Preprint Article Version 1 This version is not peer-reviewed

Pathway-Phenotypes of Non-responders and Partial Responders to Treatment With Antipsychotics in Schizophrenia: A Machine Learning Study

Version 1 : Received: 14 April 2020 / Approved: 15 April 2020 / Online: 15 April 2020 (08:19:08 CEST)

How to cite: Al-Hakeim, H.K.; Mousa, R.F.; Al-Dujaili, A.H.; Maes, M. Pathway-Phenotypes of Non-responders and Partial Responders to Treatment With Antipsychotics in Schizophrenia: A Machine Learning Study. Preprints 2020, 2020040231 (doi: 10.20944/preprints202004.0231.v1). Al-Hakeim, H.K.; Mousa, R.F.; Al-Dujaili, A.H.; Maes, M. Pathway-Phenotypes of Non-responders and Partial Responders to Treatment With Antipsychotics in Schizophrenia: A Machine Learning Study. Preprints 2020, 2020040231 (doi: 10.20944/preprints202004.0231.v1).

Abstract

Objective: About a third of schizophrenia patients are treatment-resistant to antipsychotic therapy. No studies established the fingerprints or pathway-phenotypes of treatment-resistant schizophrenia. The present study aimed to delineate the pathway-phenotypes of non-responders (NRTT) and partial responders (PRTT) to treatment using machine learning. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured schizophrenia symptom dimensions, 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. Results: Machine learning showed that the NRTT group is a qualitatively distinct class and is significantly discriminated from PRTT with an accuracy of 100% using a neuro-immune-opioid-cognitive (NIOC) pathway-phenotype with as main determinants list learning, controlled word association, and Tower of London test scores, CCL11, IL-6, and EM2. The top-5 symptom domains separating NRTT from PRTT were in descending order: psychomotor retardation, negative symptoms, psychosis, depression, and mannerism. Moreover, a NIOC pathway also discriminated PRTT from healthy controls with an accuracy of 100% while all PRTT and controls were authenticated as belonging to their respective classes. Conclusion: A non-response to treatment with antipsychotics is determined by increased severity of specific symptom profiles coupled with deficits in executive functions, and episodic and semantic memory, and aberrations in neuro-immune and opioid pathways. No patients showed complete remission after treatment indicating that non-remitting in PRTT is attributable to increased HMGB1 and residual deficits in attention, executive functions, and semantic memory.

Subject Areas

schizophrenia; neuroimmunomodulation; inflammation; biomarkers; major depression; treatment resistance

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