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In schizophrenia, non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy

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Abstract

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and μ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

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Data availability

The dataset generated during and/or analyzed during the current study will be available from the corresponding author upon reasonable request and once the dataset has been fully exploited by the authors.

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Acknowledgments

We thank the staff of the Psychiatry Unit at Al-Imam Al-Hussain Medical City in Karbala city for their help in the collection of samples and the high-skilled staff members of Asia Clinical Laboratory, Najaf city, for their help in the assays.

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Authors and Affiliations

  1. Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq

    Hussein Kadhem Al-Hakeim

  2. Faculty of Veterinary Medicine, University of Kerbala, Kerbala, Iraq

    Rana Fadhil Mousa

  3. Senior Clinical Psychiatrist at the Faculty of Medicine, University of Kufa, Kufa, Iraq

    Arafat Hussein Al-Dujaili

  4. Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand

    Michael Maes

  5. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  6. School of Medicine, IMPACT Strategic Research Centre, Deakin University, PO Box 281, Geelong, VIC, 3220, Australia

    Michael Maes

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  1. Hussein Kadhem Al-Hakeim
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  3. Arafat Hussein Al-Dujaili
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Contributions

All the contributing authors have participated in the preparation of the manuscript. H.K.A.-H., R.F.M., A.H.A.-D. and M.M. conceived and designed the experiments; H.K.A.-H. and R.F.M. performed the experiments; A.H.A.-D. diagnosed the patients and completed the psychiatric rating scales of patients and controls. M.M., and H.K.A.-H. analyzed the data; H.K.A.-H., R.F.M., A.H.A.-D., and M.M. wrote the paper. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Michael Maes.

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Approval for the study was obtained from the Institutional Review Board of the University of Karbala (418/2019) and Karbala Health Department (1331/2019), Iraq.

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Al-Hakeim, H.K., Mousa, R.F., Al-Dujaili, A.H. et al. In schizophrenia, non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy. Metab Brain Dis 36, 939–955 (2021). https://doi.org/10.1007/s11011-021-00685-9

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