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Identifying the Molecular Mechanisms of Psychiatric Disorders to Define New Therapeutic Targets 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 January 2024) | Viewed by 4560

Special Issue Editor

Dr. Shira Knafo

E-Mail Website
Guest Editor
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, The National Institute for Biotechnology in the Negev, Beer-Sheva 84105, Israel
Interests: cognition; plasticity; psychiatry; molecular biology; electrophysiology; Alzheimer's; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Psychiatric disorders constitute a broad group of diseases, including anxiety, depression, schizophrenia, bipolar disorder, and autism. Psychiatric disorders have specific behavioral and mental patterns and are characterized by atypical behavior, ideas, perceptions, emotions, and relationships. Currently, therapeutic approaches revolve around correcting the imbalance in the function of neurotransmitters such as dopamine, serotonin, GABA, and norepinephrine for most psychiatric disorders. However, although new generations of neurotransmitter-based therapies (including antipsychotics, serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors) are available, the efficacy of these medications is limited. In addition, relapse rates in psychiatric disorders are relatively high, indicating the potential involvement of other pathological mechanisms. Indeed, recent genetics and molecular biology studies have shown that the pathogenesis of major psychiatric illnesses involves hundreds of genes and numerous signaling pathways. This Special Issue aims to present new data regarding cellular and molecular mechanisms contributing to such disorders to nominate new candidate targets for future drug development.

Dr. Shira Knafo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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30 pages, 2924 KiB  
Article
Molecular Mechanism Biomarkers Predict Diagnosis in Schizophrenia and Schizoaffective Psychosis, with Implications for Treatment
by Stephanie Fryar-Williams, Graeme Tucker, Jörg Strobel, Yichao Huang and Peter Clements
Int. J. Mol. Sci. 2023, 24(21), 15845; https://doi.org/10.3390/ijms242115845 - 31 Oct 2023
Cited by 1 | Viewed by 1200
Abstract
Diagnostic uncertainty and relapse rates in schizophrenia and schizoaffective disorder are relatively high, indicating the potential involvement of other pathological mechanisms that could serve as diagnostic indicators to be targeted for adjunctive treatment. This study aimed to seek objective evidence of methylenetetrahydrofolate reductase [...] Read more.
Diagnostic uncertainty and relapse rates in schizophrenia and schizoaffective disorder are relatively high, indicating the potential involvement of other pathological mechanisms that could serve as diagnostic indicators to be targeted for adjunctive treatment. This study aimed to seek objective evidence of methylenetetrahydrofolate reductase MTHFR C677T genotype-related bio markers in blood and urine. Vitamin and mineral cofactors related to methylation and indolamine-catecholamine metabolism were investigated. Biomarker status for 67 symptomatically well-defined cases and 67 asymptomatic control participants was determined using receiver operating characteristics, Spearman’s correlation, and logistic regression. The 5.2%-prevalent MTHFR 677 TT genotype demonstrated a 100% sensitive and specific case-predictive biomarkers of increased riboflavin (vitamin B2) excretion. This was accompanied by low plasma zinc and indicators of a shift from low methylation to high methylation state. The 48.5% prevalent MTHFR 677 CC genotype model demonstrated a low-methylation phenotype with 93% sensitivity and 92% specificity and a negative predictive value of 100%. This model related to lower vitamin cofactors, high histamine, and HPLC urine indicators of lower vitamin B2 and restricted indole-catecholamine metabolism. The 46.3%-prevalent CT genotype achieved high predictive strength for a mixed methylation phenotype. Determination of MTHFR C677T genotype dependent functional biomarker phenotypes can advance diagnostic certainty and inform therapeutic intervention. Full article
(This article belongs to the Special Issue Identifying the Molecular Mechanisms of Psychiatric Disorders to Define New Therapeutic Targets 2.0)
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Review

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26 pages, 2480 KiB  
Review
Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes
by Adonis Sfera, Hassan Imran, Dan O. Sfera, Jacob J. Anton, Zisis Kozlakidis and Sabine Hazan
Int. J. Mol. Sci. 2024, 25(11), 5904; https://doi.org/10.3390/ijms25115904 - 28 May 2024
Viewed by 172
Abstract
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over [...] Read more.
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists. Full article
(This article belongs to the Special Issue Identifying the Molecular Mechanisms of Psychiatric Disorders to Define New Therapeutic Targets 2.0)
17 pages, 749 KiB  
Review
Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target
by Rinako Tanaka and Kiyofumi Yamada
Int. J. Mol. Sci. 2023, 24(21), 15623; https://doi.org/10.3390/ijms242115623 - 26 Oct 2023
Cited by 1 | Viewed by 1511
Abstract
Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity [...] Read more.
Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in Arhgap10 S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways. Full article
(This article belongs to the Special Issue Identifying the Molecular Mechanisms of Psychiatric Disorders to Define New Therapeutic Targets 2.0)
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17 pages, 1851 KiB  
Review
Molecular Mechanisms Provide a Landscape for Biomarker Selection for Schizophrenia and Schizoaffective Psychosis
by Stephanie Fryar-Williams, Jörg Strobel and Peter Clements
Int. J. Mol. Sci. 2023, 24(20), 15296; https://doi.org/10.3390/ijms242015296 - 18 Oct 2023
Cited by 2 | Viewed by 1232
Abstract
Research evaluating the role of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) gene in schizophrenia has not yet provided an extended understanding of the proximal pathways contributing to the 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme’s activity and the distal pathways being affected by its activity. [...] Read more.
Research evaluating the role of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) gene in schizophrenia has not yet provided an extended understanding of the proximal pathways contributing to the 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme’s activity and the distal pathways being affected by its activity. This review investigates these pathways, describing mechanisms relevant to riboflavin availability, trace mineral interactions, and the 5-methyltetrahydrofolate (5-MTHF) product of the MTHFR enzyme. These factors remotely influence vitamin cofactor activation, histamine metabolism, catecholamine metabolism, serotonin metabolism, the oxidative stress response, DNA methylation, and nicotinamide synthesis. These biochemical components form a broad interactive landscape from which candidate markers can be drawn for research inquiry into schizophrenia and other forms of mental illness. Candidate markers drawn from this functional biochemical background have been found to have biomarker status with greater than 90% specificity and sensitivity for achieving diagnostic certainty in schizophrenia and schizoaffective psychosis. This has implications for achieving targeted treatments for serious mental illness. Full article
(This article belongs to the Special Issue Identifying the Molecular Mechanisms of Psychiatric Disorders to Define New Therapeutic Targets 2.0)
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