Skip to main content

Advertisement

Log in

The pathophysiology and treatment of autism

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

This article critically reviews research done in the past 2 years concerning the pathophysiology and treatment of autism. Recent research in genetics, neuroimaging, neurochemistry, and pharmacologic treatment has advanced the body of knowledge about the pathophysiology of autism. Relatively new imaging technologies (eg, positron emission tomography) are increasingly being applied to the study of subjects with autism and have produced promising results that await replication. Neurochemical and challenge studies continue to suggest a role for 5-HT dysregulation in autism. Additional research is needed to determine the role of neuroendocrine and autoimmune factors in autism. Significant gains have been made in determining which pharmacologic treatments are efficacious in autism. Additional research is needed on agents that might ameliorate the core and associated symptoms of autism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4. Washington, DC: American Psychiatric Association; 1994.

  2. Wassink TH, Piven J: The molecular genetics of autism. Curr Psychiatry Rep 2000, 2:170–175.

    PubMed  CAS  Google Scholar 

  3. Potenza MN, McDougle CJ: The role of serotonin in autism-spectrum disorders. CNS Spectrums 1997, 2:25–42.

    Google Scholar 

  4. Posey DJ, McDougle CJ: The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harvard Rev Psychiatry 2000, 8:45–63.

    Article  CAS  Google Scholar 

  5. Anderson GM, Hoshino Y: Neurochemical studies of autism. In Handbook of Autism and Pervasive Developmental Disorders, edn 2. Edited by Cohen DJ, Volkmar FR. New York: Wiley; 1997:325–343.

    Google Scholar 

  6. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL: A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993, 50:441–447.

    PubMed  CAS  Google Scholar 

  7. McDougle CJ, Naylor ST, Cohen DJ, et al.: A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996, 53:1001–1008.

    PubMed  CAS  Google Scholar 

  8. Lesch KP, Bengel D, Heils A, et al.: Association of anxietyrelated traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527–1531.

    Article  PubMed  CAS  Google Scholar 

  9. Cook EH, Courchesne R, Lord C, et al.: Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997, 2:247–250.

    Article  PubMed  Google Scholar 

  10. Klauck SM, Poustka F, Benner A, et al.: Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997, 6:2233–2238.

    Article  PubMed  CAS  Google Scholar 

  11. Maestrini E, Lai C, Marlow A, et al. and the IMGSA Consortium: Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit B3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 1999, 88:492–496. One of several recent studies that failed to replicate previous data demonstrating an association between autism and polymorphisms of the serotonin transporter gene and gamma-aminobutyric acid receptor gene.

    Article  PubMed  CAS  Google Scholar 

  12. Persico AM, Militerni R, Bravaccio C, et al.: Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000, 96:123–127.

    Article  PubMed  CAS  Google Scholar 

  13. Zhong N, Lingling Y, Ju W, et al.: 5-HTTLPR variants not associated with autistic spectrum disorders. Neurogenet 1999, 2:129–131.

    Article  CAS  Google Scholar 

  14. Lassig JP, Vachirasomtoon K, Hartzell K, et al.: Physical mapping of the serotonin 5-HT7 receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder. Am J Med Genet 1999, 88:472–475.

    Article  PubMed  CAS  Google Scholar 

  15. Baker P, Piven J, Schwartz S, Patil S: Duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Dis 1994, 24:529–535.

    Article  CAS  Google Scholar 

  16. Cook EH, Courchesne RY, Cox NJ, et al.: Linkage disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet 1998, 62:1077–1083.

    Article  PubMed  CAS  Google Scholar 

  17. Salmon B, Hallmayer J, Rogers T, et al.: Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism. Am J Med Genet 1999, 88:551–556.

    Article  PubMed  CAS  Google Scholar 

  18. Martin ER, Menold MM, Wolpert CM, et al.: Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 2000, 96:43–48.

    Article  PubMed  Google Scholar 

  19. International Molecular Genetic Study of Autism Consortium: A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Molec Genet 1998, 7:571-578. The first study to report results of a genome-wide screen for susceptibility loci in affected sib pairs with autism. This study identified chromosome 7q as the most promising region that could contain candidate genes for autism.

    Google Scholar 

  20. Philippe A, Martinez M, Guilloud-Bataille M, et al.: Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Molec Genet 1999, 8:805–812.

    Article  PubMed  CAS  Google Scholar 

  21. Barrett S, Beck JC, Bernier R, et al.: An autosomal genomic screen for autism. Am J Med Genet 1999, 88:609–615.

    Article  PubMed  CAS  Google Scholar 

  22. Risch N, Spiker D, Lotspeich L, et al.: A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999, 65:493–507.

    Article  PubMed  CAS  Google Scholar 

  23. Abell F, Krams M, Ashburner J, et al.: The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 1999, 10:1647–1651.

    Article  PubMed  CAS  Google Scholar 

  24. Levitt JG, Blanton R, Capetillo-Cunliffe L, et al.: Cerebellar vermis lobules VIII-X in autism. Prog Neuropsychopharmacol Biol Psychiatry 1999, 23:625–633.

    Article  PubMed  CAS  Google Scholar 

  25. Sears LL, Vest C, Mohamed S, et al.: An MRI study of the basal ganglia in autism. Prog Neuropsychopharmacol Biol Psychiatry 1999, 23:613–624.

    Article  PubMed  CAS  Google Scholar 

  26. Ryu YH, Lee JD, Yoon PH, et al.: Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with findings on magnetic resonance imaging. Euro J Nuc Med 1999, 26:253–259.

    Article  CAS  Google Scholar 

  27. Ohnishi T, Matsuda H, Hashimoto T, et al.: Abnormal regional cerebral blood flow in childhood autism. Brain 2000, 123:1838–1844.

    Article  PubMed  Google Scholar 

  28. Chugani DC, Sundram BS, Behen M, et al.: Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry 1999, 23:635–641.

    Article  PubMed  CAS  Google Scholar 

  29. Otsuka H, Harada M, Mori K, et al.: Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an 1H-MR spectroscopy study. Neuroradiology 1999, 41:517–519.

    Article  PubMed  CAS  Google Scholar 

  30. Chugani DC, Muzik O, Behen M, et al.: Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999, 45:287–295. A recent PET study that demonstrated abnormalities in age-dependent changes in 5-HT synthesis capacity in autistic children compared with normal subjects.

    Article  PubMed  CAS  Google Scholar 

  31. Chugani DC, Muzik O, Rothermel R, et al.: Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 1997, 14:666–669.

    Article  Google Scholar 

  32. Baron-Cohen S, Ring HA, Wheelwright S, et al.: Social intelligence in the normal and autistic brain: an fMRI study. Euro J Neurosci 1999, 11:1891–1898.

    Article  CAS  Google Scholar 

  33. Ring HA, Baron-Cohen S, Wheelwright S, et al.: Cerebral correlates of preserved cognitive skills in autism: a functional MRI study of embedded figures task performance. Brain 1999, 122:1305–1315.

    Article  PubMed  Google Scholar 

  34. Schultz RT, Gauthier I, Klin A, et al.: Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry 2000, 57:331–346. kA recent fMRI study that demonstrated that subjects with autism show increased activation of the inferior temporal gyrus during facial recognition instead of the fusiform gyrus. This pattern of activation is more similar to how nonautistic subjects process objects.

    Article  PubMed  CAS  Google Scholar 

  35. McBride PA, Anderson GM, Hertzig ME, et al.: Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1998, 37:767–776. This study demonstrated that prepubertal subjects with autism had significant elevations of platelet 5-HT that were not apparent following puberty. It also suggested that there are marked racial differences in platelet 5-HT levels with prepubertal white children having much lower levels than black and Latino children.

    Article  PubMed  CAS  Google Scholar 

  36. Cook EH, Leventhal BL, Heller W, et al.: Autistic children and their first degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990, 2:268–274.

    PubMed  Google Scholar 

  37. Leboyer M, Philippe A, Bouvard M, et al.: Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol Psychiatry 1999, 45:158–163.

    Article  PubMed  CAS  Google Scholar 

  38. Croonenberghs J, Delmeire L, Verkerk R, et al.: Peripheral markers of serotonergic and nonandrenergic function in post-pubertal, caucasian males with autistic disorder. Neuropsychopharmacology 2000, 22:275–283.

    Article  PubMed  CAS  Google Scholar 

  39. Hollander E, DelGiudice-Asch G, Simon L, et al.: B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am J Psychiatry 1999, 156:317–320.

    PubMed  CAS  Google Scholar 

  40. Goodman WK, Price LH, Rasmussen SA, et al.: The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry 1989, 46:1006–1011.

    PubMed  CAS  Google Scholar 

  41. Connolly AM, Chez MG, Pestronk A, et al.: Serum antibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Ped 1999, 134:607–613. One of several studies providing preliminary evidence of a role for autoimmune mechanisms in the pathophysiology of autism. This study found high levels of anti-brain autoantibodies in a minority of children with autism and other neurologic disorders compared with children without neurologic disorders.

    Article  CAS  Google Scholar 

  42. Modahl C, Green L, Fein D, et al.: Plasma oxytocin levels in autistic children. Biol Psychiatry 1998, 43:270–277. In this study, plasma oxytocin levels in 29 autistic children were significantly reduced compared with 30 age-matched control subjects. This provides preliminary evidence that oxytocin may play a role in the social impairment of autism.

    Article  PubMed  CAS  Google Scholar 

  43. Novotny SL, Hollander E, Allen A, et al.: Decreased repetitive behaviors in response to oxytocin challenge in adult autistic disorders. American Psychiatric Association 2000 Annual Meeting. Chicago, IL; May 13–18, 2000.

  44. Novotny S, Hollander E, Allen A, et al.: Increased growth hormone response to sumatriptan challenge in adult autistic disorders. Psychiatry Res 2000, 94:173–177.

    Article  PubMed  CAS  Google Scholar 

  45. Hollander E, Novotny S, Allen A, et al.: The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 2000, 22:163–167.

    Article  PubMed  CAS  Google Scholar 

  46. Alberti A, Pirrone P, Elia M, et al.: Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry 1999, 46:420–424.

    Article  PubMed  CAS  Google Scholar 

  47. McDougle CJ, Holmes JP, Carlson DC, et al.: A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998, 55:633–641. The only double-blind, placebo-controlled study of an atypical antipsychotic in autism. In this study of 31 adults with PDDs, risperidone resulted in improvement in eight of 14 (57%), compared with zero of 16 in the placebo group.

    Article  PubMed  CAS  Google Scholar 

  48. McDougle CJ, Scahill L, McCracken JT, et al.: Research Units on Pediatric Psychopharmacology (RUPP) Autism Network: background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatric Clin N Am 2000, 9:201–224.

    CAS  Google Scholar 

  49. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ: Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999, 19:37–44.

    Article  PubMed  CAS  Google Scholar 

  50. Kemner C, Van Engelend H, Tuynman-Qua H: An openlabel study of olanzapine in children with PDD. Schiz Res 2000, 41:194.

    Article  Google Scholar 

  51. Martin A, Koenig K, Scahill L, Bregman J: Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 1999, 9:99–107.

    Article  PubMed  CAS  Google Scholar 

  52. Findling RL, McNamara NK, Gracious BL: Paediatric uses of atypical antipsychotics. Exp Opin Pharmacother 2000, 1:935–945.

    Article  CAS  Google Scholar 

  53. Posey DJ, Litwiller M, Kohburn A, McDougle CJ: Paroxetine in autism. J Am Acad Child Adolesc Psychiatry 1999, 38:111–112.

    Article  PubMed  CAS  Google Scholar 

  54. Posey DJ, Guenin K, Kohburn A, et al.: An open-label trial of mirtazapine in autism and related disorders. 47th Annual Meeting of the American Academy of Child & Adolescent Psychiatry. New York, NY; October 24–29, 2000.

  55. Hollander E, Kaplan A, Cartwright C, Reichman D: Venlafaxine in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report. J Child Neurol 2000, 15:132–135.

    PubMed  CAS  Google Scholar 

  56. Horvath K, Stefanatos G, Sokolski KN, et al.: Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys 1998, 9:9–15.

    PubMed  CAS  Google Scholar 

  57. Owley T, Steele E, Corsello C, et al.: A double-blind, placebocontrolled trial of secretin for the treatment of autistic disorder. Medscape Gen Med 1999, 1(10) [Available online at http://www.medscape.com].

  58. Sandler AD, Sutton KA, DeWeese J, et al.: Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med 1999, 341:1801–1806. The largest of the controlled studies of secretin in autism, which showed that secretin was no better than placebo in 60 children with autism and pervasive development disorder not otherwise specified.

    Article  PubMed  CAS  Google Scholar 

  59. Chez MG, Buchanan CP, Bagan BT, et al.: Secretin and autism: a two-part clinical investigation. J Autism Dev Disord 2000, 30:87–94.

    Article  PubMed  CAS  Google Scholar 

  60. King BH, Cook EH, Sikich L, et al.: A controlled trial of amantadine in the treatment of autistic children. 46th Annual Meeting of the American Academy of Child & Adolescent Psychiatry. Chicago, IL; October 19–24, 2000.

  61. Aman MG, Singh NN, Stewart AW, Field CJ: The Aberrant Behavior Checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 1985, 89:485–491.

    PubMed  CAS  Google Scholar 

  62. Bolman WM, Richmond JA: A double-blind, placebo-controlled, crossover pilot trial of low dose dimethylglycine in patients with autistic disorder. J Autism Dev Disord 1999, 29:191–194.

    Article  PubMed  CAS  Google Scholar 

  63. Rossi PG, Posar A, Parmeggiani A, et al.: Niaprazine in the treatment of autistic disorder. J Child Neurol 1999, 14:547–550.

    PubMed  CAS  Google Scholar 

  64. Chez MG, Nowinski CV, Buchanan CP, Jones C: Donepezil (Aricept) use in children with autistic spectrum disorders. Am Neurol 2000, 48:541.

    Google Scholar 

  65. DelGiudice-Asch G, Simon L, Schmeidler J, et al.: Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord 1999, 29:157–160.

    Article  PubMed  CAS  Google Scholar 

  66. Bolte ER: Autism and Clostridium tetani. Med Hypoth 1998, 51:133–144.

    Article  CAS  Google Scholar 

  67. Sandler RH, Finegold SM, Bolte ER, et al.: Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 2000, 15:429–435.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Posey, D.J., McDougle, C.J. The pathophysiology and treatment of autism. Curr Psychiatry Rep 3, 101–108 (2001). https://doi.org/10.1007/s11920-001-0006-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-001-0006-1

Keywords

Navigation