Anxiety Disorders: National Institutes of Health

Gould TD, Gottesman II. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD 20892, USA. · Genes Brain Behav. · Pubmed #16507002 No free full text.

Abstract: Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.

Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA. · Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health/NIH, 10 Center Drive, Bethesda, MD 20892, USA. · Curr Pharm Des. · Pubmed #19442176 No free full text.

Abstract: There have been no recent advances in drug development for mood disorders in terms of identifying drug targets that are mechanistically distinct from existing ones. As a result, existing antidepressants are based on decades-old notions of which targets are relevant to the mechanisms of antidepressant action. Low rates of remission, a delay of onset of therapeutic effects, continual residual depressive symptoms, relapses, and poor quality of life are unfortunately common in patients with mood disorders. Offering alternative options is requisite in order to reduce the individual and societal burden of these diseases. The glutamatergic system is a promising area of research in mood disorders, and likely to offer new possibilities in therapeutics. There is increasing evidence that mood disorders are associated with impairments in neuroplasticity and cellular resilience, and alterations of the glutamatergic system are known to play a major role in cellular plasticity and resilience. Existing antidepressants and mood stabilizers have prominent effects on the glutamate system, and modulating glutamatergic ionotropic or metabotropic receptors results in antidepressant-like properties in animal models. Several glutamatergic modulators targeting various glutamate components are currently being studied in the treatment of mood disorders, including release inhibitors of glutamate, N-methyl-D-aspartate (NMDA) antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput enhancers, and glutamate transporter enhancers. This paper reviews the currently available knowledge regarding the role of the glutamatergic system in the etiopathogenesis of mood disorders and putative glutamate modulators.

Savitz J, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health/NIH, Bethesda, MD 20892, USA. · Neurosci Biobehav Rev. · Pubmed #19428491 No free full text.

Abstract: Both major depressive disorder and bipolar disorder are the subject of a voluminous imaging and genetics literature. Here, we attempt a comprehensive review of MRI and metabolic PET studies conducted to date on these two disorders, and interpret our findings from the perspective of developmental and degenerative models of illness. Elevated activity and volume loss of the hippocampus, orbital and ventral prefrontal cortex are recurrent themes in the literature. In contrast, dorsal aspects of the PFC tend to display hypometabolism. Ventriculomegaly and white matter hyperintensities are intimately associated with depression in elderly populations and likely have a vascular origin. Important confounding influences are medication, phenotypic and genetic heterogeneity, and technological limitations. We suggest that environmental stress and genetic risk variants interact with each other in a complex manner to alter neural circuitry and precipitate illness. Imaging genetic approaches hold out promise for advancing our understanding of affective illness.

Kalra SK, Swedo SE. · National Institute of Mental Health, NIH, Bethesda, Maryland 20892, USA. · J Clin Invest. · Pubmed #19339765 No free full text.

Abstract: Childhood-onset obsessive-compulsive disorder (OCD) affects 1%-2% of children and adolescents. It is characterized by recurrent obsessions and compulsions that create distress and interfere with daily life. The symptoms reported by children are similar to those seen among individuals who develop OCD in adulthood, and the two groups of patients are treated with similar symptom-relieving behavior therapies and medications. However, there are differences in sex ratios, patterns of comorbidity, and the results of neuroimaging studies that might be important. Here we review the diagnosis and treatment of childhood-onset OCD in light of pediatric and adult studies. We also discuss current knowledge of the pathophysiology of the disorder. Despite advances in this area, further research is needed to understand better the etiopathogenesis of the disorder and to develop new, more effective therapeutic options.

Khairova RA, Machado-Vieira R, Du J, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Int J Neuropsychopharmacol. · Pubmed #19224657 No free full text.

Abstract: A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder (MDD). Several pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) have been found to be significantly increased in patients with MDD. This review focuses on these two cytokines based on multiple lines of evidence from genetic, animal behaviour, and clinical studies showing that altered levels of serum TNF-alpha and IL-1 are associated with increased risk of depression, cognitive impairments, and reduced responsiveness to treatment. In addition, recent findings have shown that centrally expressed TNF-alpha and IL-1 play a dual role in the regulation of synaptic plasticity. In this paper, we review and critically appraise the mechanisms by which cytokines regulate synaptic and neural plasticity, and their implications for the pathophysiology and treatment of MDD. Finally, we discuss the therapeutic potential of anti-inflammatory-based approaches for treating patients with severe mood disorders. This is a promising field for increasing our understanding of the mechanistic interaction between the immune system, synaptic plasticity, and antidepressants, and for the ultimate development of novel and improved therapeutics for severe mood disorders.

Huey ED, Zahn R, Krueger F, Moll J, Kapogiannis D, Wassermann EM, Grafman J. · The National Institute of Neurological Disorders and Stroke, Cognitive Neuroscience Section, NIH/NINDS, Bethesda, MD 20892-1440, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #19196924 No free full text.

Abstract: Imaging, surgical, and lesion studies suggest that the prefrontal cortex (orbitofrontal and anterior cingulate cortexes), basal ganglia, and thalamus are involved in the pathogenesis of obsessive-compulsive disorder (OCD). On the basis of these findings several models of OCD have been developed, but have had difficulty fully integrating the psychological and neuroanatomical findings of OCD. Recent research in the field of cognitive neuroscience on the normal function of these brain areas demonstrates the role of the orbitofrontal cortex in reward, the anterior cingulate cortex in error detection, the basal ganglia in affecting the threshold for activation of motor and behavioral programs, and the prefrontal cortex in storing memories of behavioral sequences (called "structured event complexes" or SECs). The authors propose that the initiation of these SECs can be accompanied by anxiety that is relieved with completion of the SEC, and that a deficit in this process could be responsible for many of the symptoms of OCD. Specifically, the anxiety can form the basis of an obsession, and a compulsion can be an attempt to receive relief from the anxiety by repeating parts of, or an entire, SEC. The authors discuss empiric support for, and specific experimental predictions of, this model. The authors believe that this model explains the specific symptoms, and integrates the psychology and neuroanatomy of OCD better than previous models.

Holmes A, Wellman CL. · Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD 20852-9411, USA. · Neurosci Biobehav Rev. · Pubmed #19111570 No free full text.

Abstract: The prefrontal cortex (PFC) mediates a range of higher order 'executive functions' that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment.

Ernst M, Fudge JL. · Mood and Anxiety Disorders, Program National Institute of Mental Health, National Institutes of Health, 15K North Drive, Bethesda, MD 20892, United States. · Neurosci Biobehav Rev. · Pubmed #19028521 No free full text.

Abstract: Adolescence is the transition period that prepares individuals for fulfilling their role as adults. Most conspicuous in this transition period is the peak level of risk-taking behaviors that characterize adolescent motivated behavior. Significant neural remodeling contributes to this change. This review focuses on the functional neuroanatomy underlying motivated behavior, and how ontogenic changes can explain the typical behavioral patterns in adolescence. To help model these changes and provide testable hypotheses, a neural systems-based theory is presented. In short, the Triadic Model proposes that motivated behavior is governed by a carefully orchestrated articulation among three systems, approach, avoidance and regulatory. These three systems map to distinct, but overlapping, neural circuits, whose representatives are the striatum, the amygdala and the medial prefrontal cortex. Each of these system-representatives will be described from a functional anatomy perspective that includes a review of their connectivity and what is known of their ontogenic changes.

DiazGranados N, Zarate CA. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, 10 Center Drive, CRC, Unit 7 Southeast, Room 7-3445, Bethesda, MD 20892, USA. · Curr Psychiatry Rep. · Pubmed #18980735 No free full text.

Abstract: In this article, we review preclinical studies investigating the role of protein kinase C (PKC) as it pertains to mania and effective antimanic agents. We then discuss clinical studies conducted with tamoxifen, a relatively selective PKC inhibitor, in acute bipolar mania. We conclude that PKC is an important target-arguably the first mechanistically distinct drug target for bipolar disorder. PKC holds considerable promise as a novel target for developing a new line of treatments for bipolar disorder.

Pine DS, Guyer AE, Leibenluft E. · Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #18931608 No free full text.

This publication has no abstract.

Crowe SL, Blair RJ. · National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Dev Psychopathol. · Pubmed #18838035 No free full text.

Abstract: The recent development of low-risk imaging technologies, such as functional magnetic resonance imaging (fMRI), have had a significant impact on the investigation of psychopathologies in children and adolescents. This review considers what we can infer from fMRI work regarding the development of conduct disorder (CD) and oppositional defiant disorder (ODD). We make two central assumptions that are grounded in the empirical literature. First, the diagnoses of CD and ODD identify individuals with heterogeneous pathologies; that is, different developmental pathologies can receive a CDD or ODD diagnosis. This is indicated by the comorbidities associated with CD/ODD, some of which appear to be mutually exclusive at the biological level (e.g., posttraumatic stress disorder [PTSD] and psychopathic tendencies). Second, two populations of antisocial individuals can be identified: those that show an increased risk for only reactive aggression and those that show an increased risk for both reactive and instrumental aggression. We review the fMRI data indicating that particular comorbidities of CD/ODD (i.e., mood and anxiety conditions such as childhood bipolar disorder and PTSD) are associated with either increased responsiveness of neural regions implicated in the basic response to threat (e.g., the amygdala) or decreased responsiveness in regions of frontal cortex (e.g., ventromedial frontal cortex) that are implicated in the regulation of the basic threat response. We suggest why such pathology would increase the risk for reactive aggression and, in turn, lead to the association with a CD/ODD diagnosis. We also review the literature on psychopathic tendencies, a condition where the individual is at significantly elevated risk for both reactive and instrumental aggression. We show that in individuals with psychopathic tendencies, the functioning of the amygdala in stimulus-reinforcement learning and of the ventromedial frontal cortex in the representation of reinforcement expectancies is impaired. We suggest why such pathology would increase the risk for reactive and instrumental aggression and thus also lead to the association with a CD/ODD diagnosis.

Nelson EE, Winslow JT. · Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA. · Neuropsychopharmacology. · Pubmed #18800061 No free full text.

Abstract: Non-human primates have been used to model psychiatric disease for several decades. The success of this paradigm has issued from comparable cognitive skills, brain morphology, and social complexity in adult monkeys and humans. Recently, interest in biological psychiatry has focused on similar brain, social, and emotional developmental processes in monkeys. In part, this is related to evidence that early postnatal experiences in human development may have profound implications for subsequent mental health. Non-human primate studies of postnatal phenomenon have generally fallen into three basic categories: experiential manipulation (largely manipulations of rearing), pharmacological manipulation (eg drug-induced psychosis), and anatomical localization (defined by strategic surgical damage). Although these efforts have been very informative each of them has certain limitations. In this review we highlight general findings from the non-human primate postnatal developmental literature and their implications for primate models in psychiatry. We argue that primates are uniquely capable of uncovering interactions between genes, environmental challenges, and development resulting in altered risk for psychopathology.

Pine DS, Helfinstein SM, Bar-Haim Y, Nelson E, Fox NA. · Mood and Anxiety Disorders Program, Intramural Research Program, The National Institute of Mental Health, Bethesda, MD 20892-2670, USA. · Neuropsychopharmacology. · Pubmed #18754004 No free full text.

Abstract: Alterations in brain development may contribute to chronic mental disorders. Novel treatments targeted toward the early-childhood manifestations of such chronic disorders may provide unique therapeutic opportunities. However, attempts to develop and deliver novel treatments face many challenges. Work on pediatric anxiety disorders illustrates both the inherent challenges as well as the unusual opportunities for therapeutic advances. The present review summarizes three aspects of translational research on pediatric anxiety disorders as the work informs efforts to develop novel interventions. First, the review summarizes data on developmental conceptualizations of anxiety from both basic neuroscience and clinical perspectives. This summary is integrated with a discussion of the two best-established treatments, cognitive behavioral therapy and selective serotonin reuptake inhibitors. Second, the review summarizes work on attention bias to threat, considering implications for both novel treatments and translational research on neural circuitry functional development. This illustrates the manner in which clinical findings inform basic systems neuroscience research. Finally, the review summarizes work in basic science on fear learning, as studied in fear conditioning, consolidation, and extinction paradigms. This summary ends by describing potential novel treatments, illustrating the manner in which basic neuroscience informs therapeutics.

Zarate CA, Manji HK. · Mark O Hatfield CRC, Bethesda, Maryland 20892, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #18721116 links to  free full text

Abstract: BACKGROUND: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent. OBJECTIVE: To assess the potential risks and benefits of riluzole treatment in psychiatric patients. METHODS: A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients. RESULTS/CONCLUSION: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.

Zarate CA, Manji HK. · Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, MD, USA. · Mt Sinai J Med. · Pubmed #18704977 No free full text.

Abstract: Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compounds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system, and the hypothalamic-pituitary adrenal axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade.

Drevets WC, Price JL, Furey ML. · Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health (NIH/NIMH DIRP), 15K North Dr., Room 210, Bethesda, MD 20892, USA. · Brain Struct Funct. · Pubmed #18704495 links to  free full text

Abstract: The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

Drevets WC, Savitz J, Trimble M. · Section on Neuroimaging in Mood and Anxiety Disorders, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. · CNS Spectr. · Pubmed #18704022 links to  free full text

Abstract: The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

Sommer WH, Saavedra JM. · Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1108, USA. · J Mol Med. · Pubmed #18449521 links to  free full text

Abstract: The brain renin-angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT(1) receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders.

Holmes A. · Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, 5625 Fishers Lane Room 2N09, Rockville, MD 20852-9411, USA. · Neurosci Biobehav Rev. · Pubmed #18439676 No free full text.

Abstract: The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

Machado-Vieira R, Salvadore G, Luckenbaugh DA, Manji HK, Zarate CA. · Mood and Anxiety Disorders Program, National Institute of Mental Health, Department of Health and Human Services, Bethesda, MD 20892-1282, USA. · J Clin Psychiatry. · Pubmed #18435563 links to  free full text

Abstract: OBJECTIVE: Current therapeutics of depression are similar in their time to antidepressant action and often take weeks to months to achieve response and remission, which commonly results in considerable morbidity and disruption in personal, professional, family, and social life, as well as risk for suicidal behavior. Thus, treatment strategies presenting a rapid improvement of depressive symptoms--within hours or even a few days--and whose effects are sustained would have an enormous impact on public health. This article reviews the published data related to different aspects of rapid improvement of depressive symptoms. DATA SOURCES: Literature for this review was obtained through a search of the MEDLINE database (1966-2007) using the following keywords and phrases: rapid response, antidepressant, time to, glutamate, sleep, therapeutics, latency, and depression. The data obtained were organized according to the following topics: clinical relevance and time course of antidepressant action, interventions showing evidence of rapid response and its potential neurobiological basis, and new technologies for better understanding rapid anti-depressant actions. DATA SYNTHESIS: A limited number of prospective studies evaluating rapid antidepressant actions have been conducted. Currently, only a few interventions have been shown to produce antidepressant response in hours or a few days. The neurobiological basis of these rapid antidepressant actions is only now being deciphered. CONCLUSIONS: Certain experimental treatments can produce antidepressant response in a much shorter period of time than existing medications. Understanding the molecular basis of these experimental interventions is likely to lead to the development of improved therapeutics rather than simply furthering our knowledge of current standard antidepressants.

Catapano LA, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD, USA. · Drug Discov Today. · Pubmed #18405841 No free full text.

Abstract: Bipolar disorder is one of the most severely debilitating of all medical illnesses, and is increasingly recognized as a major public health problem. For many patients with bipolar disorder, current pharmacotherapy is insufficient. Exciting recent data suggest that regulation of signaling molecules may be involved in the pathophysiology of the disorder, and in the mechanisms of action of mood stabilizers and antidepressants. Through our developing understanding of the biochemical targets of effective medications, several potential targets for new therapies have emerged. This short review will focus on two of the most promising such targets: glycogen synthase-3 and protein kinase C.

Davis MI. · Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. · Pharmacol Ther. · Pubmed #18394710 links to  free full text

Abstract: Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism.

Lau JY, Pine DS. · Mood and Anxiety Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #18343966 No free full text.

Abstract: Recent findings of gene-environment interaction on child and adolescent anxiety generate interest in mechanisms through which genetic risks are expressed. Current findings from neuroscience suggest avenues for exploring putative mechanisms. Specifically recent documentations of abnormality in brain function among anxious adolescents may reflect the end-result of gene expression. In turn these inherited predispositions may increase the likelihood of psychopathology in the presence of stress. The aim of the current article is to consider putative mechanisms reflecting genetic sensitivity to the environment (G x E). Thus we review data implicating biased processing of threat information and anomalies in brain circuitry in the expression of pediatric anxiety. These data suggest that links across development among genes, brain, psychological processes, and behavior are far from established. Accordingly, the article proposes strategies for examining these links. Exploring these relationships during development is crucial, given that these early life processes may potentially shape longer-term patterns of emotional behavior, and therefore life-long trajectories of anxiety.

Zarate CA, Manji HK. · Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health/NIH, 10 Center Drive, Bethesda, MD 20892, USA. · Exp Neurol. · Pubmed #18291371 links to  free full text

This publication has no abstract.

Kalueff AV, Murphy DL. · Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892-1264, USA. · Neural Plast. · Pubmed #18288249 links to  free full text

Abstract: Cognitive dysfunctions are commonly seen in many stress-related disorders, including anxiety and depression-the world's most common neuropsychiatric illnesses. Various genetic, pharmacological, and behavioral animal models have long been used to establish animal anxiety-like and depression-like phenotypes, as well as to assess their memory, learning, and other cognitive functions. Mounting clinical and animal evidences strongly supports the notion that disturbed cognitions represent an important pathogenetic factor in anxiety and depression, and may also play a role in integrating the two disorders within a common stress-precipitated developmental pathway. This paper evaluates why and how the assessment of cognitive and emotional domains may improve our understanding of animal behaviors via different high-throughput tests and enable a better translation of animal phenotypes into human brain disorders.