A core symptom that is frequently linked with dysregulation of glutamatergic neurotransmission in regard to schizophrenia is impairment or damage of executive functioning as a component of cognitive deficiency. The amino acid D-serine plays the role of an endogenous coagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor glycine modulatory site. Considerably reduced serum levels of D-serine were found in patients suffering from schizophrenia compared with healthy control participants. An increase in D-serine led to augmented cognitive functionality in patients suffering from schizophrenia who were undergoing clinical trials and given the treatment of first- and second-generation antipsychotics. The study proposed the hypothesis that the D-serine blood serum levels may be linked with the extent of executive functionality in those suffering from the mental illness in question. For the purpose of examining executive function in such patients, the Rey-Osterrieth Complex Figure, Trail Making, and Wisconsin Card Sorting tests were applied (n = 50). High-performance liquid chromatography was used to gauge the total serine and D-serine levels. The extent of damage was examined through neuropsychological tests and was found to be considerably linked to D-serine serum level and the D-serine/total serine ratio (p < 0.05) in the sample being considered. A lower average serum level of D-serine and lower D-serine/total serine ratio were observed in participants with the worst performance compared with those displaying the best performance-this was true when the patients were split into quartile groups based on their results (p < 0.05). The findings of modified D-serine serum levels and the D-serine/total serine ratio linked to the extent of damage in executive functioning indicate that serine metabolism that is coresponsible for NMDA receptor dysfunction has been changed.

Biomedical Research Center University Hospital Hradec Kralove Hradec Kralove Czechia

Center for Psychiatry Regional Hospital Liberec Liberec Czechia

Department of Neurology Faculty of Medicine in Hradec Kralove University Hospital Hradec Kralove and Charles University Prague Hradec Kralove Czechia

Department of Psychiatry 1st Faculty of Medicine General Teaching Hospital and Charles University Prague Prague Czechia

Department of Psychiatry Faculty of Medicine in Hradec Kralove University Hospital Hradec Kralove and Charles University Prague Hradec Kralove Czechia

Faculty of Science University of Hradec Kralove Hradec Kralove Czechia

Institute of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove and Charles University Prague Hradec Kralove Czechia

Institute of Health Studies Technical University of Liberec Liberec Czechia

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Davidson M, Harvey P, Welsh KA, Powchik P, Putnam KM, Mohs RC. Cognitive functioning in late-life schizophrenia: comparison of elderly schizophrenic patients and patients with Alzheimer's disease. Am J Psychiatry. (1996) 153:1274–9. 10.1176/ajp.153.10.1274 PubMed DOI

Palmer BW, Heaton RK, Paulsen JS, Kuck J, Braff D, Harris MJ, et al. . Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychol. (1997) 11:437–46. 10.1037/0894-4105.11.3.437 PubMed DOI

Krystal JH, Pery EB, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, et al. . Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry. (2005) 62:985–95. 10.1001/archpsyc.62.9.985 PubMed DOI

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. (1991) 148:1301–8. 10.1176/ajp.148.10.1301 PubMed DOI

Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, et al. . NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacol. (1996) 14:301–7. 10.1016/0893-133X(95)00137-3 PubMed DOI

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. 10.1001/archpsyc.1994.03950030035004 PubMed DOI

Micallef J, Tardieu S, Gentile S, Fakra E, Jouve E, Sambuc R, et al. . Effects of a subanaesthetic dose of ketamine on emotional and behavioral state in healthy subjects. Neurophysiol Clin. (2003) 33:138–47. 10.1016/S0987-7053(03)00028-5 PubMed DOI

Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, et al. . Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol. (2001) 4:385–91. 10.1017/S1461145701002590 PubMed DOI

Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Brit J Psychiatry. (1996) 169:610–7. 10.1192/bjp.169.5.610 PubMed DOI

Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. (2004) 55:165–71. 10.1016/S0006-3223(03)00707-8 PubMed DOI

Tsai G, Yang P, Chung L, Lange N, Coyle JT. D-serine added to antipsychotics for treatment of schizophrenia. Biol Psychiatry. (1998) 44:1081–9. 10.1016/S0006-3223(98)00279-0 PubMed DOI

Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, et al. . D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. (2005) 57:577–85. 10.1016/j.biopsych.2004.12.037 PubMed DOI

Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, et al. . High dose D-serine in the treatment of schizophrenia. Schizophr Res. (2010) 121:125–30. 10.1016/j.schres.2010.05.012 PubMed DOI PMC

D'Souza DC, Radhakrishnan R, Perry E, Bhakta S, Singh NM, Yadav R, et al. . Feasibility, safety, and efficacy of the combination of D-serine and computerized cognitive retraining in schizophrenia: an international collaborative pilot study. Neuropsychopharmacol. (2013) 38:492–503. 10.1038/npp.2012.208 PubMed DOI PMC

Kantrowitz JT, Epstein ML, Lee M, Lehrfeld M, Nolan KA, Shope C, et al. . Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: correlations with symptoms. Schizophr Res. (2018) 191:70–9. 10.1016/j.schres.2017.02.027 PubMed DOI

Tsai GE, Lin P. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Desig. (2010) 6:522–37. 10.2174/138161210790361452 PubMed DOI

Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res. (2005) 72:225–34. 10.1016/j.schres.2004.05.005 PubMed DOI

Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. (2000) 157:826–8. 10.1176/appi.ajp.157.5.826 PubMed DOI

Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry. (1999) 156:145–7. 10.1176/ajp.156.1.145 PubMed DOI

Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, et al. . The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. (2007) 164:1593–602. 10.1176/appi.ajp.2007.06081358 PubMed DOI

Lane H, Chang Y, Liu Y, Chiu C, Tsai G. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia. Arch Gen Psychiatry. (2005) 62:1196–204. 10.1001/archpsyc.62.11.1196 PubMed DOI

Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. (2004) 55:452–6. 10.1016/j.biopsych.2003.09.012 PubMed DOI

Lane H, Huang C, Wu P, Liu Y, Chang Y, Lin P, et al. . Glycine transporter I inhibitor, N-methylglycine (Sarcosine) added to clozapine for the treatment of schizophrenia. Biol Psychiatry. (2006) 60:645–9. 10.1016/j.biopsych.2006.04.005 PubMed DOI

Scolari MJ, Acosta GB. D-serine: a new word in the glutamatergic neuro-glial language. Amin Acid. (2007) 33:563–74. 10.1007/s00726-006-0481-0 PubMed DOI

Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. . Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry. (2003) 60:572–6. 10.1001/archpsyc.60.6.572 PubMed DOI

Yamada K, Ohnishi T, Hashimoto K, Ohba H, Iwayama-Shigeno Y, Toyoshima M, et al. . Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. Biol Psychiatry. (2005) 57:1493–503. 10.1016/j.biopsych.2005.03.018 PubMed DOI

Panizzutti R, Fisher M, Garrett C, Man WH, Sena W, Madeira C, et al. . Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia. Schizophr Res. (2019) 207:63–9. 10.1016/j.schres.2018.04.011 PubMed DOI PMC

Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, et al. . A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res. (2007) 90:41–51. 10.1016/j.schres.2006.10.010 PubMed DOI

Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neur Psychopharmacol Biol Psych. (2005) 29:767–9. 10.1016/j.pnpbp.2005.04.023 PubMed DOI

MacKay MB, Kravtsenyuk M, Thomas R, Mitchell ND, Dursun SM, Baker GB. D-Serine: potential therapeutic agent and/or biomarker in schizophrenia and depression? Front Psychiatry. (2019) 10:25. 10.3389/fpsyt.2019.00025 PubMed DOI PMC

Kantrowitz JT, Epstein ML, Beggel O, Rohrig S, Lehrfeld JM, Revheim N, et al. . Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain. (2016) 139:3281–95. 10.1093/brain/aww262 PubMed DOI PMC

Tsai G, Yang P, Chung L, Tsai I, Tsai C, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. (1999) 156:1822–5. PubMed

WHO . The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization; (1993).

Kutlan D, Presits P, Molnar-Perl I. Behavior and characteristics of amine derivatives obtained with o-phthaldialdehyde/3-mercaptopropionic acid and with o-phthaldialdehyde/N-acetyl-cysteine reagents. J Chromatogr A. (2002) 949:235–48. 10.1016/S0021-9673(01)01610-7 PubMed DOI

Molnar-Perl I. Quantification of amino acids and amines in the same matrix by high-performance liquid chromatography, either simultaneously or separately. J Chromatogr A. (2003) 987:291–309. 10.1016/S0021-9673(02)01537-6 PubMed DOI

Vasanits A, Kutlan D, Sass P, Molnar-Perl I. Retention/quantification properties of the o-phthaldialdehyde-3-mercaptopropionic acid and the o-phthaldialdehyde-N-acetyl-L-cysteine amino acid derivatives in reversed-phase high-performance liquid chromatography. J Chromatogr A. (2000) 870:271–87. 10.1016/S0021-9673(99)00942-5 PubMed DOI

Kutlan D, Molnar-Perl I. New aspects of the simultaneous analysis of amino acids and amines as their o-phthaldialdehyde derivatives by high-performance liquid chromatography. Analysis of wine, beer and vinegar. J Chromatogr A. (2003) 987:311–22. 10.1016/S0021-9673(02)01538-8 PubMed DOI

Zhao M, Bada JL. Determination of α-dialkylamino acids and their enantiomers in geological samples by high-performance liquid chromatography after derivatization with chiral adduct of o-phthaldialdehyde. J Chromatogr A. (1995) 690:55–63. 10.1016/0021-9673(94)00927-2 PubMed DOI

Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. (1987) 13:261–76. 10.1093/schbul/13.2.261 PubMed DOI

Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry. (1989) 7:49–58. 10.1192/S0007125000291496 PubMed DOI

Arbuthnott K, Frank J. Trail making test, part B as a measure of executive control: validation using a set-switching paradigm. J Clin Exp Neuropsychol. (2000) 22:518–28. 10.1076/1380-3395(200008)22:4;1-0;FT518 PubMed DOI

Mitrushina M, Boone KB, Razani J, D'Elia LF. Handbook of Normative Data for Neuropsychological Assessment. 2nd ed. Oxford University Press. (2005).

Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G. Wisconsin Card Sorting Test – Manual. PAR Psychol Assess Resourses; (1993).

Kortte KB, Horner MD, Windham WK. The trail making test, part B: cognitive flexibility or ability to maintain set? Appl Neuropsychol. (2002) 9:106–9. 10.1207/S15324826AN0902_5 PubMed DOI

Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. (2012) 213:11–37. 10.1007/978-3-642-25758-2_2 PubMed DOI

Gold JM. Cognitive deficits as treatment targets in schizophrenia. Schizophr Res. (2004) 72:21–8. 10.1016/j.schres.2004.09.008 PubMed DOI

Keefe RSE, Bilder RM, Harvey PD, Davis SM, Palmer BW, Gold JM, et al. . Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacol. (2006) 31:2033–46. 10.1038/sj.npp.1301072 PubMed DOI

Bagney A, Rodriguez-Jimenez R, Martinez-Gras I, Sanchez-Morla EM, Santos JL, Jimenez-Arriero MA, et al. . Negative symptoms and executive function in schizophrenia: does their relationship change with illness duration? Psychopatol. (2013) 46:241–8. 10.1159/000342345 PubMed DOI

Saleem MM, Harte MK, Marshall KM, Scally A, Brewin A, Neill JC. First episode psychosis patients show impaired cognitive function – a study of a South Asian population in the UK. J Psychopharmacol. (2013) 27:366–73. 10.1177/0269881113477746 PubMed DOI