TABLE 1.
The summary of clinical researches on drugs augmenting NMDAR function in schizophrenia.
| Pharmacology | Time | Sample | Method | Significant effects on symptom clusters | References | |
| Glycine, adjunctive therapy | Initially 2 g/d, upward to 0.4 g/kg/day | 8 W | 14 SCZ patients | PANSS | A 17.1% reduction in negative symptoms | Javitt et al., 1994 |
| 0.8 g/kg/d | 6 W | 11 treatment-resistant SCZ patients | PANSS | A 7% reduction in negative symptoms | Heresco-Levy et al., 1996 | |
| 0.8 g/kg/d | 6 W | 22 treatment-resistant SCZ patients | BPRS, PANSS | A 30 ± 16% reduction in negative symptom, reduction in extrapyramidal Symptoms. | Heresco-Levy et al., 1999 | |
| 60 g/d | 8 W | 20 SCZ patients | PANSS | No significant outcome | Evins et al., 2000 | |
| 0.8 g/kg/d | 6 W | 12 SCZ patients | PANSS | A 34% reduction in Negative symptoms | Javitt et al., 2001 | |
| 0.8 g/kg/d | 1 W | 16 healthy participants | MMN | Reduction in duration MMN amplitude | Leung et al., 2008 | |
| Acute administration: 0.2 g/kg; chronic treatment: incremented to 0.6 g/kg/d | 6 W | 22 SCZ patients | MMN, PANSS | Acute glycine administration increased duration MMN; chronic glycine administration improved negative symptoms | Greenwood et al., 2018 | |
| GlyT1 inhibitor- sarcosine, adjunctive therapy | 2 g/d sarcosine | 6 W | 65 SCZ patients | PANSS,SANS | All three symptom clusters (≥30% reduction in the PANSS total score) | Lane et al., 2005 |
| 2 g or 1 g/d sarcosine | 6 W | 20 acutely symptomatic drug-free SCZ patients | PANSS | A ≥20% reduction in the total scores in PANSS | Lane et al., 2008 | |
| Sarcosine (in the first stage 5 patients received 2 gm/d of sarcosine for 1 week and in the second stage 17 patients received 4 gm/d for one week) | 8 D | 22 SCZ patients | PANSS, CGI, MCCB | Improvements in positive symptoms, negative symptoms, speed of processing | Amiaz et al., 2015 | |
| GlyT1 inhibitor- bitopertin, monotherapy | Bitopertin (10, 30, or 60 mg/d) | 8 W | phase 2 proof-of-concept trial involved 323 SCZ patients with predominant negative symptoms | PANSS | Negative symptoms improved in the 10, 30 mg/d group (response rate = 65% in the 10 mg/d) | Umbricht et al., 2014 |
| Bitopertin 10, 30 mg/d alone | 4 W | 301 SCZ patients | PANSS | No significant Outcome | Bugarski-Kirola et al., 2014 | |
| GlyT1 inhibitor- org 25935, adjunctive therapy | Org 25935 (4 to 8 mg twice daily and 12 to 16 mg twice daily) | 12 W | 187 SCZ patients | SANS the Scale for Assessment of Negative Symptoms 1-22 | No significant Outcome | Schoemaker et al., 2014 |
| GlyT1 inhibitor- AMG747, adjunctive therapy | AMG747 orally receive daily AMG 747 (5 mg, 15 mg, or 40 mg) | 12 W | 153 SCZ patients | Negative Symptom Assessment (NSA)-16 total score | No significant outcome | Dunayevich et al., 2017 |
| D-serine, monotherapy | D-serine (Week 1: 1.5 g/d Week 2-10: 3 g/d) versus olanzapine (Week 1: 15 mg/d Week 2-10: 30 mg/d) | 10 W | 18 SCZ treatment-resistant patients | PANSS | Compared to olanzapine, D-serine has less improvement in PANSS total scores | Ermilov et al., 2013 |
| 60 mg/kg/d D-serine | 16 W | 35 participants at clinical high risk of schizophrenia | SOPS | A 35.7% reduction in prodromal symptoms at high-risk group | Kantrowitz et al., 2015 | |
| 60 mg/kg/d D-serine | 6 W | 16 SCZ patients | MMN | Improvement in MMN | Kantrowitz et al., 2018 | |
| D-serine, adjunctive therapy | 30 mg/kg/d | 6 W | 31 SCZ patients | Wisconsin Card Sorting Test | Improvement in all three symptom clusters; a 17% reduction in positive symptoms; a 21% reduction in negative symptoms; 12% improvements in cognition | Tsai et al., 1998 |
| 30 mg/kg/d, added to clozapine | 6 W | 20 SCZ patients | CGI, PANSS | No significant Outcome | Tsai et al., 1999 | |
| 30 mg/kg/d D-serine | 6 W | 39 SCZ patients | PANSS | Improvement in three symptom clusters; 39% showed a >20% improvement in total BPRS score | Heresco-Levy et al., 2005 | |
| 30, 60, or 120 mg/kg/day D-serine | 4 W | 42 SCZ patients | PANSS, MATRICS | Improvement in all three symptom clusters | Kantrowitz et al., 2010 | |
| 2 g/d | 16 W | 195 SCZ patients | SANS, MATRICS | No significant Outcome | Weiser et al., 2012 | |
| D-cycloserine, adjunctive therapy | 5, 15, 50, and 250 mg/d DCS | 2 W | 9 SCZ patients | SANS | A 21% improvement in negative symptoms | Goff et al., 1995 |
| 50 mg/d DCS, clozapine | 13 W | 17 SCZ patients | PANSS, SANS, GAS | Worsened negative symptoms | Goff et al., 1999 | |
| 50 mg/d DCS, risperidone | 2 W | 10 SCZ patients | SANS | A 10% improvement in negative symptoms | Evins et al., 2002 | |
| 50 mg/d | 4 W | 22 SCZ patients | SANS | No significant Outcome | Rothbaum et al., 2014 | |
| 50 mg/W | 8 W | 33 SCZ patients | The Logical Memory Test, SANS | A 16.6% net reduction in negative symptoms | Goff et al., 2008 | |
| 50 mg/W | 8 W | 36 SCZ patients | The auditory discrimination task, SANS, MATRICS | Improvement in long-term memory (LTM) on the practiced auditory discrimination task; 26% reduction in SANS scores | Cain et al., 2014 | |
| 50 mg/d | 6 W | 41 SCZ patients | PANSS, SANS | No significant outcome in three symptoms | Takiguchi et al., 2017 | |
| DCS, monotherapy | 100 mg | 3 h | 45 SCZ patients | EEG paradigm | Cognition (working memory, experience-dependent neuroplasticity) | Forsyth et al., 2017 |
| 100 mg | 32 healthy participants | LTP EEG paradigm, cognitive tasks | Cognition (experience-dependent neuroplasticity) | Forsyth et al., 2015 | ||
| DAAO inhibitor- sodium benzoate, adjunctive therapy | 1 g/d sodium benzoate | 6 W | 52 SCZ patients | PANSS | All three symptom clusters. (a 21% reduction of PANSS scores) | Lane et al., 2013 |
| 1 g/d, 2 g/d sodium benzoate, added to Clozapine | 6 W | 60 clozapine-resistant SCZ | PANSS, SANS, GAF, | Small improvements in overall symptomatology | Lin et al., 2018 | |
| Antioxidant | ||||||
| NAC, monotherapy | 2.4 g/d NAC | 1 W | 20 SCZ patients | MRI | NAC can reduce medial frontal resting-state functional connectivity (rs-FC) | McQueen et al., 2019 |
| NAC, adjunctive therapy | 1 g/d | 24W | 140 chronic SCZ patients | PANSS, CGI | Moderate benefits Negative symptoms | Berk et al., 2008 |
| 2 g/d | 16W | 11 SCZ patients | MMN | Improvement in MMN generation | Lavoie et al., 2008 | |
| 2 g/d | crossover design, 16 W | 11 SCZ patients | resting-state EEGs | NAC modulates EEG synchronization | Carmeli et al., 2012 | |
| NAC (up to 2 g/d), risperidone (up to 6 mg/d) | 8 W | 42 SCZ chronic patients with predominant negative symptoms | PANSS negative subscale | Negative symptoms | Farokhnia et al., 2013 | |
| 0.6 g/d NAC, risperidone (up to 4-6 m g / d) | 8 W | 121 SCZ first-phase patients | PANSS, weight, lipid metabolism | Positive and negative symptoms, lipid metabolism, and weight control | Zhang et al., 2015 | |
| 3.6 g/d | 52 W | 60 early phase schizophrenia patient | PANSS, CGI, PSP, BACS, MRI | Negative symptoms | Breier et al., 2018 | |
| 2.7 g/d | 72W | 15 early psychosis patients | low-level auditory processing | Cognitive dysfunction (low-level auditory processing) | Retsa et al., 2018 | |
| 2.7 g/d | 72W | 63 early psychosis patients | PANSS, neurocognition, and redox markers | Neurocognition (processing speed) and brain redox state. | Conus et al., 2018 | |
| 1.2 g/d | 12 W | 84 SCZ patients | PANSS | All three symptom clusters: cognition (speed of processing and attention, working memory) | Sepehrmanesh et al., 2018 | |
| 1.2_2.4 g/d NAC, clozapine | 4 W | 5 SCZ patients developed sialorrhea during clozapine treatment (300–450 mg/day) | the Visual Analog Scale | Clozapine-induced sialorrhea | Uzun et al., 2019 | |
| Sulforaphane, adjunctive therapy | 30 mg/d sulforaphane-glucosinolate | 8 W | 10 SCZ patients | PANSS | Cognitive dysfunction | Shiina et al., 2015 |
| 100 μmol sulforaphane | 1 W | 9 healthy participants | MRS | Improvement in brain GSH levels and redox state. | Sedlak et al., 2018 |
SCZ, schizophrenia/schizophrenic; GlyT1, Glycine transporter-1; DCS, D-cycloserine; DAAO, D-amino acid oxidase; NAC, N-acetylcysteine; SANS, the Scale for the Assessment of Negative Symptoms; MATRICS, the Measurement and Treatment Research to Improve Cognition; SOPS, the Scale of Prodromal Symptoms; NAS, the Negative Symptom Assessment; BPRS, the Brief Psychiatric Rating Scale; CGI, the Clinical Global Impression Severity and Improvement scales; PSP, the Personal and Social Performance Scale; GAS, Global Assessment Scale; GAF, the Global Assessment of Functioning; BACS, the Brief Assessment of Cognition in Schizophrenia.