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  • Cited by 13
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    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.
    Valton, Vincent Romaniuk, Liana Douglas Steele, J. Lawrie, Stephen and Seriès, Peggy 2017. Comprehensive review: Computational modelling of schizophrenia. Neuroscience & Biobehavioral Reviews, Vol. 83, Issue. , p. 631.
    Wright, Dean J. Renoir, Thibault Gray, Laura J. and Hannan, Anthony J. 2017. Neurodegenerative Diseases. Vol. 15, Issue. , p. 93.
    White, Thomas P Wigton, Rebekah Joyce, Dan W Collier, Tracy Fornito, Alex and Shergill, Sukhwinder S 2016. Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia. Neuropsychopharmacology, Vol. 41, Issue. 5, p. 1274.
    Zink, Mathias and Correll, Christoph U 2015. Glutamatergic agents for schizophrenia: current evidence and perspectives. Expert Review of Clinical Pharmacology, Vol. 8, Issue. 3, p. 335.
    Lockwood, Jonathan Tomas and Remington, Gary 2015. Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials. Expert Opinion on Emerging Drugs, Vol. 20, Issue. 3, p. 407.
    Rose, Diana Papoulias, Constantina MacCabe, James and Walke, Jennifer 2015. Service users’ and carers’ views on research towards stratified medicine in psychiatry: a qualitative study. BMC Research Notes, Vol. 8, Issue. 1,
    Strube, Wolfgang Falkai, Peter and Hasan, Alkomiet 2015. Neue Ansätze in der Schizophrenietherapie. DNP - Der Neurologe und Psychiater, Vol. 16, Issue. 1, p. 46.
    Pollak, T. A. McCormack, R. Peakman, M. Nicholson, T. R. and David, A. S. 2014. Prevalence of anti-N-methyl-d-aspartate (NMDA) receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychological Medicine, Vol. 44, Issue. 12, p. 2475.
    Zink, Mathias Englisch, Susanne and Schmitt, Andrea 2014. Antipsychotic treatment modulates glutamate transport and NMDA receptor expression. European Archives of Psychiatry and Clinical Neuroscience, Vol. 264, Issue. S1, p. 67.
    Caddy, Caroline Giaroli, Giovanni White, Thomas P. Shergill, Sukhwinder S. and Tracy, Derek K. 2014. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology, Vol. 4, Issue. 2, p. 75.
    Iasevoli, Felice Buonaguro, Elisabetta F. Sarappa, Chiara Marmo, Federica Latte, Gianmarco Rossi, Rodolfo Eramo, Anna Tomasetti, Carmine and de Bartolomeis, Andrea 2014. Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: Relevance to schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 54, Issue. , p. 299.
    Mohr, Christine and Ettinger, Ulrich 2014. An Overview of the Association between Schizotypy and Dopamine. Frontiers in Psychiatry, Vol. 5, Issue. ,
    Chue, Pierre S and Baker, Glen B 2013. Glycine reuptake inhibition: a promising therapeutic strategy in the treatment of schizophrenia?. Future Medicinal Chemistry, Vol. 5, Issue. 13, p. 1475.
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When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia

  • Evangelos Papanastasiou (a1), James M. Stone (a2) and Sukhi Shergill (a3)
Summary

Currently available antipsychotic drugs target dopaminergic neurotransmission. Many patients do not respond fully to these treatments, and there has been considerable effort to investigate alternative targets. Here we summarise the rationale and recent evidence supporting efforts to develop glutamatergic antipsychotic drugs.

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Copyright
COPYRIGHT: © Royal College of Psychiatrists, 2013 
Corresponding author
Evangelos Papanastasiou, MD, MSc, Institute of Psychiatry, King's College London, Department of Psychosis Studies, CSI Lab, Box PO63, De Crespigny Park, Denmark Hill, London SE5 8AF. Email: evangelos.papanastasiou@kcl.ac.uk
Footnotes
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*

These authors contributed equally to the work.

Declaration of interest

S.S. has received funding from GlaxoSmithKline and Roche for conducting clinical trials and unrestricted investigator-led study funding from Novartis. J.M.S. has received a non-restricted academic fellowship from GlaxoSmithKline, and honoraria from Roche, AstraZeneca, Pfizer and Behrenberg Bank.

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References
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1 Haro, JM, Novick, D, Bertsch, J, Karagianis, J, Dossenbach, M, Jones, PB. Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry 2011; 199: 194–201.
2 Stone, JM. Glutamatergic antipsychotic drugs: a new dawn in the treatment of schizophrenia? Ther Adv Psychopharmacol 2011; 1: 5–18.
3 Krystal, JH, Karper, LP, Seibyl, JP, Freeman, GK, Delaney, R, Bremner, JD, et al Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.
4 Lahti, AC, Holcomb, HH, Medoff, DR, Tamminga, CA. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 1995; 6: 869–72.
5 Olney, JW, Farber, NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995; 52: 998–1007.
6 Moghaddam, B, Adams, B, Verma, A, Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921–7.
7 Ayalew, M, Le-Niculescu, H, Levey, DF, Jain, N, Changala, B, Patel, SD, et al Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012; 17: 887–905.
8 Pilowsky, LS, Bressan, RA, Stone, JM, Erlandsson, K, Mulligan, RS, Krystal, JH, et al First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 2006; 11: 118–9.
9 Law, AJ, Deakin, JF. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 2001; 12: 2971–4.
10 Marsman, A, van den Heuvel, MP, Klomp, DW, Kahn, RS, Luijten, PR, Hulshoff Pol, HE. Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull 2011; July 11 (Epub ahead of print).
11 Egerton, A, Brugger, S, Raffin, M, Barker, GJ, Lythgoe, DJ, McGuire, PK, et al Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 2012; 37: 2515–21.
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15 Kinon, BJ, Zhang, L, Millen, BA, Osuntokun, OO, Williams, JE, Kollack-Walker, S, et al A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31: 349–55.
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  • Cited by 13
  • Cited by
    Crossref Citations
    Crossref logo
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.
    Valton, Vincent Romaniuk, Liana Douglas Steele, J. Lawrie, Stephen and Seriès, Peggy 2017. Comprehensive review: Computational modelling of schizophrenia. Neuroscience & Biobehavioral Reviews, Vol. 83, Issue. , p. 631.
    Wright, Dean J. Renoir, Thibault Gray, Laura J. and Hannan, Anthony J. 2017. Neurodegenerative Diseases. Vol. 15, Issue. , p. 93.
    White, Thomas P Wigton, Rebekah Joyce, Dan W Collier, Tracy Fornito, Alex and Shergill, Sukhwinder S 2016. Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia. Neuropsychopharmacology, Vol. 41, Issue. 5, p. 1274.
    Zink, Mathias and Correll, Christoph U 2015. Glutamatergic agents for schizophrenia: current evidence and perspectives. Expert Review of Clinical Pharmacology, Vol. 8, Issue. 3, p. 335.
    Lockwood, Jonathan Tomas and Remington, Gary 2015. Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials. Expert Opinion on Emerging Drugs, Vol. 20, Issue. 3, p. 407.
    Rose, Diana Papoulias, Constantina MacCabe, James and Walke, Jennifer 2015. Service users’ and carers’ views on research towards stratified medicine in psychiatry: a qualitative study. BMC Research Notes, Vol. 8, Issue. 1,
    Strube, Wolfgang Falkai, Peter and Hasan, Alkomiet 2015. Neue Ansätze in der Schizophrenietherapie. DNP - Der Neurologe und Psychiater, Vol. 16, Issue. 1, p. 46.
    Pollak, T. A. McCormack, R. Peakman, M. Nicholson, T. R. and David, A. S. 2014. Prevalence of anti-N-methyl-d-aspartate (NMDA) receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychological Medicine, Vol. 44, Issue. 12, p. 2475.
    Zink, Mathias Englisch, Susanne and Schmitt, Andrea 2014. Antipsychotic treatment modulates glutamate transport and NMDA receptor expression. European Archives of Psychiatry and Clinical Neuroscience, Vol. 264, Issue. S1, p. 67.
    Caddy, Caroline Giaroli, Giovanni White, Thomas P. Shergill, Sukhwinder S. and Tracy, Derek K. 2014. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology, Vol. 4, Issue. 2, p. 75.
    Iasevoli, Felice Buonaguro, Elisabetta F. Sarappa, Chiara Marmo, Federica Latte, Gianmarco Rossi, Rodolfo Eramo, Anna Tomasetti, Carmine and de Bartolomeis, Andrea 2014. Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: Relevance to schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 54, Issue. , p. 299.
    Mohr, Christine and Ettinger, Ulrich 2014. An Overview of the Association between Schizotypy and Dopamine. Frontiers in Psychiatry, Vol. 5, Issue. ,
    Chue, Pierre S and Baker, Glen B 2013. Glycine reuptake inhibition: a promising therapeutic strategy in the treatment of schizophrenia?. Future Medicinal Chemistry, Vol. 5, Issue. 13, p. 1475.
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When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia

  • Evangelos Papanastasiou (a1), James M. Stone (a2) and Sukhi Shergill (a3)
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