Leading compounds for the validation of animal models of psychopathology

Modelling of complex psychiatric disorders, e.g., depression and schizophrenia, in animals is a major challenge, since they are characterized by certain disturbances in functions that are absolutely unique to humans. Furthermore, we still have not identified the genetic and neurobiological mechanisms, nor do we know precisely the circuits in the brain that function abnormally in mood and psychotic disorders. Consequently, the pharmacological treatments used are mostly variations on a theme that was started more than 50 years ago. Thus, progress in novel drug development with improved therapeutic efficacy would benefit greatly from improved animal models. Here, we review the available animal models of depression and schizophrenia and focus on the way that they respond to various types of potential candidate molecules, such as novel antidepressant or antipsychotic drugs, as an index of predictive validity. We conclude that the generation of convincing and useful animal models of mental illnesses could be a bridge to success in drug discovery.     

The Texture of the Real: Experimentation and Experience in Schizophrenia

The dominance of the neurosciences in psychiatric research raises questions about the relationship between research practices and the lived experience of mental illness. Here, I use data from a group of researchers focusing on neurocognition in schizophrenia to explore the problem of representation in psychiatric research and the forms that neuroscientific evidence assumes for those who produce it. These researchers grappled with the complexity of schizophrenia not by narrowing disease concepts to biological facts but by referencing measurement techniques to generate new versions of schizophrenia. By linking experimental findings to inchoate concepts of personhood and social experience, I found that they reframed and reinforced cultural values, including that those with schizophrenia are destined to a debased and deficient existence. I argue that cognition has emerged as an essential feature of schizophrenia not only because of its representational utility but also because of the ontological work the concept performs. In closing, I present some implications for the neurobiological and social sciences.     

Role of proteomics in biomarker discovery and psychiatric disorders: current status,potentials, limitations and future challenges

Proteomic approaches have advanced clinical research towards more reliable, sensitive and specific biological diagnostic markers for diseases. Mood disorders are most difficult to diagnose and very much prevalent in society; hence, their proper diagnosis becomes essential. Despite tremendous research efforts to dissect the neurobiological basis of psychiatric disorders, the diagnosis and evaluation for such diseases is still poor. Biomarker discovery in psychiatry research has been accelerated by proteomic technologies, accepting the challenges in order to meet disease state-related investigations. Proteomics-based research for disease-specific protein signatures is expected to give a new direction in psychiatry research. Therefore, this may become a more powerful tool to predict the development, course and outcome of the disease towards personalized psychiatric ailments. The review discusses the role of proteomics in elucidating mechanisms of psychiatric disorders, current status, prospects, limitations and new possibilities towards a strong diagnostic tool in the clinical laboratory.     

Antipsychotics inhibit TREK but not TRAAK channels

Schizophrenia is a chronic mental illness affecting 0.4% of the population. Existing antipsychotic drugs are mainly used to treat positive symptoms such as hallucinations but have only poor effects on negative symptoms such as cognitive deficits or depression. TREK and TRAAK channels are two P domain background potassium channels activated by polyunsaturated fatty acids and mechanical stress. TREK but not TRAAK channels are regulated by Gs- and Gq-coupled pathways. The inactivation of the TREK-1 but not the TRAAK channel in mice results in a depression-resistant phenotype. In addition, it has been shown that antidepressants such as fluoxetine or paroxetine directly inhibit TREK channel activity. Here we show that different antipsychotic drugs directly inhibit TREK currents with IC(50) values of approximately 1 to approximately 20 microM. No effect is seen on TRAAK channel activity. We conclude that TREK channels might be involved in the therapeutic action of antipsychotics or in their secondary effects. Furthermore, TREK channels could play a role in the pathophysiology of psychiatric disorders such as depression and schizophrenia.     

Public attitudes towards psychiatry and psychiatric treatment at the beginning of the 21st century: a systematic review and meta‐analysis of population surveys

Public attitudes towards psychiatry are crucial determinants of help‐seeking for mental illness. It has been argued that psychiatry as a discipline enjoys low esteem among the public, and a “crisis” of psychiatry has been noted. We conducted a systematic review and meta‐analysis of population studies examining public attitudes towards various aspects of psychiatric care. Our search in PubMed, Web of Science, PsychINFO and bibliographies yielded 162 papers based on population surveys conducted since 2000 and published no later than 2015. We found that professional help for mental disorders generally enjoys high esteem. While general practitioners are the preferred source of help for depression, mental health professionals are the most trusted helpers for schizophrenia. If respondents have to rank sources of help, they tend to favor mental health professionals, while open questions yield results more favorable to general practitioners. Psychiatrists and psychologists/psychotherapists are equally recommended for the treatment of schizophrenia, while for depression psychologists/psychotherapists are more recommended, at least in Europe and America. Psychotherapy is consistently preferred over medication. Attitudes towards seeking help from psychiatrists or psychologists/psychotherapists as well as towards medication and psychotherapy have markedly improved over the last twenty‐five years. Biological concepts of mental illness are associated with stronger approval of psychiatric help, particularly medication. Self‐stigma and negative attitudes towards persons with mental illness decrease the likelihood of personally considering psychiatric help. In conclusion, the public readily recommends psychiatric help for the treatment of mental disorders. Psychotherapy is the most popular method of psychiatric treatment. A useful strategy to further improve the public image of psychiatry could be to stress that listening and understanding are at the core of psychiatric care.     

Prevention of Mental Disorder—The Role of the General Practitioner

As prevention in psychiatry really refers to early detection and consequent prevention of complications and chronicity, the general practitioner is the most important person in the medical community in preventing mental disorders. As more postgraduate courses in psychiatry become available to practicing family physicians, the majority of patients with psychiatric disorders will be effectively managed by the general medical practitioner.The family physician is already doing this, although not as well as he could. In some instances, he may be unaware of the extent to which the disease with which he deals is psychic disease. As the number of community health centers increases, family physicians will play a vital role in their function. With the necessary knowledge to detect psychic disturbance and to treat emotional disorders effectively, the family physician will prevent many of the instances of progression to chronic psychiatric illness with which we are now plagued. The psychiatrist of the future will act as consultant, treating only patients with the more complicated mental disorders.     

Schizophrenia: moving beyond monoamine antagonists

Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.     

Naming the problem that has no name: creating targets for standardized drugs

Many of the most common types of mental health problems that are found in outpatient psychiatric and general medical practices are diffuse, undifferentiated, and amorphous. Before the 1970s this lack of specificity did not conflict with the dominant theories and treatments of the American psychiatric profession or the demands of third party insurers and regulators. However, since that time the legitimacy and solvency of the psychiatric profession has come to depend on the perception that it treats specific disease entities. The establishment of the DSM-III in 1980 provided American psychiatry with many standardized disease entities that could be precisely measured, quantified, and abstracted from their particular contexts. In the late 1980s, these entities became the targets of the new class of psychoactive drugs, the Selective Serotonin Reuptake Inhibitors. Professional, political, economic, and cultural forces that arose in a particular historical era account for the standardization of mental illnesses.     

The nature of psychiatric disorders

A foundational question for the discipline of psychiatry is the nature of psychiatric disorders. What kinds of things are they? In this paper, I review and critique three major relevant theories: realism, pragmatism and constructivism. Realism assumes that the content of science is real and independent of human activities. I distinguish two “flavors” of realism: chemistry‐based, for which the paradigmatic example is elements of the periodic table, and biology‐based, for which the paradigm is species. The latter is a much better fit for psychiatry. Pragmatism articulates a sensible approach to psychiatric disorders just seeking categories that perform well in the world. But it makes no claim about the reality of those disorders. This is problematic, because we have a duty to advocate for our profession and our patients against other physicians who never doubt the reality of the disorders they treat. Constructivism has been associated with anti‐psychiatry activists, but we should admit that social forces play a role in the creation of our diagnoses, as they do in many sciences. However, truly socially constructed psychiatric disorders are rare. I then describe powerful arguments against a realist theory of psychiatric disorders. Because so many prior psychiatric diagnoses have been proposed and then abandoned, can we really claim that our current nosologies have it right? Much of our current nosology arose from a series of historical figures and events which could have gone differently. If we re‐run the tape of history over and over again, the DSM and ICD would not likely have the same categories on every iteration. Therefore, we should argue more confidently for the reality of broader constructs of psychiatric illness rather than our current diagnostic categories, which remain tentative. Finally, instead of thinking that our disorders are true because they correspond to clear entities in the world, we should consider a coherence theory of truth by which disorders become more true when they fit better into what else we know about the world. In our ongoing project to study and justify the nature of psychiatric disorders, we ought to be broadly pragmatic but not lose sight of an underlying commitment, despite the associated difficulties, to the reality of psychiatric illness.     

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.     

Mental illness from the perspective of theoretical neuroscience

Theoretical neuroscience, which characterizes neural mechanisms using mathematical and computational models, is highly relevant to central problems in the philosophy of psychiatry. These models can help to solve the explanation problem of causally connecting neural processes with the behaviors and experiences found in mental illnesses. Such explanations will also be useful for generating better classifications and treatments of psychiatric disorders. The result should help to eliminate concerns that mental illnesses such as depression and schizophrenia are not objectively real. A philosophical approach to mental illness based on neuroscience need not neglect the inherently social and historical nature of mental phenomena.     

精神分裂症患者中的高泌乳素血症研究进展

高泌乳素血症在精神分裂症患者中发生率高,主要原因为抗精神病药物和精神分裂症本身的作用。精神分裂症患者服用抗精神病药物后泌乳素水平较快升高,长期服用后泌乳素水平可能趋向于稳定甚至降低,但仍高于正常值。高泌乳素血症会导致肥胖等诸多不良后果。而精神分裂症患者服用抗精神病药物后另一常见的副反应是代谢相关不良反应,越来越多的研究开始关注兼顾治疗高泌乳素血症及肥胖、糖脂代谢异常的方法。溴隐亭、阿立哌唑及芍药甘草汤等中药具有一定的降低泌乳素水平的作用,但使用有限制性,且不能改善抗精神病药物所致代谢相关的不良反应。二甲双胍除了能改善糖脂代谢紊乱,还具有潜在的降泌乳素作用,对于同时有代谢异常如肥胖、糖脂代谢异常及高泌乳素血症的患者来说可能具有双重治疗效果,但其降泌乳素的疗效和剂量需要进一步的大样本临床研究。     

Network-assisted investigation of antipsychotic drugs and their targets

Antipsychotic drugs are tranquilizing psychiatric medications primarily used in the treatment of schizophrenia and similar severe mental disorders. So far, most of these drugs have been discovered without knowing much on the molecular mechanisms of their actions. The available large amount of pharmacogenetics, pharmacometabolomics, and pharmacoproteomics data for many drugs makes it possible to systematically explore the molecular mechanisms underlying drug actions. In this study, we applied a unique network-based approach to investigate antipsychotic drugs and their targets. We first retrieved 43 antipsychotic drugs, 42 unique target genes, and 46 adverse drug interactions from the DrugBank database and then generated a drug-gene network and a drug-drug interaction network. Through drug-gene network analysis, we found that seven atypical antipsychotic drugs tended to form two clusters that could be defined by drugs with different target receptor profiles. In the drug-drug interaction network, we found that three drugs (zuclopenthixol, ziprasidone, and thiothixene) tended to have more adverse drug interactions than others, while clozapine had fewer adverse drug interactions. This investigation indicated that these antipsychotics might have different molecular mechanisms underlying the drug actions. This pilot network-assisted investigation of antipsychotics demonstrates that network-based analysis is useful for uncovering the molecular actions of antipsychotics.     

The interrelationship of tropical disease and mental disorder: conceptual framework and literature review (part I — malaria)

Substantial interactions between tropical diseases and psychiatric illness have long been recognized, but the impact of biological factors in the field of cross-cultural psychiatry has been less well studied than psychosocial factors. In reviewing the literature at the intersection of tropical medicine and psychiatry in order to summarize the existing data base in this field, a generalized interactive model informed by the theoretical contributions of George Engel, the WHO Scientific Working Group on Social and Economic Research, Arthur Kleinman, P. M. Yap, Edward Sapir and others has been developed to serve as a conceptual framework for this analysis of the literature and to guide further research. The clinical literature of tropical medicine and psychiatry which recognizes the significance of concurrent tropical disease and mental disorders is reviewed along with the more specific literature on malaria and concomitant psychiatric illness. Many authors have focused on the role of organic mental disorders, especially in connection with cerebral malaria, but several have also addressed psychosocial parameters through which the interrelationship between malaria and a full range of mental disorders is also mediated. The effects of malaria may serve as biological, psychological or social stressors operating in a cultural context which precipitate or shape features of psychiatric symptomatology. Psychiatric illness may likewise precipitate an episode of malaria with typical symptoms in a patient with a previously subclinical infection. Implications of the literature and this generalized interactive model are considered as they apply to clinical practice, public health and the application of social science theory in medicine.[/p]     

A meta‐review of “lifestyle psychiatry”: the role of exercise,smoking, diet and sleep in the prevention and treatment of mental disorders

There is increasing academic and clinical interest in how “lifestyle factors” traditionally associated with physical health may also relate to mental health and psychological well‐being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta‐review of the top‐tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta‐analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta‐reviews, and two meta‐analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress‐related disorders, schizophrenia, bipolar disorder, and attention‐deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non‐pharmacological sleep‐focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.     

SNARE proteins and schizophrenia: linking synaptic and neurodevelopmental hypotheses

Much of the focus of neurobiological research into schizophrenia is based on the concept that disrupted synaptic connectivity underlies the pathology of the disorder. Disruption of synaptic connectivity is proposed to be a consequence of both disrupted synaptic transmission in adulthood and abnormalities in the processes controlling synaptic connectivity during development of the central nervous system. This synaptic hypothesis fits with neurodevelopmental models of schizophrenia and our understanding of the mechanisms of antipsychotic medication. This conceptual model has fostered efforts to define the exact synaptic pathology further. Synaptic proteins are obvious candidates for such studies, and the integral role of the SNARE complex, and SNARE-associated proteins, in synaptic transmission will ensure that it is the focus of much of this research. Significant new insights into the role of this complex are arising from new mouse models of human disease. Here the evidence from both animal and human clinical studies showing that the SNARE complex has a key role to play in the aetiology and pathogenesis of schizophrenia is discussed.