serine and Schizophrenia studies

Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.
serine : An alpha-amino acid that is alanine substituted at position 3 by a hydroxy group.

Schizophrenia: A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, HALLUCINATIONS, emotional disharmony, and regressive behavior.

Research Excerpts

Excerpt	Relevance	Reference
"Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each."	9.69	Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine. ( Carlson, M; Choo, TH; De Baun, HM; Dias, E; Gangwisch, J; Girgis, RR; Iosifescu, DV; Kantrowitz, JT; Kegeles, LS; Mayer, MR; Medalia, A; Saperstein, AM; Sehatpour, P; Shope, C; Sobeih, T; Wall, MM, 2023)
"These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia."	9.27	Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. ( Epstein, ML; Javitt, DC; Kantrowitz, JT; Lee, M; Lehrfeld, N; Nolan, KA; Petkova, E; Shope, C; Silipo, G, 2018)
"This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia."	9.20	D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. ( Chen, H; Corcoran, CM; Cornblatt, B; Javitt, DC; Kantrowitz, JT; Petkova, E; Silipo, G; Woods, SW, 2015)
"Recent evidence indicates that enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia."	9.14	A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. ( Chang, YC; Huang, YJ; Lane, HY; Liao, CH; Lin, CH; Tsai, GE, 2010)
"D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia."	9.14	High dose D-serine in the treatment of schizophrenia. ( Balla, A; Cornblatt, B; D'Souza, C; Javitt, DC; Kantrowitz, JT; Malhotra, AK; Saksa, J; Silipo, G; Suckow, RF; Woods, SW, 2010)
"Based on the hypothesis of NMDA receptor hypofunction in schizophrenia, plasma glycine, L-serine, and D-serine levels have been studied, since they could serve as biological markers."	9.13	Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). ( Abe, S; Arai, H; Hanzawa, R; Hatano, T; Kida, S; Maeshima, H; Ohnuma, T; Sakai, Y; Shibata, N; Suzuki, T, 2008)
"We consecutively recruited 100 schizophrenia patients and assessed clinical improvement after 4 weeks of risperidone treatment."	9.13	Could HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting. ( Choi, EY; Joo, YH; Kim, B; Kim, CY; Song, K, 2008)
"Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ)."	9.12	Serine racemase binds to PICK1: potential relevance to schizophrenia. ( Balkissoon, R; Fujii, K; Hikida, T; Huganir, RL; Kawahara, R; Maeda, K; Mustafa, AK; Okawa, M; Ozeki, Y; Sawa, A; Snyder, SH; Ujike, H; Xia, J; Yamada, T, 2006)
"Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine."	9.11	High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. ( Bar, G; Ermilov, M; Heresco-Levy, U; Javitt, DC; Lichtenberg, P, 2004)
"D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia."	9.11	D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. ( Bar, G; Catinari, S; Ebstein, R; Ermilov, M; Heresco-Levy, U; Javitt, DC; Lichtenberg, P; Vass, A, 2005)
"We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms."	9.11	Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia. ( Jayathilake, K; Jin, D; Lee, M; Meltzer, HY; Sumiyoshi, T, 2005)
"This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia."	9.11	Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. ( Chang, YC; Chiu, CC; Lane, HY; Liu, YC; Tsai, GE, 2005)
"The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia."	9.08	D-serine added to antipsychotics for the treatment of schizophrenia. ( Chung, LC; Coyle, JT; Lange, N; Tsai, G; Yang, P, 1998)
"An increasing amount of evidence indicates that d-serine, a potent and selective endogenous coagonist of the N-methyl-d-aspartate receptor (NMDAR), is efficacious in the treatment of schizophrenia."	8.93	Low d-serine levels in schizophrenia: A systematic review and meta-analysis. ( Cho, SE; Cho, SJ; Kang, SG; Na, KS, 2016)
"Based upon the evidence that N-methyl-D-aspartate (NMDA) type glutamate receptor antagonists including phencyclidine cause schizophrenia-like treatment-resistant negative symptoms as well as antipsychotic-responsive dopamine-related positive symptoms, the facilitation of the NMDA receptor function has been considered to be a rational therapeutic approach to ameliorate both of the above schizophrenic symptomatologies."	8.86	[Development of a novel pharmacotherapy targeted at the N-methyl-D-aspartate receptor-D-serine system for schizophrenia]. ( Nishikawa, T, 2010)
" Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine."	8.12	Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response. ( Akkouh, IA; Andreassen, OA; Budinska, E; Djurovic, S; Grabiec, M; Hribkova, H; Kasparek, T; Sun, YM; Szabo, A, 2022)
"This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life."	7.79	Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine. ( Hagiwara, H; Hashimoto, K; Iyo, M, 2013)
"Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders."	7.79	Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. ( Abazyan, B; Abazyan, S; Ma, TM; Nomura, J; Pletnikov, MV; Sawa, A; Seshadri, S; Snyder, SH; Yang, C, 2013)
"Changes in D-serine availability in the brain may contribute to the hypofunction of NMDA-glutamate receptors in schizophrenia; however, measurements of blood levels of D-serine in individuals with schizophrenia have not been consistent amongst previous studies."	7.78	Plasma levels of D-serine in Brazilian individuals with schizophrenia. ( Alheira, FV; Brasil, MA; Calcia, MA; Ferreira, ST; Goldenstein, N; Madeira, C; Panizzutti, R; Silva, TC; Tannos, FM; Vargas-Lopes, C, 2012)
"3) has been proposed to play a main role in the degradation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the human brain, and to be associated with the onset of schizophrenia."	7.77	Is rat an appropriate animal model to study the involvement of D-serine catabolism in schizophrenia? Insights from characterization of D-amino acid oxidase. ( Frattini, LF; Molla, G; Piubelli, L; Pollegioni, L; Sacchi, S, 2011)
"D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia."	7.76	The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. ( Abou El-Magd, RM; Chung, SP; Fukui, K; Iwana, S; Kawazoe, T; Miyano, M; Ono, K; Park, HK; Sakai, T; Yorita, K, 2010)
"Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia."	7.74	Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. ( Labrie, V; Lipina, T; Roder, JC, 2008)
"Decreased, not increased, serum levels of total serine negatively associated with intensity of negative symptoms were detected in patients with schizophrenia."	7.74	D-serine serum levels in patients with schizophrenia: relation to psychopathology and comparison to healthy subjects. ( Cermakova, E; Hons, J; Libiger, J; Ulrychova, M; Zirko, R, 2008)
"Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease."	7.74	A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. ( Agam, G; Amar, S; Bendikov, I; De Miranda, J; Nadri, C; Panizzutti, R; Wolosker, H, 2007)
"The NMDA receptor co-agonists D-serine and glycine are thought to contribute to glutamatergic dysfunction in schizophrenia."	7.74	Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia. ( Brandon, NJ; Burnet, PW; Gilbert, EJ; Harrison, PJ; Hutchinson, L; Hutson, PH; Rutter, AR; von Hesling, M, 2008)
"The SRR/DAO are not likely to be major genetic determinants in the development of schizophrenia or control of serum D-serine levels."	7.73	Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. ( Hashimoto, K; Itokawa, M; Iwayama-Shigeno, Y; Iyo, M; Minabe, Y; Mori, N; Nakamura, K; Ohba, H; Ohnishi, T; Okuno, A; Shimizu, E; Takao, H; Toyoshima, M; Toyota, T; Yamada, K; Yoshikawa, T, 2005)
"These findings support the hypothesis that altered levels of glycine and homocysteine may coexist in patients with schizophrenia and contribute to pathophysiological aspects of this illness."	7.73	Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. ( Blanaru, M; Bloch, B; Ermilov, M; Heresco-Levy, U; Javitt, DC; Kremer, I; Neeman, G, 2005)
"Serum levels of D-serine in the patients with schizophrenia were significantly (z = -3."	7.72	Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. ( Fukushima, T; Hasegawa, H; Hashimoto, K; Imai, K; Iyo, M; Komatsu, N; Kumakiri, C; Nakazato, M; Okada, S; Shimizu, E; Shinoda, N; Watanabe, H, 2003)
"Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance."	6.82	Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. ( Ahissar, M; Beggel, O; Epstein, ML; Javitt, DC; Kantrowitz, JT; Lehrfeld, JM; Lehrfeld, NP; Parker, E; Reep, J; Revheim, N; Rohrig, S; Silipo, G, 2016)
"Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms."	6.77	A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. ( Abramovich, Y; Amital, D; Davidson, M; Doron, A; Gershon, AA; Heresco-Levy, U; Javitt, DC; Konas, S; Levkovitz, Y; Liba, D; Mashiach, M; Teitelbaum, A; Weiser, M; Werbeloff, N; Zimmerman, Y, 2012)
"Schizophrenia is a severe psychiatric illness that is characterized by reduced cortical connectivity, for which the underlying biological and genetic causes are not well understood."	6.52	The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. ( Balu, DT; Coyle, JT, 2015)
"These approaches may provide novel treatments to schizophrenia, provided that some of the known adverse effects associated with existing GlyT1 agents can be safely and adequately dealt with."	6.44	Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. ( Svensson, KA; Yang, CR, 2008)
"Schizophrenia is a psychiatric disorder that affects over 20 million people globally."	5.72	Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia. ( Anisimova, M; Barragan, EV; Gray, JA; Park, DK; Petshow, S; Stein, IS; Zito, K, 2022)
"Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each."	5.69	Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine. ( Carlson, M; Choo, TH; De Baun, HM; Dias, E; Gangwisch, J; Girgis, RR; Iosifescu, DV; Kantrowitz, JT; Kegeles, LS; Mayer, MR; Medalia, A; Saperstein, AM; Sehatpour, P; Shope, C; Sobeih, T; Wall, MM, 2023)
"Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability."	5.51	N-Methyl-d-aspartate receptor co-agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse. ( Bergman, J; Carlezon, WA; Coyle, JT; Desai, RI; Donahue, RJ; Doyle, MR; Landino, SM; Presti, KT; Puhl, MD; Takagi, S, 2019)
"Schizophrenia has a considerable genetic background."	5.43	The inverse link between genetic risk for schizophrenia and migraine through NMDA (N-methyl-D-aspartate) receptor activation via D-serine. ( Degenhardt, F; Grabe, HJ; Hertel, J; Homuth, G; John, U; Lucht, MJ; Nauck, M; Nöthen, MM; Rietschel, M; Schulze, T; Teumer, A; Van der Auwera, S; Völker, U, 2016)
"Schizophrenia is a severe, complex mental disorder."	5.42	Correlation of functional GRIN2A gene promoter polymorphisms with schizophrenia and serum D-serine levels. ( Dang, W; Du, Y; Jiao, K; Liu, R; Liu, Z; Zhou, Q, 2015)
"Twenty-two patients with treatment-resistant schizophrenia and 22 age- and gender-matched healthy controls were enrolled."	5.40	Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment. ( Fujimoto, M; Fujita, Y; Hashimoto, K; Hashimoto, R; Ito, A; Numata, S; Ohi, K; Ohmori, T; Takeda, M; Umeda-Yano, S; Yamamori, H; Yasuda, Y, 2014)
"Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function."	5.39	Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. ( Balu, DT; Basu, AC; Benneyworth, MA; Bolshakov, VY; Coyle, JT; Li, Y; Puhl, MD; Takagi, S, 2013)
"Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively."	5.33	Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. ( Labrie, V; Lipina, T; Roder, J; Weiner, I, 2005)
"These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia."	5.27	Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. ( Epstein, ML; Javitt, DC; Kantrowitz, JT; Lee, M; Lehrfeld, N; Nolan, KA; Petkova, E; Shope, C; Silipo, G, 2018)
"This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia."	5.20	D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. ( Chen, H; Corcoran, CM; Cornblatt, B; Javitt, DC; Kantrowitz, JT; Petkova, E; Silipo, G; Woods, SW, 2015)
"Recent evidence indicates that enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia."	5.14	A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. ( Chang, YC; Huang, YJ; Lane, HY; Liao, CH; Lin, CH; Tsai, GE, 2010)
"D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia."	5.14	High dose D-serine in the treatment of schizophrenia. ( Balla, A; Cornblatt, B; D'Souza, C; Javitt, DC; Kantrowitz, JT; Malhotra, AK; Saksa, J; Silipo, G; Suckow, RF; Woods, SW, 2010)
"Based on the hypothesis of NMDA receptor hypofunction in schizophrenia, plasma glycine, L-serine, and D-serine levels have been studied, since they could serve as biological markers."	5.13	Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). ( Abe, S; Arai, H; Hanzawa, R; Hatano, T; Kida, S; Maeshima, H; Ohnuma, T; Sakai, Y; Shibata, N; Suzuki, T, 2008)
"We consecutively recruited 100 schizophrenia patients and assessed clinical improvement after 4 weeks of risperidone treatment."	5.13	Could HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting. ( Choi, EY; Joo, YH; Kim, B; Kim, CY; Song, K, 2008)
"N-Methyl D-aspartate (NMDA)-receptor hypofunction has been implicated in the pathophysiology of schizophrenia and D-serine and glycine add-on therapy to antipsychotics has shown beneficial effects in schizophrenic patients."	5.13	Cerebrospinal fluid D-serine and glycine concentrations are unaltered and unaffected by olanzapine therapy in male schizophrenic patients. ( Berger, R; Cahn, W; De Barse, MM; de Koning, TJ; de Sain-van der Velden, MG; Dorland, L; Fuchs, SA; Kahn, RS; Klomp, LW; Scheepers, FE, 2008)
"Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ)."	5.12	Serine racemase binds to PICK1: potential relevance to schizophrenia. ( Balkissoon, R; Fujii, K; Hikida, T; Huganir, RL; Kawahara, R; Maeda, K; Mustafa, AK; Okawa, M; Ozeki, Y; Sawa, A; Snyder, SH; Ujike, H; Xia, J; Yamada, T, 2006)
"Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine."	5.11	High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. ( Bar, G; Ermilov, M; Heresco-Levy, U; Javitt, DC; Lichtenberg, P, 2004)
"Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia."	5.11	Dopamine D3 receptor Ser9Gly polymorphism and risperidone response. ( Chang, WH; Chang, YC; Hsu, SK; Huang, CH; Lane, HY; Liu, YC, 2005)
"D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia."	5.11	D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. ( Bar, G; Catinari, S; Ebstein, R; Ermilov, M; Heresco-Levy, U; Javitt, DC; Lichtenberg, P; Vass, A, 2005)
"We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms."	5.11	Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia. ( Jayathilake, K; Jin, D; Lee, M; Meltzer, HY; Sumiyoshi, T, 2005)
"This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia."	5.11	Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. ( Chang, YC; Chiu, CC; Lane, HY; Liu, YC; Tsai, GE, 2005)
"The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia."	5.08	D-serine added to antipsychotics for the treatment of schizophrenia. ( Chung, LC; Coyle, JT; Lange, N; Tsai, G; Yang, P, 1998)
"D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia."	4.98	Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies. ( Ferenczy, GG; Keserű, GM; Szilágyi, B, 2018)
"An increasing amount of evidence indicates that d-serine, a potent and selective endogenous coagonist of the N-methyl-d-aspartate receptor (NMDAR), is efficacious in the treatment of schizophrenia."	4.93	Low d-serine levels in schizophrenia: A systematic review and meta-analysis. ( Cho, SE; Cho, SJ; Kang, SG; Na, KS, 2016)
"Based upon the evidence that N-methyl-D-aspartate (NMDA) type glutamate receptor antagonists including phencyclidine cause schizophrenia-like treatment-resistant negative symptoms as well as antipsychotic-responsive dopamine-related positive symptoms, the facilitation of the NMDA receptor function has been considered to be a rational therapeutic approach to ameliorate both of the above schizophrenic symptomatologies."	4.86	[Development of a novel pharmacotherapy targeted at the N-methyl-D-aspartate receptor-D-serine system for schizophrenia]. ( Nishikawa, T, 2010)
"Polymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which Glycine(B) sites are located."	4.82	N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. ( Millan, MJ, 2005)
"N-methyl-D-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, D-serine, in clinical trials has shown positive effects in patients."	4.31	Luvadaxistat: A Novel Potent and Selective D-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia. ( Almond, S; Burley, R; Carlton, M; Davies, CH; Delgado García, JM; Fradley, R; Gaskin, P; Goetghebeur, P; Gray, I; Grayson, B; Gruart I Massó, A; Howley, E; Miller, D; Neill, JC; Serrats, J; Zhu, B, 2023)
" Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine."	4.12	Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response. ( Akkouh, IA; Andreassen, OA; Budinska, E; Djurovic, S; Grabiec, M; Hribkova, H; Kasparek, T; Sun, YM; Szabo, A, 2022)
"Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents."	3.96	Activation of Astroglial Connexin is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine. ( Fukuyama, K; Murata, M; Okada, M; Okubo, R; Shiroyama, T, 2020)
"Serine racemase knockout mice demonstrate abnormalities in socio-communicative behaviors consistent with an impairment in sociality, a negative symptom of schizophrenia."	3.91	Sociality deficits in serine racemase knockout mice. ( Gewirtz, JC; Matveeva, TM; Miller, RF; Pisansky, MT; Young, A, 2019)
"Prenatal maternal infection contributes to the etiology of schizophrenia, with D-serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, playing a role in the pathophysiology of this disease."	3.83	Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation. ( Fujita, Y; Hashimoto, K; Ishima, T, 2016)
"This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life."	3.79	Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine. ( Hagiwara, H; Hashimoto, K; Iyo, M, 2013)
"Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders."	3.79	Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. ( Abazyan, B; Abazyan, S; Ma, TM; Nomura, J; Pletnikov, MV; Sawa, A; Seshadri, S; Snyder, SH; Yang, C, 2013)
"Changes in D-serine availability in the brain may contribute to the hypofunction of NMDA-glutamate receptors in schizophrenia; however, measurements of blood levels of D-serine in individuals with schizophrenia have not been consistent amongst previous studies."	3.78	Plasma levels of D-serine in Brazilian individuals with schizophrenia. ( Alheira, FV; Brasil, MA; Calcia, MA; Ferreira, ST; Goldenstein, N; Madeira, C; Panizzutti, R; Silva, TC; Tannos, FM; Vargas-Lopes, C, 2012)
"3) has been proposed to play a main role in the degradation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the human brain, and to be associated with the onset of schizophrenia."	3.77	Is rat an appropriate animal model to study the involvement of D-serine catabolism in schizophrenia? Insights from characterization of D-amino acid oxidase. ( Frattini, LF; Molla, G; Piubelli, L; Pollegioni, L; Sacchi, S, 2011)
"D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia."	3.76	The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. ( Abou El-Magd, RM; Chung, SP; Fukui, K; Iwana, S; Kawazoe, T; Miyano, M; Ono, K; Park, HK; Sakai, T; Yorita, K, 2010)
"Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia."	3.74	Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. ( Labrie, V; Lipina, T; Roder, JC, 2008)
"Decreased, not increased, serum levels of total serine negatively associated with intensity of negative symptoms were detected in patients with schizophrenia."	3.74	D-serine serum levels in patients with schizophrenia: relation to psychopathology and comparison to healthy subjects. ( Cermakova, E; Hons, J; Libiger, J; Ulrychova, M; Zirko, R, 2008)
"A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser(704)Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities."	3.74	Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. ( Bertolino, A; Blasi, G; Caforio, G; Callicott, JH; Di Giorgio, A; Gambi, F; Kolachana, B; Latorre, V; Nardini, M; Papazacharias, A; Popolizio, T; Rampino, A; Rizzo, M; Romano, R; Sambataro, F; Weinberger, DR, 2008)
"Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease."	3.74	A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. ( Agam, G; Amar, S; Bendikov, I; De Miranda, J; Nadri, C; Panizzutti, R; Wolosker, H, 2007)
"The NMDA receptor co-agonists D-serine and glycine are thought to contribute to glutamatergic dysfunction in schizophrenia."	3.74	Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia. ( Brandon, NJ; Burnet, PW; Gilbert, EJ; Harrison, PJ; Hutchinson, L; Hutson, PH; Rutter, AR; von Hesling, M, 2008)
"Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia."	3.73	Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. ( Engberg, G; Hashimoto, K; Iyo, M; Lindström, LH; Nordin, C; Shimizu, E, 2005)
"The SRR/DAO are not likely to be major genetic determinants in the development of schizophrenia or control of serum D-serine levels."	3.73	Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. ( Hashimoto, K; Itokawa, M; Iwayama-Shigeno, Y; Iyo, M; Minabe, Y; Mori, N; Nakamura, K; Ohba, H; Ohnishi, T; Okuno, A; Shimizu, E; Takao, H; Toyoshima, M; Toyota, T; Yamada, K; Yoshikawa, T, 2005)
"These findings support the hypothesis that altered levels of glycine and homocysteine may coexist in patients with schizophrenia and contribute to pathophysiological aspects of this illness."	3.73	Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. ( Blanaru, M; Bloch, B; Ermilov, M; Heresco-Levy, U; Javitt, DC; Kremer, I; Neeman, G, 2005)
"D-Amino acid oxidase (DAAO) has been proposed to be involved in the oxidation of D-serine, an allosteric activator of the NMDA-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia."	3.73	Characterization of human D-amino acid oxidase. ( Bernasconi, M; Fukui, K; Molla, G; Pilone, MS; Polegioni, L; Sacchi, S, 2006)
"Serum levels of D-serine in the patients with schizophrenia were significantly (z = -3."	3.72	Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. ( Fukushima, T; Hasegawa, H; Hashimoto, K; Imai, K; Iyo, M; Komatsu, N; Kumakiri, C; Nakazato, M; Okada, S; Shimizu, E; Shinoda, N; Watanabe, H, 2003)
"There is some disagreement in the literature concerning the use of plasma serine concentrations as a biological marker for psychoses including schizophrenia."	3.68	Is plasma serine a marker for psychosis? ( Brogan, MP; Carl, GF; Young, BK, 1992)
"Fasting plasma serine and glycine concentrations, determined by ion-exchange amino acid chromatography, were similar in a large group of psychotic patients with various forms of schizophrenia and in healthy control subjects."	3.67	Interconversion of serine and glycine is normal in psychotic patients. ( Hansen, S; Perry, TL, 1985)
"Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance."	2.82	Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. ( Ahissar, M; Beggel, O; Epstein, ML; Javitt, DC; Kantrowitz, JT; Lehrfeld, JM; Lehrfeld, NP; Parker, E; Reep, J; Revheim, N; Rohrig, S; Silipo, G, 2016)
"Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms."	2.77	A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. ( Abramovich, Y; Amital, D; Davidson, M; Doron, A; Gershon, AA; Heresco-Levy, U; Javitt, DC; Konas, S; Levkovitz, Y; Liba, D; Mashiach, M; Teitelbaum, A; Weiser, M; Werbeloff, N; Zimmerman, Y, 2012)
"Aripiprazole has high affinity for dopamine D2 and D3 receptors (DRD2 and DRD3)."	2.74	Effects of the DRD3 Ser9Gly polymorphism on aripiprazole efficacy in schizophrenic patients as modified by clinical factors. ( Chen, CH; Chen, SF; Shen, YC, 2009)
"Schizophrenia is a severe psychiatric illness that is characterized by reduced cortical connectivity, for which the underlying biological and genetic causes are not well understood."	2.52	The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. ( Balu, DT; Coyle, JT, 2015)
"Current treatments for schizophrenia, although effective for positive symptoms, have not proven as effective for negative symptoms and cognitive dysfunction."	2.50	Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. ( Citrome, L, 2014)
"Schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide."	2.46	Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Ser311Cys polymorphisms of the dopamine D2-receptor gene and schizophrenia. ( Arinami, T; Itokawa, M; Toru, M, 2010)
"These approaches may provide novel treatments to schizophrenia, provided that some of the known adverse effects associated with existing GlyT1 agents can be safely and adequately dealt with."	2.44	Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. ( Svensson, KA; Yang, CR, 2008)
"Schizophrenia is a neurodevelopmental disorder with dendrite and dendritic spine dysfunction."	1.72	Protein Kinase B/Akt1 Phosphorylates Dysbindin-1A at Serine 10 to Regulate Neuronal Development. ( Chen, P; Fei, E; Zhang, Q; Zhong, Y; Zhou, T, 2022)
"Schizophrenia is a psychiatric disorder that affects over 20 million people globally."	1.72	Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia. ( Anisimova, M; Barragan, EV; Gray, JA; Park, DK; Petshow, S; Stein, IS; Zito, K, 2022)
"Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability."	1.51	N-Methyl-d-aspartate receptor co-agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse. ( Bergman, J; Carlezon, WA; Coyle, JT; Desai, RI; Donahue, RJ; Doyle, MR; Landino, SM; Presti, KT; Puhl, MD; Takagi, S, 2019)
"Schizophrenia has a considerable genetic background."	1.43	The inverse link between genetic risk for schizophrenia and migraine through NMDA (N-methyl-D-aspartate) receptor activation via D-serine. ( Degenhardt, F; Grabe, HJ; Hertel, J; Homuth, G; John, U; Lucht, MJ; Nauck, M; Nöthen, MM; Rietschel, M; Schulze, T; Teumer, A; Van der Auwera, S; Völker, U, 2016)
"Schizophrenia is a severe, complex mental disorder."	1.42	Correlation of functional GRIN2A gene promoter polymorphisms with schizophrenia and serum D-serine levels. ( Dang, W; Du, Y; Jiao, K; Liu, R; Liu, Z; Zhou, Q, 2015)
"Twenty-two patients with treatment-resistant schizophrenia and 22 age- and gender-matched healthy controls were enrolled."	1.40	Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment. ( Fujimoto, M; Fujita, Y; Hashimoto, K; Hashimoto, R; Ito, A; Numata, S; Ohi, K; Ohmori, T; Takeda, M; Umeda-Yano, S; Yamamori, H; Yasuda, Y, 2014)
"Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function."	1.39	Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. ( Balu, DT; Basu, AC; Benneyworth, MA; Bolshakov, VY; Coyle, JT; Li, Y; Puhl, MD; Takagi, S, 2013)
" Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma D-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia."	1.38	Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice. ( Brandon, NJ; Engle, SJ; Jaaro-Peled, H; Rais, R; Rojas, C; Sawa, A; Slusher, BS; Strick, CA; Thomas, AG; Tsukamoto, T; Wozniak, K; Wu, Y, 2012)
"Schizophrenia is a highly heritable neuropsychiatric disorder affecting ∼1% of the world's population."	1.37	D-amino acid oxidase activity is inhibited by an interaction with bassoon protein at the presynaptic active zone. ( Brandon, NJ; Chanda, P; Charych, E; Gundelfinger, ED; Moss, SJ; Pausch, MH; Popiolek, M; Ross, JF, 2011)
"Schizophrenia is a heritable, complex mental disorder."	1.37	Association study of DRD3 gene in schizophrenia in Mexican sib-pairs. ( Aguilar, A; Apiquián, R; Camarena, B; Carnevale, A; Fresán, A; Nicolini, H; Orozco, L; Urraca, N, 2011)
" The right medial superior frontal gyrus volume was significantly correlated with daily dosage of antipsychotic medication in Ser homozygote schizophrenia patients."	1.35	The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain morphology in schizophrenia. ( Hagino, H; Kawasaki, Y; Kobayashi, S; Kurachi, M; Maeno, N; Niu, L; Ozaki, N; Sasaoka, T; Seto, H; Suzuki, M; Takahashi, T; Tsuneki, H; Tsunoda, M; Zhou, SY, 2009)
" We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats."	1.35	The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors. ( Abeywickrema, P; Almond, S; Brandon, N; Byrne, N; Campbell, A; Hutson, PH; Jacobson, M; Jones, B; Munshi, S; Pascarella, D; Pike, A; Prasad, GS; Sachs, N; Sakatis, M; Sardana, V; Sparey, T; Venkatraman, S; Young, MB, 2008)
"Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively."	1.33	Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. ( Labrie, V; Lipina, T; Roder, J; Weiner, I, 2005)
"The etiology of schizophrenia has been suggested to be associated with the dysfunction of the glutamatergic system."	1.33	No association between the ionotropic glutamate receptor kainate 3 gene ser310ala polymorphism and schizophrenia. ( Chen, JY; Lai, IC; Liou, YJ; Wang, YC, 2005)

Research

Studies (194)

Authors

Clinical Trials (17)

Trial Overview

Trial Outcomes

MATRICS

Timeframe	Studies, this research(%)	All Research%
pre-1990	5 (2.58)	18.7374
1990's	28 (14.43)	18.2507
2000's	72 (37.11)	29.6817
2010's	71 (36.60)	24.3611
2020's	18 (9.28)	2.80

Authors	Studies
Fei, E	1
Chen, P	1
Zhang, Q	1
Zhong, Y	1
Zhou, T	1
Tang, H	1
Jensen, K	1
Houang, E	1
McRobb, FM	1
Bhat, S	1
Svensson, M	1
Bochevarov, A	1
Day, T	1
Dahlgren, MK	1
Bell, JA	1
Frye, L	1
Skene, RJ	1
Lewis, JH	1
Osborne, JD	1
Tierney, JP	1
Gordon, JA	1
Palomero, MA	1
Gallati, C	1
Chapman, RSL	1
Jones, DR	1
Hirst, KL	1
Sephton, M	1
Chauhan, A	1
Sharpe, A	1
Tardia, P	1
Dechaux, EA	1
Taylor, A	1
Waddell, RD	1
Valentine, A	1
Janssens, HB	1
Aziz, O	1
Bloomfield, DE	1
Ladha, S	1
Fraser, IJ	1
Ellard, JM	1
Park, DK	1
Petshow, S	1
Anisimova, M	1
Barragan, EV	1
Gray, JA	1
Stein, IS	1
Zito, K	1
Murtas, G	1
Pollegioni, L	9
Molla, G	8
Sacchi, S	10
Li, X	1
Yang, C	2
Liang, X	1
Li, D	1
Zhou, Z	1
Xiao, H	1
Liu, X	1
Li, J	1
Yang, D	1
Li, M	1
Kuo, CY	1
Lin, CH	2
Lane, HY	4
Nasyrova, RF	2
Khasanova, AK	2
Altynbekov, KS	2
Asadullin, AR	2
Markina, EA	2
Gayduk, AJ	2
Shipulin, GA	2
Petrova, MM	2
Shnayder, NA	2
O'Donnell, P	1
Dong, C	1
Murthy, V	1
Asgharnejad, M	1
Du, X	1
Summerfelt, A	1
Lu, H	1
Xu, L	1
Wendland, JR	1
Dunayevich, E	1
Buhl, DL	1
Litman, R	1
Hetrick, WP	1
Hong, LE	1
Rosen, LB	1
Sehatpour, P	2
Iosifescu, DV	2
De Baun, HM	1
Shope, C	2
Mayer, MR	2
Gangwisch, J	1
Dias, E	1
Sobeih, T	2
Choo, TH	2
Wall, MM	2
Medalia, A	1
Saperstein, AM	1
Kegeles, LS	1
Girgis, RR	1
Carlson, M	1
Kantrowitz, JT	7
Fradley, R	1
Goetghebeur, P	1
Miller, D	1
Burley, R	1
Almond, S	2
Gruart I Massó, A	1
Delgado García, JM	1
Zhu, B	1
Howley, E	1
Neill, JC	1
Grayson, B	1
Gaskin, P	1
Carlton, M	1
Gray, I	1
Serrats, J	1
Davies, CH	1
Nemani, K	1
Goff, DC	1
Govani, V	1
Shastry, AM	1
Govil, P	1
Garip, B	1
Kayir, H	1
Matveeva, TM	1
Pisansky, MT	1
Young, A	1
Miller, RF	1
Gewirtz, JC	1
Fone, KCF	1
Watson, DJG	1
Billiras, RI	1
Sicard, DI	1
Dekeyne, A	1
Rivet, JM	1
Gobert, A	1
Millan, MJ	2
Fukuyama, K	1
Okubo, R	1
Murata, M	1
Shiroyama, T	1
Okada, M	2
Guo, C	1
Liu, Y	1
Fang, MS	1
Li, Y	2
Li, W	1
Mahaman, YAR	1
Zeng, K	1
Xia, Y	1
Ke, D	1
Liu, R	2
Wang, JZ	1
Shen, H	1
Shu, X	1
Wang, X	1
Guercio, GD	1
Anjos-Travassos, Y	1
Rangel, I	1
Costa, S	1
Poleto, A	1
Costa, D	1
Chaiben, R	1
de Villers-Sidani, E	1
Panizzutti, R	5
Crosta, CM	1
Hernandez, K	1
Bhattiprolu, AK	1
Fu, AY	1
Moore, JC	1
Clarke, SG	1
Dudzinski, NR	1
Brzustowicz, LM	1
Paradiso, KG	1
Firestein, BL	1
Akkouh, IA	1
Hribkova, H	1
Grabiec, M	1
Budinska, E	1
Szabo, A	1
Kasparek, T	1
Andreassen, OA	1
Sun, YM	1
Djurovic, S	1
Epstein, ML	2
Lee, M	3
Lehrfeld, N	1
Nolan, KA	1
Petkova, E	2
Silipo, G	4
Javitt, DC	11
Papouin, T	1
Dunphy, JM	1
Tolman, M	1
Dineley, KT	1
Haydon, PG	1
Puhl, MD	2
Desai, RI	1
Takagi, S	2
Presti, KT	1
Doyle, MR	1
Donahue, RJ	1
Landino, SM	1
Bergman, J	1
Carlezon, WA	1
Coyle, JT	7
Balu, DT	5
Swerdlow, NR	1
Dunn, W	1
Vinogradov, S	3
Fisher, M	2
Garrett, C	1
Man, WH	1
Sena, W	1
Madeira, C	2
Keller, S	1
Punzo, D	1
Cuomo, M	1
Affinito, O	1
Coretti, L	1
Florio, E	1
Lembo, F	1
Carella, M	1
Copetti, M	1
Cocozza, S	1
Errico, F	1
Usiello, A	1
Chiariotti, L	1
Li, C	1
Wang, A	1
Wang, C	1
Ramamurthy, J	1
Zhang, E	1
Guadagno, E	1
Trakadis, Y	1
Li, YX	1
Yang, JY	1
Alcantara, M	1
Abelian, G	1
Kulkarni, A	1
Staubli, U	1
Foster, AC	1
Szilágyi, B	1
Ferenczy, GG	1
Keserű, GM	1
Koshiyama, D	1
Kirihara, K	1
Tada, M	1
Nagai, T	1
Fujioka, M	1
Usui, K	1
Koike, S	1
Suga, M	1
Araki, T	1
Hashimoto, K	13
Kasai, K	1
Hayakawa, E	1
Ohgidani, M	1
Fujimura, Y	1
Kanba, S	1
Miura, D	1
Kato, TA	1
Hagiwara, H	1
Iyo, M	5
Benneyworth, MA	1
Basu, AC	2
Bolshakov, VY	1
Ermilov, M	5
Gelfin, E	1
Levin, R	1
Lichtenberg, P	3
Heresco-Levy, U	7
Citrome, L	1
Terry-Lorenzo, RT	1
Chun, LE	1
Brown, SP	1
Heffernan, ML	1
Fang, QK	1
Orsini, MA	1
Hardy, LW	1
Spear, KL	1
Large, TH	1
Pandey, GN	1
Rizavi, HS	1
Tripathi, M	1
Ren, X	1
Takahashi, T	3
Nakamura, M	1
Nakamura, Y	1
Aleksic, B	1
Kido, M	1
Sasabayashi, D	1
Takayanagi, Y	1
Furuichi, A	1
Nishikawa, Y	1
Noguchi, K	1
Ozaki, N	4
Suzuki, M	3
Yamamori, H	1
Hashimoto, R	1
Fujita, Y	2
Numata, S	1
Yasuda, Y	1
Fujimoto, M	1
Ohi, K	1
Umeda-Yano, S	1
Ito, A	1
Ohmori, T	1
Takeda, M	1
Kawaura, K	1
Koike, H	1
Kinoshita, K	1
Kambe, D	1
Kaku, A	1
Karasawa, J	1
Chaki, S	1
Hikichi, H	1
Durrant, AR	1
Miya, K	1
Mori, H	2
Möller, HJ	2
Czobor, P	1
Dang, W	1
Du, Y	1
Zhou, Q	1
Liu, Z	1
Jiao, K	1
Woods, SW	2
Cornblatt, B	2
Corcoran, CM	1
Chen, H	1
Ozeki, Y	3
Sekine, M	1
Fujii, K	3
Watanabe, T	1
Okayasu, H	1
Takano, Y	1
Shinozaki, T	1
Aoki, A	1
Akiyama, K	1
Homma, H	1
Shimoda, K	1
Van der Auwera, S	1
Teumer, A	1
Hertel, J	1
Homuth, G	1
Völker, U	1
Lucht, MJ	1
Degenhardt, F	1
Schulze, T	1
Rietschel, M	2
Nöthen, MM	2
John, U	1
Nauck, M	1
Grabe, HJ	1
Birolo, L	1
Smaldone, G	2
Leo, G	1
Caldinelli, L	3
Pirone, L	2
Eliometri, P	1
Di Gaetano, S	1
Orefice, I	1
Pedone, E	2
Pucci, P	1
Cho, SE	1
Na, KS	1
Cho, SJ	1
Kang, SG	1
Ishima, T	1
Beggel, O	1
Rohrig, S	1
Lehrfeld, JM	1
Revheim, N	1
Lehrfeld, NP	1
Reep, J	1
Parker, E	1
Ahissar, M	1
Cappelletti, P	2
Nishikawa, T	4
Konno, R	2
Bernasconi, M	2
Martineau, M	1
Mothet, JP	1
Ruzzene, M	1
Pilone, MS	2
Labrie, V	5
Lipina, T	2
Roder, JC	4
Hons, J	2
Zirko, R	1
Ulrychova, M	1
Cermakova, E	2
Libiger, J	2
Yang, CR	1
Svensson, KA	1
Ohnuma, T	3
Sakai, Y	2
Maeshima, H	3
Hatano, T	2
Hanzawa, R	3
Abe, S	1
Kida, S	1
Shibata, N	3
Suzuki, T	1
Arai, H	3
Di Giorgio, A	1
Blasi, G	1
Sambataro, F	1
Rampino, A	1
Papazacharias, A	1
Gambi, F	1
Romano, R	1
Caforio, G	1
Rizzo, M	1
Latorre, V	1
Popolizio, T	1
Kolachana, B	1
Callicott, JH	1
Nardini, M	2
Weinberger, DR	1
Bertolino, A	1
Smith, SM	1
Uslaner, JM	2
Yao, L	1
Mullins, CM	1
Surles, NO	1
Huszar, SL	2
McNaughton, CH	2
Pascarella, DM	1
Kandebo, M	1
Hinchliffe, RM	1
Sparey, T	2
Brandon, NJ	4
Jones, B	2
Venkatraman, S	2
Young, MB	2
Sachs, N	2
Jacobson, MA	1
Hutson, PH	4
Rizos, EN	1
Siafakas, N	1
Katsantoni, E	1
Lazou, V	1
Sakellaropoulos, K	1
Kastania, A	1
Kossida, S	1
Chatzigeorgiou, KS	1
Arsenis, G	1
Zerva, L	1
Katsafouros, K	1
Lykouras, L	1
Zai, CC	2
Tiwari, AK	1
De Luca, V	2
Müller, DJ	1
Bulgin, N	2
Hwang, R	2
Zai, GC	1
King, N	1
Voineskos, AN	1
Meltzer, HY	5
Lieberman, JA	2
Potkin, SG	1
Remington, G	2
Kennedy, JL	4
Baba, H	1
Chen, SF	1
Shen, YC	1
Chen, CH	2
Tsunoda, M	2
Maeno, N	2
Kawasaki, Y	2
Zhou, SY	2
Hagino, H	2
Niu, L	2
Tsuneki, H	2
Kobayashi, S	2
Sasaoka, T	2
Seto, H	2
Kurachi, M	2
Abou El-Magd, RM	1
Park, HK	1
Kawazoe, T	1
Iwana, S	1
Ono, K	1
Chung, SP	1
Miyano, M	1
Yorita, K	1
Sakai, T	1
Fukui, K	2
Al Hadithy, AF	1
Ivanova, SA	1
Pechlivanoglou, P	1
Semke, A	1
Fedorenko, O	1
Kornetova, E	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
Effect of an NMDA-based Intervention on Biomarker Measures of Cognitive Dysfunction in Schizophrenia[NCT00817336]	Phase 2	16 participants (Actual)	Interventional	2009-06-30	Completed
PK/PD Study of Escalating Dose D-serine as Adjunctive Treatment in Schizophrenia[NCT00322023]	Phase 2	55 participants (Actual)	Interventional	2006-03-31	Completed
A Randomized, Double-Blind, Placebo-Controlled Parallel Arm Study of the Effect of RO4917838 on Biomarker Measures of Cognitive Dysfunction in Schizophrenia and Schizoaffective Disorder[NCT01116830]	Phase 1	29 participants (Actual)	Interventional	2010-11-30	Completed
D-Serine vs Placebo for the Schizophrenia Prodrome[NCT00826202]	Phase 2	44 participants (Actual)	Interventional	2009-03-31	Completed
D-serine and Cognitive Remediation in Schizophrenia: Open Label Pilot[NCT02156908]	Phase 2	8 participants (Actual)	Interventional	2014-08-31	Completed
Evaluating Two Types of Cognitive Training in Veterans With Schizophrenia[NCT01891721]		105 participants (Actual)	Interventional	2013-11-21	Completed
NMDA Enhancers in the Treatment of Schizophrenia: Sarcosine vs. D-Serine[NCT00491569]	Phase 2	60 participants (Actual)	Interventional	2005-01-31	Completed
D-Serine Adjuvant Pharmacotherapy for the Treatment of Schizophrenia[NCT00138775]	Phase 2	200 participants	Interventional	2004-10-31	Recruiting
Predictive Coding Abnormalities in Psychosis: EEG and fMRI[NCT03068806]		202 participants (Actual)	Observational	2014-12-01	Completed
Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase[NCT01720316]	Phase 2	2 participants (Actual)	Interventional	2012-12-10	Completed
D-Serine Augmentation of Cognitive Retraining in Schizophrenia[NCT00237848]	Phase 3	72 participants (Anticipated)	Interventional	2005-02-28	Completed
D-Serine Treatment of Negative Symptoms and Cognitive Deficits in Schizophrenia[NCT00237809]	Phase 3	104 participants (Actual)	Interventional	2002-09-30	Completed
The Effects of Glycine Transport Inhibition on Brain Glycine Concentration[NCT00538070]		68 participants (Actual)	Interventional	2007-08-31	Completed
NMDA Enhancers in the Treatment of Schizophrenia[NCT00328276]	Phase 2	20 participants	Interventional	2004-12-31	Completed
Longitudinal Family/Molecular Genetic Study to Validate Research Domain Criteria[NCT02415647]		2,800 participants (Anticipated)	Observational	2014-10-31	Recruiting
A Trial of the Effects of Glycine Loading on Clinical Symptoms and Logical Memory in Patients With Schizophrenia[NCT00575848]	Phase 1	16 participants (Anticipated)	Interventional	2007-12-31	Terminated (stopped due to Slow enrollment and due to personnel change there was no viable way to quantify glycine levels through imaging)
Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine[NCT02304432]	Early Phase 1	2 participants (Actual)	Interventional	2015-09-27	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment. (NCT00817336)
Timeframe: 6 weeks

MMN Amplitude

PANSS Total

Intervention	T score (Mean)
D-serine	26.2
Placebo	25.7

Intervention	micro volts (Mean)
D-serine	-1.21
Placebo	-.21

Positive and Negative Symptom Scale (PANSS) range 30-210 (NCT00817336)
Timeframe: 6 weeks

Visual P1

Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery

Intervention	units on a scale (Mean)
D-serine	77.9
Placebo	80

Intervention	micro volts (Mean)
D-serine	-.21
Placebo	-.54

Change over 4 weeks. The MATRICS is a scale measuring cognition, and reported as T-score, with 50 as the population average and every 10 points representing a change of 1 standard deviation from the population average. Higher scores represent an improvement (NCT00322023)
Timeframe: Measured at Week 4

Positive and Negative Symptoms Scale (PANSS)

Intervention	units on a scale (Mean)
D-serine 30 mg/kg	0.8
D-serine 60 mg/kg	3.9
D Serine 120 mg/kg	2.8

Absolute Change in PANSS over four weeks (change between baseline and final measurements). The PANSS is a 30-item rating scale widely used in assessment of medication effects in schizophrenia. The PANSS ranges from 30-210, with lower scores showing less symptoms. Larger change is better. (NCT00322023)
Timeframe: Measured at Week 4

Renal Safety Measures

Intervention	units on a scale (Mean)
D-serine 30 mg/kg	5.1
D-serine 60 mg/kg	4.4
D Serine 120 mg/kg	6.3

number of renal adverse events (serum and urinalysis) (NCT00322023)
Timeframe: Measured at Week 4

IL6 Levels

Intervention	adverse events (Number)
D-serine 30 mg/kg	0
D-serine 60 mg/kg	0
D Serine 120 mg/kg	1

Final IL6 levels (pg/ml) in available subjects (NCT00826202)
Timeframe: 16 weeks

Pittsburgh Sleep Quality Index Score

Intervention	final IL6 level (pg/ml)) (Mean)
D Serine	.49
Placebo	.79

The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-rated questions and five questions rated by the bed partner or roommate. The latter five questions are used for clinical information only, are not tabulated in the scoring of the PSQI. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These I9 items are grouped into seven component scores, each weighted equally on a 0-3 scale. The seven component scores are then summed to yield a global PSQI score, which has a range of 0-21; higher scores (NCT00826202)
Timeframe: 16 weeks

Scale of Prodromal Symptoms (SOPS) Negative Scale

Intervention	final score (Mean)
D Serine	4
Placebo	7.7

The SOPS Negative symptom scale consists of six Negative Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 36. (NCT00826202)
Timeframe: 16 weeks

Scale of Prodromal Symptoms (SOPS) Total

Intervention	SOPS negative final score (Mean)
D Serine	7.6
Placebo	11.3

The SOPS Total consists of five Positive Symptom items, six Negative Symptom items, four Disorganization Symptom items, and four General Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme-and Psychotic, for the positive items). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 114. (NCT00826202)
Timeframe: 16 weeks

Mismatch Negativity (MMN)

Intervention	units on a scale (Mean)
D Serine	23.9
Placebo	30.5

"An MMN event is evoked by a discernible change in the pitch of a repetitive auditory stimulation. The stronger the response to a difference (i.e., the more negative the amplitude of the MMN), the better the outcome.~MMN was obtained to pitch deviant stimuli pre-post auditory plasticity training, utilizing deviants to the same base frequencies as the auditory plasticity sessions, (i.e. 500, 1000, and 2000 Hz), with ~10 minutes of each base frequency. MMN will be conducted at baseline and after the final session. Reported outcome is change in MMN between baseline and final within session." (NCT02156908)
Timeframe: 3 weeks

Tone Matching Threshold

Intervention	micro volts (Mean)
D-serine	.086
no Intervention	0.31

Change tone matching threshold (the percent difference in pitch of two consecutively played tones that can be distinguished), higher numbers represent better outcomes. D-serine outcomes are for 2 consecutive D-serine sessions (NCT02156908)
Timeframe: three weeks

Functional Capacity

Intervention	percentage of difference in pitch (Mean)
D-serine	11
No Intervention	2.3

The University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA) was used to assess functional capacity. The UPSA total score served as a secondary functional outcome measure. Minimum and maximum values are 40 and 100. Higher scores mean a better outcome. (NCT01891721)
Timeframe: Within one week of training completion

Neurocognition

Intervention	score on a scale (Mean)
Specific Auditory Training - Brain Fitness Program (BFP)	76.50
Broad Cognitive Training - Cognitive Package (Cogpack)	75.96
Control Treatment - Commercial Computer Games (Sporcle)	76.77

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) was used to assess basic cognition. It includes tests representing 6 separable cognitive domains. The MCCB composite score (average of 6 domain t-scores) served as the primary cognitive outcome measure. Minimum and maximum values are 20 and 68. Higher scores mean a better outcome. (NCT01891721)
Timeframe: Within one week of training completion

Electroencephalography (EEG)

Intervention	score on a scale (Mean)
Specific Auditory Training - Brain Fitness Program (BFP)	42.02
Broad Cognitive Training - Cognitive Package (Cogpack)	41.92
Control Treatment - Commercial Computer Games (Sporcle)	41.94

A Mismatch Negativity (MMN) Paradigm was used to assess basic auditory processing. MMN amplitude was measured as the mean voltage in the 145-200 ms latency range at pooled frontocentral electodes. Minimum and maximum values are -8 and +2 microvolts. More negative scores mean a better outcome. (NCT01891721)
Timeframe: After 6 weeks of training and within one week of training completion

Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Intervention	units on a scale (Mean)
	MMN at 12 weeks	MMN at 6 weeks
Broad Cognitive Training - Cognitive Package (Cogpack)	-2.17	-2.16
Control Treatment - Commercial Computer Games (Sporcle)	-2.09	-2.21
Specific Auditory Training - Brain Fitness Program (BFP)	-2.04	-1.78

Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment. (NCT01720316)
Timeframe: Recordings at baseline and week 6 of glycine

Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Intervention	ratio (Number)
Auditory ERPs Amplitude (Deg) Baseline: Subject 2	44.51
Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2	35.67

Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment. (NCT01720316)
Timeframe: Recordings at baseline and week 6 of glycine

Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Intervention	microvolts (Number)
	P300 amplitude at fz	P300 amplitude at cz	P300 amplitude at pz	N100 amplitude at fz	N100 amplitude at cz	P200 amplitude at fz	P200 amplitude at cz	P50 S1 amplitude	P50 S2 amplitude	MMN amplitude at fz	MMN amplitude at cz
Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2	3.74	6.6	5.57	-4.71	-3.89	6.29	7.8	2.2	0.78	-1.004	-1.322
Auditory ERPs Amplitude (Deg) Baseline: Subject 2	-0.635	6.53	5.34	-3.93	-3.62	1.662	6.59	2.76	1.23	-3.356	-4.13

Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment. (NCT01720316)
Timeframe: Recordings at baseline and week 6 of glycine

Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE

Intervention	microvolts squared (Number)
	G40 fz	G40 cz	G20 fz	G20 cz	G30 fz	G30 cz
Auditory ERPs Gamma 6 Weeks of Glycine: Subject 2	0.255	0.29	0.107	0.108	0.177	0.242
Auditory ERPs Gamma Baseline: Subject 2	0.135	0.168	0.023	0.03	0.19	0.163

Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment. (NCT01720316)
Timeframe: Recordings at baseline and week 6 of glycine

Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Intervention	msec (Number)
	P300 latency at fz	P300 latency at cz	P300 latency at pz	N100 latency at fz	N100 latency at cz	P200 latency at fz	P200 latency at cz
Auditory ERPs Latency (ms) 6 Weeks of Glycine: Subject 2	300.78	293	294.92	94	94	205	203
Auditory ERPs Latency (ms) Baseline: Subject 2	279.3	279.3	279.3	97.66	91.8	197.27	193.4

Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex. (NCT01720316)
Timeframe: Baseline and week 6 of glycine

Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Intervention	ratio (Number)
	Baseline GABA/Cr	Week 6 of glycine tx GABA/Cr
Subject1: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine	0.16	0.22
Subject2: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine	0.27	0.24

magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex. (NCT01720316)
Timeframe: baseline and week 6 of glycine

Brain Glycine/CR Ratio

Intervention	ratio (Number)
	Baseline brain glutamate/Cr ratio	Week 6 brain glutamate/Cr ratio
Subject1: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine	0.98	0.84
Subject2: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine	2.053	1.13

magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex (NCT01720316)
Timeframe: baseline (pre-challenge, 60, 80, 100, 120 minutes post-challenge), and week 6 of glycine (pre-dose and 60, 80, 100, 120 minutes post-dose

Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine

Intervention	ratio (Number)
	Baseline - pre-challenge drink	Baseline 60 minutes post challenge drink	Baseline 80 minutes post challenge drink	Baseline 100 minutes post challenge drink	Baseline 120 minutes post challenge drink	Week 6 of glycine - pre-glycine dose	Week 6 of glycine - 60 minutes post glycine dose	Week 6 of glycine - 80 minutes post glycine dose	Week 6 of glycine - 100 minutes post glycine dose	Week 6 of glycine - 120 minutes post glycine dose
Subject 2:Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine	0.5691	0.3918	0.6428	0.6363	0.9559	0.3235	0.3807	0.5591	0.4142	0.3545
Subject1: Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine	0.2558	0.6157	0.6631	0.5938	0.6953	0.6573	0.2983	0.4577	0.5751	0.3842

Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms. (NCT01720316)
Timeframe: baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period

Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Intervention	units on a scale (Number)
	BPRS at baseline	BPRS at 2 weeks intervention 1	BPRS at 4 weeks intervention 1	BPRS at 6 weeks intervention 1	BPRS, end of washout1	BPRS at 2 weeks intervention 2	BPRS at 4 weeks intervention 2	BPRS at 6 weeks intervention 2	BPRS, end of washout2	BPRS at 2 weeks open label	BPRS at 4 weeks open label	BPRS at 6 weeks open label	BPRS, end of washout3
Glycine, Then Placebo	39	38	32	21	22	37	31	37	32	23	22	21	19
Placebo, Then Glycine	46	38	39	28	34	32	20	23	24	20	18	19	23

Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients. (NCT01720316)
Timeframe: CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period

Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Intervention	units on a scale (Number)
	CGI severity score at baseline	CGI severity score at 2 weeks intervention 1	CGI severity score at 4 weeks intervention 1	CGI severity score at 6 weeks intervention 1	CGI severity score, end of washout1	CGI severity score at 2 weeks intervention 2	CGI severity score at 4 weeks intervention 2	CGI severity score at 6 weeks intervention 2	CGI severity score, end of washout2	CGI severity score at 2 weeks open label	CGI severity score at 4 weeks open label	CGI severity score at 6 weeks open label	CGI severity score, end of washout3
Glycine, Then Placebo	4	4	3	2	2	4	4	4	4	3	3	2	2
Placebo, Then Glycine	4	4	4	4	4	4	4	3	3	3	3	2	2

Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13). (NCT01720316)
Timeframe: at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Intervention	score (Number)
	CGI therapeutic effect at 2 weeks intervention 1	CGI therapeutic effect at 4 weeks intervention 1	CGI therapeutic effect at 6 weeks intervention 1	CGI therapeutic effect, end of washout1	CGI therapeutic effect at 2 weeks intervention 2	CGI therapeutic effect at 4 weeks intervention 2	CGI therapeutic effect at 6 weeks intervention 2	CGI therapeutic effect, end of washout2	CGI therapeutic effect at 2 weeks open label	CGI therapeutic effect at 4 weeks open label	CGI therapeutic effect at 6 weeks open label	CGI therapeutic effect, end of washout3
Glycine, Then Placebo	13	5	5	5	13	13	13	13	5	5	1	1
Placebo, Then Glycine	5	5	5	5	13	5	5	5	1	1	1	1

Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. (NCT01720316)
Timeframe: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Intervention	units on a scale (Number)
	Depression symptoms at baseline	Depression symptoms at 2 weeks intervention 1	Depression symptoms at 4 weeks intervention 1	Depression symptoms at 6 weeks intervention 1	Depression symptoms, end of washout1	Depression symptoms at 2 weeks intervention 2	Depression symptoms at 4 weeks intervention 2	Depression symptoms at 6 weeks intervention 2	Depression symptoms, end of washout2	Depression symptoms at 2 weeks open label	Depression symptoms at 4 weeks open label	Depression symptoms at 6 weeks open label	Depression symptoms, end of washout3
Glycine, Then Placebo	18	17	11	3	1	19	5	7	3	2	2	1	2
Placebo, Then Glycine	12	5	5	0	3	3	2	1	1	1	1	1	0

Plasma glycine levels; normal range is 122-467 nM/mL (NCT01720316)
Timeframe: At baseline, during glycine treatment, during placebo treatment and during open-label glycine

Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Intervention	nM/mL (Number)
	Baseline	Glycine double-blind	Placebo	Glycine open-label
Glycine Then Placebo	216	410	194	516
Placebo Then Glycine	271	761	347	634

Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms. (NCT01720316)
Timeframe: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Intervention	units on a scale (Number)
	Manic symptoms at baseline	Manic symptoms at 2 weeks intervention 1	Manic symptoms at 4 weeks intervention 1	Manic symptoms at 6 weeks intervention 1	Manic symptoms, end of washout1	Manic symptoms at 2 weeks intervention 2	Manic symptoms at 4 weeks intervention 2	Manic symptoms at 6 weeks intervention 2	Manic symptoms, end of washout2	Manic symptoms at 2 weeks open label	Manic symptoms at 4 weeks open label	Manic symptoms at 6 weeks open label	Manic symptoms, end of washout3
Glycine, Then Placebo	4	1	0	0	0	17	0	2	2	1	0	0	0
Placebo, Then Glycine	7	7	6	0	0	0	0	0	0	0	0	0	0

Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered. (NCT01720316)
Timeframe: At baseline, during glycine treatment, during placebo treatment and during open-label glycine

Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine

Intervention	units on a scale (Number)
	Participant 1	Participant 2
Baseline	45	48
Composite Score on Glycine, Double-blind	52	52
Composite Score on Glycine, Open-label	49	46
Composite Score on Placebo	52	55

Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms. (NCT01720316)
Timeframe: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period

Heinrichs-Carpenter Quality of Life Scale

Intervention	units on a scale (Number)
	Positive symptoms at baseline	Positive symptoms at 2 weeks intervention 1	Positive symptoms at 4 weeks intervention 1	Positive symptoms at 6 weeks intervention 1	Positive symptoms, end of washout1	Positive symptoms at 2 weeks intervention 2	Positive symptoms at 4 weeks intervention 2	Positive symptoms at 6 weeks intervention 2	Positive symptoms, end of washout2	Positive symptoms at 2 weeks open label	Positive symptoms at 4 weeks open label	Positive symptoms at 6 weeks open label	Positive symptoms, end of washout3
Glycine, Then Placebo	13	12	9	8	7	12	11	14	14	9	9	7	7
Placebo, Then Glycine	19	20	19	13	13	12	10	11	11	8	7	8	8

The Heinrichs-Carpenter Quality of Life Scale is a testing device. It has a range of possible scores, 0-126 used to evaluate social functioning & behavior in patients with schizophrenia-lower scores represent poorer mental health. (NCT00237809)
Timeframe: 12 weeks

Hopkins Verbal Learning Test

Intervention	units on a scale (Mean)
D-serine/Control	67.26
Placebo/Cog Rehab	68.30
D-serine/Cog Rehab	63.25
Placebo/Control	63.92

The Hopkins Verbal Learning Test is designed to assess verbal learning and memory (immediate recall, delayed recall, delayed recognition). The assessment takes approximately 5-10 minutes with a 25-minute delay to complete and 2 minutes to score. The greater the score, the greater the measured recall. The score ranges from 0 to 24. (NCT00237809)
Timeframe: 12 weeks

Positive and Negative Syndrome Scale (PANSS)

Intervention	units on a scale (Mean)
D-serine/Control	20.74
Placebo/Cog Rehab	19.80
D-serine/Cog Rehab	20.42
Placebo/Control	21.45

The PANSS is a handscored instrument. It uses 25 PANSS items organized into five scales: Negative, Positive, Dysphoric Mood, Activation, and Autistic Preoccupation. The PANSS is based on findings that schizophrenia comprises at least two distinct syndromes. The positive syndrome consists of productive symptoms, while the negative syndrome consists of deficit features. This distinction is useful when developing treatment plans because you can focus on the type of symptoms the patient is experiencing. It is also useful when studying the effects of medication (e.g., in clinical drug trials) because it allows you to determine which type of symptoms are being affected. PANSS Total score minimum = 30, maximum = 210. The greater the score, the greater the symptoms. (NCT00237809)
Timeframe: 12 weeks

Simpson-Angus Neurological Rating Scale

Intervention	units on a scale (Mean)
D-serine/Control	53.30
Placebo/Cog Rehab	52.01
D-serine/Cog Rehab	53.79
Placebo/Control	53.96

Simpson-Angus Scale (SAS) is a 10-item rating scale that has been used widely for assessment in both clinical practice and research settings. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The highest possible score is 40. (NCT00237809)
Timeframe: 12 weeks

Spatial Span- Total Score

Intervention	units on a scale (Mean)
D-serine/Control	1.41
Placebo/Cog Rehab	0.72
D-serine/Cog Rehab	1.04
Placebo/Control	1.81

The Spatial Span subtest of the Wechsler Memory Scale can be used as an indicator of working memory and visuospatial processing. An increase in severity of impairment results in a decrease in Spatial Span Total Score. The range is 1 to 28. (NCT00237809)
Timeframe: 12 weeks

UCSD Performance-Based Skills Assessment (UPSA)

Intervention	units on a scale (Mean)
D-serine/Control	13.59
Placebo/Cog Rehab	13.88
D-serine/Cog Rehab	13.21
Placebo/Control	13.58

The UCSD Performance-Based Skills Assessment (UPSA) is a role-play test designed to evaluate a person's functional capacity in two selected areas of basic living skills. These areas include Finance and Communication. Subjects being tested utilize props to demonstrate how they perform everyday activities and are assessed on their actual performance. The higher the score, the better the performance of an individual. The scores range from 0 to 100. (NCT00237809)
Timeframe: 12 weeks

Wisconsin Card Sorting Test (WCST)

Intervention	units on a scale (Mean)
D-serine/Control	34.19
Placebo/Cog Rehab	32.80
D-serine/Cog Rehab	32.60
Placebo/Control	31.39

"The WCST allows the clinician to speculate to the following frontal lobe functions: strategic planning, organized searching, utilizing environmental feedback to shift cognitive sets, directing behavior toward achieving a goal, and modulating impulsive responding. The test can be administered to those from 6.5 years to 89 years of age.The test takes approximately 12-20 minutes to carry out and generates a number of psychometric scores, including numbers, percentages, and percentiles of: categories achieved, trials, errors, and perseverative errors. Can be interpreted as: the greater the percentage, the greater the measured ability." (NCT00237809)
Timeframe: 12 weeks

Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)

Intervention	percentage of correct responses (Mean)
D-serine/Control	38.43
Placebo/Cog Rehab	35.79
D-serine/Cog Rehab	43.14
Placebo/Control	39.57

Auditory evoked potential amplitude: P50 ratio (P50 S2/S1) (NCT02304432)
Timeframe: Baseline and Week 8 of DCS treatment

Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)

Intervention	ratio (Number)
	P50 ratio: Baseline	P50 ratio: Week 8 of DCS
First Open Label DCS	44.51	30

Auditory evoked potential amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2; mismatch negativity (MMN) at fz and cz. (NCT02304432)
Timeframe: Baseline and Week 8 of DCS treatment

Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared)

Intervention	microvolts (Number)
	P300 at fz: Baseline	P300 at cz: Baseline	P300 at pz: Baseline	N100 at fz: Baseline	N100 at cz: Baseline	P200 at fz: Baseline	P200 at cz: Baseline	P50 S1: Baseline	P50 S2: Baseline	MMN at fz: Baseline	MMN at cz: Baseline	P300 at fz: Week 8 of DCS	P300 at cz: Week 8 of DCS	P300 at pz: Week 8 of DCS	N100 at fz: Week 8 of DCS	N100 at cz: Week 8 of DCS	P200 at fz: Week 8 of DCS	P200 at cz: Week 8 of DCS	P50 S1: Week 8 of DCS	P50 S2: Week 8 of DCS	MMN at fz: Week 8 of DCS	MMN at cz: Week 8 of DCS
First Open Label DCS	-0.635	6.529	5.340	-3.926	-3.615	1.662	6.591	2.759	1.23	-3.356	-4.130	3.030	6.810	6.620	-3.260	-3.940	8.200	8.160	1.36	0.4	-3.330	-1.540

Auditory evoked potential gamma: G40 hz phase locking at fz and cz; G30 hz phase locking at fz and cz; G20 hz phase locking at fz and cz (NCT02304432)
Timeframe: Baseline and Week 8 of DCS treatment

Auditory Evoked Potentials in Latency (Msec)

Intervention	microvolts squared (Number)
	G40 hz phase locking at fz: Baseline	G40 hz phase locking at cz: Baseline	G30 hz phase locking at fz: Baseline	G30 hz phase locking at cz: Baseline	G20 hz phase locking at fz: Baseline	G20 hz phase locking at cz: Baseline	G40 hz phase locking at fz: Week 8 of DCS	G40 hz phase locking at cz: Week 8 of DCS	G30 hz phase locking at fz: Week 8 of DCS	G30 hz phase locking at cz: Week 8 of DCS	G20 hz phase locking at fz: Week 8 of DCS	G20 hz phase locking at cz: Week 8 of DCS
First Open Label DCS	0.135	0.168	0.190	0.163	0.023	0.030	0.344	0.381	0.168	0.19	0.01	-0.01

Auditory evoked potential latency: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz. (NCT02304432)
Timeframe: Baseline and Week 8 of DCS treatment

Brain Glycine/CR Ratio

Intervention	msec (Number)
	P300 at fz: Baseline	P300 at cz: Baseline	P300 at pz: Baseline	N100 at fz: Baseline	N100 at cz: Baseline	P200 at fz: Baseline	P200 at cz: Baseline	P300 at fz: Week 8 of DCS	P300 at cz: Week 8 of DCS	P300 at pz: Week 8 of DCS	N100 at fz: Week 8 of DCS	N100 at cz: Week 8 of DCS	P200 at fz: Week 8 of DCS	P200 at cz: Week 8 of DCS
First Open Label DCS	279.297	279.297	279.297	97.656	91.797	197.266	193.359	294.920	294.000	294	87.9	88.000	212.890	212.000

Proton magnetic resonance spectroscopy at 4T: brain glycine/CR ratio. Participants were assessed at baseline (pre-glycine challenge dose and 60, 80, 100 and 120 minutes post glycine dose) and in week 8 of of open-label DCS treatment: pre-DCS dose, and 60, 80, 100 and 120 minutes post DCS dose. Measured in posterior occipital cortex. (NCT02304432)
Timeframe: Baseline and Week 8 of DCS treatment

Brief Psychiatric Rating Scale (BPRS) Scores

Intervention	ratio (Median)
	Baseline	Baseline at 60 minutes	Baseline at 80 minutes	Baseline at 100 minutes	Baseline at 120 minutes	Week 8 of DCS: Baseline	Week 8 of DCS: 60 minutes	Week 8 of DCS: 80 minutes	Week 8 of DCS: 100 minutes	Week 8 of DCS: 120 minutes
Open Label DCS	0.41245	0.50375	0.65295	0.61505	0.8256	0.10977	0.248885	0.32609	0.32052	0.312155

Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms. (NCT02304432)
Timeframe: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

Brief Psychiatric Rating Scale (BPRS) Scores

Intervention	units on a scale (Median)
	Baseline BPRS	2 weeks BPRS	4 weeks BPRS	6 weeks BPRS	8 weeks BPRS	10 weeks BPRS	12 weeks BPRS	14 weeks BPRS	16 weeks BPRS	18 weeks BPRS	20 weeks BPRS	22 weeks BPRS	24 weeks BPRS
First Open Label DCS	37	25	26	24	24.5	NA	NA	NA	NA	NA	NA	NA	NA
Second Open Label DCS	31.5	30.5	28	25.5	26	26.5	26	25.5	28.5	27	25	24.5	26.5

Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms. (NCT02304432)
Timeframe: Baseline, 2, 4, & 6 weeks (crossover periods)

Clinical Global Impression (CGI) Severity Scores

Intervention	units on a scale (Number)
	Baseline BPRS for first intervention	2 weeks BPRS for first intervention	4 weeks BPRS for first intervention	6 weeks BPRS for first intervention	Baseline BPRS for second intervention	2 weeks BPRS for second intervention	4 weeks BPRS for second intervention	6 weeks BPRS for second intervention
DCS First, Then Placebo	26	25	25	26	39	45	45	38
Placebo First, Then DCS	29	35	33	35	36	30	27	28

CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients. (NCT02304432)
Timeframe: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

Clinical Global Impression (CGI) Severity Scores

Intervention	units on a scale (Median)
	Baseline CGI	2 weeks CGI	4 weeks CGI	6 weeks CGI	8 weeks CGI	10 weeks CGI	12 weeks CGI	14 weeks CGI	16 weeks CGI	18 weeks CGI	20 weeks CGI	22 weeks CGI	24 weeks CGI
First Open Label DCS	4	2	2	2	2	NA	NA	NA	NA	NA	NA	NA	NA
Second Open Label DCS	2.5	2.5	2.5	2.5	2.5	3	2.5	2	2.5	2.5	2.5	2.5	2.5

Depression Symptom Scores

Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms. (NCT02304432)
Timeframe: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

Depression Symptom Scores

Mania Symptom Scores

Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms. (NCT02304432)
Timeframe: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

Mania Symptom Scores

Neurocognitive Function

Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution, standard deviation of 10. Higher scores signify better functioning. (NCT02304432)
Timeframe: Baseline and Week 8 of open-label DCS treatment

Positive and Negative Symptom Scores

Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms. (NCT02304432)
Timeframe: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

Positive and Negative Symptom Scores

Intervention	units on a scale (Number)
	Baseline CGI for first intervention	2 weeks CGI for first intervention	4 weeks CGI for first intervention	6 weeks CGI for first intervention	Baseline CGI for second intervention	2 weeks CGI for second intervention	4 weeks CGI for second intervention	6 weeks CGI for second intervention
DCS First, Then Placebo	2	2	2	2	3	3	3	3
Placebo First, Then DCS	1	3	3	3	3	2	2	2

Intervention	units on a scale (Median)
	Baseline HAM	2 weeks HAM	4 weeks HAM	6 weeks HAM	8 weeks HAM	10 weeks HAM	12 weeks HAM	14 weeks HAM	16 weeks HAM	18 weeks HAM	20 weeks HAM	22 weeks HAM	24 weeks HAM
First Open Label DCS	5	1.5	1	0.5	1.5	NA	NA	NA	NA	NA	NA	NA	NA
Second Open Label DCS	0.5	1	1	0	2.5	0	0	0	3.5	0	0	0	0

Intervention	units on a scale (Number)
	Baseline HAM for first intervention	2 weeks HAM for first intervention	4 weeks HAM for first intervention	6 weeks HAM for first intervention	Baseline HAM for second intervention	2 weeks HAM for second intervention	4 weeks HAM for second intervention	6 weeks HAM for second intervention
DCS First, Then Placebo	0	1	0	0	2	12	9	2
Placebo First, Then DCS	4	5	2	10	0	0	0	0

Intervention	units on a scale (Median)
	Baseline YMRS	2 weeks YMRS	4 weeks YMRS	6 weeks YMRS	8 weeks YMRS	10 weeks YMRS	12 weeks YMRS	14 weeks YMRS	16 weeks YMRS	18 weeks YMRS	20 weeks YMRS	22 weeks YMRS	24 weeks YMRS
First Open Label DCS	2	1	1	0	0	NA	NA	NA	NA	NA	NA	NA	NA
Second Open Label DCS	0	0	0	0	0	0	0	0	0	0	0	0	1

Intervention	units on a scale (Number)
	Baseline YMRS for first intervention	2 weeks YMRS for first intervention	4 weeks YMRS for first intervention	6 weeks YMRS for first intervention	Baseline YMRS for second intervention	2 weeks YMRS for second intervention	4 weeks YMRS for second intervention	6 weeks YMRS for second intervention
DCS First, Then Placebo	0	0	0	0	0	0	0	0
Placebo First, Then DCS	1	0	0	0	4	1	1	1

Intervention	T scores (Median)
	Baseline Processing Speed	Baseline Attention/Vigilance	Baseline Working Memory	Baseline Verbal Learning	Baseline Visual Learning	Baseline Reasoning/Problem Solving	Baseline Social Cognition	Baseline Overall Composite Score	Week 8 of open-label DCS Processing Speed	Week 8 of open-label DCS Attention/Vigilance	Week 8 of open-label DCS Working Memory	Week 8 of open-label DCS Verbal Learning	Week 8 of open-label DCS Visual Learning	Week 8 of open-label DCS Reasoning/Problem Solving	Week 8 of open-label DCS Social Cognition	Week 8 of open-label DCS Overall Composite Score
Open Label DCS	48.5	44.5	38.5	54	50.5	52.5	48	46.5	52.5	47.5	50.5	43.5	54.5	66.5	44.5	51.5

Intervention	units on a scale (Median)
	Baseline positive	Baseline negative	2 weeks positive	2 weeks negative	4 weeks positive	4 weeks negative	6 weeks positive	6 weeks negative	8 weeks positive	8 weeks negative	10 weeks positive	10 weeks negative	12 weeks positive	12 weeks negative	14 weeks positive	14 weeks negative	16 weeks positive	16 weeks negative	18 weeks positive	18 weeks negative	20 weeks positive	20 weeks negative	22 weeks positive	22 weeks negative	24 weeks positive	24 weeks negative
First Open Label DCS	14.5	14.5	10	12	10.5	12	9	12	9	12	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Second Open Label DCS	11	14	11	14	10.5	13.5	9	13	9.5	12	10.5	13	11	12	10	12	10.5	12	10.5	12	10.5	12	9.5	12	10	12

Intervention	units on a scale (Number)
	Baseline positive for first intervention	Baseline negative symptoms for first intervention	2 weeks positive for first intervention	2 weeks negative for first intervention	4 weeks positive for first intervention	4 weeks negative for first intervention	6 weeks positive for first intervention	6 weeks negative for first intervention	Baseline positive for second intervention	Baseline negative for second intervention	2 weeks positive for second intervention	2 weeks negative for second intervention	4 weeks positive for second intervention	4 weeks negative for second intervention	6 weeks positive for second intervention	6 weeks negative for second intervention
DCS First, Then Placebo	10	15	10	15	10	15	10	15	15	18	15	18	15	18	14	18
Placebo First, Then DCS	11	9	12	15	11	13	13	13	13	13	10	11	9	11	9	11

Article	Year
Biochemical Properties and Physiological Functions of pLG72: Twenty Years of Investigations. Biomolecules, 2022, 06-20, Volume: 12, Issue:6 Topics: Animals; Bipolar Disorder; Intracellular Signaling Peptides and Proteins; Receptors, N-Methyl-D-Aspa	2022
The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia. Nutrients, 2022, Dec-02, Volume: 14, Issue:23 Topics: Aspartic Acid; D-Aspartic Acid; Glutamic Acid; Humans; Receptors, N-Methyl-D-Aspartate; Schizophreni	2022
The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia. Nutrients, 2022, Dec-02, Volume: 14, Issue:23 Topics: Aspartic Acid; D-Aspartic Acid; Glutamic Acid; Humans; Receptors, N-Methyl-D-Aspartate; Schizophreni	2022
The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia. Nutrients, 2022, Dec-02, Volume: 14, Issue:23 Topics: Aspartic Acid; D-Aspartic Acid; Glutamic Acid; Humans; Receptors, N-Methyl-D-Aspartate; Schizophreni	2022
The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia. Nutrients, 2022, Dec-02, Volume: 14, Issue:23 Topics: Aspartic Acid; D-Aspartic Acid; Glutamic Acid; Humans; Receptors, N-Methyl-D-Aspartate; Schizophreni	2022
Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function. Biological psychiatry. Cognitive neuroscience and neuroimaging, 2018, Volume: 3, Issue:7 Topics: Auditory Perception; Cognitive Dysfunction; Excitatory Amino Acid Agonists; Excitatory Amino Acid An	2018
Metabolomics in patients with psychosis: A systematic review. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2018, Volume: 177, Issue:6 Topics: 3-Hydroxybutyric Acid; Aspartic Acid; Biomarkers; Bipolar Disorder; Creatine; Female; Glutamic Acid;	2018
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies. Expert opinion on drug discovery, 2018, Volume: 13, Issue:10 Topics: Animals; Antipsychotic Agents; D-Amino-Acid Oxidase; Disease Models, Animal; Drug Development; Drug	2018
Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. The Journal of clinical psychiatry, 2014, Volume: 75 Suppl 1 Topics: alpha7 Nicotinic Acetylcholine Receptor; Antipsychotic Agents; Cognition Disorders; Glycine; Humans;	2014
The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. Current opinion in pharmacology, 2015, Volume: 20 Topics: Animals; Antipsychotic Agents; Cognition Disorders; Dopamine; Glycine; Humans; Receptors, N-Methyl-D	2015
Pharmacological treatment of negative symptoms in schizophrenia. European archives of psychiatry and clinical neuroscience, 2015, Volume: 265, Issue:7 Topics: Antidepressive Agents; Antipsychotic Agents; Excitatory Amino Acid Agents; Glycine; Glycine Agents;	2015
Low d-serine levels in schizophrenia: A systematic review and meta-analysis. Neuroscience letters, 2016, Nov-10, Volume: 634 Topics: Antipsychotic Agents; Case-Control Studies; Humans; Schizophrenia; Serine; Stereoisomerism	2016
[Metabolism and functions of brain D-serine in mammals: relevance to neuropsychiatric disorders]. Seikagaku. The Journal of Japanese Biochemical Society, 2008, Volume: 80, Issue:4 Topics: Animals; Brain; Drug Design; Glycine; Humans; Isomerism; Mental Disorders; Nervous System Diseases;	2008
[Mutant mouse lacking D-amino-acid oxidase activity]. Seikagaku. The Journal of Japanese Biochemical Society, 2008, Volume: 80, Issue:4 Topics: Amino Acids; Animals; Brain; D-Amino-Acid Oxidase; Isomerism; Mice; Mice, Mutant Strains; Receptors,	2008
Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. Pharmacology & therapeutics, 2008, Volume: 120, Issue:3 Topics: Allosteric Regulation; Animals; Glycine; Glycine Plasma Membrane Transport Proteins; Humans; Recepto	2008
When top-down meets bottom-up: auditory training enhances verbal memory in schizophrenia. Schizophrenia bulletin, 2009, Volume: 35, Issue:6 Topics: Acoustic Stimulation; Adult; Attention; Auditory Cortex; Auditory Perceptual Disorders; Brain-Derive	2009
[Schizophrenia and glutamate transport systems]. Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica, 2009, Volume: 111, Issue:7 Topics: Antipsychotic Agents; Brain; Dopamine; Drug Design; Glutamates; Humans; Receptors, N-Methyl-D-Aspart	2009
Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Ser311Cys polymorphisms of the dopamine D2-receptor gene and schizophrenia. Journal of pharmacological sciences, 2010, Volume: 114, Issue:1 Topics: Alleles; Animals; Cysteine; Dopamine; Drug Discovery; Humans; Mental Disorders; Polymorphism, Geneti	2010
[Analysis of mouse strain-dependent prepulse inhibition points to a role for Shmt1 (SHMT1) in mice and in schizophrenia]. Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 2010, Volume: 30, Issue:5-6 Topics: Animals; Glycine; Glycine Hydroxymethyltransferase; Humans; Mice; Mice, Inbred Strains; Neural Inhib	2010
[Development of a novel pharmacotherapy targeted at the N-methyl-D-aspartate receptor-D-serine system for schizophrenia]. Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 2010, Volume: 30, Issue:5-6 Topics: Animals; Clinical Trials as Topic; Drug Design; Glycine; Humans; Molecular Targeted Therapy; Phencyc	2010
Contributions of the D-serine pathway to schizophrenia. Neuropharmacology, 2012, Volume: 62, Issue:3 Topics: Animals; Glutamic Acid; Humans; Mice; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serine; Signal	2012
Recent advances in the discovery of D-amino acid oxidase inhibitors and their therapeutic utility in schizophrenia. Current pharmaceutical design, 2011, Volume: 17, Issue:2 Topics: Animals; Antipsychotic Agents; Brain; D-Amino-Acid Oxidase; Enzyme Inhibitors; Humans; Mice; Molecul	2011
D-serine and schizophrenia: an update. Expert review of neurotherapeutics, 2012, Volume: 12, Issue:7 Topics: Animals; Antipsychotic Agents; Humans; Schizophrenia; Serine	2012
D-Amino acids in the brain and mutant rodents lacking D-amino-acid oxidase activity. Amino acids, 2012, Volume: 43, Issue:5 Topics: Amyotrophic Lateral Sclerosis; Animals; Behavior, Animal; Brain; D-Amino-Acid Oxidase; D-Aspartic Ac	2012
D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy. Current pharmaceutical design, 2013, Volume: 19, Issue:14 Topics: Brain; D-Amino-Acid Oxidase; Enzyme Inhibitors; Humans; Ligands; Models, Molecular; Protein Binding;	2013
Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter. Neurochemistry international, 2002, Volume: 41, Issue:5 Topics: Animals; Humans; Neuroglia; Neurotransmitter Agents; Racemases and Epimerases; Receptors, N-Methyl-D	2002
Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatric genetics, 2003, Volume: 13, Issue:1 Topics: Amino Acid Substitution; Case-Control Studies; Genetic Variation; Glycine; Homozygote; Humans; Recep	2003
N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology, 2005, Volume: 179, Issue:1 Topics: Animals; Antipsychotic Agents; Glycine; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Seri	2005
The role of group I metabotropic glutamate receptors in schizophrenia. Amino acids, 2007, Volume: 32, Issue:2 Topics: Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Glycine; Humans; Mice; Mice, Knockout;	2007
[Update on the animal models of schizophrenia]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 2006, Volume: 128, Issue:3 Topics: Animals; Behavior, Animal; Brain; Disease Models, Animal; Drug Design; Excitatory Amino Acid Antagon	2006
D-serine: a new word in the glutamatergic neuro-glial language. Amino acids, 2007, Volume: 33, Issue:4 Topics: Alzheimer Disease; Animals; Astrocytes; Cell Death; Cell Movement; Glutamic Acid; Humans; Neuroglia;	2007
Novel therapeutics for schizophrenia: targeting glycine modulation of NMDA glutamate receptors. CNS spectrums, 2007, Volume: 12, Issue:6 Topics: Amino Acid Transport Systems; Antipsychotic Agents; Glycine; Glycine Agents; Humans; Receptors, N-Me	2007
Bridging pharmacology and neurodevelopment in schizophrenia. The international journal of neuropsychopharmacology, 2007, Volume: 10, Issue:6 Topics: Antipsychotic Agents; Humans; Psychopharmacology; Schizophrenia; Schizophrenic Psychology; Serine	2007
[Role of D-serine in the mammalian brain]. Brain and nerve = Shinkei kenkyu no shinpo, 2007, Volume: 59, Issue:7 Topics: Animals; Astrocytes; Brain; Cell Death; Mice; Neuronal Plasticity; Neurotransmitter Agents; Pain; Ra	2007
Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. European archives of psychiatry and clinical neuroscience, 2008, Volume: 258, Issue:1 Topics: Acetamides; Alanine; Antipsychotic Agents; Clozapine; Cognition; Cycloserine; Dopamine Agents; Drug	2008
[Glycine therapy of schizophrenia; its rationale and a review of clinical trials]. Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 1998, Volume: 18, Issue:3 Topics: Acetamides; Alanine; Amino Acid Transport Systems, Neutral; Animals; Carrier Proteins; Cycloserine;	1998
[Endogenous D-serine in mammalian brains]. Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 2000, Volume: 20, Issue:1 Topics: Animals; Brain; Glutamic Acid; Glycine; Humans; Racemases and Epimerases; Rats; Receptors, N-Methyl-	2000
Treatment of negative and cognitive symptoms. Current psychiatry reports, 1999, Volume: 1, Issue:1 Topics: Antimetabolites; Antipsychotic Agents; Cognition Disorders; Cycloserine; Glycine; Humans; Receptors,	1999
Methylation & schizophrenia. The Alabama journal of medical sciences, 1975, Volume: 12, Issue:2 Topics: Amines; Amino Acids; Animals; Behavior, Animal; Catecholamines; Cats; Cystathionine; Cysteine; Dihyd	1975

serine and Schizophrenia

Research Excerpts

Research

Studies (194)

Authors

Clinical Trials (17)

Trial Overview

Trial Outcomes

MATRICS

MMN Amplitude

PANSS Total

Visual P1

Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery

Positive and Negative Symptoms Scale (PANSS)

Renal Safety Measures

IL6 Levels

Pittsburgh Sleep Quality Index Score

Scale of Prodromal Symptoms (SOPS) Negative Scale

Scale of Prodromal Symptoms (SOPS) Total

Mismatch Negativity (MMN)

Tone Matching Threshold

Functional Capacity

Neurocognition

Electroencephalography (EEG)

Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE

Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT

Brain Glycine/CR Ratio

Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine

Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period

Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine

Heinrichs-Carpenter Quality of Life Scale

Hopkins Verbal Learning Test

Positive and Negative Syndrome Scale (PANSS)

Simpson-Angus Neurological Rating Scale

Spatial Span- Total Score

UCSD Performance-Based Skills Assessment (UPSA)

Wisconsin Card Sorting Test (WCST)

Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)

Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)

Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared)

Auditory Evoked Potentials in Latency (Msec)

Brain Glycine/CR Ratio

Brief Psychiatric Rating Scale (BPRS) Scores

Brief Psychiatric Rating Scale (BPRS) Scores

Clinical Global Impression (CGI) Severity Scores

Clinical Global Impression (CGI) Severity Scores

Depression Symptom Scores

Depression Symptom Scores

Mania Symptom Scores

Mania Symptom Scores

Neurocognitive Function

Positive and Negative Symptom Scores

Positive and Negative Symptom Scores

Reviews

Trials

Other Studies