogeneity in autism spectrum disorders: role of rare variants.  Oxford: Academic press 2013; pp. 113-44.
[http://dx.doi.org/10.1016/B978-0-12-391924-3.00008-9] 
[8] 
Bozzi Y, Provenzano G, Casarosa S. Neurobiological bases of autism-epilepsy comorbidity: a focus on excitation/inhibition imbalance. Eur J Neurosci  2018; 47(6): 534-48.
[http://dx.doi.org/10.1111/ejn.13595] [PMID:  28452083] 
[9] 
Jeste SS, Tuchman R. Autism spectrum disorder and epilepsy: two sides of the same coin? J Child Neurol  2015; 30(14): 1963-71.
[http://dx.doi.org/10.1177/0883073815601501] [PMID:  26374786] 
[10] 
Srivastava S, Sahin M. Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. J Neurodev Disord  2017; 9: 23.
[http://dx.doi.org/10.1186/s11689-017-9202-0] [PMID:  28649286] 
[11] 
Robert C, Pasquier L, Cohen D, et al. Role of genetics in the etiology of autistic spectrum disorder: towards a hierarchical diagnostic strategy. Int J Mol Sci  2017; 18(3): 618.
[http://dx.doi.org/10.3390/ijms18030618] [PMID:  28287497] 
[12] 
van Eeghen AM, Pulsifer MB, Merker VL, et al. Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach. Dev Med Child Neurol  2013; 55(2): 146-53.
[http://dx.doi.org/10.1111/dmcn.12044] [PMID:  23205844] 
[13] 
Dröge W. Free radicals in the physiological control of cell function. Physiol Rev  2002; 82(1): 47-95.
[http://dx.doi.org/10.1152/physrev.00018.2001] [PMID:  11773609] 
[14] 
Siddiqui MF, Elwell C, Johnson MH. Mitochondrial dysfunction in autism spectrum disorders Autism Open Access 2016; 6(5): 1000190 
[http://dx.doi.org/10.4172/2165-7890.1000190] 
[15] 
Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry  2012; 17(3): 290-314.
[http://dx.doi.org/10.1038/mp.2010.136] [PMID:  21263444] 
[16] 
Chauhan A, Gu F, Essa MM, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem  2011; 117(2): 209-20.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07189.x] [PMID:  21250997] 
[17] 
Friedman SD, Shaw DW, Artru AA, et al. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology  2003; 60(1): 100-7.
[http://dx.doi.org/10.1212/WNL.60.1.100] [PMID:  12525726] 
[18] 
Ipser JC, Syal S, Bentley J, Adnams CM, Steyn B, Stein DJ. 1H-MRS in autism spectrum disorders: a systematic meta-analysis. Metab Brain Dis  2012; 27(3): 275-87.
[http://dx.doi.org/10.1007/s11011-012-9293-y] [PMID:  22426803] 
[19] 
James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr  2004; 80(6): 1611-7.
[http://dx.doi.org/10.1093/ajcn/80.6.1611] [PMID:  15585776] 
[20] 
Bennuri SC, Rose S, Frye RE. Mitochondrial dysfunction is inducible in lymphoblastoid cell lines from children with autism and may involve the TORC1 pathway. Front Psychiatry  2019; 10: 269.
[http://dx.doi.org/10.3389/fpsyt.2019.00269] [PMID:  31133888] 
[21] 
Rose S, Niyazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE. Clinical and molecular characteristics of mitochondrial dysfunction in autism spectrum disorder. Mol Diagn Ther  2018; 22(5): 571-93.
[http://dx.doi.org/10.1007/s40291-018-0352-x] [PMID:  30039193] 
[22] 
Naviaux RK. Antipurinergic therapy for autism-an in-depth review. Mitochondrion  2018; 43: 1-15.
[http://dx.doi.org/10.1016/j.mito.2017.12.007] [PMID:  29253638] 
[23] 
Sander LE, Garaude J. The mitochondrial respiratory chain: A metabolic rheostat of innate immune cell-mediated antibacterial responses. Mitochondrion  2018; 41: 28-36.
[http://dx.doi.org/10.1016/j.mito.2017.10.008] [PMID:  29054472] 
[24] 
Sipe GO, Lowery RL, Tremblay ME, Kelly EA, Lamantia CE, Majewska AK. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun  2016; 7: 10905.
[http://dx.doi.org/10.1038/ncomms10905] [PMID:  26948129] 
[25] 
Rose S, Melnyk S, Pavliv O, et al. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry  2012; 2 e134
[http://dx.doi.org/10.1038/tp.2012.61] [PMID:  22781167] 
[26] 
Tang G, Gutierrez Rios P, Kuo SH, et al. Mitochondrial abnormalities in temporal lobe of autistic brain. Neurobiol Dis  2013; 54: 349-61.
[http://dx.doi.org/10.1016/j.nbd.2013.01.006] [PMID:  23333625] 
[27] 
Palmieri L, Papaleo V, Porcelli V, et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry  2010; 15(1): 38-52.
[http://dx.doi.org/10.1038/mp.2008.63] [PMID:  18607376] 
[28] 
Hardan AY, Fung LK, Frazier T, et al. A proton spectroscopy study of white matter in children with autism. Prog Neuropsychopharmacol Biol Psychiatry  2016; 66: 48-53.
[http://dx.doi.org/10.1016/j.pnpbp.2015.11.005] [PMID:  26593330] 
[29] 
James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet  2006; 141B(8): 947-56.
[http://dx.doi.org/10.1002/ajmg.b.30366] [PMID:  16917939] 
[30] 
Rose S, Melnyk S, Trusty TA, et al. Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res Treat  2012; 2012 986519
[http://dx.doi.org/10.1155/2012/986519] [PMID:  22928106] 
[31] 
James SJ, Rose S, Melnyk S, et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J  2009; 23(8): 2374-83.
[http://dx.doi.org/10.1096/fj.08-128926] [PMID:  19307255] 
[32] 
Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol  2014; 5: 150.
[http://dx.doi.org/10.3389/fphys.2014.00150] [PMID:  24795645] 
[33] 
Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids  2002; 67(5): 341-3.
[http://dx.doi.org/10.1054/plef.2002.0439] [PMID:  12445495] 
[34] 
Gu F, Chauhan V, Chauhan A. Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: alterations in the activities and protein expression of glutathione-related enzymes. Free Radic Biol Med  2013; 65: 488-96.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.07.021] [PMID:  23892356] 
[35] 
Griffiths KK, Levy RJ. Evidence of mitochondrial dysfunction in autism: biochemical links, genetic-based associations, and non-energy-related mechanisms. Oxid Med Cell Longev  2017; 2017 4314025
[http://dx.doi.org/10.1155/2017/4314025] [PMID:  28630658] 
[36] 
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids  2005; 73(5): 379-84.
[http://dx.doi.org/10.1016/j.plefa.2005.06.002] [PMID:  16081262] 
[37] 
Frye RE, Slattery JC, Quadros EV. Folate metabolism abnormalities in autism: potential biomarkers. Biomarkers Med  2017; 11(8): 687-99.
[http://dx.doi.org/10.2217/bmm-2017-0109] [PMID:  28770615] 
[38] 
Hill BG, Higdon AN, Dranka BP, Darley-Usmar VM. Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation. Biochim Biophys Acta  2010; 1797(2): 285-95.
[http://dx.doi.org/10.1016/j.bbabio.2009.11.005] [PMID:  19925774] 
[39] 
Dranka BP, Benavides GA, Diers AR, et al. Assessing bioenergetic function in response to oxidative stress by metabolic profiling. Free Radic Biol Med  2011; 51(9): 1621-35.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.08.005] [PMID:  21872656] 
[40] 
Frye RE, Melnyk S, Macfabe DF. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry  2013; 3 e220
[http://dx.doi.org/10.1038/tp.2012.143] [PMID:  23340503] 
[41] 
Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity  2015; 42(3): 406-17.
[http://dx.doi.org/10.1016/j.immuni.2015.02.002] [PMID:  25786173] 
[42] 
Sacco R, Lenti C, Saccani M, et al. Cluster analysis of autistic patients based on principal pathogenetic components. Autism Res  2012; 5(2): 137-47.
[http://dx.doi.org/10.1002/aur.1226] [PMID:  22431251] 
[43] 
Hughes HK, Mills Ko E, Rose D, Ashwood P. Immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders. Front Cell Neurosci  2018; 12: 405.
[http://dx.doi.org/10.3389/fncel.2018.00405] [PMID:  30483058] 
[44] 
Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LA. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun  2015; 46: 232-6.
[http://dx.doi.org/10.1016/j.bbi.2015.02.001] [PMID:  25681541] 
[45] 
Li X, Chauhan A, Sheikh AM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol  2009; 207(1-2): 111-6.
[http://dx.doi.org/10.1016/j.jneuroim.2008.12.002] [PMID:  19157572] 
[46] 
Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull  2012; 87(1): 10-20.
[http://dx.doi.org/10.1016/j.brainresbull.2011.10.004] [PMID:  22024597] 
[47] 
Wei H, Zou H, Sheikh AM, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation  2011; 8: 52.
[http://dx.doi.org/10.1186/1742-2094-8-52] [PMID:  21595886] 
[48] 
Young AM, Campbell E, Lynch S, et al. Aberrant NF-kappa B expression in autism spectrum condition: a mechanism for neuroinflammation. Front Psychiatry  2011; 2: 27.
[49] 
Rodriguez JI, Kern JK. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol  2011; 7(2-4): 205-13.
[http://dx.doi.org/10.1017/S1740925X12000142] [PMID:  22874006] 
[50] 
Morgan JT, Chana G, Pardo CA, et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry  2010; 68(4): 368-76.
[http://dx.doi.org/10.1016/j.biopsych.2010.05.024] [PMID:  20674603] 
[51] 
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun  2009; 23(1): 64-74.
[http://dx.doi.org/10.1016/j.bbi.2008.07.007] [PMID:  18706993] 
[52] 
Wills S, Rossi CC, Bennett J, et al. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol Autism  2011; 2: 5.
[http://dx.doi.org/10.1186/2040-2392-2-5] [PMID:  21521495] 
[53] 
Sweeten TL, Posey DJ, Shankar S, McDougle CJ. High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biol Psychiatry  2004; 55(4): 434-7.
[http://dx.doi.org/10.1016/j.biopsych.2003.09.001] [PMID:  14960298] 
[54] 
Marchezan J, Winkler Dos Santos EGA, Deckmann I, Riesgo RDS. Immunological dysfunction in autism spectrum disorder: a potential target for therapy. Neuroimmunomodulation  2018; 25(5-6): 300-19.
[http://dx.doi.org/10.1159/000492225] [PMID:  30184549] 
[55] 
Brenna JT, Carlson SE. Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development. J Hum Evol  2014; 77: 99-106.
[http://dx.doi.org/10.1016/j.jhevol.2014.02.017] [PMID:  24780861] 
[56] 
Hibbeln JR, Linnoila M, Umhau JC, Rawlings R, George DT, Salem N Jr. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol Psychiatry  1998; 44(4): 235-42.
[http://dx.doi.org/10.1016/S0006-3223(98)00141-3] [PMID:  9715354] 
[57] 
Wurtman RJ. Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism  2008; 57(Suppl. 2): S6-S10.
[http://dx.doi.org/10.1016/j.metabol.2008.07.007] [PMID:  18803968] 
[58] 
Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, Kang JX. Autistic children exhibit decreased levels of essential fatty acids in red blood cells. Int J Mol Sci  2015; 16(5): 10061-76.
[http://dx.doi.org/10.3390/ijms160510061] [PMID:  25946342] 
[59] 
Simopoulos AP. Evolutionary aspects of diet: the ω-6/ω-3 ratio and the brain. Mol Neurobiol  2011; 44(2): 203-15.
[http://dx.doi.org/10.1007/s12035-010-8162-0] [PMID:  21279554] 
[60] 
Parletta N, Niyonsenga T, Duff J. Omega-3 and Omega-6 polyunsaturated fatty acid levels and correlations with symptoms in children with attention deficit hyperactivity disorder, autistic spectrum disorder and typically developing controls. PLoS One  2016; 11(5) e0156432
[http://dx.doi.org/10.1371/journal.pone.0156432] [PMID:  27232999] 
[61] 
Mazahery H, Stonehouse W, Delshad M, et al. Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: systematic review and meta-analysis of case-control and randomised controlled trials. Nutrients  2017; 9(2) E155
[http://dx.doi.org/10.3390/nu9020155] [PMID:  28218722] 
[62] 
Howsmon DP, Adams JB, Kruger U, Geis E, Gehn E, Hahn J. Erythrocyte fatty acid profiles in children are not predictive of autism spectrum disorder status: a case control study. Biomark Res  2018; 6: 12.
[http://dx.doi.org/10.1186/s40364-018-0125-z] [PMID:  29568526] 
[63] 
Jiang X, Suenaga J, Pu H, et al. Post-stroke administration of omega-3 polyunsaturated fatty acids promotes neurovascular restoration after ischemic stroke in mice: efficacy declines with aging. Neurobiol Dis  2019; 126: 62-75.
[http://dx.doi.org/10.1016/j.nbd.2018.09.012] [PMID:  30218758] 
[64] 
Volpato M, Hull MA. Omega-3 polyunsaturated fatty acids as adjuvant therapy of colorectal cancer. Cancer Metastasis Rev  2018; 37(2-3): 545-55.
[http://dx.doi.org/10.1007/s10555-018-9744-y] [PMID:  29971573] 
[65] 
Yoshino J, Smith GI, Kelly SC, Julliand S, Reeds DN, Mittendorfer B. Effect of dietary n-3 PUFA supplementation on the muscle transcriptome in older adults. Physiol Rep  2016; 4(11) e12785
[http://dx.doi.org/10.14814/phy2.12785] [PMID:  27252251] 
[66] 
Mulder EJ, Anderson GM, Kemperman RFJ, Oosterloo-Duinkerken A, Minderaa RB, Kema IP. Urinary excretion of 5-hydroxyindoleacetic acid, serotonin and 6-sulphatoxymelatonin in normoserotonemic and hyperserotonemic autistic individuals. Neuropsychobiology  2010; 61(1): 27-32.
[http://dx.doi.org/10.1159/000258640] [PMID:  19923863] 
[67] 
Croonenberghs J, Delmeire L, Verkerk R, et al. Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder. Neuropsychopharmacology  2000; 22(3): 275-83.
[http://dx.doi.org/10.1016/S0893-133X(99)00131-1] [PMID:  10693155] 
[68] 
Uzunova G, Pallanti S, Hollander E. Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. World J Biol Psychiatry  2015; 1-13.
[PMID:  26469219] 
[69] 
El-Ansary A, Al Dera H. Biomarkers directed strategies to treat autism.In: Role of Biomarkers in Medicine.  In Tech Publisher 2016; pp. 205-28.
[http://dx.doi.org/10.5772/62566] 
[70] 
Wei H, Ding C, Jin G, Yin H, Liu J, Hu F. Abnormal glutamate release in aged BTBR mouse model of autism. Int J Clin Exp Pathol  2015; 8(9): 10689-97.
[PMID:  26617779] 
[71] 
Tanaka K. [Role of glutamate transporters in the pathophysiology of major mental illnesses Nihon Shinkei Seishin Yakurigaku Zasshi  2009; 29(4): 161-4.
[PMID:  19764483] 
[72] 
Liu J, Zhang M, Kong X. Gut microbiome and autism: recent advances and future perspectives. North Am J Med Sci  2016; 9(3): 104-15.
[73] 
Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell  2013; 155(7): 1451-63.
[http://dx.doi.org/10.1016/j.cell.2013.11.024] [PMID:  24315484] 
[74] 
Sandler RH, Finegold SM, Bolte ER, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol  2000; 15(7): 429-35.
[http://dx.doi.org/10.1177/088307380001500701] [PMID:  10921511] 
[75] 
Rodakis J. An n=1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean. Microb Ecol Health Dis  2015; 26: 26382.
[PMID:  25808801] 
[76] 
Xu M, Xu X, Li J, Li F. Association between Gut microbiota and autism spectrum disorder: a systematic review and meta-analysis. Front Psychiatry  2019; 10: 473.
[http://dx.doi.org/10.3389/fpsyt.2019.00473] [PMID:  31404299] 
[77] 
Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol  2004; 70(11): 6459-65.
[http://dx.doi.org/10.1128/AEM.70.11.6459-6465.2004] [PMID:  15528506] 
[78] 
Söderholm JD, Yang PC, Ceponis P, et al. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology  2002; 123(4): 1099-108.
[http://dx.doi.org/10.1053/gast.2002.36019] [PMID:  12360472] 
[79] 
Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap Adv Gastroenterol  2013; 6(4): 295-308.
[http://dx.doi.org/10.1177/1756283X13482996] [PMID:  23814609] 
[80] 
Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology  2014; 146(6): 1500-12.
[http://dx.doi.org/10.1053/j.gastro.2014.02.037] [PMID:  24583088] 
[81] 
Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci  2010; 13(3): 135-43.
[http://dx.doi.org/10.1179/147683010X12611460763968] [PMID:  20423563] 
[82] 
Nankova BB, Agarwal R, MacFabe DF, et al. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells--possible relevance to autism spectrum disorders. PLoS One  2014; 9 e103740
[83] 
Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci  2011; 12(9): 524-38.
[http://dx.doi.org/10.1038/nrn3044] [PMID:  21852800] 
[84] 
Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry  1998; 43(4): 270-7.
[http://dx.doi.org/10.1016/S0006-3223(97)00439-3] [PMID:  9513736] 
[85] 
Andari E, Duhamel J-R, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA  2010; 107(9): 4389-94.
[http://dx.doi.org/10.1073/pnas.0910249107] [PMID:  20160081] 
[86] 
Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol  2011; 53(9): 783-92.
[http://dx.doi.org/10.1111/j.1469-8749.2011.03980.x] [PMID:  21518346] 
[87] 
Tordjman S, Anderson GM, Bellissant E, et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology  2012; 37(12): 1990-7.
[http://dx.doi.org/10.1016/j.psyneuen.2012.04.013] [PMID:  22613035] 
[88] 
Hardeland R, Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab (Lond)  2005; 2: 22.
[http://dx.doi.org/10.1186/1743-7075-2-22] [PMID:  16153306] 
[89] 
Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AI, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res  2005; 7(4): 293-318.
[http://dx.doi.org/10.1007/BF03033887] [PMID:  16179266] 
[90] 
Sarowar T, Chhabra R, Vilella A, Boeckers TM, Zoli M, Grabrucker AM. Activity and circadian rhythm influence synaptic Shank3 protein levels in mice. J Neurochem  2016; 138(6): 887-95.
[http://dx.doi.org/10.1111/jnc.13709] [PMID:  27329942] 
[91] 
Anderson G. Mitochondria and the Gut as crucial hubs for the interactions of melatonin with sirtuins, inflammation, butyrate, tryptophan metabolites, and alpha 7 nicotinic receptor across a host of medical conditions. Melatonin Res  2019; 2(2): 70-85.
[http://dx.doi.org/10.32794/mr11250022] 
[92] 
Delhey LM, Nur Kilinc E, Yin L, et al. The effect of mitochondrial supplements on mitochondrial activity in children with autism spectrum disorder. J Clin Med  2017; 6(2): 18.
[http://dx.doi.org/10.3390/jcm6020018] [PMID:  28208802] 
[93] 
Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. Relative carnitine deficiency in autism. J Autism Dev Disord  2004; 34(6): 615-23.
[http://dx.doi.org/10.1007/s10803-004-5283-1] [PMID:  15679182] 
[94] 
Lv QQ, You C, Zou XB, Deng HZ. Acyl-carnitine, C5DC, and C26 as potential biomarkers for diagnosis of autism spectrum disorder in children. Psychiatry Res  2018; 267: 277-80.
[http://dx.doi.org/10.1016/j.psychres.2018.06.027] [PMID:  29945069] 
[95] 
Geier DA, Kern JK, Davis G, et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit  2011; 17(6): PI15-23.
[http://dx.doi.org/10.12659/MSM.881792] [PMID:  21629200] 
[96] 
Fahmy SF, El-Hamamsy M, Zaki O, Badary OA. Effect of L-carnitine on behavioral disorder in autistic children. Value Health  2013; 16(3): A15.
[http://dx.doi.org/10.1016/j.jval.2013.03.092] 
[97] 
Wawrzeńczyk A, Sacher A, Mac M, Nałecz MJ, Nałecz KA. Transport of L-carnitine in isolated cerebral cortex neurons. Eur J Biochem  2001; 268(7): 2091-8.
[http://dx.doi.org/10.1046/j.1432-1327.2001.02087.x] [PMID:  11277932] 
[98] 
Pastural E, Ritchie S, Lu Y, et al. Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Essent Fatty Acids  2009; 81(4): 253-64.
[http://dx.doi.org/10.1016/j.plefa.2009.06.003] [PMID:  19608392] 
[99] 
Yubero D, Adin A, Montero R, et al. A statistical algorithm showing coenzyme Q10 and citrate synthase as biomarkers for mitochondrial respiratory chain enzyme activities. Sci Rep  2016; 6(1): 15.
[http://dx.doi.org/10.1038/s41598-016-0008-1] [PMID:  28442759] 
[100] 
Faust K, Gehrke S, Yang Y, et al. Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson’s disease. BMC Neurosci  2009; 1(10): 109.
[http://dx.doi.org/10.1186/1471-2202-10-109] 
[101] 
Carmona MC, Lefebvre P, Lefebvre B, et al. Consortium of the french ministry of research and technology: ‘Molecules and new therapeutic targets’. Coadministration of coenzyme Q prevents rosiglitazone-induced adipogenesis in ob/ob mice. Int J Obes  2009; 33(2): 204-11.
[http://dx.doi.org/10.1038/ijo.2008.265] [PMID:  19125161] 
[102] 
Mousavinejad E, Ghaffari MA, Riahi F, Hajmohammadi M, Tiznobeyk Z, Mousavinejad M. Coenzyme Q10 supplementation reduces oxidative stress and decreases antioxidant enzyme activity in children with autism spectrum disorders. Psychiatry Res  2018; 265: 62-9.
[http://dx.doi.org/10.1016/j.psychres.2018.03.061] [PMID:  29684771] 
[103] 
Fan L, Feng Y, Chen GC, Qin LQ, Fu CL, Chen LH. Effects of coenzyme Q10 supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res  2017; 119: 128-36.
[http://dx.doi.org/10.1016/j.phrs.2017.01.032] [PMID:  28179205] 
[104] 
Gvozdjáková A, Kucharská J, Ostatníková D, Babinská K, Nakládal D, Crane FL. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev  2014; 2014 798957
[http://dx.doi.org/10.1155/2014/798957] [PMID:  24707344] 
[105] 
Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve  2010; 42(5): 739-48.
[http://dx.doi.org/10.1002/mus.21758] [PMID:  20886510] 
[106] 
Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve  2007; 35(2): 235-42.
[http://dx.doi.org/10.1002/mus.20688] [PMID:  17080429] 
[107] 
Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc  2005; 37(12): 2086-93.
[http://dx.doi.org/10.1249/01.mss.0000177341.89478.06] [PMID:  16331134] 
[108] 
Legido A, Goldenthal M, Garvin B, et al. Effect of a combination of carnitine, coenzyme Q10 and alpha-lipoic acid (MitoCocktail) on mitochondrial function and neurobehavioral performance in children with autism spectrum disorder (P3.313). Neurology 2018; 90(Suppl. 15).
[109] 
James SJ. Autism and folate-dependent one-carbon metabolism: serendipity and critical branch-point decisions in science. Glob Adv Health Med  2013; 2(6): 48-51.
[http://dx.doi.org/10.7453/gahmj.2013.088] [PMID:  24416708] 
[110] 
Frye RE, James SJ. Metabolic pathology of autism in relation to redox metabolism. Biomarkers Med  2014; 8(3): 321-30.
[http://dx.doi.org/10.2217/bmm.13.158] [PMID:  24712422] 
[111] 
Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry  2013; 18(3): 369-81.
[http://dx.doi.org/10.1038/mp.2011.175] [PMID:  22230883] 
[112] 
Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry  2018; 23(2): 247-56.
[http://dx.doi.org/10.1038/mp.2016.168] [PMID:  27752075] 
[113] 
Ramaekers V, Sequeira JM, Quadros EV. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med  2013; 51(3): 497-511.
[http://dx.doi.org/10.1515/cclm-2012-0543] [PMID:  23314536] 
[114] 
Gao Y, Sheng C, Xie R-H, et al. New perspective on impact of folic acid supplementation during pregnancy on neurodevelopment/autism in the offspring children - a systematic review. PLoS One  2016; 11(11) e0165626
[http://dx.doi.org/10.1371/journal.pone.0165626] [PMID:  27875541] 
[115] 
James SJ, Melnyk S, Fuchs G, et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr  2009; 89(1): 425-30.
[http://dx.doi.org/10.3945/ajcn.2008.26615] [PMID:  19056591] 
[116] 
Bottiglieri T. Folate, vitamin B12, and S-adenosylmethionine. Psychiatr Clin North Am  2013; 36(1): 1-13.
[http://dx.doi.org/10.1016/j.psc.2012.12.001] [PMID:  23538072] 
[117] 
Bertoglio K, Jill James S, Deprey L, Brule N, Hendren RL. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med  2010; 16(5): 555-60.
[http://dx.doi.org/10.1089/acm.2009.0177] [PMID:  20804367] 
[118] 
Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, Bent S. Randomized, placebo-controlled trial of methyl B12 for children with autism. J Child Adolesc Psychopharmacol  2016; 26(9): 774-83.
[http://dx.doi.org/10.1089/cap.2015.0159] [PMID:  26889605] 
[119] 
Adams JB. Vitamin/mineral supplements for children and adults with autism. Vitam Miner  2015; 3: 127.
[http://dx.doi.org/10.4172/2376-1318.1000127] 
[120] 
Nakamura YK, Read MH, Elias JW, Omaye ST. Oxidation of serum low-density lipoprotein (LDL) and antioxidant status in young and elderly humans. Arch Gerontol Geriatr  2006; 42(3): 265-76.
[http://dx.doi.org/10.1016/j.archger.2005.08.002] [PMID:  16214244] 
[121] 
Mahmood LA, Al Saadi R, Matthews L. Dietary and antioxidant therapy for autistic children: does it really work? Arch Med Health Sci  2018; 6: 73-80.
[http://dx.doi.org/10.4103/amhs.amhs_82_17] 
[122] 
Adams JB, George F, Audhya T. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med  2006; 12(1): 59-63.
[http://dx.doi.org/10.1089/acm.2006.12.59] [PMID:  16494569] 
[123] 
Adams JB, Audhya T, Geis E, et al. Comprehensive nutritional and dietary intervention for autism spectrum disorder-a randomized, controlled 12-month trial. Nutrients  2018; 10(3): 369.
[http://dx.doi.org/10.3390/nu10030369] [PMID:  29562612] 
[124] 
Frye R, Rossignol D. Treatments for mitochondrial dysfunction associated with autism spectrum disorders. J Pediatr Biochem  2012; 2(4): 241-9.
[125] 
Adams JB, Audhya T, McDonough-Means S, et al. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr  2011; 11: 111.
[http://dx.doi.org/10.1186/1471-2431-11-111] [PMID:  22151477] 
[126] 
Spilioti M, Evangeliou AE, Tramma D, et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci  2013; 7: 858.
[http://dx.doi.org/10.3389/fnhum.2013.00858] [PMID:  24399946] 
[127] 
Sghaier R, Zarrouk A, Nury T, et al. Biotin attenuation of oxidative stress, mitochondrial dysfunction, lipid metabolism alteration and 7β-hydroxycholesterol-induced cell death in 158N murine oligodendrocytes. Free Radic Res  2019; 53(5): 535-61.
[http://dx.doi.org/10.1080/10715762.2019.1612891] [PMID:  31039616] 
[128] 
Rimland B, Callaway E, Dreyfus P. The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study. Am J Psychiatry  1978; 135(4): 472-5.
[http://dx.doi.org/10.1176/ajp.135.4.472] [PMID:  345827] 
[129] 
Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. Effects of pyridoxine and magnesium on autistic symptoms--initial observations. J Autism Dev Disord  1981; 11(2): 219-30.
[http://dx.doi.org/10.1007/BF01531686] [PMID:  6765503] 
[130] 
Martineau J, Barthelemy C, Cheliakine C, Lelord G. Brief report: an open middle-term study of combined vitamin B6-magnesium in a subgroup of autistic children selected on their sensitivity to this treatment. J Autism Dev Disord  1988; 18(3): 435-47.
[http://dx.doi.org/10.1007/BF02212198] [PMID:  3170459] 
[131] 
Nye C, Brice A. Combined vitamin B6-magnesium treatment in autism spectrum disorder. Cochrane Database Syst Rev  2005; 4(4) CD003497
[http://dx.doi.org/10.1002/14651858.CD003497.pub2] [PMID:  16235322] 
[132] 
Findling RL, Maxwell K, Scotese-Wojtila L, Huang J, Yamashita T, Wiznitzer M. High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study. J Autism Dev Disord  1997; 27(4): 467-78.
[http://dx.doi.org/10.1023/A:1025861522935] [PMID:  9261669] 
[133] 
Obara T, Ishikuro M, Tamiya G, et al. Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods. Sci Rep  2018; 8(1): 14840.
[http://dx.doi.org/10.1038/s41598-018-33110-w] [PMID:  30287864] 
[134] 
Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuropsychopharmacol Biol Psychiatry  1993; 17(5): 765-74.
[http://dx.doi.org/10.1016/0278-5846(93)90058-Z] [PMID:  8255984] 
[135] 
Frustaci A, Neri M, Cesario A, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med  2012; 52(10): 2128-41.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.03.011] [PMID:  22542447] 
[136] 
Frye RE, Huffman LC, Elliott GR. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics  2010; 7(3): 241-9.
[http://dx.doi.org/10.1016/j.nurt.2010.05.004] [PMID:  20643376] 
[137] 
Danfors T, von Knorring AL, Hartvig P, et al. Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study. J Clin Psychopharmacol  2005; 25(5): 485-9.
[http://dx.doi.org/10.1097/01.jcp.0000177667.35016.e9] [PMID:  16160627] 
[138] 
Naruse H, Takesada M, Nakane Y, et al. Clinical evaluation of R-tetrahydrobiopterin (SUN 0588) on infantile autism: a double-blind comparative study using placebo as a control. Rinsho Iyaku  1990; 6: 1343-68.
[139] 
Klaiman C, Huffman L, Masaki L, Elliott GR. Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol  2013; 23(5): 320-8.
[http://dx.doi.org/10.1089/cap.2012.0127] [PMID:  23782126] 
[140] 
Frye RE, DeLatorre R, Taylor HB, et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry  2013; 3 e237
[http://dx.doi.org/10.1038/tp.2013.14] [PMID:  23462988] 
[141] 
Delhey LM, Tippett M, Rose S, et al. Comparison of Treatment for metabolic disorders associated with autism:reanalysis of three clinical trials. Front Neurosci  2018; 12: 19.
[http://dx.doi.org/10.3389/fnins.2018.00019] [PMID:  29483858] 
[142] 
Vargason T, Kruger U, Roth E, et al. Comparison of three clinical trial treatments for autism spectrum disorder through multivariate analysis of changes in metabolic profiles and adaptive behavior. Front Cell Neurosci  2018; 12: 503.
[http://dx.doi.org/10.3389/fncel.2018.00503] [PMID:  30618645] 
[143] 
Deepmala D, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev  2015; 55: 294-321.
[http://dx.doi.org/10.1016/j.neubiorev.2015.04.015] [PMID:  25957927] 
[144] 
Hardan AY, Fung LK, Libove RA, et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry  2012; 71(11): 956-61.
[http://dx.doi.org/10.1016/j.biopsych.2012.01.014] [PMID:  22342106] 
[145] 
Dean OM, Gray KM, Villagonzalo KA, et al. A randomised, double blind, placebo-controlled trial of a fixed dose of N-acetyl cysteine in children with autistic disorder. Aust N Z J Psychiatry  2017; 51(3): 241-9.
[http://dx.doi.org/10.1177/0004867416652735] [PMID:  27316706] 
[146] 
Wink LK, Adams R, Wang Z, et al. A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Mol Autism  2016; 7(7): 26.
[http://dx.doi.org/10.1186/s13229-016-0088-6] [PMID:  27103982] 
[147] 
Ghanizadeh A, Moghimi-Sarani E. A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry  2013; 13: 196.
[http://dx.doi.org/10.1186/1471-244X-13-196] [PMID:  23886027] 
[148] 
Mazahery H, Stonehouse W, Delshad M, et al. Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: systematic review and meta- analysis of case-control and randomised controlled trials. Nutrients  2017; 9(2) E155
[http://dx.doi.org/10.3390/nu9020155] [PMID:  28218722] 
[149] 
Layé S, Nadjar A, Joffre C, Bazinet RP. Antiinflammatory effects of omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology. Pharmacol Rev  2018; 70(1): 12-38.
[http://dx.doi.org/10.1124/pr.117.014092] [PMID:  29217656] 
[150] 
Madore C, Leyrolle Q, Lacabanne C, et al. Neuroinflammation in autism: plausible role of maternal inflammation, dietary omega 3, and microbiota. Neural Plast  2016; 2016 3597209
[http://dx.doi.org/10.1155/2016/3597209] [PMID:  27840741] 
[151] 
Posar A, Visconti P. Omega-3 supplementation in autism spectrum disorders: a still open question? J Pediatr Neurosci  2016; 11(3): 225-7.
[http://dx.doi.org/10.4103/1817-1745.193363] [PMID:  27857792] 
[152] 
Farjadian S, Moghtaderi M, Kalani M, Gholami T, Hosseini Teshnizi S. Effects of omega-3 fatty acids on serum levels of T-helper cytokines in children with asthma. Cytokine  2016; 85: 61-6.
[http://dx.doi.org/10.1016/j.cyto.2016.06.002] [PMID:  27288633] 
[153] 
Brigandi SA, Shao H, Qian SY, et al. Autistic children exhibit decreased levels of essential fatty acids in red blood cells. Int J Mol Sci  2015; 16(5): 10061-76.
[http://dx.doi.org/10.3390/ijms160510061] 
[154] 
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(4): 551-3.
[http://dx.doi.org/10.1016/j.biopsych.2006.05.007] [PMID:  16920077] 
[155] 
Yui K, Koshiba M, Nakamura S, Kobayashi Y. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial. J Clin Psychopharmacol  2012; 32(2): 200-6.
[http://dx.doi.org/10.1097/JCP.0b013e3182485791] [PMID:  22370992] 
[156] 
Bent S, Bertoglio K, Ashwood P, Bostrom A, Hendren RL. A pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorder. J Autism Dev Disord  2011; 41(5): 545-54.
[http://dx.doi.org/10.1007/s10803-010-1078-8] [PMID:  20683766] 
[157] 
Bent S, Hendren RL, Zandi T, et al. Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism. J Am Acad Child Adolesc Psychiatry  2014; 53(6): 658-66.
[http://dx.doi.org/10.1016/j.jaac.2014.01.018] [PMID:  24839884] 
[158] 
Voigt RG, Mellon MW, Katusic SK, et al. Dietary docosahexaenoic acid supplementation in children with autism. J Pediatr Gastroenterol Nutr  2014; 58(6): 715-22.
[PMID:  24345834] 
[159] 
Mankad D, Dupuis A, Smile S, et al. A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. Mol Autism  2015; 6(1): 18.
[http://dx.doi.org/10.1186/s13229-015-0010-7] [PMID:  25798215] 
[160] 
Keim SA, Gracious B, Boone KM, et al. ω-3 and ω-6 fatty acid supplementation may reduce autism symptoms based on parent report in preterm toddlers. J Nutr  2018; 148(2): 227-35.
[http://dx.doi.org/10.1093/jn/nxx047] [PMID:  29490101] 
[161] 
Cheng YS, Tseng PT, Chen YW, et al. Supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in children with autism spectrum disorders: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat  2017; 13(13): 2531-43.
[http://dx.doi.org/10.2147/NDT.S147305] [PMID:  29042783] 
[162] 
Gogou M, Kolios G. The effect of dietary supplements on clinical aspects of autism spectrum disorder: a systematic review of the literature. Brain Dev  2017; 39(8): 656-64.
[http://dx.doi.org/10.1016/j.braindev.2017.03.029] [PMID:  28438367] 
[163] 
Li YJ, Ou JJ, Li YM, Xiang DX. Dietary supplement for core symptoms of autism spectrum disorder: where are we now and where should we go? Front Psychiatry  2017; 8: 155.
[http://dx.doi.org/10.3389/fpsyt.2017.00155] [PMID:  28878697] 
[164] 
Huang Y-N, Ho Y-J, Lai C-C, Chiu CT, Wang JY. 1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures. J Neuroinflammation  2015; 12(1): 147.
[http://dx.doi.org/10.1186/s12974-015-0370-0] [PMID:  26259787] 
[165] 
Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J  2014; 28(6): 2398-413.
[http://dx.doi.org/10.1096/fj.13-246546] [PMID:  24558199] 
[166] 
Schmidt RJ, Niu Q, Eyles DW, Hansen RL, Iosif AM. Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case-control study. Autism Res  2019; 12(6): 976-88.
[http://dx.doi.org/10.1002/aur.2118] [PMID:  31094097] 
[167] 
Mazahery H, Conlon CA, Beck KL, et al. A randomised-controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of core symptoms of autism spectrum disorder in children. J Autism Dev Disord  2019; 49(5): 1778-94.
[http://dx.doi.org/10.1007/s10803-018-3860-y] [PMID:  30607782] 
[168] 
Kerley CP, Power C, Gallagher L, Coghlan D. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child  2017; 102(11): 1030-6.
[http://dx.doi.org/10.1136/archdischild-2017-312783] [PMID:  28626020] 
[169] 
Hajizadeh-Zaker R, Ghajar A, Mesgarpour B, Afarideh M, Mohammadi MR, Akhondzadeh S. L-carnosine as an adjunctive therapy to risperidone in children with autistic disorder: a randomized, double-blind, placebo- controlled trial. J Child Adolesc Psychopharmacol  2018; 28(1): 74-81.
[http://dx.doi.org/10.1089/cap.2017.0026] [PMID:  29027815] 
[170] 
Chez MG, Buchanan CP, Aimonovitch MC, et al. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol  2002; 17(11): 833-7.
[http://dx.doi.org/10.1177/08830738020170111501] [PMID:  12585724] 
[171] 
Kang DW, Adams JB, Coleman DM, et al. Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota. Sci Rep  2019; 9(1): 5821.
[http://dx.doi.org/10.1038/s41598-019-42183-0] [PMID:  30967657] 
[172] 
Parker KJ, Oztan O, Libove RA, et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci USA  2017; 114(30): 8119-24.
[http://dx.doi.org/10.1073/pnas.1705521114] [PMID:  28696286] 
[173] 
Caldwell HK, Aulino EA, Freeman AR, Miller TV, Witchey SK. Oxytocin and behavior: lessons from knockout mice. Dev Neurobiol  2017; 77(2): 190-201.
[http://dx.doi.org/10.1002/dneu.22431] [PMID:  27513442] 
[174] 
Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry  2016; 21(9): 1225-31.
[http://dx.doi.org/10.1038/mp.2015.162] [PMID:  26503762] 
[175] 
Anagnostou E, Soorya L, Chaplin W, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism  2012; 3(1): 16.
[http://dx.doi.org/10.1186/2040-2392-3-16] [PMID:  23216716] 
[176] 
Yamasue H, Okada T, Munesue T, et al. Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial. Mol Psychiatry 2018.
[http://dx.doi.org/10.1038/s41380-018-0097-2] [PMID:  29955161] 
[177] 
Guastella AJ, Gray KM, Rinehart NJ, et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry  2015; 56(4): 444-52.
[http://dx.doi.org/10.1111/jcpp.12305] [PMID:  25087908] 
[178] 
Quintana DS, Westlye LT, Hope S, et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel breath powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry  2017; 7(5) e1136
[http://dx.doi.org/10.1038/tp.2017.103] [PMID:  28534875] 
[179] 
Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord  2014; 44(3): 521-31.
[http://dx.doi.org/10.1007/s10803-013-1899-3] [PMID:  23888359] 
[180] 
Cortesi F, Giannotti F, Sebastiani T, Panunzi S, Valente D. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res  2012; 21(6): 700-9.
[http://dx.doi.org/10.1111/j.1365-2869.2012.01021.x] [PMID:  22616853] 
[181] 
Wright B, Sims D, Smart S, et al. Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord  2011; 41(2): 175-84.
[http://dx.doi.org/10.1007/s10803-010-1036-5] [PMID:  20535539] 
[182] 
Garstang J, Wallis M. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev  2006; 32(5): 585-9.
[http://dx.doi.org/10.1111/j.1365-2214.2006.00616.x] [PMID:  16919138] 
[183] 
Wirojanan J, Jacquemont S, Diaz R, et al. The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J Clin Sleep Med  2009; 5(2): 145-50.
[PMID:  19968048] 
[184] 
Wasdell MB, Jan JE, Bomben MM, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res  2008; 44(1): 57-64.
[PMID:  18078449] 
[185] 
Gagnon K, Godbout R. Melatonin and comorbidities in children with autism spectrum disorder. Curr Dev Disord Rep  2018; 5(3): 197-206.
[http://dx.doi.org/10.1007/s40474-018-0147-0] [PMID:  30148039] 
[186] 
Gottfried C, Bambini-Junior V, Francis F, Riesgo R, Savino W. The impact of neuroimmune alterations in autism spectrum disorder. Front Psychiatry  2015; 6: 121.
[http://dx.doi.org/10.3389/fpsyt.2015.00121] [PMID:  26441683] 
[187] 
Meltzer A, Van de Water J. The role of the immune system in autism spectrum disorder. Neuropsychopharmacology  2017; 42(1): 284-98.
[http://dx.doi.org/10.1038/npp.2016.158] [PMID:  27534269] 
[188] 
Akhondzadeh S, Fallah J, Mohammadi M-R, et al. Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism. Prog Neuropsychopharmacol Biol Psychiatry  2010; 34(1): 32-6.
[http://dx.doi.org/10.1016/j.pnpbp.2009.09.012] [PMID:  19772883] 
[189] 
Singh K, Connors SL, Macklin EA, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA  2014; 111(43): 15550-5.
[http://dx.doi.org/10.1073/pnas.1416940111] [PMID:  25313065] 
[190] 
Sedlak TW, Nucifora LG, Koga M, et al. Sulforaphane Augments glutathione and influences brain metabolites in human subjects: a clinical pilot study. Mol Neuropsychiatry  2018; 3(4): 214-22.
[http://dx.doi.org/10.1159/000487639] [PMID:  29888232] 
[191] 
Egner PA, Chen JG, Zarth AT, et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev Res (Phila)  2014; 7(8): 813-23.
[http://dx.doi.org/10.1158/1940-6207.CAPR-14-0103] [PMID:  24913818] 
[192] 
Zimmerman A, Diggins E, Connors S, Singh K. Sulforaphane treatment of children with autism spectrum disorder (ASD) - a progress report (N1.002). Neurology 2018; 90(Suppl. 15).
[193] 
Sareddy GR, Geeviman K, Ramulu C, Babu PP. The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-κB pathway. J Neurooncol  2012; 106(1): 99-109.
[http://dx.doi.org/10.1007/s11060-011-0662-x] [PMID:  21847707] 
[194] 
Asadabadi M, Mohammadi M-R, Ghanizadeh A, et al. Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl)  2013; 225(1): 51-9.
[http://dx.doi.org/10.1007/s00213-012-2796-8] [PMID:  22782459] 
[195] 
Ghaleiha A, Rasa SM, Nikoo M, Farokhnia M, Mohammadi MR, Akhondzadeh S. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: effects on aberrant behavior in children with autism. Psychiatry Res  2015; 229(1-2): 181-7.
[http://dx.doi.org/10.1016/j.psychres.2015.07.043] [PMID:  26208985] 
[196] 
Ghaleiha A, Alikhani R, Kazemi M-R, et al. Minocycline as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind placebo-controlled trial. J Child Adolesc Psychopharmacol  2016; 26(9): 784-91.
[http://dx.doi.org/10.1089/cap.2015.0175] [PMID:  27128958] 
[197] 
Buitelaar JK, Dekker MEM, van Ree JM, van Engeland H. A controlled trial with ORG 2766, an ACTH-(4-9) analog, in 50 relatively able children with autism. Eur Neuropsychopharmacol  1996; 6(1): 13-9.
[http://dx.doi.org/10.1016/0924-977X(95)00049-U] [PMID:  8866933] 
[198] 
Niederhofer H, Staffen W, Mair A. Immunoglobulins as an alternative strategy of psychopharmacological treatment of children with autistic disorder. Neuropsychopharmacology  2003; 28(5): 1014-5.
[http://dx.doi.org/10.1038/sj.npp.1300130] [PMID:  12700706] 
[199] 
Boris M, Goldblatt A, Edelson S. Improvement in children with autism treated with intravenous gamma globulin. J Nutr Environ Med  2005; 15(4): 169-76.
[http://dx.doi.org/10.1080/13590840600681827] 
[200] 
Connery K, Tippett M, Delhey LM, et al. Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Transl Psychiatry  2018; 8(1): 148.
[http://dx.doi.org/10.1038/s41398-018-0214-7] [PMID:  30097568] 
[201] 
Melamed IR, Heffron M, Testori A, Lipe K. A pilot study of high-dose intravenous immunoglobulin 5% for autism: impact on autism spectrum and markers of neuroinflammation. Autism Res  2018; 11(3): 421-33.
[http://dx.doi.org/10.1002/aur.1906] [PMID:  29427532] 
[202] 
Handen BL, Melmed RD, Hansen RL, et al. A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder. J Autism Dev Disord  2009; 39(5): 796-805.
[http://dx.doi.org/10.1007/s10803-008-0687-y] [PMID:  19148734] 
[203] 
Naviaux RK, Zolkipli Z, Wang L, et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS One  2013; 8(3) e57380
[http://dx.doi.org/10.1371/journal.pone.0057380] [PMID:  23516405] 
[204] 
Ginsberg MR, Rubin RA, Falcone T, Ting AH, Natowicz MR. Brain transcriptional and epigenetic associations with autism. PLoS One  2012; 7(9) e44736
[http://dx.doi.org/10.1371/journal.pone.0044736] [PMID:  22984548] 
[205] 
Naviaux RK, Curtis B, Li K, et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann Clin Transl Neurol  2017; 4(7): 491-505.
[http://dx.doi.org/10.1002/acn3.424] [PMID:  28695149] 
[206] 
Gogou M, Evangeliou A. Is metabolic screening necessary in children with autism spectrum disorder? A mini review. J Pediatr Neurol  17(06): 199-205.
[http://dx.doi.org/10.1055/s-0038-1676633] 
[207] 
Smith AM, King JJ, West PR, et al. Amino acid dysregulation metabotypes: potential biomarkers for diagnosis and individualized treatment for subtypes of autism spectrum disorder. Biol Psychiatry  2019; 85(4): 345-54.
[http://dx.doi.org/10.1016/j.biopsych.2018.08.016] [PMID:  30446206] 
Rights & Permissions Print Cite
Article Metrics
36
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1381612825666191205091312	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286
Current Pharmaceutical Design

Targeted Biomedical Treatment for Autism Spectrum Disorders

Abstract Play Pause

Related Journals

Related Books

Related Articles

Abstract
