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| Drugs | Сlass | Mechanism of action | Studies | Outcome |
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| Antioxidant drugs |
| N-Acetylcysteine (NAC) | Cysteine precursor | NAC
(i) Activates the synthesis of glutathione, the main endogenous antioxidant mediator in the brain (the most important mechanism)
(ii) Has its own nonspecific activity in neutralizing various free radical groups | Yolland et al., 2020 (meta-analysis) [364] | Total PANSS and in the negative PANSS subscale and total scores as well as the cognitive domain of working memory were significantly improved with N-acetylcysteine supplementation after 24 weeks of treatment |
| Berk et al., 2008 [368]; Farokhnia et al., 2013 [369] | Significant reduction of the Positive and Negative Syndrome Scale (PANSS) negative, PANSS total, and Clinical Global Impression (CGI) scales in comparison to placebo |
| No significant change on the PANSS positive subscale was seen |
| There was no significant difference with the control group in the frequency of side effects. |
| Lavoie et al., 2008 [370] | Administration of NAC to schizophrenia patients resulted in improved auditory cortical functioning, improved mismatch negativity (MMN) generation |
| Zheng et al., 2018 [371] | Adjunctive NAC significantly improved total (positive and negative) symptoms in schizophrenia |
| Rapado-Castro et al., 2017 [372] | Significantly higher working memory performance compared with placebo |
| Sepehrmanesh et al., 2018 [373] | Significant improvement in total PANSS and in the positive and negative PANSS subscales |
| Improvements in attention, short-term and working memory, executive functioning and speed of processing |
| Conus et al., 2018 [374] | NAC therapy improved neurocognition and reduced positive symptoms among patients with high peripheral oxidative status |
| No changes in negative or positive symptoms or functional outcome were observed with NAC |
| Klauser et al., 2018 [375] | Significant improvements in neurocognition and a reduction of positive symptoms |
| Increase in GSH levels in the medial prefrontal cortex |
| Breier et al., 2018 [377] | Significant improvement in PANSS total, negative, and disorganized thought symptom scores |
| No changes in PANSS positive symptoms and BACS cognitive scores |
| McQueen et al., 2020 [376] | A single dose of NAC was associated with decreases in rs-FC in prefrontal cortical regions of the DMN and SN network in patients with established schizophrenia |
| Ginkgo biloba extract | Contains flavonoids, tricyclic diterpenes (ginkgolides A, B, C, and J), sesquiterpenes (bilobalide A) | Ginko biloba extract
(i) Scavenger of superoxide anion, hydroxyl radicals, peroxyl
(ii) Reduces the concentration of primary and secondary products of lipid peroxidation (diene conjugates, TBA-active products)
(iii) Induces the enzymatic activity of superoxide dismutase and catalase | Singh et al., 2010 (meta-analysis) [381] | Statistically significant moderate improvement in total and negative symptoms of chronic schizophrenia |
| Doruk et al., 2008 [378] | Significant reduction of the PANSS negative |
| No significant change on the PANSS total and in the positive PANSS subscale |
| Zhang et al., 2011 [379] | A significant decrease in the Abnormal Involuntary Movement Scale (AIMS) total score |
| No between-group differences in the PANSS total score or cognitive measures from baseline |
| Rathbone et al., 2005 [380] | Treatment with Ginkgo biloba resulted in moderate improvement in total and negative symptoms of schizophrenia |
| Selegiline | Selective inhibitor of MAO-B | The antioxidant effect of selegiline may be associated with the protection of neurons from oxygen free radicals that are released as a result of MAO-B activity | Amiri et al., 2008 [382] | Decline of negative symptoms and PANSS total scores |
| Bordbar et al., 2008 [383] | No significant change on the PANSS negative subscale was seen |
| Bodkin et al., 2005 [384] | Significant improvements in negative symptoms |
| Allopurinol | Xanthine oxidase inhibitor | Allopurinol prevents the formation of free radicals:
(i) Inhibits the xanthine oxidase reaction, during which superoxide anion radical is actively formed | Akhondzadeh et al., 2005 [385] | A significant superiority in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores |
| Decreased Extrapyramidal Symptoms Rating Scale (ESRS) |
| Brunstein et al., 2005 [386] | Significant improvement in PANSS total, positive, negative, and general scores, particularly for positive symptoms |
| Dickerson et al., 2009 [387] | At least a 20% reduction in total PANSS score |
| Weiser et al., 2012 [388] | No differences with control group on the PANSS |
| Vitamin E | Vitamin | Vitamin E is a natural antioxidant that neutralizes free radicals:
(i) There is a transfer of hydrogen of the phenyl group to the peroxide radical
(ii) Performs structural function by interacting with phospholipids of biological membranes | Adler et al., 1993 [389] | Significant reduction of AIMS score |
| Adler et al., 1999 [390] | No significant reduction of AIMS and Brief Psychiatric Rating Scale (BPRS) |
| Dorevitch et al., 1997 [391] | No significant differences between vitamin E and placebo-treated patients in AIMS score |
| Lohr et al., 1996 [392] | Significant reduction of AIMS score |
| Significant change on the PANSS positive subscale |
| Zhang et al., 2004 [393] | Significant reduction of AIMS score |
| Sajjad, 1998 [394] | Significant reduction of AIMS score |
| Soares-Weiser et al., 2018 [395] | No clear difference between vitamin E and placebo for the outcome of TD (not improved to a clinically important extent) |
| Vitamin C | Vitamin | Vitamin C antioxidant activity:
(i) The formation of a redox pair of ascorbic acid/dehydroascorbic acid, restores the active form of vitamin E
(ii) Prevents or reverses the oxidation process of reduced glutathione (GSH) to its functionally inactive form (GSSG) | Dakhale et al., 2005 [396] | Significant change on the BPRS |
| Vitamins C and E | Vitamins | Ascorbic acid has a synergistic effect for vitamin E:
(i) Restores the oxidation product of tocopherol (α-tocopheroxide) to α-tocopherol | Nicolaus et al., 2002 [397] | Significant reduction in dyskinetic movement total score
High dietary intake will lead to prooxidant action |
| Vitamins E and C and fatty acids | Vitamins and dietary supplements | Q.V. mechanisms of action of vitamins E and C and fatty acids | Arvindakshan et al., 2003 [398] | Significant reduction of PANSS and BPRS and increase of QOL (Henrich’s Quality of Life scale) |
| Sivrioglu et al., 2007 [399] | Significant reduction of BPRS, Scale for Assessment of Negative Symptoms, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale |
| Polyunsaturated fatty acids (PUFAs) | Dietary supplements | The detailed mechanisms of action are mostly unknown, but PUFAs have anti-inflammatory and antiatherogenic effects | Emsley et al., 2002 [400] | Significant reduction in PANSS total scale |
| Emsley et al., 2006 [404] | No significant difference in the Extrapyramidal Symptom Rating Scale |
| Fenton et al., 2001 [405] | No significant change in PANSS, Abnormal Involuntary Movement Syndrome scale, Clinical Global Impression scale |
| Peet et al., 2001 [401]; Peet et al., 2002 [402] | Significant reduction in PANSS total |
| Amminger et al. 2010 [403] | Significantly reduced positive, negative, and general symptoms and improved functioning compared with placebo |
|
| Transcription factor-targeting drugs |
| Sulforaphane | Nrf2 transcription factor activator | Inhibit Keap1 protein through electrophilic modification, which leads to Nrf2 activation. The transcription factor Nrf2 plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress | Sedlak et al. 2017 [406] | Isothiocyanate sulforaphane increased blood and brain GSH levels in healthy human subjects following 7 days of administration |
| Shiina et al. 2015 [407] | Sulforaphane may have the potential to improve cognitive impairments in patients with schizophrenia, but the differences before and after treatment are not significant |
| Shirai et al., 2015 (animal model) [408] | Sulforaphane exhibited an atypical antipsychotic activity in PCP-induced cognitive deficits in animal models. Genetic analysis showed an epistatic interaction between Nrf2 and Keap1 gene variants on working memory in schizophrenia |
| DDO-7263 | Nrf2 transcription factor activator | Nrf2 activation and NLRP3 inflammasome inhibition | Xu et al., 2019 (animal model) [409] | The neuroprotective effects of DDO-7263 have been proven in mice, through Nrf2 activation and NLRP3 inflammasome inhibition |
| Curcumin | Polyphenolic compound | Inhibit Keap1 protein through electrophilic modification, which leads to Nrf2 activation | Miodownik et al. 2019 [410] | Significant reduction in total PANSS and in the negative symptoms subscale. There were no differences in the positive and general PANSS subscales, and the Calgary Depression Scale for Schizophrenia scores |
| Resveratrol | Anthocyanins | Resveratrol is
(i) An activator of NAD-dependent deacetylase sirtuin-1 (SIRT1), which activates the transcription factor FoxO
(ii) An inhibitor of NF-κB (anti-inflammatory effect) | Zortea et al., 2016 [411] | Oral resveratrol in sufficiently low doses has not brought improvement |
| Zortea et al., 2016 [412] | No significant improvement in psychopathology severity |
| Magaji et al., 2017 (animal model) [413] | Anxiolytic and antipsychotic potentials of resveratrol in murine models of anxiety and schizophrenia in mice was found |
| Salvianolic acid B | Polyphenolic compound | Salvianolic acid B like resveratrol is an activator of SIRT1 and an inhibitor of NF-κB | Huang et al., 2019 (animal model) [414] | Study has confirmed the antidepressant activity in an induced depression rat model |
| Yu et al., 2016 (animal model) [415] | Treatment of stress-challenged rats with fluoxetine and fluoxetine combined with salvianolic acid could alleviate depression-like symptoms and cognitive deficit |
| Liao et al., 2020 (animal model) [154] | SalB relieved CMS-induced depressive-like state in mice through the mitigation of inflammatory status, oxidative stress, and the activation of the AMPK/SIRT1 signaling pathway |
| Metformin | Antidiabetic agent | Activate FoxO3 via AMP-activated protein kinase activation | Jiang et al., 2020 [416] | Significantly reduce antipsychotic-induced weight gain, dyslipidemia, and metabolic abnormalities in schizophrenia |
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