PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology. Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophic factors, and circadian rhythms. Because all theories of depression apply to only some types of depressed patients but not others, and because depressive pathophysiology may vary considerably across the course of illness, the current extant knowledge argues against a unified hypothesis of depression. As a consequence, antidepressant treatments, including psychological and biological approaches, should be tailored for individual patients and disease states. Individual depression hypotheses based on neurobiological knowledge are discussed in terms of their interest to both clinicians in daily practice and clinical researchers developing novel therapies.     

Genetic biomarkers of depression

Depression is a term that has been used to describe a variety of ailments, ranging from minor to incapacitating. Clinically significant depression, termed as major depression, is a serious condition characterized not only by depressed mood but also by a cluster of somatic, cognitive, and motivational symptoms. Significant research efforts are aimed to understand the neurobiological as well as psychiatric disorders, and the evaluation of treatment of these disorders is still based solely on the assessment of symptoms. In order to identify the biological markers for depression, we have focused on gathering information on different factors responsible for depression including stress, genetic variations, neurotransmitters, and cytokines and chemokines previously suggested to be involved in the pathophysiology of depression. The present review illustrates the potential of biomarker profiling for psychiatric disorders, when conducted in large collections. The review highlighted the biomarker signatures for depression, warranting further investigation.     

Modeling depression in adult female cynomolgus monkeys (Macaca fascicularis)

Depressive disorders are prevalent, costly, and poorly understood. Male rodents in stress paradigms are most commonly used as animal models, despite the two-fold increased prevalence of depression in women and sex differences in response to stress. Although these models have provided valuable insights, new models are needed to move the field forward. Social stress-associated behavioral depression in adult female cynomolgus macaques closely resembles human depression in physiological, neurobiological, and behavioral characteristics, including reduced body mass, hypothalamic-pituitary-adrenal axis perturbations, autonomic dysfunction, increased cardiovascular disease risk, reduced hippocampal volume, altered serotonergic function, decreased activity levels, and increased mortality. In addition, behaviorally depressed monkeys also have low ovarian steroid concentrations, even though they continue to have menstrual cycles. Although this type of ovarian dysfunction has not been reported in depressed women and is difficult to identify, it may be the key to understanding the high prevalence of depression in women. Depressive behavior in female cynomolgus monkeys is naturally occurring and not induced by experimental manipulation. Different social environmental challenges, including isolation vs. subordination, may elicit the depression-like response in some animals and not others. Similarly, social subordination is stressful and depressive behavior is more common in socially subordinate monkeys. Yet, not all subordinates exhibit behavioral depression, suggesting individual differences in sensitivity to specific environmental stressors and enhanced risk of behavioral depression in some individuals. The behavior and neurobiology of subordinates is distinctly different than that of behaviorally depressed monkeys, which affords the opportunity to differentiate between stressed and depressed states. Thus, behaviorally depressed monkeys exhibit numerous physiological, neurobiological, and behavioral characteristics same as those of depressed human beings. The nonhuman primate model represents a new animal model of depression with great promise for furthering our understanding of this prevalent and debilitating disease and identifying novel therapeutic targets.     

非药物干预治疗物质使用障碍

物质使用障碍（substance use disorder,SUD）是一个全球性的卫生和社会问题。针对大多数成瘾性物质，目前还没有有效的治疗药物，普遍还是采用心理治疗和行为矫治。近年来，针刺、深部脑刺激（DBS）、重复经颅磁刺激（rTMS）、经颅直流电刺激（tDCS）和运动等非药物干预手段在治疗神经系统疾病的有效性逐渐得到重视。越来越多的研究也开始关注非药物干预手段在治疗SUD中的应用。本综述在文献检索（如PubMed、Google Scholar等）的基础上总结了针刺、DBS、rTMS、tDCS和运动等非药物干预手段对阿片类药物、精神活性物质、尼古丁、酒精等不同成瘾性物质的心理渴求、戒断时间、使用剂量和成瘾伴随的情绪、认知功能障碍等的影响。研究表明，针刺、DBS、rTMS、tDCS和运动等非药物干预手段可以有效降低成瘾性物质引起的心理渴求、降低物质摄入量、增加戒断时间，同时改善长期使用成瘾性物质引起的认知障碍、焦虑和抑郁样行为等。如果非药物干预手段结合药物、心理等治疗方式，效果更佳。尽管非药物干预方法在现阶段主要作为辅助性治疗手段，未来的研究应注重明确非药物干预手段的神经生物学机制，...     

Hereditary catalepsy: genetic and molecular mechanisms of catalepsy in mice

The results of experiments on the inheritance and neurobiological mechanism of high predisposition to tonic immobility (catalepsy) in CBA mice are discussed. Genetic analysis has demonstrated a monogenic inheritance of the predisposition to catalepsy. A set of polymorphic microsatellite markers has been used to demonstrate that the predisposition to catalepsy is linked to the distal fragment of mouse chromosome 13, which contains the gene of the 5-HT1A-serotonin receptor. Pharmacological and biochemical evidence for the association between hereditary catalepsy and 5-HT1A-receptor dysfunction are presented. The use of CBA mice for studying the mechanisms of depression and the effects of antidepressants is discussed.     

Neurobiology of depression

Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.     

Decisions,decisions, decisions: choosing a biological science of choice

Behavioral ecologists argue that evolution drives animal behavior to efficiently solve the problems animals face in their environmental niches. The ultimate evolutionary causes of decision making, they contend, can be found in economic analyses of organisms and their environments. Neurobiologists interested in how animals make decisions have, in contrast, focused their efforts on understanding the neurobiological hardware that serves as a more proximal cause of that same behavior. Describing the flow of information within the nervous system without regard to these larger goals has been their focus. Recent work in a number of laboratories has begun to suggest that these two approaches are beginning to fuse. It may soon be possible to view the nervous system as a representational process that solves the mathematically defined economic problems animals face by making efficient decisions. These developments in the neurobiological theory of choice, and the new schema they imply, form the subject of this article.     

Hereditary Catalepsy: Genetic and Molecular Mechanisms of Catalepsy in Mice

The results of experiments on the inheritance and neurobiological mechanism of high predisposition to tonic immobility (catalepsy) in CBA mice are discussed. Genetic analysis has demonstrated a monogenic inheritance of the predisposition to catalepsy. A set of polymorphic microsatellite markers has been used to demonstrate that the predisposition to catalepsy is linked to the distal fragment of mouse chromosome 13, which contains the gene of the 5-HT_1A serotonin receptor. Pharmacological and biochemical evidence for the association between hereditary catalepsy and 5-HT_1A receptor dysfunction are presented. The use of CBA mice for studying the mechanisms of depression and the effects of antidepressants is discussed.     

Modeling motivational deficits in mouse models of schizophrenia: behavior analysis as a guide for neuroscience

In recent years it has become possible to develop animal models of psychiatric disease in genetically modified mice. While great strides have been made in the development of genetic and neurobiological tools with which to model psychiatric disease, elucidation of neural and molecular mechanisms thought to underlie behavioral phenotypes has been hindered by an inadequate analysis of behavior. This is unfortunate given the fact that the experimental analysis of behavior has created powerful methods for isolating and describing the functional properties of behavioral mechanisms that are capable of providing deep understanding of behavioral phenotypes. A better understanding of the biological basis of normal behavior and its disturbance in psychiatric disease will require the application of these rigorous behavior analytic tools to animal models. In this review we provide an example of a merging of genetic and behavioral methods and illustrate its utility in the analysis of a mouse model of the motivational deficits in schizophrenia. The synergy between basic behavior analysis, neuroscience, and animal models of psychiatric disease has great potential for achieving a deeper understanding of behavior and its neurobiological mechanisms as well as for leading to improvements in diagnosis and treatment in clinical settings.     

Cognitive impairments in psychotic disorders: common mechanisms and measurement

Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a “generalized deficit”, in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM‐5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Neural mechanisms of the cognitive model of depression

In the 40 years since Aaron Beck first proposed his cognitive model of depression, the elements of this model--biased attention, biased processing, biased thoughts and rumination, biased memory, and dysfunctional attitudes and schemas--have been consistently linked with the onset and maintenance of depression. Although numerous studies have examined the neural mechanisms that underlie the cognitive aspects of depression, their findings have not been integrated with Beck's cognitive model. In this Review, we identify the functional and structural neurobiological architecture of Beck's cognitive model of depression. Although the mechanisms underlying each element of the model differ, in general the negative cognitive biases in depression are facilitated by increased influence from subcortical emotion processing regions combined with attenuated top-down cognitive control.     

Placebos and painkillers: is mind as real as matter?

Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind-body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.     

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.     

Animal models of social anxiety disorder and their validity criteria

Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.     

Diabetes-induced abnormalities in the myocardium

One of the leading causes of mortality in diabetics is myocardial disease. In the past few years this subject has generated a significant amount of interest with the result that myocardial problems associated with diabetes are far better understood. Though originally thought to occur as a result of atherosclerosis, various studies have shown that heart disease can occur in the absence of atherosclerosis, suggesting a diabetic cardiomyopathy. Using diabetic animals, it has been possible to characterize diabetes-induced myocardial abnormalities. Diabetic rat hearts do not respond to conditions of high stress as well as controls. The functional depression is accompanied by altered cardiac enzyme systems. A decrease in myosin ATPase activity which appears to be a result of diabetes-induced hypothyroidism is seen. Also, a depression of sarcoplasmic reticular calcium ATPase, along with a depression of calcium uptake by the SR, is seen in diabetic rat hearts. Na+, K+ ATPase activity has also been shown to be depressed and the depression appears to correlate with depressed atrial contractility. High levels of circulating fats in diabetics may alter the integrity of membranes leading to altered enzyme activities. Insulin treatment has been relatively successful at reversing or preventing myocardial changes in the diabetic rat. Other treatments that have been studied include thyroid hormone treatment, since the depression of myosin ATPase can be corrected by such treatment; and carnitine treatment, as the elevation of long chain acyl carnitines (LCAC) and the resulting depression of calcium uptake in the SR can be so normalized. These treatments have not been successful at normalizing cardiac function. A combination of the two treatments normalized function only partially, suggesting that factors besides myosin ATPase and SR calcium uptake are involved. Other treatments that have been tried include vanadate, methyl palmoxirate, and choline and methionine. Vanadate treatment has proved to be encouraging in that it normalizes both function and hyperglycemia. Methyl palmoxirate, a fatty acid analog, normalized only the elevation of LCAC but did not affect function. Methionine and choline were only partially successful in preventing the functional alterations of diabetic rat hearts. The purpose of the present article is to review our understanding of diabetes-induced myocardial problems and their possible causes. Findings from our laboratory and others are described in which attempts have been made to normalize cardiac function.     

网络成瘾者奖赏系统和认知控制系统的神经机制

网络成瘾作为一种行为成瘾,已成为严重影响人们心理健康的全球性问题.根据大脑发育的神经生物模型,揭示网络成瘾者奖赏和认知控制系统的神经机制是解决网络成瘾问题的关键,也是心理学研究的重大问题.行为研究探讨了网络成瘾具有高奖赏寻求和低认知控制特征;神经机制研究揭示了奖赏和认知控制系统的缺陷是网络成瘾行为的高风险因素;与药物成瘾的比较研究发现,网络成瘾有着独特的奖赏机制.这些研究深化了对网络成瘾心理和神经机制的理解,但仍存在网络成瘾筛查和入组标准不科学、分型笼统、因果研究匮乏、干预和治疗效果具有争议、研究范式存在漏洞等一些急需解决的问题.     

The circadian system of Drosophila melanogaster and its light input pathways

The fruit fly Drosophila melanogaster has been a grateful object for circadian rhythm researchers over several decades. Behavioral, genetic, and molecular studies in the little fly have aided in understanding the bases of circadian time keeping and rhythmic behaviors not only in Drosophila, but also in other organisms, including mammals. This review summarizes our present knowledge about the fruit fly's circadian system at the molecular and neurobiological level, with special emphasis on its entrainment by environmental light-dark cycles. The results obtained for Drosophila are discussed with respect to parallel findings in mammals.