Skip to main content
Search
Search
    Quick Search anywhere
    Quick search in Citations
Advanced Search
Skip main navigationClose Drawer MenuOpen Drawer Menu
Previous article
Next article
Free AccessReview Article

Glutamaterge Substanzen in der Behandlung von Zwanghaftigkeit und Impulsivität in der Kinder- und Jugendpsychiatrie: eine systematische Übersichtsarbeit

Published Online:September 18, 2017https://doi.org/10.1024/1422-4917/a000546

Abstract

Abstract.Objective: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. Method: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. Results: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. Conclusions: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).


Glutamaterge Substanzen in der Behandlung von Zwanghaftigkeit und Impulsivität in der Kinder- und Jugendpsychiatrie: eine systematische Übersichtsarbeit

Zusammenfassung.Fragestellung: Forschungsergebnisse legen eine wesentliche Beteiligung von glutamatergen Bahnen zwischen den subfrontalen Hirnarealen bei der Pathogenese von Zwanghaftigkeit und Impulsivität nahe. Daher stellen eine Reduktion der Freisetzung von Glutamat im Striatum oder die Antagonisierung von Glutamat am Rezeptor mögliche Behandlungsansätze dar. Diverse glutamaterge Substanzen sind in anderen Indikationsbereichen zugelassen, könnten aber auch von Nutzen bei der Behandlung von Zwanghaftigkeit und Impulsivität im Rahmen kinder- und jugendpsychiatrischer Störungsbilder sein. Methodik: Diese Übersichtsarbeit wurde gemäß der PRISMA-Leitlinien erstellt und evaluiert die verfügbare wissenschaftliche Literatur hinsichtlich der Wirksamkeit und Verträglichkeit von glutamatergen Substanzen in der Behandlung von Zwangsstörungen, Autismus-Spektrum-Störungen und Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen bei Kindern und Jugendlichen. Ergebnisse: Aus einer Gesamtzahl von 1‘426 Veröffentlichungen wurden 21 Studien, welche sechs glutamaterge Substanzen in diesen Populationen untersuchten, in die Auswertung eingeschlossen. Schlussfolgerungen: Designs und Ergebnisse der eingeschlossenen Studien zeigten eine deutliche Heterogenität. Deren Vergleichbarkeit war daher eingeschränkt. Die verfügbaren Daten unterstützen die Hypothese, dass glutamaterge Substanzen einen potentiellen Nutzen in der Behandlung von Zwanghaftigkeit und Impulsivität bei Kindern und Jugendlichen haben. Darüber hinaus ließen die Ergebnisse für Memantin und N-Acetylcystein das beste Risiko-Nutzen-Profil für zukünftige klinische Studien bei Kindern und Jugendlichen mit Zwangsstörungen und Autismus-Spektrum-Störungen vermuten. Riluzol sollte zunächst in Studien an erwachsenen Patienten weiter untersucht werden.

Literature

  • Abdel-Ahad, P. & Kazour, F. (2013). Non-Antidepressant Pharmacological Treatment of Obsessive Compulsive Disorder: A Comprehensive Review. Curr Clin Pharmacol. First citation in articleGoogle Scholar

  • Aman, M. G., Burrow, W. H. & Wolford, P. L. (1995). The Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homes. Am J Ment Retard, 100(3), 283–292. First citation in articleGoogle Scholar

  • American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders: DSM-5 (A. American Psychiatric, Trans. Fifth ed.). Washington, DC American Psychiatric Assoc. First citation in articleCrossref, Google Scholar

  • Berk, M., Malhi, G. S., Gray, L. J. & Dean, O. M. (2013). The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci, 34(3), 167–177. doi: 10.1016/j.tips.2013.01.001. First citation in articleGoogle Scholar

  • Berry-Kravis, E., Krause, S. E., Block, S. S., Guter, S., Wuu, J., Leurgans, S. & Hagerman, R. (2006). Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol, 16(5), 525–540. doi: 10.1089/cap.2006.16.525. First citation in articleGoogle Scholar

  • Biederman, J. & Faraone, S. V. (2005). Attention-deficit hyperactivity disorder. Lancet, 366(9481), 237–248. doi: 10.1016/S0140-6736 (05)66915-2. First citation in articleGoogle Scholar

  • Billstedt, E., Gillberg, I. C. & Gillberg, C. (2007). Autism in adults: symptom patterns and early childhood predictors. Use of the DISCO in a community sample followed from childhood. J Child Psychol Psychiatry, 48(11), 1102–1110. doi: 10.1111/j.1469-7610.2007.01774.x. First citation in articleGoogle Scholar

  • Bloch, M. H., Panza, K. E., Grant, J. E., Pittenger, C. & Leckman, J. F. (2013). N-acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry, 52(3), 231–240. doi: 10.1016/j.jaac.2012.12.020. First citation in articleGoogle Scholar

  • Brennan, B. P., Rauch, S. L., Jensen, J. E. & Pope, H. G. Jr. (2013). A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder. Biol Psychiatry, 73(1), 24–31. doi: 10.1016/j.biopsych.2012.06.023. First citation in articleGoogle Scholar

  • Bristot Silvestrin, R., Bambini-Junior, V., Galland, F., Daniele Bobermim, L., Quincozes-Santos, A., Torres Abib, R. & Gottfried, C. (2013). Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res, 1495, 52–60. doi: 10.1016/j.brainres.2012.11.048. First citation in articleGoogle Scholar

  • Budimirovic, D. B. & Kaufmann, W. E. (2011). What Can We Learn about Autism from Studying Fragile X Syndrome? Developmental Neuroscience, 33(5), 379–394. doi: 10.1159/000330213. First citation in articleGoogle Scholar

  • Carlsson, M. L. (1998). Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate – serotonin interactions for pharmacotherapy. J Neural Transm, 105(4–5), 525–535. First citation in articleGoogle Scholar

  • Carlsson, M. L. (2000). On the role of cortical glutamate inobsessive-compulsive disorder and attention-deficit hyperactivity disorder, two phenomenologically antithetical conditions. Acta Psychiatr Scand, 102(6), 401–413. doi: 10.1034/j.1600-0447. 2000.102006401.x. First citation in articleGoogle Scholar

  • Carlsson, M. L. (2001). On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry, 25(1), 5–26. First citation in articleGoogle Scholar

  • Carrey, N., MacMaster, F. P., Sparkes, S. J., Khan, S. C. & Kusumakar, V. (2002). Glutamatergic changes with treatment in attention deficit hyperactivity disorder: a preliminary case series. J Child Adolesc Psychopharmacol, 12(4), 331–336. doi: 10.1089/ 104454602762599871. First citation in articleGoogle Scholar

  • Chakrabarty, K., Bhattacharyya, S., Christopher, R. & Khanna, S. (2005). Glutamatergic dysfunction in OCD. Neuropsychopharmacology, 30(9), 1735–1740. First citation in articleGoogle Scholar

  • Chamberlain, S. R., Fineberg, N. A., Blackwell, A. D., Robbins, T. W. & Sahakian, B. J. (2006). Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psychiatry, 163(7), 1282–1284. First citation in articleGoogle Scholar

  • Chez, M. G., Burton, Q., Dowling, T., Chang, M., Khanna, P. & Kramer, C. (2007). Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol, 22(5), 574–579. First citation in articleGoogle Scholar

  • Ciociola, A. A., Cohen, L. B. & Kulkarni, P. (2014). How drugs are developed and approved by the FDA: current process and future directions. Am J Gastroenterol, 109(5), 620–623. doi: 10.1038/ajg.2013.407. First citation in articleGoogle Scholar

  • Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences: Lawrence Erlbaum Associates. First citation in articleGoogle Scholar

  • Collier, R. (2009). Drug development cost estimates hard to swallow. CMAJ, 180(3), 279–280. doi: 10.1503/cmaj.082040. First citation in articleGoogle Scholar

  • Conners, C. K., Sitarenios, G., Parker, J. D. & Epstein, J. N. (1998). The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol, 26(4), 257–268. First citation in articleGoogle Scholar

  • Constantino, J. N., Davis, S. A., Todd, R. D., Schindler, M. K., Gross, M. M., Brophy, S. L. & Reich, W. (2003). Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord, 33(4), 427–433. First citation in articleGoogle Scholar

  • Coric, V., Milanovic, S., Wasylink, S., Patel, P., Malison, R. & Krystal, J. H. (2003). Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology (Berl), 167(2), 219–220. First citation in articleGoogle Scholar

  • Coric, V., Taskiran, S., Pittenger, C., Wasylink, S., Mathalon, D. h., Valentine, G. & Krystal, J. H. (2005). Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry, 58(5), 424–428. First citation in articleGoogle Scholar

  • Davis, C., Levitan, R. D., Kaplan, A. S., Carter, J., Reid, C., Curtis, C. & Kennedy, J. L. (2007). Dopamine transporter gene (DAT1) associated with appetite suppression to methylphenidate in a case-control study of binge eating disorder. Neuropsychopharmacology, 32(10), 2199–2206. doi: 10.1038/sj.npp.1301348. First citation in articleGoogle Scholar

  • Dean, O., Giorlando, F. & Berk, M. (2011). N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci, 36(2), 78–86. doi: 10.1503/jpn.100057 First citation in articleGoogle Scholar

  • Dean, O. M., Data-Franco, J., Giorlando, F. & Berk, M. (2012). Minocycline: therapeutic potential in psychiatry. CNS Drugs, 26(5), 391–401. doi: 10.2165/11632000-000000000-00000. First citation in articleGoogle Scholar

  • Douglass, H. M., Moffitt, T. E., Dar, R., McGee, R. & Silva, P. (1995). Obsessive-compulsive disorder in a birth cohort of 18-year-olds: prevalence and predictors. J Am Acad Child Adolesc Psychiatry, 34(11), 1424–1431. doi: 10.1097/00004583-199511000-00008. First citation in articleGoogle Scholar

  • DuPaul, G. J., Power, T. J., Anastopoulos, A. D. & Reid, R. (1998). ADHD rating scale-IV : checklists, norms, and clinical interpretation. New York: Guilford Press. First citation in articleGoogle Scholar

  • Durston, S., van Belle, J. & de Zeeuw, P. (2011). Differentiating frontostriatal and fronto-cerebellar circuits in attention-deficit/hyperactivity disorder. Biol Psychiatry, 69(12), 1178–1184. doi: 10.1016/j.biopsych.2010.07.037. First citation in articleGoogle Scholar

  • Erickson, C. A., Posey, D. J., Stigler, K. A., Mullett, J., Katschke, A. R. & McDougle, C. J. (2007). A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl), 191(1), 141–147. First citation in articleGoogle Scholar

  • Erickson, C. A., Weng, N., Weiler, I. J., Greenough, W. T., Stigler, K. A., Wink, L. K. & McDougle, C. J. (2011). Open-label riluzole in fragile X syndrome. Brain Res, 1380, 264–270. doi: 10.1016/j.brainres. 2010.10.108. First citation in articleGoogle Scholar

  • Erickson, C. A., Wink, L. K., Ray, B., Early, M. C., Stiegelmeyer, E., Mathieu-Frasier, L. & … McDougle, C. J. (2013). Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl), 228(1), 75–84. doi: 10.1007/s00213-013-3022-z. First citation in articleGoogle Scholar

  • European Medicines Agency. (2014). Product Information: Axura 10 mg film-coated tablets. from http://www.google.de/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CCEQFjAA&url=http%3A%2F%2Fwww.ema.europa.eu%2Fdocs%2Fen_GB%2Fdocument_library%2FEPAR_-_Product_Information%2Fhuman%2F000378 %2FWC500029678.pdf&ei=5ehmVdK-KYGOU_PVgMAL&usg=AFQjCNFogx7BKvr_fLns8dnwpmOvQDSoPg&bvm=bv.93990622,d.d24&cad=rja. First citation in articleGoogle Scholar

  • European Medicines Agency. (2015a). EPAR Product Information: RILUTEK 50 mg film-coated tablets. First citation in articleGoogle Scholar

  • European Medicines Agency. (2015b). EPAR summary for the public: Memantine Merz (memantine hydrochloride). from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002711/human_med_001599.jsp&mid=WC0b01ac058001d124. First citation in articleGoogle Scholar

  • Farrell, L. J., Waters, A. M., Boschen, M. J., Hattingh, L., McConnell, H., Milliner, E. L. & Storch, E. A. (2013). Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of D-cycloserine-augmented behavior therapy. Depress Anxiety, 30(8), 723–731. doi: 10.1002/da.22132. First citation in articleGoogle Scholar

  • Findling, R. L., McNamara, N. K., Stansbrey, R. J., Maxhimer, R., Periclou, A., Mann, A. & Graham, S. M. (2007). A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. J Child Adolesc Psychopharmacol, 17(1), 19–33. First citation in articleGoogle Scholar

  • Fineberg, N. A., Potenza, M. N., Chamberlain, S. R., Berlin, H. A., Menzies, L., Bechara, A. & Hollander, E. (2010). Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology, 35(3), 591–604. First citation in articleGoogle Scholar

  • Flament, M. F., Whitaker, A., Rapoport, J. L., Davies, M., Berg, C. Z., Kalikow, K. & Shaffer, D. (1988). Obsessive Compulsive Disorder in Adolescence: An Epidemiological Study. Journal of the American Academy of Child & Adolescent Psychiatry, 27(6), 764–771. doi: http://dx.doi.org/10.1097/00004583-198811000-00018. First citation in articleGoogle Scholar

  • Food and Drug Administration, U. (2006). Package Insert: Acetadote® (acetylcysteine) Injection. from http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021539s004lbl.pdf. First citation in articleGoogle Scholar

  • Food and Drug Administration, U. (2009). DESCRIPTION: RILUTEK® (riluzole). from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000109/human_med_001039.jsp&mid=WC0b01ac058001d124. First citation in articleGoogle Scholar

  • Food and Drug Administration, U. (2010). Mecial Review NDA 22525, Namenda® XR, Forest Laboratories. from http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022525s000lbl.pdf. First citation in articleGoogle Scholar

  • Food and Drug Administration, U. (2015). PROVIGIL® MEDICATION GUIDE (modafinil) from http://www.fda.gov/downloads/Drugs/DrugSafety/UCM231722.pdf. First citation in articleGoogle Scholar

  • Gantois, I., Pop, A. S., de Esch, C. E., Buijsen, R. A., Pooters, T., Gomez-Mancilla, B. & Willemsen, R. (2013). Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res, 239, 72–79. doi: 10.1016/j.bbr.2012.10.059. First citation in articleGoogle Scholar

  • Garber, K. B., Visootsak, J. & Warren, S. T. (2008). Fragile X syndrome. Eur J Hum Genet, 16(6), 666–672. doi: 10.1038/ejhg.2008.61. First citation in articleGoogle Scholar

  • Gerrard, P. & Malcolm, R. (2007). Mechanisms of modafinil: A review of current research. Neuropsychiatr Dis Treat, 3(3), 349–364. First citation in articleGoogle Scholar

  • Ghaleiha, A., Asadabadi, M., Mohammadi, M. R., Shahei, M., Tabrizi, M., Hajiaghaee, R. & Akhondzadeh, S. (2013). Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol, 16(4), 783–789. doi: 10.1017/s146114 5712000880. First citation in articleGoogle Scholar

  • Ghaleiha, A., Mohammadi, E., Mohammadi, M. R., Farokhnia, M., Modabbernia, A., Yekehtaz, H. & Akhondzadeh, S. (2013). Riluzole as an adjunctive therapy to risperidone for the treatment of irritability in children with autistic disorder: a double-blind, placebo-controlled, randomized trial. Paediatr Drugs, 15(6), 505–514. doi: 10.1007/s40272-013-0036-2. First citation in articleGoogle Scholar

  • Ghanizadeh, A., Derakhshan, N. & Berk, M. (2013). N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial. Antiinflamm Antiallergy Agents Med Chem, 12(3), 223–228. First citation in articleGoogle Scholar

  • Ghanizadeh, A. & Moghimi-Sarani, E. (2013). A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry, 13, 196. doi: 10.1186/1471-244x-13-196. First citation in articleGoogle Scholar

  • Goldfield, G. S., Lorello, C. & Doucet, E. (2007). Methylphenidate reduces energy intake and dietary fat intake in adults: a mechanism of reduced reinforcing value of food? Am J Clin Nutr, 86(2), 308–315. First citation in articleGoogle Scholar

  • Grados, M. & Riddle, M. A. (2008). Do all obsessive-compulsive disorder subtypes respond to medication? Int Rev Psychiatry, 20(2), 189–193. doi: 10.1080/09540260801889153. First citation in articleGoogle Scholar

  • Grant, J. E., Odlaug, B. L. & Kim, S. W. (2009). N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry, 66(7), 756–763. doi: 10.1001/archgenpsychiatry.2009.60. First citation in articleGoogle Scholar

  • Grant, P., Lougee, L., Hirschtritt, M. & Swedo, S. E. (2007). An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol, 17(6), 761–767. First citation in articleGoogle Scholar

  • Grant, P., Song, J. Y. & Swedo, S. E. (2010). Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol, 20(4), 309–315. doi: 10.1089/cap.2010.0009. First citation in articleGoogle Scholar

  • Grant, P. J., Joseph, L. A., Farmer, C. A., Luckenbaugh, D. A., Lougee, L. C., Zarate, C. A. Jr. & Swedo, S. E. (2014). 12-Week, Placebo-Controlled Trial of Add-on Riluzole in the Treatment of Childhood-Onset Obsessive-Compulsive Disorder. Neuropsychopharmacology, 39(6), 1453–1459. First citation in articleGoogle Scholar

  • Guy, W. (1976). ECDEU assessment manual for psychopharmacology: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs. First citation in articleGoogle Scholar

  • Hagerman, R., Lauterborn, J., Au, J. & Berry-Kravis, E. (2012). Fragile X syndrome and targeted treatment trials. Results Probl Cell Differ, 54, 297–335. doi: 10.1007/978-3-642-21649-7_17. First citation in articleGoogle Scholar

  • Hall, S. S., Lightbody, A. A. & Reiss, A. L. (2008). Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome. Am J Ment Retard, 113(1), 44–53. doi: 10.1352/0895-8017(2008)113[44:csaabi]2.0.co;2. First citation in articleGoogle Scholar

  • Hardan, A. (2014). Efficacy and Safety of Memantine in a Global, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study in Children With Autism Spectrum Disorder: Poster Session: The 167th annual meeting of the American Psychiatric Association. P&T® • June 2014 •, 39(450). First citation in articleGoogle Scholar

  • Hendren, R. (2014). Memantine in Children with Autism: Results From a Two-Part, Open-Label/Double-Blind Randomized, Placebo-Controlled Trial and an Open-Label Extension: Poster Session 6, The 167th annual meeting of the American Psychiatric Association. First citation in articleGoogle Scholar

  • Hersh, J. H. & Saul, R. A. (2011). Health supervision for children with fragile X syndrome. Pediatrics, 127(5), 994–1006. doi: 10.1542/peds.2010-3500. First citation in articleGoogle Scholar

  • Heyman, I., Fombonne, E., Simmons, H., Ford, T., Meltzer, H. & Goodman, R. (2001). Prevalence of obsessive-compulsive disorder in the British nationwide survey of child mental health. Br J Psychiatry, 179, 324–329. First citation in articleGoogle Scholar

  • Hollander, E., Kwon, J. H., Stein, D. J., Broatch, J., Rowland, C. T. & Himelein, C. A. (1996). Obsessive-compulsive and spectrum disorders: overview and quality of life issues. J Clin Psychiatry, 57 Suppl 8, 3–6. First citation in articleGoogle Scholar

  • Horder, J., Lavender, T., Mendez, M. A., O’Gorman, R., Daly, E., Craig, M. C. & Murphy, D. G. (2013). Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study. Transl Psychiatry, 3(7), e279. doi: 10.1038/tp.2013.53. First citation in articleGoogle Scholar

  • Hosenbocus, S. & Chahal, R. (2013). Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry, 22(2), 166–171. First citation in articleGoogle Scholar

  • Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J. & Gomez-Mancilla, B. (2011). Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med, 3(64), 64ra61. doi: 10.1126/scitranslmed.3001708. First citation in articleGoogle Scholar

  • Javitt, D. C. (2004). Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry, 9(11), 984–997, 979. doi: 10.1038/sj.mp.4001551. First citation in articleGoogle Scholar

  • Jensen, P. S., Martin, D. & Cantwell, D. P. (1997). Comorbidity in ADHD: implications for research, practice, and DSM-V. J Am Acad Child Adolesc Psychiatry, 36(8), 1065–1079. doi: 10.1097/00004583- 199708000-00014. First citation in articleGoogle Scholar

  • Johnson, J. W. & Kotermanski, S. E. (2006). Mechanism of action of memantine. Curr Opin Pharmacol, 6(1), 61–67. doi: 10.1016/j.coph.2005.09.007. First citation in articleGoogle Scholar

  • Joshi, G., Wozniak, J., Petty, C., Martelon, M. K., Fried, R., Bolfek, A. & Biederman, J. (2013). Psychiatric comorbidity and functioning in a clinically referred population of adults with autism spectrum disorders: a comparative study. J Autism Dev Disord, 43(6), 1314–1325. doi: 10.1007/s10803-012-1679-5. First citation in articleGoogle Scholar

  • Kamath, P., Reddy, Y. C. & Kandavel, T. (2007). Suicidal behavior in obsessive-compulsive disorder. J Clin Psychiatry, 68(11), 1741–1750. First citation in articleGoogle Scholar

  • Kessler, R. C., Adler, L. A., Barkley, R., Biederman, J., Conners, C. K., Faraone, S. V. & Zaslavsky, A. M. (2005). Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry, 57(11), 1442–1451. doi: 10.1016/j.biopsych. 2005.04.001. First citation in articleGoogle Scholar

  • Klassen, A. F., Miller, A. & Fine, S. (2004). Health-related quality of life in children and adolescents who have a diagnosis of attention-deficit/hyperactivity disorder. Pediatrics, 114(5), e541–547. doi: 10.1542/peds.2004–0844. First citation in articleGoogle Scholar

  • Koob, G. F. & Le Moal, M. (1997). Drug abuse: hedonic homeostatic dysregulation. Science, 278(5335), 52–58. First citation in articleGoogle Scholar

  • Kotecha, S. A., Oak, J. N., Jackson, M. F., Perez, Y., Orser, B. A., Van Tol, H. H. & MacDonald, J. F. (2002). A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron, 35(6), 1111–1122. First citation in articleGoogle Scholar

  • Kretschmer, B. D., Kratzer, U. & Schmidt, W. J. (1998). Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn Schmiedebergs Arch Pharmacol, 358(2), 181–190. First citation in articleGoogle Scholar

  • Lafleur, D. L., Pittenger, C., Kelmendi, B., Gardner, T., Wasylink, S., Malison, R. T. & Coric, V. (2006). N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl), 184(2), 254–256. doi: 10.1007/s00213-005-0246-6. First citation in articleGoogle Scholar

  • Lambert, M. P. & Neuhaus, F. C. (1972). Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W. J Bacteriol, 110(3), 978–987. First citation in articleGoogle Scholar

  • Laupacis, A., Sackett, D. L. & Roberts, R. S. (1988). An assessment of clinically useful measures of the consequences of treatment. N Engl J Med, 318(26), 1728–1733. doi: 10.1056/nejm1988063031 82605. First citation in articleGoogle Scholar

  • Leigh, M. J., Nguyen, D. V., Mu, Y., Winarni, T. I., Schneider, A., Chechi, T. & Hagerman, R. J. (2013). A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr, 34(3), 147–155. doi: 10.1097/DBP.0b013e318287cd17. First citation in articleGoogle Scholar

  • Lewin, A. B., Storch, E. A., Geffken, G. R., Goodman, W. K. & Murphy, T. K. (2006). A neuropsychiatric review of pediatric obsessive-compulsive disorder: etiology and efficacious treatments. Neuropsychiatr Dis Treat, 2(1), 21–31. First citation in articleGoogle Scholar

  • Ludolph, A. G., Udvardi, P. T., Schaz, U., Henes, C., Adolph, O., Weigt, H. U. & Fohr, K. J. (2010). Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol, 160(2), 283–291. doi: 10.1111/j.1476-5381.2010.00707.x. First citation in articleGoogle Scholar

  • Mahgoub, N., Asemota, B. & Alexopoulos, G. S. (2011). The effect of riluzole augmentation in a patient with treatment-resistant obsessive-compulsive disorder, taking two other glutaminergic agents. J Neuropsychiatry Clin Neurosci, 23(2), E24–25. doi: 10.1176/appi.neuropsych.23.2.E24. First citation in articleGoogle Scholar

  • Mancuso, E., Faro, A., Joshi, G. & Geller, D. A. (2010). Treatment of pediatric obsessive-compulsive disorder: a review. J Child Adolesc Psychopharmacol, 20(4), 299–308. First citation in articleGoogle Scholar

  • Martinez-Raga, J., Szerman, N., Knecht, C. & de Alvaro, R. (2013). Attention deficit hyperactivity disorder and dual disorders. Educational needs for an underdiagnosed condition. Int J Adolesc Med Health, 25(3), 231–243. doi: 10.1515/ijamh-2013-0057. First citation in articleGoogle Scholar

  • Marzullo, L. (2005). An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr, 17(2), 239–245. First citation in articleGoogle Scholar

  • McDougle, C. J., Erickson, C. A., Stigler, K. A. & Posey, D. J. (2005). Neurochemistry in the pathophysiology of autism. J Clin Psychiatry, 66 Suppl 10, 9–18. First citation in articleGoogle Scholar

  • McLennan, Y., Polussa, J., Tassone, F. & Hagerman, R. (2011). Fragile x syndrome. Curr Genomics, 12(3), 216–224. doi: 10.2174/ 138920211795677886. First citation in articleGoogle Scholar

  • McQuay, H. J. & Moore, R. A. (1997). Using numerical results from systematic reviews in clinical practice. Ann Intern Med, 126(9), 712–720. First citation in articleGoogle Scholar

  • Melmed, R. (2014). Safety and Tolerability of Memantine in Children With Autism Spectrum Disorder (ASD): Results From an Open-Label, International Trial. Poster Session, The 167th annual meeting of the American Psychiatric Association. 2014. First citation in articleGoogle Scholar

  • Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & Group, P. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol, 62(10), 1006–1012. doi: 10.1016/j.jclinepi.2009.06.005. First citation in articleGoogle Scholar

  • Moher, D., Schulz, K. F. & Altman, D. G. (2001). The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials. BMC Med Res Methodol, 1, 2. First citation in articleGoogle Scholar

  • Monaghan, D. T., Yao, D. & Cotman, C. W. (1985). L-[3H] Glutamate binds to kainate-, NMDA- and AMPA-sensitive binding sites: an autoradiographic analysis. Brain Res, 340(2), 378–383. First citation in articleGoogle Scholar

  • Naaijen, J., Lythgoe, D. J., Amiri, H., Buitelaar, J. K. & Glennon, J. C. (2015). Fronto-striatal glutamatergic compounds in compulsive and impulsive syndromes: A review of magnetic resonance spectroscopy studies. Neurosci Biobehav Rev. doi: 10.1016/j.neubiorev.2015.02.009. First citation in articleGoogle Scholar

  • Nestadt, G., Di, C. Z., Riddle, M. A., Grados, M. A., Greenberg, B. D., Fyer, A. J. & Roche, K. B. (2009). Obsessive-compulsive disorder: subclassification based on co-morbidity. Psychol Med, 39(9), 1491–1501. doi: 10.1017/s0033291708004753. First citation in articleGoogle Scholar

  • Owley, T., Salt, J., Guter, S., Grieve, A., Walton, L., Ayuyao, N., … Cook, EH. (2006). A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol, 16(5), 517–24. First citation in articleGoogle Scholar

  • Parellada, M., Penzol, M. J., Pina, L., Moreno, C., Gonzalez-Vioque, E., Zalsman, G. & Arango, C. (2014). The neurobiology of autism spectrum disorders. Eur Psychiatry, 29(1), 11–19. doi: 10.1016/j.eurpsy.2013.02.005. First citation in articleGoogle Scholar

  • Paribello, C., Tao, L., Folino, A., Berry-Kravis, E., Tranfaglia, M., Ethell, I. M. & Ethell, D. W. (2010). Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol, 10, 91. doi: 10.1186/1471-2377-10-91. First citation in articleGoogle Scholar

  • Parsons, C. G., Stoffler, A. & Danysz, W. (2007). Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system – too little activation is bad, too much is even worse. Neuropharmacology, 53(6), 699–723. doi: 10.1016/j.neuropharm.2007.07.013 First citation in articleGoogle Scholar

  • Pittenger, C., Bloch, M. H. & Williams, K. (2011). Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther, 132(3), 314–332. doi: 10.1016/j.pharmthera.2011.09.006. First citation in articleGoogle Scholar

  • Pittenger, C., Kelmendi, B., Wasylink, S., Bloch, M. H. & Coric, V. (2008). Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a series of 13 cases, with long-term follow-up. J Clin Psychopharmacol, 28(3), 363–367. doi: 10.1097/JCP.0b013e 3181727548. First citation in articleGoogle Scholar

  • Polanczyk, G. & Rohde, L. A. (2007). Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry, 20(4), 386–392. doi: 10.1097/YCO.0b013e3281568d7a. First citation in articleGoogle Scholar

  • Polanczyk, G. V., Willcutt, E. G., Salum, G. A., Kieling, C. & Rohde, L. A. (2014). ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol, 43(2), 434–442. doi: 10.1093/ije/dyt261. First citation in articleGoogle Scholar

  • Pop, A. S., Levenga, J., de Esch, C. E., Buijsen, R. A., Nieuwenhuizen, I. M., Li, T. & Willemsen, R. (2014). Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant. Psychopharmacology (Berl), 231(6), 1227–1235. doi: 10.1007/s00213-012-2947-y. First citation in articleGoogle Scholar

  • Posey, D. J., Kem, D. L., Swiezy, N. B., Sweeten, T. L., Wiegand, R. E. & McDougle, C. J. (2004). A pilot study of D-cycloserine in subjects with autistic disorder. Am J Psychiatry, 161(11), 2115–2117. doi: 10.1176/appi.ajp.161.11.2115. First citation in articleGoogle Scholar

  • Prosser, G. A. & de Carvalho, L. P. (2013). Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine. Febs j, 280(4), 1150–1166. doi: 10.1111/febs.12108. First citation in articleGoogle Scholar

  • Ramachandran, G. & Swaminathan, S. (2015). Safety and Tolerability Profile of Second-Line Anti-Tuberculosis Medications. Drug Safety, 38(3), 253–269. doi: 10.1007/s40264-015-0267-y. First citation in articleGoogle Scholar

  • Rodriguez, C. I., Bender, J. Jr., Marcus, S. M., Snape, M., Rynn, M. & Simpson, H. B. (2010). Minocycline augmentation of pharmacotherapy in obsessive-compulsive disorder: an open-label trial. J Clin Psychiatry, 71(9), 1247–1249. doi: 10.4088/JCP.09l05805blu. First citation in articleGoogle Scholar

  • Rosenberg, D. R. & Hanna, G. L. (2000). Genetic and imaging strategies in obsessive-compulsive disorder: potential implications for treatment development. Biol Psychiatry, 48(12), 1210–1222. First citation in articleGoogle Scholar

  • Rosenberg, D. R., MacMaster, F. P., Keshavan, M. S., Fitzgerald, K. D., Stewart, C. M. & Moore, G. J. (2000). Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry, 39(9), 1096–1103. First citation in articleGoogle Scholar

  • Rubia, K., Cubillo, A., Smith, A. B., Woolley, J., Heyman, I. & Brammer, M. J. (2010). Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder. Hum Brain Mapp, 31(2), 287–299. doi: 10.1002/hbm.20864. First citation in articleGoogle Scholar

  • Rubia, K., Cubillo, A., Woolley, J., Brammer, M. J. & Smith, A. (2011). Disorder-specific dysfunctions in patients with attention-deficit/hyperactivity disorder compared to patients with obsessive-compulsive disorder during interference inhibition and attention allocation. Hum Brain Mapp, 32(4), 601–611. doi: 10.1002/hbm.21048. First citation in articleGoogle Scholar

  • Scahill, L., Riddle, M. A., McSwiggin-Hardin, M., Ort, S. I., King, R. A., Goodman, W. K. & Leckman, J. F. (1997). Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry, 36(6), 844–852. First citation in articleGoogle Scholar

  • Shaffer, D., Gould, M. S. & Brasic, J., et al. (1983). A childrens global assessment scale (cgas). Arch Gen Psychiatry, 40(11), 1228–1231. First citation in articleGoogle Scholar

  • Silverman, J. L., Tolu, S. S., Barkan, C. L. & Crawley, J. N. (2010). Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology, 35(4), 976–989. doi: 10.1038/npp. 2009.201. First citation in articleGoogle Scholar

  • Sourial, M., Cheng, C. & Doering, L. C. (2013). Progress toward therapeutic potential for AFQ056 in Fragile X syndrome. Journal of Experimental Pharmacology, 5, 45–54. doi: 10.2147/JEP.S27044. First citation in articleGoogle Scholar

  • Starcevic, V. & Brakoulias, V. (2008). Symptom subtypes of obsessive-compulsive disorder: are they relevant for treatment? Aust N Z J Psychiatry, 42(8), 651–661. doi: 10.1080/00048670802203442. First citation in articleGoogle Scholar

  • Storch, E. A., Murphy, T. K., Goodman, W. K., Geffken, G. R., Lewin, A. B., Henin, A. & Geller, D. A. (2010). A preliminary study of D-cycloserine augmentation of cognitive-behavioral therapy in pediatric obsessive-compulsive disorder. Biol Psychiatry, 68(11), 1073–1076. doi: 10.1016/j.biopsych.2010.07.015. First citation in articleGoogle Scholar

  • Thalheimer, W. & Cook, S. (2002). How to calculate effect sizes from published research: A simplified methodology. Work-Learning Research. First citation in articleGoogle Scholar

  • Ting, J. T. & Feng, G. (2008). Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder. Curr Chem Genomics, 2, 62–75. doi: 10.2174/1875397300802010062. First citation in articleGoogle Scholar

  • Turic, D., Langley, K., Mills, S., Stephens, M., Lawson, D., Govan, C. & Thapar, A. (2004). Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatry, 9(2), 169–173. doi: 10.1038/sj.mp.4001387. First citation in articleGoogle Scholar

  • U. S. National Library of Medicine. (2014). HUMAN PRESCRIPTION DRUG LABEL: ACETYLCYSTEINE. from http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f56b4087-db48-4fd7-84ec-9c927962b805. First citation in articleGoogle Scholar

  • Utari, A., Chonchaiya, W., Rivera, S. M., Schneider, A., Hagerman, R. J., Faradz, S. M. & Nguyen, D. V. (2010). Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil, 115(5), 433–443. doi: 10.1352/1944-7558-115.5.433. First citation in articleGoogle Scholar

  • Virring, A., Lambek, R., Jennum, P. J., Møller, L. R. & Thomsen, P. H. (2017). Sleep Problems and Daily Functioning in Children With ADHD: An Investigation of the Role of Impairment, ADHD Presentations, and Psychiatric Comorbidity. J Atten Disord, 21(9), 731–740. doi: 10.1177/1087054714542001. First citation in articleGoogle Scholar

  • Vrij, F. M. de, Levenga, J., van der Linde, H. C., Koekkoek, S. K., De Zeeuw, C. I., Nelson, D. L. & Willemsen, R. (2008). Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis, 31(1), 127–132. doi: 10.1016/j.nBd. 2008.04.002. First citation in articleGoogle Scholar

  • Wigal, S. B., Biederman, J., Swanson, J. M., Yang, R. & Greenhill, L. L. (2006). Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry, 8(6), 352–360. First citation in articleGoogle Scholar

  • Wolff, J. J., Hazlett, H. C., Lightbody, A. A., Reiss, A. L. & Piven, J. (2013). Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome. J Neurodev Disord, 5(1), 12. doi: 10.1186/1866-1955-5-12. First citation in articleGoogle Scholar

  • Zeeuw, P. de, Mandl, R. C., Hulshoff Pol, H. E., van Engeland, H. & Durston, S. (2012). Decreased frontostriatal microstructural organization in attention deficit/hyperactivity disorder. Hum Brain Mapp, 33(8), 1941–1951. doi: 10.1002/hbm.21335. First citation in articleGoogle Scholar