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. 2010 Jul;7(3):293–301. doi: 10.1016/j.nurt.2010.05.008

Immune therapy in autism: Historical experience and future directions with immunomodulatory therapy

Michael G Chez 1,✉, Natalie Guido-Estrada 2
PMCID: PMC5084233  PMID: 20643382

Summary

Autism affects 1 in 110 new births, and it has no single etiology with uniform agreement. This has a significant impact on the quality of life for individuals who have been diagnosed with autism. Although autism has a spectrum quality with a shared diagnosis, it presents a uniquely different clinical appearance in each individual. Recent research of suspected immunological factors have provided more support for a probable immunological process or for processes that may play a role in the acquisition of an autistic condition. These factors include prenatal, genetic, and postnatal findings, as well as the discovery of a dysfunctional chronic pro-inflammatory state in brain tissue and cerebrospinal fluid in subsets of autistic patients. These findings offer new theories that may lead to the development of disease modification or preventative therapeutic options in the near future. This article reviews prenatal, genetic, and observed immune aspects of the autism condition that may be risk factors in the presentation of the autistic clinical phenotype. Historical immune interventions in autism are reviewed and potential new therapies and interventions are discussed.

Key Words: Autism, immune therapy, immune dysfunction, autoimmunity

References

  • 1.Rice C. Prevalence of autism spectrum disorders. Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR. 2009;58:1–1. [PubMed] [Google Scholar]
  • 2.American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4th edition. Washington, DC: Skyscape; 1994. [Google Scholar]
  • 3.Shattuck PT. The contribution of diagnostic substitution to the growing administrative prevalence of autism in US special education. Pediatrics. 2006;117:1028–1037. doi: 10.1542/peds.2005-1516. [DOI] [PubMed] [Google Scholar]
  • 4.Department of Developmental Services. Autistic spectrum disorders: changes in the California caseload: an update 1999–2002. Sacramento, CA: State of California; 2003.
  • 5.Croen LA, Grether JK, Hoogstrate J, et al. The changing prevalence of autism in California. J Autism Dev Disord. 2002;32:207–215. doi: 10.1023/A:1015453830880. [DOI] [PubMed] [Google Scholar]
  • 6.Institute MIND . Report to the legislature on the principle findings from the epidemiology of autism in California. Sacramento, CA: University of California, Davis; 2002. [Google Scholar]
  • 7.Chez MG, Chang M, Krasne V, et al. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav. 2006;8:267–271. doi: 10.1016/j.yebeh.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • 8.Olsson I, Steffenburg S, Gillberg C. Epilepsy in autism and autisticlike conditions. A population-based study. Arch Neurol. 1988;45:666–668. doi: 10.1001/archneur.1988.00520300086024. [DOI] [PubMed] [Google Scholar]
  • 9.Spence SJ. The genetics of autism. Semin Pediatr Neurol. 2004;11:196–204. doi: 10.1016/j.spen.2004.07.003. [DOI] [PubMed] [Google Scholar]
  • 10.Wassink TH, Piven J, Patil SR. Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatr Genet. 2001;11:57–63. doi: 10.1097/00041444-200106000-00001. [DOI] [PubMed] [Google Scholar]
  • 11.Campbell DB, Sutcliffe JS, Ebert PJ, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A. 2006;103:16834–16839. doi: 10.1073/pnas.0605296103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Patterson P. Pregnancy, immunity, schizophrenia, and autism. Eng Sci. 2006;69:10–21. [Google Scholar]
  • 13.Connolly AM, Chez MG, Pestronk A, et al. Serum auto-antibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999;134:607–613. doi: 10.1016/S0022-3476(99)70248-9. [DOI] [PubMed] [Google Scholar]
  • 14.Nelson KB, Grether JK, Croen LA, et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001;49:597–606. doi: 10.1002/ana.1024. [DOI] [PubMed] [Google Scholar]
  • 15.Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17:485–495. doi: 10.1080/02646830500381930. [DOI] [PubMed] [Google Scholar]
  • 16.Todd RD, Hickok JM, Anderson GM, et al. Antibrain antibodies in infantile autism. Biol Psychiatry. 1988;23:644–647. doi: 10.1016/0006-3223(88)90012-1. [DOI] [PubMed] [Google Scholar]
  • 17.Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67–81. doi: 10.1002/ana.20315. [DOI] [PubMed] [Google Scholar]
  • 18.Atladottir HO, Pedersen MG, Thorsen P, et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics. 2009;124:687–694. doi: 10.1542/peds.2008-2445. [DOI] [PubMed] [Google Scholar]
  • 19.Comi AM, Zimmerman AW, Frye VH, et al. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999;14:388–394. doi: 10.1177/088307389901400608. [DOI] [PubMed] [Google Scholar]
  • 20.Daniels WW, Warren RP, Odell JD, et al. Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology. 1995;32:120–123. doi: 10.1159/000119223. [DOI] [PubMed] [Google Scholar]
  • 21.Warren RP, Margaretten NC, Pace NC, et al. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986;16:189–197. doi: 10.1007/BF01531729. [DOI] [PubMed] [Google Scholar]
  • 22.Connolly AM. Brain-derived neurotrophic factor and auto-antibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiat. 2006;59:354–363. doi: 10.1016/j.biopsych.2005.07.004. [DOI] [PubMed] [Google Scholar]
  • 23.Singh VK, Lin SX, Yang VC. Serological association of measles virus and human herpesvirus-6 with brain auto-antibodies in autism. Clin Immunol Immunopathol. 1998;89:105–108. doi: 10.1006/clin.1998.4588. [DOI] [PubMed] [Google Scholar]
  • 24.Singh VK, Warren RP, Odell JD, et al. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun. 1993;7:97–103. doi: 10.1006/brbi.1993.1010. [DOI] [PubMed] [Google Scholar]
  • 25.Warren RP, Yonk LJ, Burger RA, et al. Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism. Immunol Invest. 1990;19:245–251. doi: 10.3109/08820139009041839. [DOI] [PubMed] [Google Scholar]
  • 26.Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7:49–55. doi: 10.1007/BF01531114. [DOI] [PubMed] [Google Scholar]
  • 27.Margaretten NC, Warren RP. Reduced natural killer cell activity and OKT4/OKT8 ratio in epileptic patients. Immunol Invest. 1986;15:159–167. doi: 10.3109/08820138609094141. [DOI] [PubMed] [Google Scholar]
  • 28.Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996;26:439–452. doi: 10.1007/BF02172828. [DOI] [PubMed] [Google Scholar]
  • 29.Plioplys A. Immunoglobulin reactivity in autism and Rett’s syndrome. Dev Brain Dysfunct. 1994;7:12–16. [Google Scholar]
  • 30.Zimmerman AW. Serum immunoglobulins and autoimmune profiles in children with autism. Ann Neurol. 1995;38:528–528. [Google Scholar]
  • 31.Gupta S. Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999;14:203–205. doi: 10.1177/088307389901400314. [DOI] [PubMed] [Google Scholar]
  • 32.Plioplys A. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. 1999;13:79–82. doi: 10.1177/088307389801300207. [DOI] [PubMed] [Google Scholar]
  • 33.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. doi: 10.1086/302497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77. doi: 10.1017/S0033291700028099. [DOI] [PubMed] [Google Scholar]
  • 35.Hallmayer J, Glasson EJ, Bower C, et al. On the twin risk in autism. Am J Hum Genet. 2002;71:941–946. doi: 10.1086/342990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psych. 1989;30:405–416. doi: 10.1111/j.1469-7610.1989.tb00254.x. [DOI] [PubMed] [Google Scholar]
  • 37.Boccone L, Dessi V, Zappu A, et al. Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation. Am J Med Genet A. 2006;140:1965–1969. doi: 10.1002/ajmg.a.31396. [DOI] [PubMed] [Google Scholar]
  • 38.Burger RA. Possible immunogenetic basis for autism. Ment Retard Dev D R. 1998;4:137–141. doi: 10.1002/(SICI)1098-2779(1998)4:2<137::AID-MRDD11>3.0.CO;2-W. [DOI] [Google Scholar]
  • 39.Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006;80:1–15. doi: 10.1189/jlb.1205707. [DOI] [PubMed] [Google Scholar]
  • 40.Shi L, Fatemi SH, Sidwell RW, et al. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003;23:297–302. doi: 10.1523/JNEUROSCI.23-01-00297.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Nawa H, Takei N. Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. Neurosci Res. 2006;56:2–13. doi: 10.1016/j.neures.2006.06.002. [DOI] [PubMed] [Google Scholar]
  • 42.Palmen SJ, van Engeland H, Hof PR, et al. Neuropathological findings in autism. Brain. 2004;127:2572–2583. doi: 10.1093/brain/awh287. [DOI] [PubMed] [Google Scholar]
  • 43.Patterson PH. Modeling features of autism in animals. Boca Raton, FL: Taylor & Francis; 2005. [Google Scholar]
  • 44.Smith SE, Li J, Garbett K, et al. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–10702. doi: 10.1523/JNEUROSCI.2178-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Urakubo A, Jarskog LF, Lieberman JA, et al. Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res. 2001;47:27–36. doi: 10.1016/S0920-9964(00)00032-3. [DOI] [PubMed] [Google Scholar]
  • 46.Meyer U, Murray PJ, Urwyler A, et al. Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling. Mol Psychiatry. 2008;13:208–221. doi: 10.1038/sj.mp.4002042. [DOI] [PubMed] [Google Scholar]
  • 47.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;17:833–837. doi: 10.1177/08830738020170111501. [DOI] [PubMed] [Google Scholar]
  • 48.Morris C. Fetal anti-brain anti-bodies in serum of mothers of children with autistic disorder: correlation with developmental regression. Ann Neurol. 2007;62:S116–S117. doi: 10.1002/ana.11635. [DOI] [Google Scholar]
  • 49.Morris C. Maternal antibodies and placental-fetal IgG transfer theory. Totowa, NJ: Humana Press; 2008. [Google Scholar]
  • 50.Singer HS. Serum anti-brain antibody differences in mothers of children with autism disorder: a study with fetal human and rodent tissue. International Meeting for Autism Research (IMFAR), 2007.
  • 51.Zimmerman AW, Connors SL, Matteson KJ, et al. Maternal anti-brain antibodies in autism. Brain Behav Immun. 2007;21:351–357. doi: 10.1016/j.bbi.2006.08.005. [DOI] [PubMed] [Google Scholar]
  • 52.Croen LA, Grether JK, Yoshida CK, et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med. 2005;159:151–157. doi: 10.1001/archpedi.159.2.151. [DOI] [PubMed] [Google Scholar]
  • 53.Chez MG, Dowling T, Patel PB, et al. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36:361–365. doi: 10.1016/j.pediatrneurol.2007.01.012. [DOI] [PubMed] [Google Scholar]
  • 54.Jander S, Schroeter M, Stoll G. Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J Neuroimmunol. 2000;109:181–187. doi: 10.1016/S0165-5728(00)00317-9. [DOI] [PubMed] [Google Scholar]
  • 55.Purcell AE, Jeon OH, Zimmerman AW, et al. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001;57:1618–1628. doi: 10.1212/wnl.57.9.1618. [DOI] [PubMed] [Google Scholar]
  • 56.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;80:1611–1617. doi: 10.1093/ajcn/80.6.1611. [DOI] [PubMed] [Google Scholar]
  • 57.James SJ, Slikker W, Melnyk S, et al. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology. 2005;26:1–8. doi: 10.1016/j.neuro.2004.07.012. [DOI] [PubMed] [Google Scholar]
  • 58.Chez MG. Superoxide dismutase overactivity, excessive selenium, and low copper in acquired epileptic aphasia (the Landau-Kleffner syndrome) Ann Neurol. 1995;39:544–544. [Google Scholar]
  • 59.Beloosesky R, Gayle DA, Amidi F, et al. N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats. Am J Obstet Gynecol. 2006;194:268–273. doi: 10.1016/j.ajog.2005.06.082. [DOI] [PubMed] [Google Scholar]
  • 60.Vezzani A. Inflammation and epilepsy. Epilepsy Curr. 2005;5:1–6. doi: 10.1111/j.1535-7597.2005.05101.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005;46:1724–1743. doi: 10.1111/j.1528-1167.2005.00298.x. [DOI] [PubMed] [Google Scholar]
  • 62.Chez MG. Treatment of electroencephalographic epileptiform activity on overnight EEG studies in children with pervasive developmental disorder or autism: defining similarities to the Landau-Kleffner syndrome. J Dev Learning Disord. 1998;2:217–229. [Google Scholar]
  • 63.Hollander E, Dolgoff-Kaspar R, Cartwright C, et al. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry. 2001;62:530–534. doi: 10.4088/JCP.v62n07a05. [DOI] [PubMed] [Google Scholar]
  • 64.Plioplys A. Autism: electroencephalogram abnormalities and clinical improvement with valproic acid. Arch Pediat Adol Med. 1994;148:220–222. doi: 10.1001/archpedi.1994.02170020106021. [DOI] [PubMed] [Google Scholar]
  • 65.Shenoy S, Arnold S, Chatila T. Response to steroid therapy in autism secondary to autoimmune lymphoproliferative syndrome. J Pediatr. 2000;136:682–687. doi: 10.1067/mpd.2000.105355. [DOI] [PubMed] [Google Scholar]
  • 66.Sandler RH, Boite ER, Chez MG, et al. Relief of psychiatric symptoms in a patient with Crohn’s disease after metronidazole therapy. Clin Infect Dis. 2000;30:213–214. doi: 10.1086/313623. [DOI] [PubMed] [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. doi: 10.1177/088307380001500701. [DOI] [PubMed] [Google Scholar]
  • 68.Boris M. Improvement in children with autism treated with intravenous gamma globulin. J Nutr Environ Med. 2005;15:169–176. doi: 10.1080/13590840600681827. [DOI] [Google Scholar]
  • 69.Arts WF, Aarsen FK, Scheltens-de Boer M, et al. Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins. Epilepsia. 2009;50(Suppl 7):55–58. doi: 10.1111/j.1528-1167.2009.02221.x. [DOI] [PubMed] [Google Scholar]
  • 70.Mikati MA, Saab R. Successful use of intravenous immunoglobulin as initial monotherapy in Landau-Kleffner syndrome. Epilepsia. 2000;41:880–886. doi: 10.1111/j.1528-1157.2000.tb00257.x. [DOI] [PubMed] [Google Scholar]
  • 71.Lewine JD, Andrews R, Chez M, et al. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics. 1999;104(3):405–418. doi: 10.1542/peds.104.3.405. [DOI] [PubMed] [Google Scholar]
  • 72.Chez M. Practical treatment with pulse-dose corticosteroids in pervasive developmental disorder of autistic patients with abnormal sleep EEG and language delay. In: Perat M, editor. New developments in child neurology. Bologna, Italy: Monduzzi Editore; 1998. [Google Scholar]
  • 73.Chez M. Pulse high-dose steroids as combination therapy with valproic acid in epileptic aphasia patients with pervasive developmental delay or autism. Ann Neurol. 1998;44:539–539. [Google Scholar]
  • 74.Trauner D. Developmental aphasia with epileptiform abnormalities on EEG: clinical features and response to Prednisone. Ann Neurol. 2002;52:66–67. doi: 10.1002/ana.5020. [DOI] [Google Scholar]
  • 75.Lewine JD. Patterns of epileptiform activity and clinical response to steroid therapy in autism. International Meeting for Autism Research (IMFAR). Chicago, IL, 2009.
  • 76.Aykut-Bingol C. Pulse methylprednisolone therapy in Landau-Kleffner syndrome. J Epilepsy. 1998;9:189–191. doi: 10.1016/0896-6974(96)00026-6. [DOI] [Google Scholar]
  • 77.Hempel A. Treatment of Landau-Kleffner syndrome with pulse dose prednisone: behavioral and language outcomes. Boston, MA: American Epilepsy Society Meeting, 2009.
  • 78.Stefanatos GA, Grover W, Geller E. Case study: corticosteroid treatment of language regression in pervasive developmental disorder. J Am Acad Child Adolesc Psychiatry. 1995;34:1107–1111. doi: 10.1097/00004583-199508000-00022. [DOI] [PubMed] [Google Scholar]
  • 79.Buitelaar JK, van Engeland H, de Kogel KH, et al. The use of adrenocorticotrophic hormone (4–9) analog ORG 2766 in autistic children: effects on the organization of behavior. Biol Psychiat. 1992;31:1119–1129. doi: 10.1016/0006-3223(92)90156-T. [DOI] [PubMed] [Google Scholar]
  • 80.Chez M. Effect of Lenalidomide on TNF-alpha elevation and behavior in autism. Presented at: International Meeting for Autism Research (IMFAR); May 20–22, 2010; Philadelphia, PA.
  • 81.Boris M, Kaiser CC, Goldblatt A, et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3–3. doi: 10.1186/1742-2094-4-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Brabers NA, Nottet HS. Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Invest. 2006;36:447–458. doi: 10.1111/j.1365-2362.2006.01657.x. [DOI] [PubMed] [Google Scholar]
  • 83.Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2–2. doi: 10.1186/1742-2094-5-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Deonna T. Reversible Behavioral autistic-like regression: a manifestation of a special (new?) Epileptic syndrome in a 28 month old child. A 2 year longitudinal study. Neurocase. 1995;1:91–95. doi: 10.1080/13554799508402352. [DOI] [Google Scholar]
  • 85.Hollander E, Chaplin W, Soorya L, et al. Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders. Neuropsychopharmacol. 2010;35:990–998. doi: 10.1038/npp.2009.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360:1597–1605. doi: 10.1056/NEJMoa0803531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Posey DJ, Kern DL, Swiezy NB, et al. A pilot study of D-cycloserine in subjects with autistic disorder. Am J Psychiatry. 2004;161:2115–2117. doi: 10.1176/appi.ajp.161.11.2115. [DOI] [PubMed] [Google Scholar]
  • 88.King B. Double-blind, placebo-controlled study of amantidine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Psy. 2001;184:254–256. doi: 10.1097/00004583-200106000-00010. [DOI] [PubMed] [Google Scholar]
  • 89.Owley T, Salt J, Guter S, et al. A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16:517–524. doi: 10.1089/cap.2006.16.517. [DOI] [PubMed] [Google Scholar]
  • 90.Chez MG, Burton Q, Dowling T, et al. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 2007;22:574–579. doi: 10.1177/0883073807302611. [DOI] [PubMed] [Google Scholar]
  • 91.Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl) 2006;184:254–256. doi: 10.1007/s00213-005-0246-6. [DOI] [PubMed] [Google Scholar]

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