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Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2017) | Viewed by 122023

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Prof. Dr. Yong-Ku Kim

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Department of Psychiatry, College of Medicine, Korea University, Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Seoul 15355, Korea
Interests: biological psychiatry
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Schizophrenia is a chronic and debilitating mental disorder. Schizophrenia is characterized by premorbid psychological deficits, onset of psychosis in late adolescence, and psychological deterioration in adulthood. The pathophysiology of the disease involves both genes and environment. The etiology of the disease is attributed to the failure of normal neuronal development due to environmental factors or a genetic defect manifesting itself during gestation or the perinatal period. Such defects alter the development of the CNS in some way. The resulting developmental deficit accounts for the premorbid cognitive and psychosocial dysfunction in schizophrenia. Schizophrenia is characterized by positive, negative, and cognitive symptoms with poor insight and impaired psychosocial function. Although acute psychosis is controlled with pharmacotherapy, negative and cognitive symptoms tend to be unresponsive to pharmacotherapy. Impaired neurogenesis and an ineffective response to antipsychotics are thought to indicate a deteriorating course of schizophrenia. Oxidative stress and excessive dopaminergic neurotransmission create a vicious cycle and consequently disturb NMDA receptor-mediated glutamatergic neurotransmission. Recent several neuroprotective therapeutic approaches are considered efficacious for improving psychopathology in schizophrenia. Intervention strategies in adolescents at ultra high-risk for psychosis are crucial for reducing conversion to schizophrenia. Early intervention in premorbid phase of schizophrenia may improve current difficulties and prevent future schizophrenia using adequate treatments. In this Special Issue, we aimed to focus on causes, diagnosis, treatments and prevention in schizophrenia.

Prof. Dr. Yong-Ku Kim
Guest Editor

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Keywords

schizophrenia
psychopathology
treatment
prevention
high-risk
cause
diagnosis
etiology
symptoms
prognosis

Related Special Issue

Biomarkers Guided Diagnosis and Therapy: Toward Precision Psychiatry in International Journal of Molecular Sciences (11 articles)

Published Papers (12 papers)

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Research

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1543 KiB

Open AccessArticle

Abnormally Increased Secretion in Olfactory Neuronal Precursors from a Case of Schizophrenia Is Modulated by Melatonin: A Pilot Study

by Montserrat G. Cercós, Tania Galván-Arrieta, Marcela Valdés-Tovar, Héctor Solís-Chagoyán, Jesús Argueta, Gloria Benítez-King and Citlali Trueta

Int. J. Mol. Sci. 2017, 18(7), 1439; https://doi.org/10.3390/ijms18071439 - 13 Jul 2017

Cited by 8 | Viewed by 4163

Abstract

The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessArticle

Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway

by Saki Shimizu, Shunsaku Sogabe, Ryoto Yanagisako, Akiyoshi Inada, Megumi Yamanaka, Higor A. Iha and Yukihiro Ohno

Int. J. Mol. Sci. 2017, 18(7), 1416; https://doi.org/10.3390/ijms18071416 - 03 Jul 2017

Cited by 11 | Viewed by 8275

Abstract

Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-N^G-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessArticle

Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia

by Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Shinya Watanabe, Hidehiro Umehara, Shinji Shimodera, Takanobu Nakazawa, Masataka Kikuchi, Akihiro Nakaya, Hitoshi Hashimoto, Issei Imoto, Ryota Hashimoto and Tetsuro Ohmori

Int. J. Mol. Sci. 2017, 18(3), 632; https://doi.org/10.3390/ijms18030632 - 14 Mar 2017

Cited by 45 | Viewed by 5719

Abstract

Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for “cell substrate adhesion” and “cell matrix adhesion” gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Review

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13 pages, 1468 KiB

Open AccessReview

Mapping the Schizophrenia Genes by Neuroimaging: The Opportunities and the Challenges

by Ayla Arslan

Int. J. Mol. Sci. 2018, 19(1), 219; https://doi.org/10.3390/ijms19010219 - 11 Jan 2018

Cited by 9 | Viewed by 6122

Abstract

Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collection, emergence of non-candidate gene (hypothesis-free) approach of neuroimaging genetics are likely to contribute to a rapid progress for gene discovery besides to gene validation studies that are related to SZ. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessReview

Unresolved Issues for Utilization of Atypical Antipsychotics in Schizophrenia: Antipsychotic Polypharmacy and Metabolic Syndrome

by Sang Won Jeon and Yong-Ku Kim

Int. J. Mol. Sci. 2017, 18(10), 2174; https://doi.org/10.3390/ijms18102174 - 18 Oct 2017

Cited by 62 | Viewed by 7422

Abstract

Atypical antipsychotics (AAP) are the prevailing form of schizophrenia treatment today due to their low side effects and superior efficacy. Nevertheless, some issues still need to be addressed. First, there are still a large number of patients with treatment-resistant schizophrenia (TRS), which has led to a growing trend to resort to AAP polypharmacy with few side effects. Most clinical treatment guidelines recommend clozapine monotherapy in TRS, but around one third of schizophrenic patients fail to respond to clozapine. For these patients, with clozapine-resistant schizophrenia AAP polypharmacy is a common strategy with a continually growing evidence base. Second, AAP generally have great risks for developing metabolic syndrome, such as weight gain, abnormality in glucose, and lipid metabolism. These metabolic side effects have become huge stumbling blocks in today’s schizophrenia treatment that aims to improve patients’ quality of life as well as symptoms. The exact reasons why this particular syndrome occurs in patients treated with AAP is as yet unclear though factors such as interaction of AAP with neurotransmitter receptors, genetic pholymorphisms, type of AAPs, length of AAP use, and life style of schizophrenic patients that may contribute to its development. The present article aimed to review the evidence underlying these key issues and provide the most reasonable interpretations to expand the overall scope of antipsychotics usage. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

731 KiB

Open AccessReview

Dysbindin-1 Involvement in the Etiology of Schizophrenia

by Haitao Wang, Jiangping Xu, Philip Lazarovici and Wenhua Zheng

Int. J. Mol. Sci. 2017, 18(10), 2044; https://doi.org/10.3390/ijms18102044 - 22 Sep 2017

Cited by 30 | Viewed by 7627

Abstract

Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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331 KiB

Open AccessReview

Multiple Sclerosis and Schizophrenia

by Borros M. Arneth

Int. J. Mol. Sci. 2017, 18(8), 1760; https://doi.org/10.3390/ijms18081760 - 12 Aug 2017

Cited by 19 | Viewed by 6912

Abstract

The psychiatric and neurological aspects of health may present methodological challenges in the diagnosis and treatment of disease. This is especially true for patients whose symptoms indicate the coexistence of multiple sclerosis (MS) and schizophrenia (SCZ). These cases raise critical questions regarding the relationship between the mind and the brain. Studies have noted that patients with MS have an increased risk of developing SCZ or bipolar disorder (BD). It is suggested here that MS and a subgroup of SCZ have similar etiologies. Factors such as gender, ethnicity, geography and season also have an influence on the occurrence of MS and SCZ. This paper aims to examine the differences and similarities between SCZ and MS. For this purpose, scientific papers examining various factors associated with these disorders were reviewed, and similarities and differences in genetic, immunological, seasonal, geographical, and gender-related risk factors and limited similarities in ethnic factors between the two diseases were identified. The findings suggest that subgroups of these two diseases may belong to the same class of disorders. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessReview

New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis

by Albert C. Yang and Shih-Jen Tsai

Int. J. Mol. Sci. 2017, 18(8), 1689; https://doi.org/10.3390/ijms18081689 - 03 Aug 2017

Cited by 175 | Viewed by 42352

Abstract

Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA) signaling, which may lead to aberrant functioning of interneurons that manifest as cognitive, behavioral, and social dysfunction through altered functioning of a broad range of macro- and microcircuits. The interactions between neurotransmitters can be modeled as nodes and edges by using graph theory, and oxidative balance, immune, and glutamatergic systems may represent multiple nodes interlocking at a central hub; imbalance within any of these nodes might affect the entire system. Therefore, this review attempts to address novel treatment targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. Furthermore, we outline that these treatment targets can be possibly integrated with novel treatment strategies aimed at different symptoms or phases of the illness. We anticipate that reversing anomalous activity in these novel treatment targets or combinations between these strategies might be beneficial in the treatment of schizophrenia. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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256 KiB

Open AccessReview

Rethinking the Epigenetic Framework to Unravel the Molecular Pathology of Schizophrenia

by Ariel Cariaga-Martinez and Raúl Alelú-Paz

Int. J. Mol. Sci. 2017, 18(4), 790; https://doi.org/10.3390/ijms18040790 - 07 Apr 2017

Cited by 9 | Viewed by 4840

Abstract

Schizophrenia is a complex mental disorder whose causes are still far from being known. Although researchers have focused on genetic or environmental contributions to the disease, we still lack a scientific framework that joins molecular and clinical findings. Epigenetic can explain how environmental variables may affect gene expression without modifying the DNA sequence. In fact, neuroepigenomics represents an effort to unify the research available on the molecular pathology of mental diseases, which has been carried out through several approaches ranging from interrogating single DNA methylation events and hydroxymethylation patterns, to epigenome-wide association studies, as well as studying post-translational modifications of histones, or nucleosomal positioning. The high dependence on tissues with epigenetic marks compels scientists to refine their sampling procedures, and in this review, we will focus on findings obtained from brain tissue. Despite our efforts, we still need to refine our hypothesis generation process to obtain real knowledge from a neuroepigenomic framework, to avoid the creation of more noise on this innovative point of view; this may help us to definitively unravel the molecular pathology of severe mental illnesses, such as schizophrenia. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

212 KiB

Open AccessReview

A Novel Bio-Psychosocial-Behavioral Treatment Model in Schizophrenia

by Yong-Ku Kim, Joonho Choi and Seon-Cheol Park

Int. J. Mol. Sci. 2017, 18(4), 734; https://doi.org/10.3390/ijms18040734 - 30 Mar 2017

Cited by 15 | Viewed by 5225

Abstract

Despite the substantial burden of illness in schizophrenia, there has been a discrepancy between the beneficial effects of an increased use of antipsychotic medications and achieving limited recovery or remission. Because the focus of the most common antipsychotic medications is on dopamine, which is associated with positive symptoms, there is an unmet need for patients with negative symptoms. Since cognitive and negative symptoms rather than positive symptoms are more closely associated with psychosocial impairments in patients with schizophrenia, the non-dopaminergic systems including glutamate and γ-aminobutyric acid (GABA) of the prefrontal cortex should be of concern as well. The balance of excitation and inhibition has been associated with epigenetic modifications and thus can be analyzed in terms of a neurodevelopmental and neural circuitry perspective. Hence, a novel bio-psychosocial-behavioral model for the treatment of schizophrenia is needed to account for the non-dopaminergic systems involved in schizophrenia, rather than dopaminergic mechanisms. This model can be understood from the viewpoint of neurodevelopment and neural circuitry and should include the staging care, personalized care, preventive care, reducing the cognitive deficits, and reducing stigma. Thomas R. Insel proposed this as a goal for schizophrenia treatment to be achieved by 2030. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessReview

Theranostic Biomarkers for Schizophrenia

by Matea Nikolac Perkovic, Gordana Nedic Erjavec, Dubravka Svob Strac, Suzana Uzun, Oliver Kozumplik and Nela Pivac

Int. J. Mol. Sci. 2017, 18(4), 733; https://doi.org/10.3390/ijms18040733 - 30 Mar 2017

Cited by 73 | Viewed by 11568

Abstract

Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

by Henry Barron, Sina Hafizi, Ana C. Andreazza and Romina Mizrahi

Int. J. Mol. Sci. 2017, 18(3), 651; https://doi.org/10.3390/ijms18030651 - 17 Mar 2017

Cited by 120 | Viewed by 9947

Abstract

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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