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World J Psychiatr. Jul 19, 2021; 11(7): 277-296
Published online Jul 19, 2021. doi: 10.5498/wjp.v11.i7.277
Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets
Matej Ľupták, Danica Michaličková, Zdeněk Fišar, Eva Kitzlerová, Jana Hroudová
Matej Ľupták, Danica Michaličková, Jana Hroudová, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12800, Czech Republic
Zdeněk Fišar, Eva Kitzlerová, Jana Hroudová, Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12000, Czech Republic
Author contributions: Ľupták M wrote a part of MS regarding genetics, stress and triggers of schizophrenia; Fišar Z wrote current hypotheses of schizophrenia; Michaličková D wrote immunologic processes in schizophrenia; Hroudová J wrote novel strategies for treatment of schizophrenia and completed the MS; all authors approved the final version.
Supported by the Projects Progres of Charles University, No. Q25/LF1 and No. Q27/LF1; the Grant Agency of Charles University, Czech Republic, No. 34119; and the Project Ministry of Health, Czech Republic for Conceptual Development of Research Organization, No. 64165.
Conflict-of-interest statement: Authors declare that there is no conflict of interest regarding the publication of this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jana Hroudová, MD, PharmD, PhD, Associate Professor, Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, Prague 12000, Czech Republic. hroudova.jana@gmail.com
Received: February 27, 2021
Peer-review started: February 27, 2021
First decision: March 30, 2021
Revised: April 6, 2021
Accepted: June 18, 2021
Article in press: June 18, 2021
Published online: July 19, 2021
Processing time: 138 Days and 2.9 Hours
Abstract

Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.

Keywords: Schizophrenia; Immune system; Inflammation; Genetics; Novel antipsychotics; Add-on therapy

Core Tip: This review discusses the newest insights in the pathophysiology and risk factors for schizophrenia and points out the novel approaches of antipsychotic treatment, potential diagnostic and theranostic biomarkers. The hypotheses focusing on neuromediators (dopamine, glutamate, serotonin), neuroinflammation, cannabinoid hypothesis, gut brain axis model, and other currently discussed hypotheses are summarized. Key genetic features and new findings in the pathophysiology of schizophrenia support the expansion of novel approaches in pharmacotherapy and development of non-dopaminergic antipsychotics.