Redox-oxidative stress and micronutrients interplay in the clinical phenotype of schizophrenia in Nigerian subjects

Abstract

Aim: Redox-oxidative dysregulation is implicated in the aetiology of several diseases, including schizophrenia, with a possible influence on clinical symptoms. This study investigated the influence of redox, lipid peroxidation, and micronutrient antioxidants on the expression of clinical phenotypes of schizophrenia.

Methods: A total of 220 consenting drug-naïve volunteers, including 120 participants with schizophrenia and 100 apparently healthy controls, were recruited. Schizophrenia symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Lipid peroxidation (malondialdehyde; MDA) was quantified using the thiobarbituric acid reactive substances (TBARS) spectrophotometric method; glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were assessed using established enzymatic activity assays; total antioxidant capacity (TAC) was determined by the phosphomolybdenum colorimetric method; vitamins C and E were measured using spectrophotometric biochemical assays; and zinc (Zn) and selenium (Se) concentrations were quantified using atomic absorption spectrophotometry (AAS).

Results: Enzymatic antioxidants, SOD (19.58 ± 0.80; 10.12 ± 0.45 U/L) and CAT (41.73 ± 1.81; 21.33 ± 0.98 U/L), increased in schizophrenia compared with controls (p < 0.05), but decreased non-enzymatic antioxidants; GSH (14.5 ± 0.28; 15.9 ± 1.59 µmol/L, p < 0.05). Furthermore, serum levels of zinc (1.8 ± 0.01; 2.7 ± 0.02 mg/L), selenium (0.08 ± 0.01; 0.10 ± 0.01 mg/L), and vitamin C (12.98 ± 0.49; 15.08 ± 0.37 mg/L) were lowered in schizophrenia compared with controls (p < 0.05). GSH had a negative correlation with positive symptoms (r = –0.285, p = 0.013) while SOD (r = 0.281, p = 0.001) and CAT (r = 0.179, p = 0.034) correlated positively with MDA (p < 0.05). In contrast, GSH (r = –0.247, p = 0.003) and TAC (r = –0.221, p = 0.009) correlated negatively with MDA (p < 0.05).

Conclusions: Drug-naïve Nigerian individuals with schizophrenia appear to exhibit a pattern of redox imbalance, including increased lipid peroxidation, altered antioxidant enzyme activity, and reduced non-enzymatic antioxidants, with lower GSH levels modestly associated with greater positive symptom severity.

Keywords

antioxidants / clinical phenotypes / redox-oxidative stress / schizophrenia / micronutrient / lipid peroxidation

References

[1] Dziwota E, Stepulak MZ, Włoszczak-Szubzda A, Olajossy M. Social functioning and the quality of life of patients diagnosed with schizophrenia. Ann Agric Environ Med. 2018; 25:50-5.

[2] Barlati S, Nibbio G, Vita A. Evidence-based psychosocial interventions in schizophrenia: a critical review. Curr Opin Psychiatry. 2024; 37:131-9.

[3] Marder SR, Umbricht D. Negative symptoms in schizophrenia: Newly emerging measurements, pathways, and treatments. Schizophr Res. 2023; 258:71-7.

[4] Gurnani R, Georgiades A. The Role of Emotion in Psychosis Onset and Symptom Persistence: A Systematic Review. Early Interv Psychiatry. 2025; 19:e70096.

[5] Jidong DE, Husain MI, Ike TJ, Husain N, Taru MY, Nnaemeka NC, et al.Bipolar disorders in Nigeria: a mixed-methods study of patients, family caregivers, clinicians, and the community members' perspectives. Int J Bipolar Disord. 2023; 11:2.

[6] Eneh OC, Eneh CA. An analysis of demographic, socio-economic and clinical variables for mental illness and mental illness relapse in south-east nigeria. Sci Rep. 2024; 14:23079.

[7] Choudhury A, Sahu T, Ramanujam PL, Banerjee AK, Chakraborty A, Kumar R A, et al.Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases. Neuropsychiatry. 2018; 8:395-424.

[8] Luvsannyam E, Jain MS, Pormento MKL, Siddiqui H, Balagtas ARA, Emuze BO, et al.Neurobiology of Schizophrenia: A Comprehensive Review. Cureus. 2022; 14:e23959.

[9] Dudzińska E, Szymona K, Bogucki J, Koch W, Cholewińska E, Sitarz R, et al.Increased Markers of Oxidative Stress and Positive Correlation Low-Grade Inflammation with Positive Symptoms in the First Episode of Schizophrenia in Drug-Naïve Patients. J Clin Med. 2022; 11:2551.

[10] Pavan T, Steullet P, Alemán-Gómez Y, Jenni R, Schilliger Z, Cleusix M, et al.Brain white matter microstructure associations with blood markers of the GSH redox cycle in schizophrenia. Neuroimage Clin. 2025; 48:103883.

[11] Ashok A, Andrabi SS, Mansoor S, Kuang Y, Kwon BK, Labhasetwar V. Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation. Antioxidants (Basel). 2022; 11:408.

[12] Liu S, Liu J, Wang Y, Deng F, Deng Z. Oxidative Stress: Signaling Pathways, Biological Functions, and Disease. MedComm (2020). 2025; 6:e70268.

[13] Chandimali N, Bak SG, Park EH, Lim H, Won Y, Kim E, et al.Free radicals and their impact on health and antioxidant defenses: a review. Cell Death Discov. 2025; 11:19.

[14] Hurşitoğlu O, Orhan FÖ, Kurutaş EB, Doğaner A, Durmuş HT, Kopar H. Diagnostic Performance of Increased Malondialdehyde Level and Oxidative Stress in Patients with Schizophrenia. Noro Psikiyatr Ars. 2021; 58:184-8.

[15] Meulmeester FL, Luo J, Martens LG, Mills K, van Heemst D, Noordam R. Antioxidant Supplementation in Oxidative Stress-Related Diseases: What Have We Learned from Studies on Alpha-Tocopherol?. Antioxidants (Basel). 2022; 11:2322.

[16] Zhang K, Zou L, Cai Y. Progress in the study of oxidative stress damage in patients with schizophrenia: challenges and opportunities. Front Psychiatry. 2025; 16:1505397.

[17] Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharmacother. 2023; 162:114606.

[18] Palmisano A, Pandit S, Smeralda CL, Demchenko I, Rossi S, Battelli L, et al.The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders. Life (Basel). 2024; 14:578.

[19] Perkins DO, Jeffries CD, Do KQ. Potential Roles of Redox Dysregulation in the Development of Schizophrenia. Biol Psychiatry. 2020; 88:326-36.

[20] Sevillano-Jiménez A, Romero-Saldaña M, García-Rodríguez M, Molina-Luque R, Molina-Recio G. Nutritional Impact and Eating Pattern Changes in Schizophrenic Spectrum Disorders after Health Education Program on Symbiotic Dietary Modulation Offered by Specialised Psychiatric Nursing-Two-Arm Randomised Clinical Trial. Nutrients. 2022; 14:5388.

[21] Moustafa AA, Hewedi DH, Eissa AM, Frydecka D, Misiak B. Homocysteine levels in schizophrenia and affective disorders-focus on cognition. Front Behav Neurosci. 2014; 8:343.

[22] Balakrishnan R, Kang S, Lee J, Rho Y, Kim B, Choi D. Gut Microbiota-Immune System Interactions in Health and Neurodegenerative Diseases: Insights into Molecular Mechanisms and Therapeutic Applications. Aging Dis. 2024; 16:3421-52.

[23] Comer AL, Carrier M, Tremblay M, Cruz-Martín A. The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Front Cell Neurosci. 2020; 14:274.

[24] Trubalski M, Markiewicz-Gospodarek A, Żerebiec M, Poleszak J, Szczotka M, Markiewicz R, et al.Oxidative Stress-Mediated Neuroinflammation in the Pathophysiology of Schizophrenia. Int J Mol Sci. 2025; 26:11139.

[25] Onaolapo OJ, Onaolapo AY. Nutrition, nutritional deficiencies, and schizophrenia: An association worthy of constant reassessment. World J Clin Cases. 2021; 9:8295-311.

[26] Mosquera FEC, Guevara-Montoya MC, Serna-Ramirez V, Liscano Y. Neuroinflammation and Schizophrenia: New Therapeutic Strategies through Psychobiotics, Nanotechnology, and Artificial Intelligence (AI). J Pers Med. 2024; 14:391.

[27] Trofin D, Sardaru D, Trofin D, Onu I, Tutu A, Onu A, et al.Oxidative Stress in Brain Function. Antioxidants (Basel). 2025; 14:297.

[28] Wu W, Gong X, Qin Z, Wang Y. Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update. Acta Pharmacol Sin. 2025; 46:3129-42.

[29] Olufunmilayo EO, Gerke-Duncan MB, Holsinger RMD. Oxidative Stress and Antioxidants in Neurodegenerative Disorders. Antioxidants (Basel). 2023; 12:517.

[30] Asatiani N, Sapojnikova N, Kartvelishvili T, Asanishvili L, Sichinava N, Chikovani Z. Blood Catalase, Superoxide Dismutase, and Glutathione Peroxidase Activities in Alcohol- and Opioid-Addicted Patients. Medicina (Kaunas). 2025; 61:204.

[31] Uddin SMN, Sultana F, Uddin MG, Dewan SMR, Hossain MK, Islam MS. Effect of antioxidant, malondialdehyde, macro-mineral, and trace element serum concentrations in Bangladeshi patients with schizophrenia: A case-control study. Health Sci Rep. 2021; 4:e291.

[32] San-Millán I. The Key Role of Mitochondrial Function in Health and Disease. Antioxidants (Basel). 2023; 12:782.

[33] Wang G, Liu S, Fan X, Li J, Xue Q, Liu K, et al.Mitochondrial Dysfunction and Cognitive Impairment in Schizophrenia: The Role of Inflammation. Schizophr Bull. 2025; 51:1092-103.

[34] Ayna A, Caglayan C, Taysi S. Cellular and Molecular Mechanisms of Oxidative DNA Damage and Repair. Medicina (Kaunas). 2025; 61:2013.

[35] Behrouzi A, Kelley MR, Fehrenbacher JC. Oxidative DNA Damage: A Role in Altering Neuronal Function. J Cell Signal. 2022; 3:160-6.

[36] Roberts RC. Mitochondrial dysfunction in schizophrenia: With a focus on postmortem studies. Mitochondrion. 2021; 56:91-101.

[37] Bilal M, Ashraf S, Zhao X. Dietary Component-Induced Inflammation and Its Amelioration by Prebiotics, Probiotics, and Synbiotics. Front Nutr. 2022; 9:931458.

[38] Jahrami H, Faris MA, Ghazzawi HA, Saif Z, Habib L, Shivappa N, et al.Increased Dietary Inflammatory Index Is Associated with Schizophrenia: Results of a Case-Control Study from Bahrain. Nutrients. 2019; 11:1867.

[39] Yang M, Li J, Yang H, Yan L, Liu D, Zhu L, et al.Cognitive Impairment and Psychopathology Are Related to Plasma Oxidative Stress in Long Term Hospitalized Patients With Chronic Schizophrenia. Front Psychiatry. 2022; 13:896694.

[40] Tang B, Zhang W, Deng S, Liu J, Hu N, Gong Q, et al.Age-associated network controllability changes in first episode drug-naïve schizophrenia. BMC Psychiatry. 2022; 22:26.

[41] Nielsen CM, Kølbæk P, Dines D, Pedersen ML, Danielsen AA, Holmgård C, et al.Validation of ratings on the six-item Positive and Negative Syndrome Scale obtained via the Simplified Negative and Positive Symptoms Interview among outpatients with schizophrenia. J Psychopharmacol. 2022; 36:1208-17.

[42] Oso TA, Owolabi J, Lawal T, Adeyemi JD, Akinloye O. Dynamism of Sex Steroids in Modulating the Phenotypic Expression of Schizophrenia. Univ Lagos J Basic Med Sci. 2021; 9:241-2.

[43] Wang W, Zhang Z, Liu X, Cao X, Wang L, Ding Y, et al.An Improved GC-MS Method for Malondialdehyde (MDA) Detection: Avoiding the Effects of Nitrite in Foods. Foods. 2022; 11:1176.

[44] Aguilar Diaz De Leon J, Borges CR. Evaluation of Oxidative Stress in Biological Samples Using the Thiobarbituric Acid Reactive Substances Assay. J Vis Exp. 2020; 159:e61122.

[45] Hadwan MH, Hussein MJ, Mohammed RM, Hadwan AM, Al-Kawaz HS, Al-Obaidy SSM, et al.An improved method for measuring catalase activity in biological samples. Biol Methods Protoc. 2024; 9:bpae015.

[46] Martins D, English AM. Catalase activity is stimulated by H₂O₂ in rich culture medium and is required for H₂O₂ resistance and adaptation in yeast. Redox Biol. 2014; 2:308-13.

[47] Lesiewska H, Woźniak A, Reisner P, Czosnyka K, Stachura J, Malukiewicz G. Is Cataract in Patients under 60 Years Associated with Oxidative Stress?. Biomedicines. 2023; 11:1286.

[48] Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972; 247:3170-5.

[49] Okafor CE, Ijoma IK, Igboamalu CA, Ezebalu CE, Eze CF, Osita-Chikeze JC, et al.Secondary metabolites, spectra characterization, and antioxidant correlation analysis of the polar and nonpolar extracts of Bryophyllum pinnatum (Lam) Oken. BioTechnologia (Pozn). 2024; 105:121-36.

[50] Elkhamlichia A, El Hajajia H, Farajb H, Alamib A, El Balia B, Lachkara M. Phytochemical screening and evaluation of antioxidant and antibacterial activities of seeds and pods extracts of Calycotome villosa subsp. Intermedia. J App Pharm Sci. 2017; 7:192-8.

[51] Aydinoglu S. Iron and Zinc Determination in Dietary Supplements by Flame Atomic Absorption Spectrophotometry. Braz J Pharm Sci. 2022; 58:e21094.

[52] Margaret Oladunni O, Joan Olayinka O, Olalekan Samuel O, Modupe Olakintan A. Implications of dehusking and aqueous soaking on anti-nutrients, phytochemical screening and antioxidants properties of jack beans (Canavalia ensiformis L. DC). J Res Chem. 2024; 5:135-42.

[53] Nojavan S, Khalilian F, Momen Kiaie F, Rahimi A, Arabanian A, Chalavi S. Extraction and quantitative determination of ascorbic acid during different maturity stages of Rosa canina L. fruit. J Food Compost Anal. 2008; 21:300-5.

[54] Sighencea MG, Trifu SC. Unravelling the Viral Hypothesis of Schizophrenia: A Comprehensive Review of Mechanisms and Evidence. Int J Mol Sci. 2025; 26:7429.

[55] Murray AJ, Rogers JC, Katshu MZUH, Liddle PF, Upthegrove R. Oxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders. Front Psychiatry. 2021; 12:703452.

[56] Güneş M, Uyar B, Dönmezdil S, Kaplan İ. Evaluation of Inflammatory and Oxidative Markers and Their Diagnostic Value in Schizophrenia. Brain Sci. 2025; 15:1137.

[57] Nayok SB, Shivakumar V, Sreeraj VS. Oxidative Stress in Schizophrenia. In: Martin CR, Preedy VR, Patel VB, Rajendram R. editors.Handbook of the Biology and Pathology of Mental Disorders. Cham: Springer Nature Switzerland; 2024pp. 1–19.

[58] Promyos N, Phienluphon PP, Wechjakwen N, Lainampetch J, Prangthip P, Kwanbunjan K. Inverse Correlation of Superoxide Dismutase and Catalase with Type 2 Diabetes among Rural Thais. Nutrients. 2023; 15:2071.

[59] Schiavone S, Trabace L. Inflammation, Stress Response, and Redox Dysregulation Biomarkers: Clinical Outcomes and Pharmacological Implications for Psychosis. Front Psychiatry. 2017; 8:203.

[60] Chen P, Wang D, Xiu M, Chen D, Lackey B, Wu HE, et al.Polymorphism of Transferrin Gene Impacts the Mediating Effects of Psychotic Symptoms on the Relationship between Oxidative Stress and Cognition in Patients with Chronic Schizophrenia. Antioxidants (Basel). 2022; 11:125.

[61] Lu Z, Wen T, Wang Y, Kan W, Xun G. Peripheral non-enzymatic antioxidants in patients with schizophrenia: a case-control study. BMC Psychiatry. 2020; 20:241.

[62] Simone GD, Mazza B, Vellucci L, Barone A, Ciccarelli M, de Bartolomeis A. Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment. Antioxidants (Basel). 2023; 12:975.

[63] Caruso F, Pedersen JZ, Incerpi S, Belli S, Sakib R, Rossi M. Interaction between Vitamins C and E When Scavenging the Superoxide Radical Shown by Hydrodynamic Voltammetry and DFT. Biophysica. 2024; 4:310-26.

[64] Moabedi M, Milajerdi A. The effect of co-administration of vitamin E and C supplements on plasma oxidative stress biomarkers and antioxidant capacity: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials with meta-regression. Front Immunol. 2025; 16:1547888.

[65] Darabi F, Keshavarzi M, Khanjani N, Yousefinejad S, Zamanian Z. Effect of Antioxidants on oxidative damage, and hematological and psychological parameters in cement-exposed workers. Hyg Environ Health Adv. 2023; 6:100060.

[66] Theleritis C, Demetriou M, Stefanou M, Alevyzakis E, Makris M, Zoumpourlis V, et al.Zinc in psychosis (Review). Mol Med Rep. 2025; 32:201.

[67] Vakili O, Motamed M, Taghizadeh M, Khatami SH. Nutritional Management of Schizophrenia: Gut-Brain Axis Mechanisms and Dietary Interventions. Mol Neurobiol. 2026; 63:460.

[68] Rog J, Łobejko Ł, Hordejuk M, Marciniak W, Derkacz R, Kiljańczyk A, et al.Pro/antioxidant status and selenium, zinc and arsenic concentration in patients with bipolar disorder treated with lithium and valproic acid. Front Mol Neurosci. 2024; 17:1441575.

[69] Peng Z, Jia Q, Mao J, Jiang S, Ma Q, Luo X, et al.The role of ferroptosis and oxidative stress in cognitive deficits among chronic schizophrenia patients: a multicenter investigation. Schizophrenia (Heidelb). 2025; 11:4.

[70] Lu Z, Pu C, Zhang Y, Sun Y, Liao Y, Kang Z, et al.Oxidative Stress and Psychiatric Disorders: Evidence from the Bidirectional Mendelian Randomization Study. Antioxidants (Basel). 2022; 11:1386.

[71] Krishnamurthy HK, Pereira M, Rajavelu I, Jayaraman V, Krishna K, Wang T, et al.Oxidative stress: fundamentals and advances in quantification techniques. Front Chem. 2024; 12:1470458.

[72] Dringen R, Arend C. Glutathione Metabolism of the Brain-The Role of Astrocytes. J Neurochem. 2025; 169:e70073.

[73] McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020; 19:15-33.

[74] Iwata Y, Nakajima S, Plitman E, Truong P, Bani-Fatemi A, Caravaggio F, et al.Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia. Schizophr Bull Open. 2021; 2:sgab006.

[75] Ahmed GK, Ramadan HKA, Elbeh K. Haridy NA. The role of infections and inflammation in schizophrenia: review of the evidence. Middle East Curr Psychiatry. 2024; 31:9.

[76] Vallée A. Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway. Int J Mol Sci. 2022; 23:2810.

[77] Sun X, Meng H, Lu T, Yue W, Zhang D, Wang L, et al.Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model. Mol Brain. 2024; 17:75.

[78] Barone A, Vellucci L, Ciccarelli M, Matrone M, Simone GD, Iannotta F, et al.Molecular Underpinning of Treatment-Resistant Schizophrenia: A Putative Different Neurobiology from Treatment-Responsive Schizophrenia. Int J Mol Sci. 2025; 26:8598.

[79] Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020; 205:107426.

[80] Xu L, Yu P, Yang H, Huang C, Sun W, Zhang X, et al.Altered serum glutathione disulfide levels in acute relapsed schizophrenia are associated with clinical symptoms and response to electroconvulsive therapy. BMC Psychiatry. 2025; 25:242.

[81] Carletti B, Banaj N, Piras F, Bossù P. Schizophrenia and Glutathione: A Challenging Story. J Pers Med. 2023; 13:1526.

[82] Al-Hakeim HK, Altufaili MF, Almulla AF, Moustafa SR, Maes M. Increased Lipid Peroxidation and Lowered Antioxidant Defenses Predict Methamphetamine Induced Psychosis. Cells. 2022; 11:3694.

[83] Cordiano R, Gioacchino MD, Mangifesta R, Panzera C, Gangemi S, Minciullo PL. Malondialdehyde as a Potential Oxidative Stress Marker for Allergy-Oriented Diseases: An Update. Molecules. 2023; 28:5979.

[84] Rarinca V, Vasile A, Visternicu M, Burlui V, Halitchi G, Ciobica A, et al.Relevance of diet in schizophrenia: a review focusing on prenatal nutritional deficiency, obesity, oxidative stress and inflammation. Front Nutr. 2024; 11:1497569.

[85] Rambaud V, Marzo A, Chaumette B. Oxidative Stress and Emergence of Psychosis. Antioxidants (Basel). 2022; 11:1870.

[86] Więdłocha M, Zborowska N, Marcinowicz P, Dębowska W, Dębowska M, Zalewska A, et al.Oxidative Stress Biomarkers among Schizophrenia Inpatients. Brain Sci. 2023; 13:490.

[87] Greenwald AG, Dasgupta N, Dovidio JF, Kang J, Moss-Racusin CA, Teachman BA. Implicit-Bias Remedies: Treating Discriminatory Bias as a Public-Health Problem. Psychol Sci Public Interest. 2022; 23:7-40.

[88] Pérez-Guerrero EE, Guillén-Medina MR, Márquez-Sandoval F, Vera-Cruz JM, Gallegos-Arreola MP, Rico-Méndez MA, et al.Methodological and Statistical Considerations for Cross-Sectional, Case-Control, and Cohort Studies. J Clin Med. 2024; 13:4005.

[89] Li H, Huang Y, Liang L, Li H, Li S, Feng Y, et al.The relationship between the gut microbiota and oxidative stress in the cognitive function of schizophrenia: A pilot study in China. Schizophr Res. 2024; 267:444-50.