Hostname: page-component-cb9f654ff-plnhv Total loading time: 0.001 Render date: 2025-08-22T18:44:16.030Z Has data issue: false hasContentIssue false
  • English
  • Français

In (deficit) schizophrenia, a general cognitive decline partly mediates the effects of neuro-immune and neuro-oxidative toxicity on the symptomatome and quality of life

Published online by Cambridge University Press:  12 April 2021

Michael Maes Open the ORCID record for Michael Maes [Opens in a new window]  and
Buranee Kanchanatawan
Michael Maes*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria IMPACT Strategic Research Center, Deakin University, Geelong, Victoria, Australia
Buranee Kanchanatawan
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
*
*Author for correspondence: Michael Maes, MD, PhD, Email: dr.michaelmaes@hotmail.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Schizophrenia and deficit schizophrenia are accompanied by neurocognitive impairments. The aim of this study was to examine whether a general factor underpins impairments in key Cambridge Neuropsychological Test Automated Battery (CANTAB) probes, verbal fluency test (VFT), world list memory (WLM), True Recall, and mini mental state examination (MMSE).

Methods

We recruited 80 patients with schizophrenia and 40 healthy controls. All patients were assessed using CANTAB tests, namely paired-association learning, rapid visual information processing, spatial working memory, one touch stockings of Cambridge, intra/extradimensional set-shifting (IED), and emotional recognition test.

Results

We found that a general factor, which is essentially unidimensional, underlies those CANTAB, VFT, WLM, True Recall, and MMSE scores. This common factor shows excellent psychometric properties and fits a reflective model and, therefore, reflects a general cognitive decline (G-CoDe) comprising deficits in semantic and episodic memory, recall, executive functions, strategy use, rule acquisition, visual sustained attention, attentional set-shifting, and emotional recognition. Partial least squares analysis showed that 40.5% of the variance in G-CoDe is explained by C-C motif ligand 11, IgA to tryptophan catabolites, and increased oxidative toxicity, and that G-CoDe explains 44.8% of the variance in a general factor extracted from psychosis, hostility, excitation, mannerism, negative symptoms, formal thought disorders, and psychomotor retardation, and 40.9% in quality-of-life scores. The G-CoDe is significantly greater in deficit than in nondeficit schizophrenia.

Conclusions

A common core shared by a multitude of neurocognitive impairments (G-CoDe) mediates the effects of neurotoxic pathways on the phenome of (deficit) schizophrenia.

Keywords

deficit schizophreniatryptophan catabolitesneuro-immuneoxidative stressantioxidantspsychiatry

Information

Type
Original Research
Information
CNS Spectrums , Volume 27 , Issue 4 , August 2022 , pp. 506 - 515
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Maes, M, Vojdani, A, Galecki, P, Kanchanatawan, B. How to construct a bottom-up nomothetic network model and disclose novel nosological classes by integrating risk resilience and adverse outcome pathways with the phenome of schizophrenia. Brain Sci. 2020;10(9):645.CrossRefGoogle ScholarPubMed
Maes, M, Vojdani, A, Geffard, M, et al. Schizophrenia phenomenology comprises a bifactorial general severity and a single-group factor, which are differently associated with neurotoxic immune and immune-regulatory pathways. Biomol Concepts. 2019;10(1):209–225.CrossRefGoogle Scholar
Almulla, AF, Al-Hakeim, HK, Maes, M. Schizophrenia phenomenology revisited: positive and negative symptoms are strongly related reflective manifestations of an underlying single trait indicating overall severity of schizophrenia. CNS Spectr. 2020;20:1–10. doi:10.1017/S1092852920001182.Google Scholar
Kanchanatawan, B, Sriswasdi, S, Maes, M. Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia. Metab Brain Dis. 2019;34(1):267–282.CrossRefGoogle Scholar
Kanchanatawan, B, Thika, S, Anderson, G, Galecki, P, Maes, M. Affective symptoms in schizophrenia are strongly associated with neurocognitive deficits indicating disorders in executive functions, visual memory, attention, and social cognition. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt C):168–176.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Maes, M. The effects of tryptophan catabolites on negative symptoms and deficit schizophrenia are partly mediated by executive impairments: results of partial least squares path modeling. CNS Neurol Disord Drug Targets . 2018;17(6):473–486.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Matsumoto, AK, et al. Lowered antioxidant defenses and increased oxidative toxicity are hallmarks of deficit schizophrenia: a nomothetic network psychiatry approach. Mol Neurobiol. 2020;57(11):4578–4597.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Sriswasdi, S, Thika, S, et al. Deficit schizophrenia is a discrete diagnostic category defined by neuro-immune and neurocognitive features: results of supervised machine learning. Metab Brain Dis. 2018;33(4):1053–1067.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Sriswasdi, S, Thika, S, et al. Towards a new classification of stable phase schizophrenia into major and simple neuro-cognitive psychosis: results of unsupervised machine learning analysis. J Eval Clin Pract. 2018;24(4):879–891.CrossRefGoogle ScholarPubMed
CERAD. CERAD—an overview: the consortium to establish a registry for Alzheimer’s disease. http://cerad.mc.duke.edu. 1986.Google Scholar
Al-Dujaili, AH, Mousa, RF, Al-Hakeim, HK, et al. High mobility group protein 1 and Dickkopf-related protein 1 in schizophrenia and treatment-resistant schizophrenia: associations with interleukin-6, symptom domains, and neurocognitive impairments. Schizophr Bull . 2021;47(2):530–541. doi:10.1093/schbul/sbaa136.CrossRefGoogle ScholarPubMed
CANTAB. The most validated cognitive research software. http://www.cambridgecognition.com/cantab. Accessed October 1, 2018.Google Scholar
Maes, M, Sirivichayakul, S, Kanchanatawan, B, Carvalho, AF. In schizophrenia, psychomotor retardation is associated with executive and memory impairments, negative and psychotic symptoms, neurotoxic immune products, and lower natural IgM to malondialdehyde. World J Biol Psychiatry . 2020;21(5):383–401.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Matsumoto, AK, et al. Increased levels of plasma tumor necrosis factor-α mediate schizophrenia symptom dimensions and neurocognitive impairments and are inversely associated with natural IgM directed to malondialdehyde and paraoxonase 1 activity. Mol Neurobiol. 2020;57(5):2333–2345.CrossRefGoogle ScholarPubMed
Sirivichayakul, S, Kanchanatawan, B, Thika, S, Carvalho, AF, Maes, M. Eotaxin, an endogenous cognitive deteriorating chemokine (ECDC), is a major contributor to cognitive decline in normal people and to executive, memory, and sustained attention deficits, formal thought disorder, and psychopathology in schizophrenia patients. Neurotox Res. 2019;35(1):122–138.CrossRefGoogle Scholar
Sirivichayakul, S, Kanchanatawan, B, Thika, S, Carvalho, AF, Maes, M. A new schizophrenia model: immune activation is associated with the induction of different neurotoxic products which together determine memory impairments and schizophrenia symptom dimensions. CNS Neurol Disord Drug Targets . 2019;18(2):124–140.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Hemrungrojn, S, Thika, S, et al. Changes in tryptophan catabolite (TRYCAT) pathway patterning are associated with mild impairments in declarative memory in schizophrenia and deficits in semantic and episodic memory coupled with increased false-memory creation in deficit schizophrenia. Mol Neurobiol. 2018;55(6):5184–5201.CrossRefGoogle ScholarPubMed
Orellana, G, Slachevsky, A. Executive functioning in schizophrenia. Front Psychiatry . 2013;4:1–15.CrossRefGoogle Scholar
Orellana, G, Alvarado, L, Muñoz-Neira, C, Ávila, R, Méndez, MF, Slachevsky, A. Psychosis-related matricide associated with a lesion of the ventromedial prefrontal cortex. J Am Acad Psychiatry Law . 2013;41(3):401–406.Google ScholarPubMed
Maes, M, Sirivichayakul, S, Kanchanatawan, B, Vodjani, A. Breakdown of the paracellular tight and adherens junctions in the gut and blood brain barrier and damage to the vascular barrier in patients with deficit schizophrenia. Neurotox Res. 2019;36(2):306–322.CrossRefGoogle Scholar
Kirkpatrick, B, Buchanan, RW, McKenney, PD, Alphs, LD, Carpenter, WT Jr. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 1989;30(2):119–123.CrossRefGoogle Scholar
Kittirathanapaiboon, P, Khamwongpin, M. The validity of the Mini International Neuropsychiatric Interview (M.I.N.I.)—Thai version: Suanprung Hospital, Department of Mental Health, 2005.Google Scholar
Andreasen, NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Brit J Psychiatry Suppl. 1989;7:49–58.CrossRefGoogle Scholar
Kay, SR, Fiszbein, A, Lindenmayer, JP, Opler, LA. Positive and negative syndromes in schizophrenia as a function of chronicity. Acta Psychiatr Scand . 1986;74(5):507–518. doi:10.1111/j.1600-0447.1986.tb06276.x.CrossRefGoogle ScholarPubMed
Overall, JE, Gorham, DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962;10:799–812.CrossRefGoogle Scholar
Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry . 1960;23:56–62.CrossRefGoogle ScholarPubMed
WHO. Study protocol for the World Health Organization project to develop a quality of life assessment instrument (WHOQOL). Qual Life Res. 1993;2(2):153–159.CrossRefGoogle Scholar
Roomruangwong, C, Matsumoto, AK, Michelin, AP, et al. The role of immune and oxidative pathways in menstrual cycle associated depressive, physio-somatic, breast and anxiety symptoms: modulation by sex hormones. J Psychosom Res. 2020;135:110158.CrossRefGoogle ScholarPubMed
Benjamini, Y, Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289–300.Google Scholar
Ferrando, PJ, Lorenzo-Seva, U. Program FACTOR at 10: origins, development, and future directions. Psicothema . 2017;29:236–240.Google ScholarPubMed
Lorenzo-Seva, U, Ferrando, PJ. A general approach for fitting pure exploratory bifactor models. Multivariate Behav Res. 2019;54(1):15–30.CrossRefGoogle ScholarPubMed
Ringle, CM, da Silva, D, Bido, D. Structural equation modeling with the SmartPLS. Braz J Mark. 2014;13(n2):56–73.CrossRefGoogle Scholar
Levaux, MN, Potvin, S, Sepehry, AA, Sablier, J, Mendrek, A, Stip, E. Computerized assessment of cognition in schizophrenia: promises and pitfalls of CANTAB. Eur Psychiatry. 2007;22(2):104–115.CrossRefGoogle ScholarPubMed
Rushe, TM, Morris, RG, Miotto, EC, Feigenbaum, JD, Woodruff, PW, Murray, RM. Problem-solving and spatial working memory in patients with schizophrenia and with focal frontal and temporal lobe lesions. Schizophr Res. 1999;37(1):21–33.CrossRefGoogle ScholarPubMed
Leavitt, VM, Goldberg, TE. Episodic memory in schizophrenia. Neuropsychol Rev. 2009;19(3):312–323.CrossRefGoogle Scholar
Seidman, LJ, Lanca, M, Kremen, WS, Faraone, SV, Tsuang, MT. Organizational and visual memory deficits in schizophrenia and bipolar psychoses using the Rey–Osterrieth complex figure: effects of duration of illness. J Clin Exp Neuropsychol. 2003;25(7):949–964.CrossRefGoogle ScholarPubMed
Kim, HS, An, YM, Kwon, JS, Shin, MS. A preliminary validity study of the Cambridge neuropsychological test automated battery for the assessment of executive function in schizophrenia and bipolar disorder. Psychiatry Investig. 2014;11(4):394–401.CrossRefGoogle ScholarPubMed
Pantelis, C, Barnes, TR, Nelson, HE, et al. Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain . 1997;120(Pt 10):1823–1843.CrossRefGoogle ScholarPubMed
Zilles, D, Gruber, E, Falkai, P, Gruber, O. Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks. Eur Arch Psychiatry Clin Neurosci. 2010;260(7):519–525.CrossRefGoogle ScholarPubMed
Pantelis, C, Stuart, GW, Nelson, HE, Robbins, TW, Barnes, TR. Spatial working memory deficits in schizophrenia: relationship with tardive dyskinesia and negative symptoms. Am J Psychiatry . 2001;158(8):1276–1285.CrossRefGoogle ScholarPubMed
Stone, M, Gabrieli, JD, Stebbins, GT, Sullivan, EV. Working and strategic memory deficits in schizophrenia. Neuropsychology . 1998;12(2):278–288.CrossRefGoogle Scholar
Badcock, JC, Michiel, PT, Rock, D. Spatial working memory and planning ability: contrasts between schizophrenia and bipolar I disorder. Cortex . 2005;41(6):753–763.CrossRefGoogle ScholarPubMed
Bonner-Jackson, A, Yodkovik, N, Csernansky, JG, Barch, DM. Episodic memory in schizophrenia: the influence of strategy use on behavior and brain activation. Psychiatry Res. 2008;164(1):1–15.CrossRefGoogle ScholarPubMed
Hilti, CC, Delko, T, Orosz, AT, et al. Sustained attention and planning deficits but intact attentional set-shifting in neuroleptic-naïve first-episode schizophrenia patients. Neuropsychobiology . 2010;61(2):79–86.CrossRefGoogle ScholarPubMed
Fraser, D, Park, S, Clark, G, Yohanna, D, Houk, JC. Spatial serial order processing in schizophrenia. Schizophr Res. 2004;70(2–3):203–213.CrossRefGoogle Scholar
Yu, M, Tang, X, Wang, X, et al. Neurocognitive impairments in deficit and non-deficit schizophrenia and their relationships with symptom dimensions and other clinical variables. PLoS One . 2015;10(9):e0138357.CrossRefGoogle ScholarPubMed
Tamminga, CA, Buchanan, RW, Gold, JM. The role of negative symptoms and cognitive dysfunction in schizophrenia outcome. Int Clin Psychopharmacol . 1998;13(suppl 3):S21–S26.CrossRefGoogle ScholarPubMed
Harvey, PD, Koren, D, Reihenberg, A, Bowie, CR. Negative symptoms, and cognitive deficits: what is the nature of their relationship? Schizophr Bull. 2006;32(2):250–258.CrossRefGoogle ScholarPubMed
Bombin, I, Mayoral, M, Castro-Fornieles, J, et al. Neuropsychological evidence for abnormal neurodevelopment associated with early-onset psychoses. Psychol Med. 2013;43(4):757–768.CrossRefGoogle ScholarPubMed
Sewell, RA, Perry, EB, Karper, LP, et al. Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale. Schizophr Res. 2010;124(1–3):1–12.CrossRefGoogle ScholarPubMed
Saleem, MM, Harte, MK, Marshall, KM, Scally, A, Brewin, A, Neill, JC. First episode psychosis patients show impaired cognitive function—a study of a South Asian population in the UK. J Psychopharmacol. 2013;27(4):366–373.CrossRefGoogle ScholarPubMed
Eack, SM, Wojtalik, JA, Newhill, CE, Keshavan, MS, Phillips, ML. Prefrontal cortical dysfunction during visual perspective-taking in schizophrenia. Schizophr Res. 2013;150(2–3):491–497.CrossRefGoogle Scholar
Sánchez, P, Peña, J, Bengoetxea, E, et al. Improvements in negative symptoms and functional outcome after a new generation cognitive remediation program: a randomized controlled trial. Schizophr Bull. 2014;40(3):707–715.CrossRefGoogle ScholarPubMed
O’Leary, DS, Flaum, M, Kesler, ML, Flashman, LA, Arndt, S, Andreasen, NC. Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia. J Neuropsychiatry Clin Neurosci. 2000;12(1):4–15.CrossRefGoogle ScholarPubMed
Lin, IM, Fan, SY, Huang, TL, Wu, WT, Li, SM. The associations between visual attention and facial expression identification in patients with schizophrenia. Psychiatry Investig. 2013;10(4):393–398.CrossRefGoogle ScholarPubMed
Stoyanov, D, Kandilarova, S, Borgwardt, S. Translational functional neuroimaging in the explanation of depression. Balkan Med J . 2017;34(6):493–503. doi:10.4274/balkanmedj.2017.1160.CrossRefGoogle ScholarPubMed
Warne, RT, Burningham, C. Spearman’s g found in 31 non-Western nations: strong evidence that g is a universal phenomenon. Psychol Bull. 2019;145(3):237–272. doi:10.1037/bul0000184.CrossRefGoogle ScholarPubMed
Fried, EI, van Borkulo, CD, Epskamp, S, Schoevers, RA, Tuerlinckx, F, Borsboom, D. Measuring depression over time … Or not? Lack of unidimensionality and longitudinal measurement invariance in four common rating scales of depression. Psychol Assess. 2016;28(11):1354–1367. doi:10.1037/pas0000275.CrossRefGoogle ScholarPubMed
Stoyanov, D, Maes, MH. How to construct neuroscience-informed psychiatric classification? Towards nomothetic networks psychiatry. World J Psychiatry . 2021;11(1):1–12. doi:10.5498/wjp.v11.i1.1.CrossRefGoogle ScholarPubMed
Maes, M, Moraes, JB, Bonifacio, KL, et al. Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach. Metab Brain Dis. 2021;36(3):509–521. doi:10.1007/s11011-020-00656-6.CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Maes and Kanchanatawan supplementary material

Maes and Kanchanatawan supplementary material 1

Download Maes and Kanchanatawan supplementary material(PDF)
PDF 186.8 KB
Supplementary material: PDF

Maes and Kanchanatawan supplementary material

Maes and Kanchanatawan supplementary material 2

Download Maes and Kanchanatawan supplementary material(PDF)
PDF 164.1 KB
Supplementary material: PDF

Maes and Kanchanatawan supplementary material

Maes and Kanchanatawan supplementary material 3

Download Maes and Kanchanatawan supplementary material(PDF)
PDF 226.5 KB