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Brain Sciences
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Peripheral Biomarkers of Mental Disorders and Related Clinical Features
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Peripheral Biomarkers of Mental Disorders and Related Clinical Features

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Psychiatric Diseases".

Deadline for manuscript submissions: closed (18 December 2020) | Viewed by 62620

Special Issue Editors

Dr. Francesco Bartoli

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Guest Editor
Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
Interests: psychiatry; psychiatric epidemiology; clinical psychopharmacology; precision psychiatry
Prof. Dr. Giuseppe Carrà

E-Mail Website
Guest Editor
University of Milano-Bicocca, Milan, Italy
Interests: psychiatry; psychiatric epidemiology; addiction psychiatry; e-health

Special Issue Information

Dear Colleagues,

In recent years, scientific research has highlighted the need to clarify the underlying biological mechanisms involved in the pathophysiology of mental disorders. There has been growing interest in the identification of biomarkers detectable in serum, plasma, saliva, and cerebrospinal fluid that may represent the peripheral counterparts of central nervous system abnormalities associated with mental disorders. Such biomarkers, in combination with individual clinical characteristics, are needed for the phenotypic characterization of different mental disorders in terms of diagnosis, prognosis, clinical course, and response to treatment.

This Special Issue will present studies focused on the identification of potential peripheral biomarkers for mental disorders and related behaviors. It will include original research articles testing relevant biomarkers for various mental disorders, including the schizophrenia spectrum, bipolar and major depressive disorders, or related clinical features, such as suicide-related and aggressive behaviors. Special attention will be given to studies with negative results, based on rigorous methods, since publication bias due to the excess of published studies with positive results may significantly affect this topic. Systematic reviews and meta-analyses of observational studies are particularly welcome. General overview articles will be also considered.

Dr. Francesco Bartoli
Prof. Dr. Giuseppe Carrà
Guest Editors

Manuscript Submission Information

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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. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). 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.

Keywords

  • biomarkers
  • schizophrenia
  • bipolar disorder
  • major depressive disorder
  • observational studies
  • systematic review
  • meta-analysis

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Published Papers (11 papers)

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Editorial

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3 pages, 219 KiB  
Editorial
Focus on Peripheral Biomarkers of Mental Disorders
by Francesco Bartoli and Giuseppe Carrà
Brain Sci. 2022, 12(6), 756; https://doi.org/10.3390/brainsci12060756 - 8 Jun 2022
Cited by 1 | Viewed by 2153
Abstract
Personalized approaches in psychiatry, albeit being extensively explored in the literature since the early 2010s [...] Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)

Research

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10 pages, 510 KiB  
Article
Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte and Monocyte-to-Lymphocyte Ratio in Bipolar Disorder
by Laura Fusar-Poli, Antimo Natale, Andrea Amerio, Patriciu Cimpoesu, Pietro Grimaldi Filioli, Eugenio Aguglia, Mario Amore, Gianluca Serafini and Andrea Aguglia
Brain Sci. 2021, 11(1), 58; https://doi.org/10.3390/brainsci11010058 - 6 Jan 2021
Cited by 55 | Viewed by 4100
Abstract
Background: Several inflammatory hypotheses have been suggested to explain the etiopathogenesis of bipolar disorder (BD) and its different phases. Neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios have been proposed as potential peripheral biomarkers of mood episodes. Methods: We recruited 294 patients affected [...] Read more.
Background: Several inflammatory hypotheses have been suggested to explain the etiopathogenesis of bipolar disorder (BD) and its different phases. Neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios have been proposed as potential peripheral biomarkers of mood episodes. Methods: We recruited 294 patients affected by BD, of which 143 were experiencing a (hypo)manic episode and 151 were in a depressive phase. A blood sample was drawn to perform a complete blood count. NLR, PLR, and MLR were subsequently calculated. A t-test was performed to evaluate differences in blood cell counts between depressed and (hypo)manic patients and a regression model was then computed. Results: Mean values of neutrophils, platelets, mean platelet volume, NLR, PLR, and MLR were significantly higher in (hypo)manic than depressed individuals. Logistic regression showed that PLR may represent an independent predictor of (hypo)mania. Conclusions: Altered inflammatory indexes, particularly PLR, may explain the onset and recurrence of (hypo)manic episodes in patients with BD. As inflammatory ratios represent economical and accessible markers of inflammation, further studies should be implemented to better elucidate their role as peripheral biomarkers of BD mood episodes. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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17 pages, 1300 KiB  
Article
How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia
by Michael Maes, Aristo Vojdani, Piotr Galecki and Buranee Kanchanatawan
Brain Sci. 2020, 10(9), 645; https://doi.org/10.3390/brainsci10090645 - 17 Sep 2020
Cited by 19 | Viewed by 3200
Abstract
Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic [...] Read more.
Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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11 pages, 251 KiB  
Article
Effects of Direct-Acting Antiviral Agents on the Mental Health of Patients with Chronic Hepatitis C: A Prospective Observational Study
by Michele Fabrazzo, Rosa Zampino, Martina Vitrone, Gaia Sampogna, Lucia Del Gaudio, Daniela Nunziata, Salvatore Agnese, Anna Santagata, Emanuele Durante-Mangoni and Andrea Fiorillo
Brain Sci. 2020, 10(8), 483; https://doi.org/10.3390/brainsci10080483 - 27 Jul 2020
Cited by 12 | Viewed by 2368
Abstract
In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients’ mental [...] Read more.
In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients’ mental status, before and 12 weeks after DAA therapy, by assessment scales and psychometric instruments. We subdivided patients into two groups, CHC patients with (Group A) or without (Group B) a current and/or past psychiatric history. After DAA treatment, Group A patients showed low anxiety and improved depression, no variation in self-report distress, but worse general health perceptions. No significant difference emerged from coping strategies. Depression and anxiety improved in Group B, and no change emerged from total self-reported distress, except for somatization. Moreover, Group B increased problem-focused strategies for suppression of competing activities, and decreased strategies of instrumental social support. Contrarily, Group B reduced significantly emotion-focused strategies, such as acceptance and mental disengagement, and improved vitality, physical and social role functioning. DAA therapy is safe and free of hepatological and psychiatric side effects in CHC patients, regardless of current and/or past psychiatric history. In particular, patients without a psychiatric history also remarkably improved their quality of life. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
11 pages, 300 KiB  
Article
Clinical Severity and Calcium Metabolism in Patients with Bipolar Disorder
by Luca Steardo, Jr., Mario Luciano, Gaia Sampogna, Elvira Anna Carbone, Vito Caivano, Arcangelo Di Cerbo, Vincenzo Giallonardo, Carmela Palummo, Alfonso Vece, Valeria Del Vecchio, Pasquale De Fazio and Andrea Fiorillo
Brain Sci. 2020, 10(7), 417; https://doi.org/10.3390/brainsci10070417 - 1 Jul 2020
Cited by 16 | Viewed by 5952
Abstract
Parathyroid hormone (PTH), vitamin D and serum calcium play a key role in several physiological and pathological conditions. Vitamin D and PTH receptors are largely expressed in the central nervous system and are involved in the modulation of inflammatory responses. Few studies investigated [...] Read more.
Parathyroid hormone (PTH), vitamin D and serum calcium play a key role in several physiological and pathological conditions. Vitamin D and PTH receptors are largely expressed in the central nervous system and are involved in the modulation of inflammatory responses. Few studies investigated the association between calcium homeostasis imbalance and psychiatric disorders. This study aims to assess calcium homeostasis imbalance in patients with bipolar disorder (BD) and its impact on clinical outcome. We recruited 199 patients with BD, who were administered with validated assessment instruments to investigate depressive, manic and anxiety symptoms, affective temperaments, childhood trauma and global functioning. Serum calcium, vitamin D and PTH levels were assessed in all patients. Levels of PTH correlated with several clinical characteristics, including the diagnosis of bipolar disorder type I (BD-I), the presence of psychotic symptoms, lithium treatment, suicidality, total number of acute episodes and of hospitalizations (p < 0.0001) and seasonality (p < 0.05). At the regression analyses, higher levels of PTH were predicted by early age at onset, number of hospitalizations, aggressive behaviors (p < 0.05), higher Childhood Trauma Questionnaire total score (CTQ) (p < 0.001) and treatment with lithium (p = 0.01). Our findings suggest that the calcium homeostasis could play a role in BD patients, and that PTH levels are correlated with the clinical severity of the disorder. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
9 pages, 278 KiB  
Communication
Markers of Regenerative Processes in Patients with Bipolar Disorder: A Case-control Study
by Artur Reginia, Jerzy Samochowiec, Marcin Jabłoński, Ewa Ferensztajn-Rochowiak, Janusz K. Rybakowski, Arkadiusz Telesiński, Maciej Tarnowski, Błażej Misiak, Mariusz Z. Ratajczak and Jolanta Kucharska-Mazur
Brain Sci. 2020, 10(7), 408; https://doi.org/10.3390/brainsci10070408 - 30 Jun 2020
Cited by 3 | Viewed by 2433
Abstract
Progress in medical science has allowed the discovery of many factors affecting the pathogenesis of bipolar disorder, and among the most recent research directions are found regenerative and inflammatory processes. The role of regenerative processes remains particularly poorly explored, but available data encourage [...] Read more.
Progress in medical science has allowed the discovery of many factors affecting the pathogenesis of bipolar disorder, and among the most recent research directions are found regenerative and inflammatory processes. The role of regenerative processes remains particularly poorly explored, but available data encourage further research, which may explain the pathogenesis of bipolar disorder (BD). The aim of this study was to evaluate the mobilization of stem cells into peripheral blood, in patients with bipolar disorder during stable phase, not treated with lithium salts. The study included 30 unrelated individuals with the diagnosis of bipolar disorder, with disease duration of at least 10 years, not treated with lithium salts for at least five years prior to the study. The control group consisted of 30 healthy subjects, matched for age, sex, body mass index (BMI), origin, socio-demographic factors and nicotine use. Blood samples underwent cytometric analyses to assess concentrations of: Very Small Embryonic Like (VSEL) CD34+, VSEL AC133+, HSC CD34+, HSC AC133+. There were no significant differences in stem cell levels between patients with BD and healthy controls. However, the level of VSEL cells AC133 + was significantly higher in type I BD patients compared to healthy controls. Our results indicate a disturbance in regenerative processes in patients with bipolar disorder. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)

Review

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12 pages, 582 KiB  
Review
The Involvement of Hypothalamus–Pituitary–Adrenal (HPA) Axis in Suicide Risk
by Isabella Berardelli, Gianluca Serafini, Natalia Cortese, Federica Fiaschè, Rory C O’Connor and Maurizio Pompili
Brain Sci. 2020, 10(9), 653; https://doi.org/10.3390/brainsci10090653 - 21 Sep 2020
Cited by 116 | Viewed by 8009
Abstract
Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal [...] Read more.
Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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37 pages, 1199 KiB  
Review
Peripheral Biomarkers in DSM-5 Anxiety Disorders: An Updated Overview
by Matteo Vismara, Nicolaja Girone, Giovanna Cirnigliaro, Federica Fasciana, Simone Vanzetto, Luca Ferrara, Alberto Priori, Claudio D’Addario, Caterina Viganò and Bernardo Dell’Osso
Brain Sci. 2020, 10(8), 564; https://doi.org/10.3390/brainsci10080564 - 17 Aug 2020
Cited by 24 | Viewed by 17025
Abstract
Anxiety disorders are prevalent and highly disabling mental disorders. In recent years, intensive efforts focused on the search for potential neuroimaging, genetic, and peripheral biomarkers in order to better understand the pathophysiology of these disorders, support their diagnosis, and characterize the treatment response. [...] Read more.
Anxiety disorders are prevalent and highly disabling mental disorders. In recent years, intensive efforts focused on the search for potential neuroimaging, genetic, and peripheral biomarkers in order to better understand the pathophysiology of these disorders, support their diagnosis, and characterize the treatment response. Of note, peripheral blood biomarkers, as surrogates for the central nervous system, represent a promising instrument to characterize psychiatric disorders, although their role has not been extensively applied to clinical practice. In this report, the state of the art on peripheral biomarkers of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) Anxiety Disorders is presented, in order to examine their role in the pathogenesis of these conditions and their potential application for diagnosis and treatment. Available data on the cerebrospinal fluid and blood-based biomarkers related to neurotransmitters, neuropeptides, the hypothalamic–pituitary–adrenal axis, neurotrophic factors, and the inflammation and immune system are reviewed. Despite the wide scientific literature and the promising results in the field, only a few of the proposed peripheral biomarkers have been defined as a specific diagnostic instrument or have been identified as a guide in the treatment response to DSM-5 Anxiety Disorders. Therefore, further investigations are needed to provide new biological insights into the pathogenesis of anxiety disorders, to help in their diagnosis, and to tailor a treatment. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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13 pages, 795 KiB  
Review
Risk Calculators in Bipolar Disorder: A Systematic Review
by Joana Silva Ribeiro, Daniela Pereira, Estela Salagre, Manuel Coroa, Pedro Santos Oliveira, Vítor Santos, Nuno Madeira, Iria Grande and Eduard Vieta
Brain Sci. 2020, 10(8), 525; https://doi.org/10.3390/brainsci10080525 - 6 Aug 2020
Cited by 16 | Viewed by 5502
Abstract
Introduction: Early recognition of bipolar disorder improves the prognosis and decreases the burden of the disease. However, there is a significant delay in diagnosis. Multiple risk factors for bipolar disorder have been identified and a population at high-risk for the disorder has been [...] Read more.
Introduction: Early recognition of bipolar disorder improves the prognosis and decreases the burden of the disease. However, there is a significant delay in diagnosis. Multiple risk factors for bipolar disorder have been identified and a population at high-risk for the disorder has been more precisely defined. These advances have allowed the development of risk calculators to predict individual risk of conversion to bipolar disorder. This review aims to identify the risk calculators for bipolar disorder and assess their clinical applicability. Methods: A systematic review of original studies on the development of risk calculators in bipolar disorder was performed. The studies’ quality was evaluated with the Newcastle-Ottawa Quality Assessment Form for Cohort Studies and according to recommendations of the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Initiative. Results: Three studies met the inclusion criteria; one developed a risk calculator of conversion from major depressive episode to bipolar disorder; one of conversion to new-onset bipolar spectrum disorders in offspring of parents with bipolar disorder; and the last one of conversion in youths with bipolar disorder not-otherwise-specified. Conclusions: The calculators reviewed in this article present good discrimination power for bipolar disorder, although future replication and validation of the models is needed. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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Other

12 pages, 9906 KiB  
Opinion
Biological Pathways Associated with Neuroprogression in Bipolar Disorder
by Bianca Wollenhaupt-Aguiar, Flavio Kapczinski and Bianca Pfaffenseller
Brain Sci. 2021, 11(2), 228; https://doi.org/10.3390/brainsci11020228 - 12 Feb 2021
Cited by 13 | Viewed by 5110
Abstract
There is evidence suggesting clinical progression in a subset of patients with bipolar disorder (BD). This progression is associated with worse clinical outcomes and biological changes. Molecular pathways and biological markers of clinical progression have been identified and may explain the progressive changes [...] Read more.
There is evidence suggesting clinical progression in a subset of patients with bipolar disorder (BD). This progression is associated with worse clinical outcomes and biological changes. Molecular pathways and biological markers of clinical progression have been identified and may explain the progressive changes associated with this disorder. The biological basis for clinical progression in BD is called neuroprogression. We propose that the following intertwined pathways provide the biological basis of neuroprogression: inflammation, oxidative stress, impaired calcium signaling, endoplasmic reticulum and mitochondrial dysfunction, and impaired neuroplasticity and cellular resilience. The nonlinear interaction of these pathways may worsen clinical outcomes, cognition, and functioning. Understanding neuroprogression in BD is crucial for identifying novel therapeutic targets, preventing illness progression, and ultimately promoting better outcomes. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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12 pages, 475 KiB  
Opinion
Purinergic Signaling and Related Biomarkers in Depression
by Francesco Bartoli, Geoffrey Burnstock, Cristina Crocamo and Giuseppe Carrà
Brain Sci. 2020, 10(3), 160; https://doi.org/10.3390/brainsci10030160 - 12 Mar 2020
Cited by 40 | Viewed by 5550
Abstract
It is established that purinergic signaling can shape a wide range of physiological functions, including neurotransmission and neuromodulation. The purinergic system may play a role in the pathophysiology of mood disorders, influencing neurotransmitter systems and hormonal pathways of the hypothalamic-pituitary-adrenal axis. Treatment with [...] Read more.
It is established that purinergic signaling can shape a wide range of physiological functions, including neurotransmission and neuromodulation. The purinergic system may play a role in the pathophysiology of mood disorders, influencing neurotransmitter systems and hormonal pathways of the hypothalamic-pituitary-adrenal axis. Treatment with mood stabilizers and antidepressants can lead to changes in purinergic signaling. In this overview, we describe the biological background on the possible link between the purinergic system and depression, possibly involving changes in adenosine- and ATP-mediated signaling at P1 and P2 receptors, respectively. Furthermore, evidence on the possible antidepressive effects of non-selective adenosine antagonist caffeine and other purinergic modulators is reviewed. In particular, A2A and P2X7 receptors have been identified as potential targets for depression treatment. Preclinical studies highlight that both selective A2A and P2X7 antagonists may have antidepressant effects and potentiate responses to antidepressant treatments. Consistently, recent studies feature the possible role of the purinergic system peripheral metabolites as possible biomarkers of depression. In particular, variations of serum uric acid, as the end product of purinergic metabolism, have been found in depression. Although several open questions remain, the purinergic system represents a promising research area for insights into the molecular basis of depression. Full article
(This article belongs to the Special Issue Peripheral Biomarkers of Mental Disorders and Related Clinical Features)
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