Differentiated approach to the pharmacotherapy of autism spectrum disorders: biochemical aspects

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Autism Spectrum Disorders (ASD) are highly heterogeneous neurodevelopmental disorders caused by a complex interaction of numerous genetic and environmental factors and leading to deviations in the nervous system formation at very early developmental stages. Currently, there are no accepted pharmacological treatments for so-called core symptoms of ASD, such as social communication disorders and restricted and repetitive behavior patterns. The lack of knowledge about biological basis of ASD, the absence of clinically significant biochemical parameters reflecting abnormalities in signaling molecular cascades controlling the nervous system development and functioning, and the lack of methods for selection of clinically and biologically homogeneous subgroups are considered among the causes for the failure of clinical trials of ASD pharmacotherapy. This review considers the possibilities of applying a differentiated clinical and biological approach to the targeted search for ASD pharmacotherapy with an emphasis on biochemical markers associated with ASD and attempts to stratify patients by biochemical parameters. The use of approach such as “target-oriented therapy and assessment of the status of the target before and during the treatment to identify patients with a positive response to treatment” is discussed using the published results of clinical trials as examples. It is concluded that the identification of biochemical parameters for the identification of distinct subgroups among ASD patients requires research on large samples reflecting the clinical and biological diversity of patients with ASD, and the use of unified approaches for such studies. An integrated approach, including clinical observation, clinical-psychological assessment of patient behavior, study of anamnesis and description of individual molecular profiles should become a new strategy for stratifying and subgrouping patients with ASD for clinical pharmacotherapeutic trials, as well as for evaluating its efficiency.

About the authors

I. S Boksha

Mental Health Research Center

Email: boksha_irina@mail.ru
115522 Moscow, Russia

T. A Prokhorova

Mental Health Research Center

Email: boksha_irina@mail.ru
115522 Moscow, Russia

O. K Savushkina

Mental Health Research Center

Email: boksha_irina@mail.ru
115522 Moscow, Russia

E. B Tereshkina

Mental Health Research Center

Email: boksha_irina@mail.ru
115522 Moscow, Russia

G. Sh Burbaeva

Mental Health Research Center

Email: boksha_irina@mail.ru
115522 Moscow, Russia

References

  1. Simashkova, N. V., Boksha, I. S., Klyushnik, T. P., Iakupova, L. P., Ivanov, M. V., and Mukaetova-Ladinska, E. B. (2019) Diagnosis and management of autism spectrum disorders in Russia: clinical-biological approaches, J. Autism Dev. Disord., 49, 3906-3914, doi: 10.1007/s10803-019-04071-4.
  2. Cheng, N., Rho, J. M., and Masino, S. A. (2017) Metabolic dysfunction underlying autism spectrum disorder and potential treatment approaches, Front. Mol. Neurosci., 10, 34, doi: 10.3389/fnmol.2017.00034.
  3. Muhle, R. A., Reed, H. E., Stratigos, K. A., and Veenstra-VanderWeele, J. (2018) The emerging clinical neuroscience of autism spectrum disorder, JAMA Psychiatry, 75, 514, doi: 10.1001/jamapsychiatry.2017.4685.
  4. Boksha, I. S., Prokhorova, T. A., Tereshkina, E. B., Savushkina, O. K., and Burbaeva, G. Sh. (2021) Protein phosphorylation signaling cascades in autism: the role of mTOR pathway, Biochemistry (Moscow), 86, 577-596, doi: 10.1134/S0006297921050072.
  5. Siafis, S., Çıray, O., Wu, H., Schneider-Thoma, J., Bighelli, I., Krause, M., Rodolico, A., Ceraso, A., Deste, G., Huhn, M., Fraguas, D., San José Cáceres, A., Mavridis, D., Charman, T., Murphy, D. G., Parellada, M., Arango, C., and Leucht, S. (2022) Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis, Mol. Autism, 13, 10, doi: 10.1186/s13229-022-00488-4.
  6. Persico, A. M., Ricciardello, A., Lamberti, M., Turriziani, L., Cucinotta, F., Brogna, C., Vitiello, B., and Arango, C. (2021) The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present, Prog. Neuropsychopharmacol. Biol. Psychiatry, 110, 110326, doi: 10.1016/j.pnpbp.2021.110326.
  7. Port, R. G., Gaetz, W., Bloy, L., Wang, D-J., Blaskey, L., Kuschner, E. S., Levy, S. E., Brodkin, E. S., and Roberts, T. P. L. (2017) Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD, Autism Res., 10, 593-607, doi: 10.1002/aur.1686.
  8. Jensen, A. R., Lane, A. L., Werner, B. A., McLees, S. E., Fletcher, T. S., and Frye, R. E. (2022) Modern biomarkers for autism spectrum disorder: future directions, Mol. Diagn. Ther., 26, 483-495, doi: 10.1007/s40291-022-00600-7.
  9. Amaral, D. G., Schumann, C. M., and Nordahl, C. W. (2008) Neuroanatomy of autism, Trends Neurosci., 31, 137-145, doi: 10.1016/j.tins.2007.12.005.
  10. Coleman, M. (2005) Advances in autism research, Dev. Med. Child Neurol., 47, 148-148, doi: 10.1017/S0012162205000277.
  11. Ecker, C., Bookheimer, S. Y., and Murphy, D. G. M. (2015) Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan, Lancet Neurol., 14, 1121-1134, doi: 10.1016/S1474-4422(15)00050-2.
  12. Lombardo, M. V., Lai, M.-C., and Baron-Cohen, S. (2019) Big data approaches to decomposing heterogeneity across the autism spectrum, Mol. Psychiatry, 24, 1435-1450, doi: 10.1038/s41380-018-0321-0.
  13. Masi, A., DeMayo, M. M., Glozier, N., and Guastella, A. J. (2017) An overview of autism spectrum disorder, heterogeneity and treatment options, Neurosci. Bull., 33, 183-193, doi: 10.1007/s12264-017-0100-y.
  14. Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., and Baird, G. (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample, J. Am. Acad. Child Adolesc. Psychiatry, 47, 921-929, doi: 10.1097/CHI.0b013e318179964f.
  15. Tang, S., Sun, N., Floris, D. L., Zhang, X., di Martino, A., and Yeo, B. T. T. (2020) Reconciling dimensional and categorical models of autism heterogeneity: a brain connectomics and behavioral study, Biol. Psychiatry, 87, 1071-1082, doi: 10.1016/j.biopsych.2019.11.009.
  16. Beversdorf, D. Q. (2016) Phenotyping, etiological factors, and biomarkers: toward precision medicine in autism spectrum disorders, J. Dev. Behav. Pediatr., 37, 659-673, doi: 10.1097/DBP.0000000000000351.
  17. Mukaetova-Ladinska, E. B., Simashkova, N. V., Mukaetova, M. S., Ivanov, M. V., and Boksha, I. S. (2018) Autism spectrum disorders in children and adults: the experience of reserches from different countries, Zh. Nevrol. Psikhiatr. Im S. S. Korsakova, 118, 92, doi: 10.17116/jnevro201811812192.
  18. Hong, S.-J., Valk, S. L., di Martino, A., Milham, M. P., and Bernhardt, B. C. (2018) Multidimensional Neuroanatomical subtyping of autism spectrum disorder, Cerebral Cortex, 28, 3578-3588, doi: 10.1093/cercor/bhx229.
  19. Feczko, E., Balba, N. M., Miranda-Dominguez, O., Cordova, M., Karalunas, S. L., Irwin, L., Demeter, D. V., Hill, A. P., Langhorst, B. H., Grieser Painter, J., Van Santen, J., Fombonne, E. J., Nigg, J. T., and Fair, D. A. (2018) Subtyping cognitive profiles in autism spectrum disorder using a functional random forest algorithm, Neuroimage, 172, 674-688, doi: 10.1016/j.neuroimage.2017.12.044.
  20. Easson, A. K., Fatima, Z., and McIntosh, A. R. (2019) Functional connectivity-based subtypes of individuals with and without autism spectrum disorder, Netw. Neurosci., 3, 344-362, doi: 10.1162/netn_a_00067.
  21. Duffy, F. H., and Als, H. (2019) Autism, spectrum or clusters? An EEG coherence study, BMC Neurol., 19, 27, doi: 10.1186/s12883-019-1254-1.
  22. Tomchek, S. D., Little, L. M., Myers, J., and Dunn, W. (2018) Sensory subtypes in preschool aged children with autism spectrum disorder, J. Autism Dev. Disord., 48, 2139-2147, doi: 10.1007/s10803-018-3468-2.
  23. Simashkova, N. V., Klyushnik, T. P., and Yakupova, L. P. (2018) Clinical and biological approaches to the diagnostics and substantiation of personalized therapy in patients with autism spectrum disorders [in Russian], Psikhiatriya, 78, 17-24.
  24. McCracken, J. T., Anagnostou, E., Arango, C., Dawson, G., Farchione, T., Mantua, V., McPartland, J., Murphy, D., Pandina, G., and Veenstra-VanderWeele, J. (2021) Drug development for Autism Spectrum Disorder (ASD): progress, challenges, and future directions, Eur. Neuropsychopharmacol., 48, 3-31, doi: 10.1016/j.euroneuro.2021.05.010.
  25. Díaz-Caneja, C., State, M., Hagerman, R., Jacquemont, S., Marín, O., Bagni, C., Umbricht, D., Simonoff, E., de Andrés-Trelles, F., Kaale, A., Pandina, G., Gómez-Mancilla, B., Wang, P. P., Cusak, J., Siafis, S., Leucht, S., Parellada, M., Loth, E., Charman, T., Buitelaar, J. K., Murphy, D., and Arango, C. (2021) A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders, Eur. Neuropsychopharmacol., 48, 49-88, doi: 10.1016/j.euroneuro.2021.02.020.
  26. Ristori, M. V., Mortera, S. L., Marzano, V., Guerrera, S., Vernocchi, P., Ianiro, G., Gardini, S., Torre, G., Valeri, G., Vicari, S., Gasbarrini, A., and Putignani, L. (2020) Proteomics and metabolomics approaches towards a functional insight onto AUTISM spectrum disorders: phenotype stratification and biomarker discovery, Int. J. Mol. Sci., 21, 6274, doi: 10.3390/ijms21176274.
  27. Klyushnik, T. P., Androsova, L. V., Simashkova, N. V., Zozulya, S. A., Otman, I. N., Shushpanova, O. V., and Brusov, O. S. (2016) Clinical and laboratory diagnosis of autism spectrum disorders in children, Lab. Sluzhba, 5, 22-27, doi: 10.17116/labs20165222-27.
  28. Simashkova, N. V., Koval-Zaytsev, A. A., Ivanov, M. V., and Nikitina, S. G. (2021) Diagnostic, clinical, psychopathological, psychological aspects of the examination of children with autism spectrum disorders, Psikhiatriya, 19, 45-53, doi: 10.30629/2618-6667-2021-19-1-45-53.
  29. Berry-Kravis, E. M., Harnett, M. D., Reines, S. A., Reese, M. A., Ethridge, L. E., Outterson, A. H., Michalak, C., Furman, J., and Gurney, M. E. (2021) Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial, Nat. Med., 27, 862-870, doi: 10.1038/s41591-021-01321-w.
  30. Lessard, M., Chouiali, A., Drouin, R., Sébire, G., and Corbin, F. (2012) Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome, Clin. Genet., 82, 472-477, doi: 10.1111/j.1399-0004.2011.01798.x.
  31. Pellerin, D., Lortie, A., and Corbin, F. (2018) Platelets as a surrogate disease model of neurodevelopmental disorders: insights from fragile X syndrome, Platelets, 29, 113-124, doi: 10.1080/09537104.2017.1317733.
  32. Pellerin, D., Çaku, A., Fradet, M., Bouvier, P., Dubé, J., and Corbin, F. (2016) Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet's signaling cascades as new outcome measures in clinical trials, Biomarkers, 21, 497-508, doi: 10.3109/1354750X.2016.1160289.
  33. Thurman, A. J., Potter, L. A., Kim, K., Tassone, F., Banasik, A., Potter, S. N., Bullard, L., Nguyen, V., McDuffie, A., Hagerman, R., and Abbeduto, L. (2020) Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome, J. Neurodev. Disord., 12, 12, doi: 10.1186/s11689-020-09315-4.
  34. Zhou, M. S., Nasir, M., Farhat, L. C., Kook, M., Artukoglu, B. B., and Bloch, M. H. (2021) Meta-analysis: pharmacologic treatment of restricted and repetitive behaviors in autism spectrum disorders, J. Am. Acad. Child Adolesc. Psychiatry, 60, 35-45, doi: 10.1016/j.jaac.2020.03.007.
  35. Ramaekers, V. Th., Segers, K., Sequeira, J. M., Koenig, M., van Maldergem, L., Bours, V., Kornak, U., and Quadros, E. V. (2018) Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome, Mol. Genet. Metab., 124, 87-93, doi: 10.1016/j.ymgme.2018.03.001.
  36. Ramaekers, V. Th., and Quadros, E. V. (2022) Cerebral folate deficiency syndrome: early diagnosis, intervention and treatment strategies, Nutrients, 14, 3096, doi: 10.3390/nu14153096.
  37. Cario, H., Bode, H., Debatin, K.-M., Opladen, T., and Schwarz, K. (2009) Congenital null mutations of the FOLR1 gene: a progressive neurologic disease and its treatment, Neurology, 73, 2127-2129, doi: 10.1212/WNL.0b013e3181c679df.
  38. Ramaekers, V. T., Rothenberg, S. P., Sequeira, J. M., Opladen, T., Blau, N., Quadros, E. V., and Selhub, J. (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome, N. Engl. J. Med., 352, 1985-1991, doi: 10.1056/NEJMoa043160.
  39. Ramaekers, V. T., Sequeira, J. M., Thöny, B., and Quadros, E. V. (2020) Oxidative stress, folate receptor autoimmunity, and CSF findings in severe infantile autism, Autism Res. Treat., 2020, 1-14, doi: 10.1155/2020/9095284.
  40. Frye, R. E., Sequeira, J. M., Quadros, E. V., James, S. J., and Rossignol, D. A. (2013) Cerebral folate receptor autoantibodies in autism spectrum disorder, Mol. Psychiatry, 18, 369-381, doi: 10.1038/mp.2011.175.
  41. Molloy, A. M., Quadros, E. V., Sequeira, J. M., Troendle, J. F., Scott, J. M., Kirke, P., N., and Mills, J. L. (2009) Lack of association between folate-receptor autoantibodies and neural-tube defects, N. Engl. J. Med., 361, 152-160, doi: 10.1056/NEJMoa0803783.
  42. Ramaekers, V. T., Quadros, E. V., and Sequeira, J. M. (2013) Role of folate receptor autoantibodies in infantile autism, Mol. Psychiatry, 18, 270-271, doi: 10.1038/mp.2012.22.
  43. Renard, E., Leheup, B., Guéant-Rodriguez, R.-M., Oussalah, A., Quadros, E. V., and Guéant, J. L. (2020) Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial, Biochimie, 173, 57-61, doi: 10.1016/j.biochi.2020.04.019.
  44. Quadros, E. V., Sequeira, J. M., Brown, W. T., Mevs, C., Marchi, E., Flory, M., Jenkins, E. C., Velinov, M. T., and Cohen, I. L. (2018) Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents, Autism Res., 11, 707-712, doi: 10.1002/aur.1934.
  45. Frye, R. E., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., Jill James, S., Sequeira, J. M., and Quadros, E. V. (2018) Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial, Mol. Psychiatry, 23, 247-256, doi: 10.1038/mp.2016.168.
  46. Rossignol, D. A., and Frye, R. E. (2021) Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (Folinic Acid) treatment in autism spectrum disorders: a systematic review and meta-analysis, J. Pers. Med., 11, 1141, doi: 10.3390/jpm11111141.
  47. Frye, R. E., Rossignol, D. A., Scahill, L., McDougle, C. J., Huberman, H., and Quadros, E. V. (2020) Treatment of folate metabolism abnormalities in autism spectrum disorder, Semin. Pediatr. Neurol., 35, 100835, doi: 10.1016/j.spen.2020.100835.
  48. Rossignol, D. A., and Frye, R. E. (2012) Substantial problems with measuring brain mitochondrial dysfunction in autism spectrum disorder using magnetic resonance spectroscopy, J. Autism Dev. Disord., 42, 640-642, doi: 10.1007/s10803-011-1276-z.
  49. Desai, A., Sequeira, J. M., and Quadros, E. V. (2016) The metabolic basis for developmental disorders due to defective folate transport, Biochimie, 126, 31-42, doi: 10.1016/j.biochi.2016.02.012.
  50. Shoffner, J., Trommer, B., Thurm, A., Farmer, C., Langley, W. A., Soskey, L., Rodriguez, A. N., D'Souza, P., Spence, S. J., Hyland, K., and Swedo, S. E. (2016) CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism, Neurology, 86, 2258-2263, doi: 10.1212/WNL.0000000000002766.
  51. Bent, S., Chen, Y., McDonald, M. G., Widjaja, F., Wahlberg, J., and Hendren, R. L. (2020) An examination of changes in urinary metabolites and behaviors with the use of leucovorin calcium in children with autism spectrum disorder (ASD), Adv. Neurodev. Disord., 4, 241-246, doi: 10.1007/s41252-020-00157-8.
  52. Watanabe, T., Abe, O., Kuwabara, H., Yahata, N., Takano, Y., Iwashiro, N., Natsubori, T., Aoki, Y., Takao, H., Kawakubo, Y., Kamio, Y., Kato, N., Miyashita, Y., Kasai, K., and Yamasue, H. (2014) Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity, JAMA Psychiatry, 71, 166, doi: 10.1001/jamapsychiatry.2013.3181.
  53. King, L. B., Walum, H., Inoue, K., Eyrich, N. W., and Young, L. J. (2016) Variation in the oxytocin receptor gene predicts brain region-specific expression and social attachment, Biol. Psychiatry, 80, 160-169, doi: 10.1016/j.biopsych.2015.12.008.
  54. Green, L., Fein, D., Modahl, C., Feinstein, C., Waterhouse, L., and Morris, M. (2001) Oxytocin and autistic disorder: alterations in peptide forms, Biol. Psychiatry, 50, 609-613, doi: 10.1016/S0006-3223(01)01139-8.
  55. Wu, S., Jia, M., Ruan, Y., Liu, J., Guo, Y., Shuang, M., Gong, X., Zhang, Y., Yang, X., and Zhang, D. (2005) Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population, Biol. Psychiatry, 58, 74-77, doi: 10.1016/j.biopsych.2005.03.013.
  56. Jacob, S., Brune, C. W., Carter, C. S., Leventhal, B. L., Lord, C., and Cook, E. H. (2007) Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism, Neurosci. Lett., 417, 6-9, doi: 10.1016/j.neulet.2007.02.001.
  57. Yrigollen, C. M., Han, S. S., Kochetkova, A., Babitz, T., Chang, J. T., Volkmar, F. R., Leckman, J. F., and Grigorenko, E. L. (2008) Genes controlling affiliative behavior as candidate genes for autism, Biol. Psychiatry, 63, 911-916, doi: 10.1016/j.biopsych.2007.11.015.
  58. Andari, E., Duhamel, J.-R., Zalla, T., Herbrecht, E., Leboyer, M., and Sirigu, A. (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders, Proc. Natl. Acad. Sci. USA, 107, 4389-4394, doi: 10.1073/pnas.0910249107.
  59. Liu, X., Kawamura, Y., Shimada, T., Otowa, T., Koishi, S., Sugiyama, T., Nishida, H., Hashimoto, O., Nakagami, R., Tochigi, M., Umekage, T., Kano, Y., Miyagawa, T., Kato, N., Tokunaga, K., and Sasaki, T. (2010) Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population, J. Hum. Genet., 55, 137-141, doi: 10.1038/jhg.2009.140.
  60. Tansey, K. E., Brookes, K. J., Hill, M. J., Cochrane, L. E., Gill, M., Skuse, D., Correia, C., Vicente, A., Kent, L., Gallagher, L., and Anney, R. J. L. (2010) Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies, Neurosci. Lett., 474, 163-167, doi: 10.1016/j.neulet.2010.03.035.
  61. Wermter, A.-K., Kamp-Becker, I., Hesse, P., Schulte-Körne, G., Strauch, K., and Remschmidt, H. (2010) Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level, Am. J. Med. Genet. B Neuropsychiatr. Genet., 153B, 629-639, doi: 10.1002/ajmg.b.31032.
  62. Campbell, D. B., Datta, D., Jones, S. T., Batey Lee, E., Sutcliffe, J. S., Hammock, E. A., and Levitt, P. (2011) Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder, J. Neurodev. Disord., 3, 101-112, doi: 10.1007/s11689-010-9071-2.
  63. Al-Ali, Z., Yasseen, A. A., Al-Dujailli, A., Al-Karaqully, A. J., McAllister, K. A., and Jumaah, A. S. (2022) The oxytocin receptor gene polymorphism rs2268491 and serum oxytocin alterations are indicative of autism spectrum disorder: A case-control paediatric study in Iraq with personalized medicine implications, PLoS One, 17, e0265217, doi: 10.1371/journal.pone.0265217.
  64. Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., Lintas, C., Abramson, R. K., Wright, H. H., Ellis, P., Langford, C. F., Worley, G., Delong, G. R., Murphy, S. K., Cuccaro, M. L., Persico, A., and Pericak-Vance, M. A. (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism, BMC Med., 7, 62, doi: 10.1186/1741-7015-7-62.
  65. Grieb, Z. A., and Lonstein, J. S. (2022) Oxytocin interactions with central dopamine and serotonin systems regulate different components of motherhood, Philos. Trans. R. Soc. Lond. B Biol. Sci., 377, 20210062, doi: 10.1098/rstb.2021.0062.
  66. Borie, A. M., Young, L. J., and Liu, R. C. (2022) Sex-specific and social experience-dependent oxytocin-endocannabinoid interactions in the nucleus accumbens: implications for social behavior, Philos Trans R. Soc Lond B Biol Sci., 377, 20210057, doi: 10.1098/rstb.2021.0057.
  67. Putnam, P. T., and Chang, S. W. C. (2022) Interplay between the oxytocin and opioid systems in regulating social behavior, Philos. Trans. R. Soc. Lond. B Biol. Sci., 377, 20210050, doi: 10.1098/rstb.2021.0050.
  68. Moerkerke, M., Peeters, M., de Vries, L., Daniels, N., Steyaert, J., Alaerts, K., and Boets, B. (2021) Endogenous oxytocin levels in autism a meta-analysis, Brain Sci., 11, 1545, doi: 10.3390/brainsci11111545.
  69. Rokicki, J., Kaufmann, T., de Lange, A. G., van der Meer, D., Bahrami, S., Sartorius, A. M., Haukvik, U. K., Steen, N. E., Schwarz, E., Stein, D. J., Naerland, T., Andreassen, O. A., Westlye, L. T., and Quintana, D. S. (2022) Oxytocin receptor expression patterns in the human brain across development, Neuropsychopharmacology, 47, 1550-1560, doi: 10.1038/s41386-022-01305-5.
  70. Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., and Hardan, A. Y. (2019) A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism, Sci. Transl. Med., 11, eaau7356, doi: 10.1126/scitranslmed.aau7356.
  71. Alaerts, K., Steyaert, J., Vanaudenaerde, B., Wenderoth, N., and Bernaerts, S. (2021) Changes in endogenous oxytocin levels after intranasal oxytocin treatment in adult men with autism: An exploratory study with long-term follow-up, Eur. Neuropsychopharmacol., 43, 147-152, doi: 10.1016/j.euroneuro.2020.11.014.
  72. Winterton, A., Westlye, L. T., Steen, N. E., Andreassen, O. A., and Quintana, D. S. (2021) Improving the precision of intranasal oxytocin research, Nat Hum Behav., 5, 9-18, doi: 10.1038/s41562-020-00996-4.
  73. Spanos, M., Chandrasekhar, T., Kim, S.-J., Hamer, R. M., King, B. H., McDougle, C. J., Sanders, K. B., Gregory, S. G., Kolevzon, A., Veenstra-VanderWeele, J., and Sikich, L. (2020) Rationale, design, and methods of the Autism Centers of Excellence (ACE) network study of oxytocin in autism to improve reciprocal social behaviors (SOARS-B), Contemp. Clin. Trials, 98, 106103, doi: 10.1016/j.cct.2020.106103.
  74. Erdman, S. E., and Poutahidis, T. (2016) Microbes and oxytocin: benefits for host physiology and behavior, Int. Rev. Neurobiol., 131, 91-126, doi: 10.1016/bs.irn.2016.07.004.
  75. Sgritta, M., Dooling, S. W., Buffington, S. A., Momin, E. N., Francis, M. B., Britton, R. A., and Costa-Mattioli, M. (2019) Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder, Neuron, 101, 246-259, doi: 10.1016/j.neuron.2018.11.018.
  76. Huang, M., Liu, K., Wei, Z., Feng, Z., Chen, J., Yang, J., Zhong, Q., Wan, G., and Kong, X. J. (2021) Serum oxytocin level correlates with gut microbiome dysbiosis in children with autism spectrum disorder, Front. Neurosci., 15, 721884, doi: 10.3389/fnins.2021.721884.
  77. Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., and Parker, K. J. (2018) Cerebrospinal fluid vasopressin and symptom severity in children with autism, Ann. Neurol., 84, 611-615, doi: 10.1002/ana.25314.
  78. Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., and Parker, K. J. (2015) Arginine vasopressin is a blood-based biomarker of social functioning in children with autism, PLoS One, 10, e0132224, doi: 10.1371/journal.pone.0132224.
  79. Parker, K. J. (2022) Leveraging a translational research approach to drive diagnostic and treatment advances for autism, Mol. Psychiatry, 27, 2650-2658, doi: 10.1038/s41380-022-01532-8.
  80. Port, R. G., Oberman, L. M., and Roberts, T. P. (2019) Revisiting the excitation/inhibition imbalance hypothesis of ASD through a clinical lens, Br. J. Radiol., 92, 20180944, doi: 10.1259/bjr.20180944.
  81. Hassan, T. H., Abdelrahman, H. M., Abdel Fattah, N. R., El-Masry, N. M., Hashim, H. M., El-Gerby, K. M., and Abdel Fattah, N. R. (2013) Blood and brain glutamate levels in children with autistic disorder, Res. Autism Spectr. Disord., 7, 541-548, doi: 10.1016/j.rasd.2012.12.005.
  82. Zhang, L., Huang, C. C., Dai, Y., Luo, Q., Ji, Y., Wang, K., Deng, S., Yu, J., Xu, M., Du, X., Tang, Y., Shen, C., Feng, J., Sahakian, B. J., Lin, C. P., and Li, F. (2020) Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios, Transl. Psychiatry, 10, 9, doi: 10.1038/s41398-020-0692-2.
  83. McCracken, J. T. (2018) Target engagement of AZD7325 in Adults with ASD, J. Am Acad Child Adolesc Psychiatry, 57, S287, doi: 10.1016/j.jaac.2018.07.683.
  84. Ajram, L. A., Horder, J., Mendez, M. A., Galanopoulos, A., Brennan, L. P., Wichers, R. H., Robertson, D. M., Murphy, C. M., Zinkstok, J., Ivin, G., Heasman, M., Meek, D., Tricklebank, M. D., Barker, G. J., Lythgoe, D. J., Edden, R. A. E., Williams, S. C., Murphy, D. G. M., and McAlonan, G. M. (2017) Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder, Transl. Psychiatry, 7, e1137, doi: 10.1038/tp.2017.104.
  85. Grabb, M. C., Cross, A. J., Potter, W. Z., and McCracken, J. T. (2016) Derisking psychiatric drug development: The NIMH's fast fail program, a novel precompetitive model, J. Clin. Psychopharmacol., 36, 419-421, doi: 10.1097/JCP.0000000000000536.
  86. De Stefano, L. A., Schmitt, L. M., White, S. P., Mosconi, M. W., Sweeney, J. A., and Ethridge, L. E. (2019) Developmental effects on auditory neural oscillatory synchronization abnormalities in autism spectrum disorder, Front. Integr. Neurosci., 13, 34, doi: 10.3389/fnint.2019.00034.
  87. Bromander, S., Anckarsäter, R., Kristiansson, M., Blennow, K., Zetterberg, H., Anckarsäter, H., and Wass, C. E. (2012) Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study, J. Neuroinflammation, 9, 758, doi: 10.1186/1742-2094-9-242.
  88. Pardo, C. A., Farmer, C. A., Thurm, A., Shebl, F. M., Ilieva, J., Kalra, S., and Swedo, S. (2017) Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study, Mol. Autism, 8, 1, doi: 10.1186/s13229-016-0115-7.
  89. Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., and Pardo, C. A. (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism, Ann. Neurol., 57, 67-81, doi: 10.1002/ana.20315.
  90. Estes, M. L., and McAllister, A. K. (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder, Nat. Rev. Neurosci., 16, 469-486, doi: 10.1038/nrn3978.
  91. Li, Q., Zhang, L., Shan, H., Yu, J., Dai, Y., He, H., Li, W. G., Langley, C., Sahakian, B. J., Yao, Y., Luo, Q., and Li, F. (2022) The immuno-behavioural covariation associated with the treatment response to bumetanide in young children with autism spectrum disorder, Transl. Psychiatry, 12, 228, doi: 10.1038/s41398-022-01987-x.
  92. Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X. M., Ji, L., Brown, T., and Malik, M. (2009) Elevated immune response in the brain of autistic patients, J. Neuroimmunol., 207, 111-116, doi: 10.1016/j.jneuroim.2008.12.002.
  93. Saghazadeh, A., Ataeinia, B., Keynejad, K., Abdolalizadeh, A., Hirbod-Mobarakeh, A., and Rezaei, N. (2019) A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: effects of age, gender, and latitude, J. Psychiatr. Res., 115, 90-102, doi: 10.1016/j.jpsychires.2019.05.019.
  94. Molloy, C. A., Morrow, A. L., Meinzen-Derr, J., Schleifer, K., Dienger, K., Manning-Courtney, P., Altaye, M., and Wills-Karp, M. (2006) Elevated cytokine levels in children with autism spectrum disorder, J. Neuroimmunol., 172, 198-205, doi: 10.1016/j.jneuroim.2005.11.007.
  95. Resta-Lenert, S., and Barrett, K. E. (2006) Probiotics and commensals reverse TNF-α- and IFN-γ-induced dysfunction in human intestinal epithelial cells, Gastroenterology, 130, 731-746, doi: 10.1053/j.gastro.2005.12.015.
  96. Bertelsen, L. S., Eckmann, L., and Barrett, K. E. (2004) Prolonged interferon-γ exposure decreases ion transport, NKCC1, and Na+-K+-ATPase expression in human intestinal xenografts in vivo, Am. J. Physiol. Gastrointest. Liver Physiol., 286, G157-G165, doi: 10.1152/ajpgi.00227.2003.
  97. Sharp, T., and Barnes, N. M. (2020) Central 5-HT receptors and their function; present and future, Neuropharmacology, 177, 108155, doi: 10.1016/j.neuropharm.2020.108155.
  98. Rose'Meyer, R. (2013) A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders, Mol. Autism, 4, 37, doi: 10.1186/2040-2392-4-37.
  99. Andersson, M., Tangen, Ä., Farde, L., Bölte, S., Halldin, C., Borg, J., and Lundberg, J. (2021) Serotonin transporter availability in adults with autism - a positron emission tomography study, Mol. Psychiatry, 26, 1647-1658, doi: 10.1038/s41380-020-00868-3.
  100. Sutcliffe, J. S., Delahanty, R. J., Prasad, H. C., McCauley, J. L., Han, Q., Jiang, L., Li, C., Folstein, S. E., and Blakely, R. D. (2005) Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors, Am. J. Hum. Genet., 77, 265-279, doi: 10.1086/432648.
  101. Adamsen, D., Ramaekers, V., Ho, H. T., Britschgi, C., Rüfenacht, V., Meili, D., Bobrowski, E., Philippe, P., Nava, C., Van Maldergem, L., Bruggmann, R., Walitza, S., Wang, J., Grünblatt, E., and Thöny, B. (2014) Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, Mol. Autism, 5, 43, doi: 10.1186/2040-2392-5-43.
  102. Murphy, D. G., Daly, E., Schmitz, N., Toal, F., Murphy, K., Curran, S., Erlandsson, K., Eersels, J., Kerwin, R., Ell, P., and Travis, M. (2006) Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study, Am. J. Psychiatry, 163, 934-936, doi: 10.1176/ajp.2006.163.5.934.
  103. Makkonen, I., Riikonen, R., Kokki, H., Airaksinen, M. M., and Kuikka, J. T. (2008) Serotonin and dopamine transporter binding in children with autism determined by SPECT, Dev. Med. Child Neurol., 50, 593-597, doi: 10.1111/j.1469-8749.2008.03027.x.
  104. Goldberg, J., Anderson, G. M., Zwaigenbaum, L., Hall, G. B., Nahmias, C., Thompson, A., and Szatmari, P. (2009) Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders, J. Autism Dev. Disord., 39, 97-104, doi: 10.1007/s10803-008-0604-4.
  105. Beversdorf, D. Q., Nordgren, R. E., Bonab, A. A., Fischman, A. J., Weise, S. B., Dougherty, D. D., Felopulos, G. J., Zhou, F. C., and Bauman, M. L. (2012) 5-HT2 receptor distribution shown by [18F] setoperone PET in high-functioning autistic adults, J. Neuropsychiatry Clin. Neurosci., 24, 191-197, doi: 10.1176/appi.neuropsych.11080202.
  106. Nakamura, K., Sekine, Y., Ouchi, Y., Tsujii, M., Yoshikawa, E., Futatsubashi, M., Tsuchiya, K. J., Sugihara, G., Iwata, Y., Suzuki, K., Matsuzaki, H., Suda, S., Sugiyama, T., Takei, N., and Mori, N. (2010) Brain serotonin and dopamine transporter bindings in adults with high-functioning autism, Arch. Gen. Psychiatry, 67, 59, doi: 10.1001/archgenpsychiatry.2009.137.
  107. Chugani, D. C., Muzik, O., Behen, M., Rothermel, R., Janisse, J. J., Lee, J., and Chugani, H. T. (1999) Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children, Ann. Neurol., 45, 287-295, doi: 10.1002/1531-8249(199903)45:3<287::aid-ana3>3.0.co;2-9.
  108. Chen, R., Davis, L. K., Guter, S., Wei, Q., Jacob, S., Potter, M. H., Cox, N. J., Cook, E. H., Sutcliffe, J. S., and Li, B. (2017) Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism, Mol. Autism, 8, 14, doi: 10.1186/s13229-017-0130-3.
  109. Gabriele, S., Sacco, R., and Persico, A. M. (2014) Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis, Eur. Neuropsychopharmacol., 24, 919-929, doi: 10.1016/j.euroneuro.2014.02.004.
  110. Wichers, R. H., Findon, J. L., Jelsma, A., Giampietro, V., Stoencheva, V., Robertson, D. M., Murphy, C. M., Blainey, S., McAlonan, G., Ecker, C., Rubia, K., Murphy, D. G. M., and Daly, E. M. (2021) Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine, Mol. Autism, 12, 14, doi: 10.1186/s13229-021-00422-0.
  111. Israelyan, N., and Margolis, K. G. (2018) Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders, Pharmacol. Res., 132, 1-6, doi: 10.1016/j.phrs.2018.03.020.
  112. Mulder, E. J., Anderson, G. M., Kemperman, R. F. J., Oosterloo-Duinkerken, A., Minderaa, R. B., and Kema, I. P. (2010) Urinary excretion of 5-hydroxyindoleacetic acid, serotonin and 6-sulphatoxymelatonin in normoserotonemic and hyperserotonemic autistic individuals, Neuropsychobiology, 61, 27-32, doi: 10.1159/000258640.
  113. Zuniga-Kennedy, M., Davoren, M., Shuffrey, L. C., Luna, R. A., Savidge, T., Prasad, V., Anderson, G. M., Veenstra-VanderWeele, J., and Williams, K. C. (2022) Intestinal predictors of whole blood serotonin levels in children with or without autism, J. Autism Dev. Disord., 52, 3780-3789, doi: 10.1007/s10803-022-05597-w.
  114. Robson, M. J., Quinlan, M. A., Margolis, K. G., Gajewski-Kurdziel, P. A., Veenstra-VanderWeele, J., Gershon, M. D., Watterson, D. M., and Blakely, R. D. (2018) p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse, Proc. Natl. Acad. Sci. USA, 115, E10245-E10254, doi: 10.1073/pnas.1809137115.
  115. Daly, E., Ecker, C., Hallahan, B., Deeley, Q., Craig, M., Murphy, C., Johnston, P., Spain, D., Gillan, N., Gudbrandsen, M., Brammer, M., Giampietro, V., Lamar, M., Page, L., Toal, F., Schmitz, N., Cleare, A., Robertson, D., Rubia, K., and Murphy, D. G. (2014) Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion, Brain, 137, 2600-2610, doi: 10.1093/brain/awu178.
  116. Boccuto, L., Chen, C. F., Pittman, A. R., Skinner, C. D., McCartney, H. J., Jones, K., Bochner, B. R., Stevenson, R. E., and Schwartz, C. E. (2013) Decreased tryptophan metabolism in patients with autism spectrum disorders, Mol. Autism, 4, 16, doi: 10.1186/2040-2392-4-16.
  117. Migliarini, S., Pacini, G., Pelosi, B., Lunardi, G., and Pasqualetti, M. (2013) Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation, Mol. Psychiatry, 18, 1106-1118, doi: 10.1038/mp.2012.128.
  118. Agus, A., Planchais, J., and Sokol, H. (2018) Gut microbiota regulation of tryptophan metabolism in health and disease, Cell Host Microbe, 23, 716-724, doi: 10.1016/j.chom.2018.05.003.
  119. Tang, W., Zhu, H., Feng, Y., Guo, R., and Wan, D. (2020) The impact of gut microbiota disorders on the blood-brain barrier, Infect. Drug Resist., 13, 3351-3363, doi: 10.2147/IDR.S254403.
  120. Luo, Y., Eran, A., Palmer, N., Avillach, P., Levy-Moonshine, A., Szolovits, P., and Kohane, I. S. (2020) A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia, Nat. Med., 26, 1375-1379, doi: 10.1038/s41591-020-1007-0.
  121. Sikora, D. M., Pettit-Kekel, K., Penfield, J., Merkens, L. S., and Steiner, R. D. (2006) The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome, Am. J. Med. Genet. A, 140, 1511-1518, doi: 10.1002/ajmg.a.31294.
  122. Gong, H., Dong, W., Rostad, S. W., Marcovina, S. M., Albers, J. J., Brunzell, J. D., and Vuletic, S. (2013) Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer's disease brains, J. Histochem. Cytochem., 61, 857-868, doi: 10.1369/0022155413505601.
  123. Beffert, U., Stolt, P. C., and Herz, J. (2004) Functions of lipoprotein receptors in neurons, J. Lipid Res., 45, 403-409, doi: 10.1194/jlr.R300017-JLR200.
  124. Kysenius, K., Muggalla, P., Mätlik, K., Arumäe, U., and Huttunen, H. J. (2012) PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling, Cell. Mol. Life Sci., 69, 1903-1916, doi: 10.1007/s00018-012-0977-6.
  125. Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., Shendure, J., and Justice, M. J. (2013) A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome, Nat. Genet., 45, 1013-1020, doi: 10.1038/ng.2714.
  126. Tierney, E., Remaley, A. T., Thurm, A., Jager, L. R., Wassif, C. A., Kratz, L. E., Bailey-Wilson, J. E., Bukelis, I., Sarphare, G., Jung, E. S., Brand, B., Noah, K. K., and Porter, F. D. (2021) Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits, Transl. Psychiatry, 11, 471, doi: 10.1038/s41398-021-01580-8.
  127. Frye, R. E. (2020) Mitochondrial dysfunction in autism spectrum disorder: unique abnormalities and targeted treatments, Semin. Pediatr. Neurol., 35, 100829, doi: 10.1016/j.spen.2020.100829.
  128. Oliveira, G., Ataíde, A., Marques, C., Miguel, T. S., Coutinho, A. M., Mota-Vieira, L., Gonçalves, E., Lopes, N. M., Rodrigues, V., Carmona da Mota, H., and Vicente, A. M. (2007) Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditionsm, Dev. Med. Child Neurol., 49, 726-733, doi: 10.1111/j.1469-8749.2007.00726.x.
  129. Demarquoy, C., and Demarquoy, J. (2019) Autism and carnitine: A possible link, World J. Biol. Chem., 10, 7-16, doi: 10.4331/wjbc.v10.i1.7.
  130. Fahmy, S. F., El-Hamamsy, M., Zaki, O., and Badary, O. A. (2013) Effect of L-carnitine on behavioral disorder in autistic children, Value Health, 16, A15, doi: 10.1016/j.jval.2013.03.092.

Copyright (c) 2023 Russian Academy of Sciences

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies