Mini-Review Article

Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant

Author(s): Chieh-Hsin Lin, Yu-Ming Chen and Hsien-Yuan Lane*

Volume 21, Issue 6, 2020

Page: [610 - 615] Pages: 6

DOI: 10.2174/1389450120666191011163539

Price: $65


Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as “clozapineresistant”, “ultra-treatment-resistant”, or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials.

Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia.

This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.

Keywords: Schizophrenia, clozapine, clozapine-resistant schizophrenia, NMDAR, DAAO, DAAO inhibitor, sodium benzoate, antioxidant.

Graphical Abstract
Remington, G.; Addington, D.; Honer, W.; Ismail, Z.; Raedler, T.; Teehan, M. Guidelines for the pharmacotherapy of schizophrenia in adults. in: canadian journal of psychiatry. SAGE Publications Inc. 2017; 62: pp. 604-16.
Bartoli, F.; Crocamo, C.; Di Brita, C. Adjunctive second-generation antipsychotics for specific symptom domains of schizophrenia resistant to clozapine: A meta-analysis. J. Psychiatr. Res., 2019, 108, 24-33.
[] [PMID: 30447508]
Lin, A.S.; Chan, H.Y.; Peng, Y.C.; Chen, W.J. Severity in sustained attention impairment and clozapine-resistant schizophrenia: a retrospective study. BMC Psychiatry, 2019, 19(1), 220.
[] [PMID: 31299940]
Siskind, D.J.; Lee, M.; Ravindran, A.; Zhang, Q.; Ma, E.; Motamarri, B. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. In: Australian and New Zealand Journal of Psychiatry. SAGE Publications Inc. 2018; 52: pp. 751-67.
Wagner, E.; Löhrs, L.; Siskind, D.; Honer, W.G.; Falkai, P.; Hasan, A. Clozapine augmentation strategies – a systematic meta-review of available evidence. Treatment options for clozapine resistance. Journal of Psychopharmacology. SAGE Publications Ltd, 2019, 33, 423-435.
Harrison, P.J. D-amino acid oxidase inhibition: a new glutamate twist for clozapine augmentation in schizophrenia? Biol. Psychiatry, 2018, 84(6), 396-398. [Internet
[] [PMID: 30165950]
Hashimoto, K.; Fujita, Y.; Horio, M. Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol. Psychiatry, 2009, 65(12), 1103-1106.
[] [PMID: 19217074]
Lane, H-Y.; Lin, C-H.; Green, M.F.; Hellemann, G.; Huang, C-C.; Chen, P-W. et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA psychiatry [Internet] 2013 [cited 2019 Sep 19];70(12): 1267-75. Available from:
Lin, C.Y.; Liang, S.Y.; Chang, Y.C. Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial. World J. Biol. Psychiatry, 2017, 18(5), 357-368.
[] [PMID: 26691576]
Miyamoto, S; Jarskog, LF; Fleischhacker, WW Schizophrenia: When clozapine fails. Current Opinion in Psychiatry. Lippincott Williams and Wilkins 2015; 28: pp. 243-8.
Lin, C.H.; Lin, C.H.; Chang, Y.C. Sodium benzoate, a d-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol. Psychiatry, 2018, 84(6), 422-432.
[] [PMID: 29397899]
Krystal, JH Food preservative enhances schizophrenia treatment, 2018.
Frankle, W.G.; Paris, J.; Himes, M.; Mason, N.S.; Mathis, C.A.; Narendran, R. Amphetamine-induced striatal dopamine release measured with an agonist radiotracer in schizophrenia. Biol. Psychiatry, 2018, 83(8), 707-714.
[] [PMID: 29325847]
Amato, D.; Kruyer, A.; Samaha, A.N.; Heinz, A. Hypofunctional dopamine uptake and antipsychotic treatment-resistant schizophrenia; Frontiers in Psychiatry. Frontiers Media S.A., 2019, Vol. 10, .
Sonnenschein, SF; Grace, AA Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia. Neuropharmacology 2019.S0028-3908(19)30159-5,
[] [PMID: 31077730]
Jauhar, S.; Veronese, M.; Nour, M.M. The effects of antipsychotic treatment on presynaptic dopamine synthesis capacity in first-episode psychosis: a positron emission tomography study. Biol. Psychiatry, 2019, 85(1), 79-87.
[] [PMID: 30122287]
Kaar, S.J.; Natesan, S.; McCutcheon, R.; Howes, O.D. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology [Internet] 2019 [cited 2019 Sep 19];107704 Available from:
Williams, L.; Newton, G.; Roberts, K.; Finlayson, S.; Brabbins, C. Clozapine-resistant schizophrenia: a positive approach. Br. J. Psychiatry, 2002, 181, 184-187.
[] [PMID: 12204919]
Lu, M.L.; Lane, H.Y. Adjunctive fluvoxamine with clozapine., Br J Psychiatry [Internet] 2003 [cited 2019 Sep 19];182-81. Available from
Jeon, S.W.; Kim, Y.K. Unresolved issues for utilization of atypical antipsychotics in schizophrenia: Antipsychotic polypharmacy and metabolic syndrome; International Journal of Molecular Sciences. MDPI AG, 2017, Vol. 18, .
Jankowska, A.; Satała, G.; Partyka, A.; Wesołowska, A.; Bojarski, A.J.; Pawłowski, M. Discovery and development of non-dopaminergic agents for the treatment of schizophrenia: overview of the preclinical and early clinical studies. Curr Med Chem [Internet] 2019 [cited 2019 Sep 19];26. Available from:,
Chuhma, N.; Mingote, S.; Kalmbach, A.; Yetnikoff, L.; Rayport, S. Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia. Biol Psychiatry [Internet] 2017 [cited 2019 Sep 20];81(1): 43-51. Available from:,
[ ]
Catts, V.S.; Lai, Y.L.; Weickert, C.S.; Weickert, T.W.; Catts, S.V. A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits? Biol. Psychol., 2016, 116, 57-67.
[] [PMID: 26549579]
Krystal, J.H.; Anticevic, A.; Yang, G.J.; Dragoi, G.; Driesen, N.R.; Wang, X.J. Impaired tuning of neural ensembles and the pathophysiology of schizophrenia: a translational and computational neuroscience perspective. Elsevier, USA. Biol. Psychiatry, 2017, 81, 874-885.
Javitt, D.C. Excitatory amino acids in schizophrenia: both what you have, and what you do with them. Elsevier, USA. Biol. Psychiatry, 2018, Vol 83, 470-472.
Iwata, Y.; Nakajima, S.; Plitman, E. Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: a cross-sectional 3t proton magnetic resonance spectroscopy study. Biol. Psychiatry, 2019, 85(7), 596-605.
[] [PMID: 30389132]
Krystal, J.H. Capitalizing on extrasynaptic glutamate neurotransmission to treat antipsychotic-resistant symptoms in schizophrenia. elsevier, USA. Biol. Psychiatry, 2008, Vol 64, 358-360.
Ohgi, Y.; Futamura, T.; Hashimoto, K. Glutamate signaling in synaptogenesis and nmda receptors as potential therapeutic targets for psychiatric disorders. Curr Mol Med [Internet] 2015 [cited 2019 Sep 19]; 15(3): 206-1. Available from:,
D’Souza, D.C.; Carson, R.E.; Driesen, N.; Johannesen, J.; Ranganathan, M.; Krystal, J.H. Dose-related target occupancy and effects on circuitry, behavior, and neuroplasticity of the glycine transporter-1 inhibitor pf-03463275 in healthy and schizophrenia subjects. Biol. Psychiatry, 2018, 84(6), 413-421.
[] [PMID: 29499855]
Nucifora, F.C.; Woznica, E.; Lee, B.J.; Cascella, N.; Sawa, A. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol. Dis., 2018.
[PMID: 30170114]
Chang, H-J.; Lane, H-Y.; Tsai, G.E. NMDA pathology and treatment of schizophrenia. Curr Pharm Des [Internet] 2014 [cited 2019 Sep 19];20(32): 5118-26. Available from:,
Kantrowitz, J.T.; Epstein, M.L.; Beggel, O.; Rohrig, S.; Lehrfeld, J.M.; Revheim, N. Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain [Internet] 2016 [cited 2019 Sep 19];139(Pt 12): 3281-95. Available from http://www.ncbi.nlm.
Lane, H.Y.; Huang, C.L.; Wu, P.L. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol. Psychiatry, 2006, 60(6), 645-649.
[] [PMID: 16780811]
Kontaxakis, V.P.; Ferentinos, P.P.; Havaki-Kontaxaki, B.J.; Roukas, D.K. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur. Psychiatry, 2005, 20(5-6), 409-415.
[] [PMID: 16171655]
Krogmann, A.; Peters, L.; von Hardenberg, L.; Bödeker, K.; Nöhles, V.B.; Correll, C.U. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities., CNS Spectr [Internet] 2019 [cited 2019 Sep 19];24(S1): 38-69. Available from:
Zhang, H.; Qi, L.; Qiao, J.; Mao, L. Determination of sodium benzoate by chiral ligand exchange CE based on its inhibitory activity in D-amino acid oxidase mediated oxidation of D-serine. Anal. Chim. Acta, 2011, 691(1-2), 103-109.
[] [PMID: 21458638]
Johnson, W; Bergfeld, WF; Belsito, D V; Hill, RA; Klaassen, CD; Liebler, DC Safety assessment of benzyl alcohol, benzoic acid and its salts, and benzyl benzoate., Int J Toxicol 2017; 36(3_suppl): 5S-30S.
Sacchi, S.; Rosini, E.; Pollegioni, L.; Molla, G. D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy. Curr. Pharm. Des., 2013, 19(14), 2499-2511.
[] [PMID: 23116391]
Brahmachari, S.; Jana, A.; Pahan, K. Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J. Immunol., 2009, 183(9), 5917-5927.
[] [PMID: 19812204]
Hardingham, G.E.; Do, K.Q. Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat. Rev. Neurosci., 2016, 17(2), 125-134.
[] [PMID: 26763624]
Solberg, D.K.; Refsum, H.; Andreassen, O.A.; Bentsen, H. A five-year follow-up study of antioxidants, oxidative stress and polyunsaturated fatty acids in schizophrenia. Acta Neuropsychiatr., 2019, 31(4), 202-212.
[] [PMID: 31178002]
Tsugawa, S.; Noda, Y.; Tarumi, R.; Mimura, Y.; Yoshida, K.; Iwata, Y. Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis Journal of Psychopharmacology; SAGE Publications Ltd, 2019.
Lennerz, B.S.; Vafai, S.B.; Delaney, N.F. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. Mol. Genet. Metab., 2015, 114(1), 73-79.
[] [PMID: 25497115]
Oxenkrug, G.; van der Hart, M.; Roeser, J.; Summergrad, P. Anthranilic Acid: A potential biomarker and treatment target for schizophrenia. ann psychiatry Ment Heal [Internet] [cited 2019 Sep 19];4(2) Available from:
Matsuura, A.; Fujita, Y.; Iyo, M.; Hashimoto, K. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr., 2015, 27(3), 159-167.
[] [PMID: 25648314]
Sershen, H.; Hashim, A.; Dunlop, D.S.; Suckow, R.F.; Cooper, T.B.; Javitt, D.C. Modulating NMDA receptor function with d-amino acid oxidase inhibitors: Understanding functional activity in PCP-treated mouse model. Neurochem. Res., 2016, 41(1-2), 398-408.
[] [PMID: 26857796]
Lin, C.H.; Chen, P.K.; Chang, Y.C. Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biol. Psychiatry, 2014, 75(9), 678-685.
[] [PMID: 24074637]
Lin, C.H.; Chen, P.K.; Wang, S.H.; Lane, H.Y. Sodium benzoate for the treatment of behavioral and psychological symptoms of dementia (BPSD): A randomized, double-blind, placebo-controlled, 6-week trial. J Psychopharmacol (Oxford), 2019, 33(8), 1030-1033.
[] [PMID: 31113277]
Madeira, C.; Alheira, F.V.; Calcia, M.A. Blood Levels of Glutamate and Glutamine in Recent Onset and Chronic Schizophrenia. Front. Psychiatry, 2018, 9, 713.
[] [PMID: 30618883]
Sedlak, T.W.; Paul, B.D.; Parker, G.M. The glutathione cycle shapes synaptic glutamate activity. Proc. Natl. Acad. Sci. USA, 2019, 116(7), 2701-2706.
[] [PMID: 30692251]
Keller, S.; Punzo, D.; Cuomo, M. DNA methylation landscape of the genes regulating D-serine and D-aspartate metabolism in post-mortem brain from controls and subjects with schizophrenia. Sci. Rep., 2018, 8(1), 10163.
[] [PMID: 29976992]
Srivastava, R.; Faust, T.; Ramos, A.; Ishizuka, K.; Sawa, A. Dynamic changes of the mitochondria in psychiatric illnesses: new mechanistic insights from human neuronal models. Elsevier, USA. Biol. Psychiatry, 2018, Vol 83, 751-760.
Dwir, D.; Giangreco, B.; Xin, L. MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients. Mol. Psychiatry, 2019.
[] [PMID: 30911107]
Lin, C.H.; Lin, P.P.; Lin, C.Y. Decreased mRNA expression for the two subunits of system xc(-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. J. Psychiatr. Res., 2016, 72, 58-63.
[] [PMID: 26540405]
Burnet, P.W.J.; Eastwood, S.L.; Bristow, G.C. D-amino acid oxidase activity and expression are increased in schizophrenia. Mol. Psychiatry, 2008, 13(7), 658-660.
[] [PMID: 18560437]
Lin, C.H.; Yang, H.T.; Chiu, C.C.; Lane, H.Y. Blood levels of D-amino acid oxidase vs. D-amino acids in reflecting cognitive aging. Sci. Rep., 2017, 7(1), 14849.
[] [PMID: 29093468]
Lin, C-H.; Chang, H-T.; Chen, Y-J.; Lin, C-H.; Huang, C-H.; Tun, R. Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals., Mol Psychiatry [Internet]2014 [cited 2019 Jul 14];19(6): 636-7. Available from:
Lim, C.; Baker, A.; Saha, S. Protocol update and statistical analysis plan for CADENCE-BZ: a randomized clinical trial to assess the efficacy of sodium benzoate as an adjunctive treatment in early psychosis. Trials, 2019, 20(1), 203.
[] [PMID: 30961658]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy