Plasma Protein Biomarkers for Depression and Schizophrenia by Multi Analyte Profiling of Case-Control Collections

Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections.     

The severity of psychiatric disorders

The issue of the severity of psychiatric disorders has great clinical importance. For example, severity influences decisions about level of care, and affects decisions to seek government assistance due to psychiatric disability. Controversy exists as to the efficacy of antidepressants across the spectrum of depression severity, and whether patients with severe depression should be preferentially treated with medication rather than psychotherapy. Measures of severity are used to evaluate outcome in treatment studies and may be used as meaningful endpoints in clinical practice. But, what does it mean to say that someone has a severe illness? Does severity refer to the number of symptoms a patient is experiencing? To the intensity of the symptoms? To symptom frequency or persistence? To the impact of symptoms on functioning or on quality of life? To the likelihood of the illness resulting in permanent disability or death? Putting aside the issue of how severity should be operationalized, another consideration is whether severity should be conceptualized similarly for all illnesses or be disorder specific. In this paper, we examine how severity is characterized in research and contemporary psychiatric diagnostic systems, with a special focus on depression and personality disorders. Our review shows that the DSM‐5 has defined the severity of various disorders in different ways, and that researchers have adopted a myriad of ways of defining severity for both depression and personality disorders, although the severity of the former was predominantly defined according to scores on symptom rating scales, whereas the severity of the latter was often linked with impairments in functioning. Because the functional impact of symptom‐defined disorders depends on factors extrinsic to those disorders, such as self‐efficacy, resilience, coping ability, social support, cultural and social expectations, as well as the responsibilities related to one's primary role function and the availability of others to assume those responsibilities, we argue that the severity of such disorders should be defined independently from functional impairment.     

Cognitive behavioral therapy for psychosomatic problems in dental settings

Cognitive behavioral therapy (CBT) has been applied for various problems, including psychiatric diseases such as depression and anxiety, and for physical symptoms such as pain. It has also been applied for dental problems. Although the effect of CBTs on temporomandibular disorders and dental anxiety are well documented, its effectiveness on other types of oral symptoms remain unclear. Little information comparing the different types of CBTs in the dental setting is currently available. Because dental professionals are often expected to conduct CBTs in the dental setting, it is important to develop proper training programs for dental professionals.In this review article, we demonstrate and discuss the application of CBTs for psychosomatic problems, including temporomandibular disorders, dental anxiety, burning mouth syndrome, and other oral complaints in dental settings.     

Could a blood test for PTSD and depression be on the horizon?

ABSTRACT

Introduction: Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients.

Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis.

Expert commentary: Potential biomarkers have already been assessed in patients’ blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.     

Convergent and Divergent Functional Connectivity Patterns in Schizophrenia and Depression

Major depression and schizophrenia are two of the most serious psychiatric disorders and share similar behavioral symptoms. Whether these similar behavioral symptoms underlie any convergent psychiatric pathological mechanisms is not yet clear. To address this issue, this study sought to investigate the whole-brain resting-state functional magnetic resonance imaging (MRI) of major depression and schizophrenia by using multivariate pattern analysis. Thirty-two schizophrenic patients, 19 major depressive disorder patients and 38 healthy controls underwent resting-state functional MRI scanning. A support vector machine in conjunction with intrinsic discriminant analysis was used to solve the multi-classification problem, resulting in a correct classification rate of 80.9% via leave-one-out cross-validation. The depression and schizophrenia groups both showed altered functional connections associated with the medial prefrontal cortex, anterior cingulate cortex, thalamus, hippocampus, and cerebellum. However, the prefrontal cortex, amygdala, and temporal poles were found to be affected differently by major depression and schizophrenia. Our preliminary study suggests that altered connections within or across the default mode network and the cerebellum may account for the common behavioral symptoms between major depression and schizophrenia. In addition, connections associated with the prefrontal cortex and the affective network showed promise as biomarkers for discriminating between the two disorders.     

Traitement des pathologies psychiatriques et stimulation magn��tique transcranienne r��p��t��e (rTMS): o�� en est-on ?

Objective

Over the past 15 years, the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) have been well studied in psychiatric disorders. We propose to conduct a qualitative review of the literature to allow a focus on the value of this technique, including its main indications.

Results

This technique, by the induction of a change in cortical excitability, can provide symptomatic improvement in various psychiatric disorders. We first focused on its effectiveness in mood disorders (mainly in uni or bipolar depressive episodes), then in schizophrenia (auditory hallucinations and negative symptoms), and lately in other psychiatric disorders. We are also considering how to implement this technique in clinical practice and future development.

Conclusion

Results reported in literature suggest that rTMS might fit into the strategies of caremainly for unipolar depression and auditory hallucinations. Recommendations should be published in this regard during 2011. Optimization of this technique and the extension to other psychiatric indications are still under study.     

Cognitive disruptions in stress-related psychiatric disorders: A role for corticotropin releasing factor (CRF)

This article is part of a Special Issue “SBN 2014”.Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF’s ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described.     

S100B蛋白在神经系统疾病中的临床意义及进展

S100B蛋白是主要由神经胶质细胞分泌的一种钙结合蛋白,在生理浓度下,S100B蛋白具有旁分泌或自分泌神经营养作用,高浓度时则具有神经毒害作用。脑脊液、血液、尿液、唾液、羊水等体液中S100B蛋白水平的升高被认为是多种疾病的生物学指标,如急性脑损伤、围产期脑损伤、脑肿瘤、神经系统炎症性或退行性疾病,精神疾病等。S100B蛋白不仅仅是一种生物学指标,也可作为疾病治疗的靶向目标。目前存在的主要问题是,S100B蛋白主要由受损细胞渗漏,还是病理生理条件下分泌的S100B蛋白造成了细胞损伤。本文就S100B蛋白在神经科疾病中的诊断、治疗及新进展做一综述,并提出进一步研究的设想。     

The Psychosomatic Emergency

Many psychiatric problems present themselves under the guise of physical rather than mental symptoms.These occur in several categories: (1) Psychological problems which work in conjunction with definitive organic pathology, such as the fear of death. (2) Symptoms produced by altered physiology or biochemistry resultant from an acute orchronic stress state. (3) A combination of A and B above. (4) Patients with an intense disease, such as hypochondriasis. (5) Psychiatric symptoms, such as depression, anxiety or apathy which develop antecedent or subsequent to a fearfully anticipated illness or procedure.These patients have certain characteristics in common. (1) They manifest a disproportionate concern over symptoms. (2) The symptoms are inconsistent with the usual pattern of organic disease. (3) The onset is concurrent with states of conflict. (4) There is usually a personal and family history of psychic and psychosomatic disorders. (5) Other psychiatric disorders are usually present. (6) Secondary gain is usually evident.These patients can be successfully treated within the hospital setting and within the framework of psychiatric consultation and psychotherapy.     

Suicidal Drownings with Psychiatric Disorders in Shanghai: A Retrospective Study from 2010.1 to 2014.6

Psychiatric disorders exhibited in 13% suicidal drownings in Southwestern Croatia and 63% in Milan, but in China is unknown. This study is committed to outline the feature of a suicidal drowning with psychiatric disorder, show mental status and reveal key factor to high incidence in China. Immersed corpses were handled by SPSBMPH in its jurisdiction range. Half of immersed corpses were suicidal, and nearly half of suicides had psychiatric disorders. 104 suicidal drownings with psychiatric disorders cases from 2010.1 to 2014.6 were reviewed (21.5% of all immersed corpses, 42.1% of suicides). Most victims clothed normally, and only 2 fastened attached weights. Male victims were more and younger than female. Psycho were prone to commit suicidal drowning in warm and hot season. Psycho were prone to choose familiar area to commit suicide, 45 decedents were found in their familiar areas. Suicidal drowings were occult without suicide attempts, suicide note or abnormal clothing, but showed abnormal mental or behavior changes prior to suicide. The three leading psychiatric disorders were depression (33.7%), depression status (30.8%) and schizophrenia (20.2%). Only 44.2% decedents had visited psychiatric disorder specialist, and merely less than 10% patients could adhere to regular medication. No regular medication on psychiatric disorder was the key factor contributing to high incidence of suicide in psycho. Professional psychiatric and psychological intervention should be taken as soon as possible when they had psychiatric symptoms or suffered misfortune. Guardians should be alert to patients’ abnormality to detect their suicidal ideation and intervene, especially in warm season.     

Biofeedback for Psychiatric Disorders: A Systematic Review

Biofeedback potentially provides non-invasive, effective psychophysiological interventions for psychiatric disorders. The encompassing purpose of this review was to establish how biofeedback interventions have been used to treat select psychiatric disorders [anxiety, autistic spectrum disorders, depression, dissociation, eating disorders, schizophrenia and psychoses] to date and provide a useful reference for consultation by clinicians and researchers planning to administer a biofeedback treatment. A systematic search of EMBASE, MEDLINE, PsycINFO, and WOK databases and hand searches in Applied Psychophysiology and Biofeedback, and Journal of Neurotherapy, identified 227 articles; 63 of which are included within this review. Electroencephalographic neurofeedback constituted the most investigated modality (31.7 %). Anxiety disorders were the most commonly treated (68.3 %). Multi-modal biofeedback appeared most effective in significantly ameliorating symptoms, suggesting that targeting more than one physiological modality for bio-regulation increases therapeutic efficacy. Overall, 80.9 % of articles reported some level of clinical amelioration related to biofeedback exposure, 65.0 % to a statistically significant (p < .05) level of symptom reduction based on reported standardized clinical parameters. Although the heterogeneity of the included studies warrants caution before explicit efficacy statements can be made. Further development of standardized controlled methodological protocols tailored for specific disorders and guidelines to generate comprehensive reports may contribute towards establishing the value of biofeedback interventions within mainstream psychiatry.     

Mitochondrial Dysfunction and Psychiatric Disorders

Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.     

Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms

Objective: To investigate psychiatric and neurological morbidity, diagnostic stability, and indicators of prognosis in patients previously identified as having medically unexplained motor symptoms. Design: Follow up study. Setting: National Hospital for Neurology and Neurosurgery, London—a secondary and tertiary referral hospital for neurological disorders. Subjects: 73 patients with medically unexplained motor symptoms admitted consecutively in 1989-91. 35 (48%) patients had absence of motor function (for example, hemiplegia) and 38 (52%) had abnormal motor activity (for example, tremor, dystonia, or ataxia). Main outcome measures: Neurological clinical diagnosis at face to face reassessment by a neurologist and a psychiatric diagnosis after a standardised assessment interview—the schedule for affective disorders and schizophrenia—conducted by a psychiatrist. Results: Good follow up data were available for 64 subjects (88%). Only three subjects had new organic neurological disorders at follow up that fully or partly explained their previous symptoms. 44/59 (75%) subjects had had psychiatric disorders; in 33 (75%) patients, the psychiatric diagnosis coincided with their unexplained motor symptoms. 31/59 (45%) patients had a personality disorder. Three subjects had developed new psychiatric illnesses at follow up, but in only one did the diagnosis account for the previous motor symptoms. Resolution of physical symptoms was associated with short length of symptoms, comorbid psychiatric disorder, and a change in marital status during follow up. Conclusions: Unlike Slater’s study of 1965, a low incidence of physical or psychiatric diagnoses which explained these patients’ symptoms or disability was found. However, a high level of psychiatric comorbidity existed.

Key messages

• Motor symptoms that remain unexplained medically despite thorough investigation are a common clinical problem, but the emergence of a subsequent organic explanation for these symptoms is rare
• The prevalence of coexistent affective and anxiety disorders is high and many patients also have a personality disorder
• Patients with a shorter duration of symptoms and coexistent anxiety or depression are likely to do better at follow up
• Reinvestigation of these patients is both expensive and potentially dangerous and should be avoided where no clear clinical indication exists

     

Proteomic and metabolomic profiling of a trait anxiety mouse model implicate affected pathways

Depression and anxiety disorders affect a great number of people worldwide. Whereas singular factors have been associated with the pathogenesis of psychiatric disorders, growing evidence emphasizes the significance of dysfunctional neural circuits and signaling pathways. Hence, a systems biology approach is required to get a better understanding of psychiatric phenotypes such as depression and anxiety. Furthermore, the availability of biomarkers for these disorders is critical for improved diagnosis and monitoring treatment response. In the present study, a mouse model presenting with robust high versus low anxiety phenotypes was subjected to thorough molecular biomarker and pathway discovery analyses. Reference animals were metabolically labeled with the stable (15)N isotope allowing an accurate comparison of protein expression levels between the high anxiety-related behavior versus low anxiety-related behavior mouse lines using quantitative mass spectrometry. Plasma metabolomic analyses identified a number of small molecule biomarkers characteristic for the anxiety phenotype with particular focus on myo-inositol and glutamate as well as the intermediates involved in the tricarboxylic acid cycle. In silico analyses suggested pathways and subnetworks as relevant for the anxiety phenotype. Our data demonstrate that the high anxiety-related behavior and low anxiety-related behavior mouse model is a valuable tool for anxiety disorder drug discovery efforts.     

Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies

Introduction: Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates.

Areas covered: The review includes the human studies found by a PubMed search using the following terms: ‘depression cerebrospinal fluid biomarker’, ‘major depression biomarker CSF’, ‘depression CSF biomarker’, ‘proteomics depression’, ‘proteomics biomarkers in depression’, ‘proteomics CSF biomarker in depression’, and ‘major depressive disorder CSF’. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies.

Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed.     

Psychiatric research: psychoproteomics,degradomics and systems biology

While proteomics has excelled in several disciplines in biology (cancer, injury and aging), neuroscience and psychiatryproteomic studies are still in their infancy. Several proteomic studies have been conducted in different areas of psychiatric disorders, including drug abuse (morphine, alcohol and methamphetamine) and other psychiatric disorders (depression, schizophrenia and psychosis). However, the exact cellular and molecular mechanisms underlying these conditions have not been fully investigated. Thus, one of the primary objectives of this review is to discuss psychoproteomic application in the area of psychiatric disorders, with special focus on substance- and drug-abuse research. In addition, we illustrate the potential role of degradomic utility in the area of psychiatric research and its application in establishing and identifying biomarkers relevant to neurotoxicity as a consequence of drug abuse. Finally, we will discuss the emerging role of systems biology and its current use in the field of neuroscience and its integral role in establishing a comprehensive understanding of specific brain disorders and brain function in general.     

Psychiatric research: psychoproteomics, degradomics and systems biology

While proteomics has excelled in several disciplines in biology (cancer, injury and aging), neuroscience and psychiatryproteomic studies are still in their infancy. Several proteomic studies have been conducted in different areas of psychiatric disorders, including drug abuse (morphine, alcohol and methamphetamine) and other psychiatric disorders (depression, schizophrenia and psychosis). However, the exact cellular and molecular mechanisms underlying these conditions have not been fully investigated. Thus, one of the primary objectives of this review is to discuss psychoproteomic application in the area of psychiatric disorders, with special focus on substance- and drug-abuse research. In addition, we illustrate the potential role of degradomic utility in the area of psychiatric research and its application in establishing and identifying biomarkers relevant to neurotoxicity as a consequence of drug abuse. Finally, we will discuss the emerging role of systems biology and its current use in the field of neuroscience and its integral role in establishing a comprehensive understanding of specific brain disorders and brain function in general.     

Developmental comorbidity in attention-deficit/hyperactivity disorder

With the present review, we intend to highlight the importance of considering the age- and development-dependent occurrence of comorbidity in ADHD and to outline distinct trajectories of symptom progression with possible impact on course and outcome of ADHD. The review will focus on introducing the concepts of "developmental epidemiology" and "developmental comorbidity". Psychiatric and non-psychiatric age-dependent comorbidity can be seen in the majority of children, adolescents and adults with ADHD, resulting in a severe impairment of everyday life with considerable functional and psychosocial problems. Concerning the temporal order of occurrence, psychiatric conditions may be present before the appearance of first definite ADHD symptoms ("pre-comorbidity", such as temperament factors, sleep disturbance, autism spectrum disorders and atopic eczema). They may coincide with the time when ADHD symptoms reach a clinically significant level ("simultaneous comorbidity": enuresis, encopresis, developmental dyslexia). The majority of comorbidity, however, appears after the onset of ADHD in the course of disease ("post-comorbidity": tic disorder, depression and suicidality, anxiety disorders, obsessive compulsive disorder, bipolar disorder, conduct and substance use disorders, obesity and personality disorders). The aetio-pathophysiology of ADHD and its comorbid disorders and also the nature of comorbidity itself being highly heterogeneous, we additionally discuss possible models of comorbidity. In the future, longitudinal data on distinct patterns of symptom and comorbidity progression would help to refine disease classification systems, strengthen the power of future genetic studies and finally allow for more specific treatment strategies.     

Epigenetic regulation in psychiatric disorders

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.