Anxiety Disorders: National Institutes of Health

Lipsky RH, Marini AM. · Section of Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20814, USA. · Ann N Y Acad Sci. · Pubmed #18077569 No free full text.

Abstract: Neurotrophins are critical to the development and maintenance of the mammalian central nervous system. Among them is brain-derived neurotrophic factor (BDNF), whose synthesis and release is targeted by activation of glutamate receptors. Perturbation of this process probably underlies neurodegenerative and psychiatric disorders. A naturally occurring variation in humans, in the form of a common single-nucleotide polymorphism in the pro region of the polypeptide at codon 66 (Val66-->Met), affects processing of the pro-BDNF polypeptide and its activation-dependent release. This variant is associated with differences in the volume of the hippocampal formation and with anxiety and depression-related phenotypes. Convergent findings supporting a role for BDNF in alterations to hippocampal structure and behavior are found in a "humanized" BDNF transgenic mouse. Also, recent human genetic studies have supported a role of BDNF signaling in addictive behaviors by allele-, genotype-, and haplotype-based association of the TrkB gene, which encodes the cognate receptor for BDNF, with alcohol dependence. A better understanding of the influence of BDNF-mediated pathways in cell survival and plasticity will aid in developing new approaches to restoring normal function in disease states.

Cameron HA, Dayer AG. · Unit on Neuroplasticity, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda , Maryland 20892, USA. <> · Biol Psychiatry. · Pubmed #18067877 links to  free full text

Abstract: During the last decade, the intense study of adult hippocampal neurogenesis has led to several new lines of inquiry in the field of psychiatry. Although it is generally believed that adult mammalian neurogenesis is restricted to the hippocampus and olfactory bulb, a growing number of studies have described new neurons in the adult neocortex in both rodents and nonhuman primates. Interestingly, all of the new neurons observed in these studies have features of interneurons rather than pyramidal cells, the largest neuronal population of the neocortex. In this review, we discuss features of these interneurons that may explain why cortical neurogenesis has been so difficult to detect. In addition, these features suggest ways that production of even a small numbers of new neurons in the adult cortex could make a significant impact on neocortical function.

Grillon C. · Unit of Affective Psychophysiology, Mood and Anxiety Disorder Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. · Psychopharmacology (Berl). · Pubmed #18058089 links to  free full text

Abstract: RATIONALE: Preclinical data indicates that threat stimuli elicit two classes of defensive behaviors, those that are associated with imminent danger and are characterized by flight or fight (fear), and those that are associated with temporally uncertain danger and are characterized by sustained apprehension and hypervigilance (anxiety). OBJECTIVE: The objectives of the study are to (1) review evidence for a distinction between fear and anxiety in animal and human experimental models using the startle reflex as an operational measure of aversive states, (2) describe experimental models of anxiety, as opposed to fear, in humans, (3) examine the relevance of these models to clinical anxiety. RESULTS: The distinction between phasic fear to imminent threat and sustained anxiety to temporally uncertain danger is suggested by psychopharmacological and behavioral evidence from ethological studies and can be traced back to distinct neuroanatomical systems, the amygdala and the bed nucleus of the stria terminalis. Experimental models of anxiety, not fear, are relevant to non-phobic anxiety disorders. CONCLUSIONS: Progress in our understanding of normal and abnormal anxiety is critically dependent on our ability to model sustained aversive states to temporally uncertain threat.

Blair RJ. · Anxiety Program, National Institute of Mental Health, Bethesda, MD 20892, USA. · Q J Exp Psychol (Colchester). · Pubmed #18038346 No free full text.

Abstract: In the current paper, the "fine cuts" approach advocated by Uta Frith is applied to our understanding of empathy and amygdala dysfunction in two disorders, psychopathy and autism. A fine cut is made between cognitive (i.e., Theory of Mind) and emotional empathy. The literature with respect to psychopathy and autism and these two functions is then considered. A fine cut is also made between the amygdala's role in stimulus-reinforcement association and specific aspects of social cognition. Again the literature with respect to psychopathy and autism and these two functions of the amygdala is considered. It is concluded that while both conditions can be considered disorders of social cognition, fine cuts can be made dissociating the impairments associated with each.

Math SB, Chandrashekar CR, Bhugra D. · Department of Psychiatry, National Institute of Mental Health & Neuro Sciences (Deemed University) Bangalore, Karnataka, India. · Indian J Med Res. · Pubmed #18037711 links to  free full text

Abstract: Epidemiological studies report prevalence rates for psychiatric disorders from 9.5 to 370/1000 populations in India. This review critically evaluates the prevalence rate of mental disorders as reported in Indian epidemiological studies. Extensive search of PubMed, NeuroMed and MEDLARS using search terms "psychiatry" and "epidemiology" was done. Manual search of literature was also done. Retrieved articles were systematically selected using inclusion and exclusion criteria. Only sixteen prevalence studies fulfilled the study criteria. Most of the epidemiological studies done in India neglected anxiety disorders, substance dependence disorders, co-morbidity and dual diagnosis. The use of poor sensitive screening instruments, single informant and systematic underreporting has added to the discrepancy in the prevalence rate. The prevalence of mental disorders reported in epidemiological surveys can be considered lower estimates rather than accurate reflections of the true prevalence in the population. Researchers have focused on broad non-specific, non-modifiable risk factors, such as age, gender and social class. Future research focused on the general population, longitudinal (prospective), multi-centre, co-morbid studies, assessment of disability, functioning, family burden and quality of life studies involving a clinical service providing approach, is required.

Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C. · Mood and Anxiety Disorders Program, MINH Molecular Imaging Branch, Bethesda, MD 20892, USA. · Nucl Med Biol. · Pubmed #17921037 links to  free full text

Abstract: INTRODUCTION: Serotonin-1A receptor (5-HT1AR) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT1AR agonists in vivo and to 5-HT1AR binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT1AR binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635, and we have demonstrated reduced 5-HT1AR BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. METHODS: Using PET and [carbonyl-(11)C]WAY-100635, 5-HT1AR BP was assessed in 16 depressed subjects and 8 healthy controls. RESULTS: Mean 5-HT1AR BP was reduced by 26% in the MTC (P<.005) and by 43% in the raphe (P<.001) in depressives versus controls. CONCLUSIONS: These data replicate our original findings, which showed that BP was reduced by 27% in the MTC (P<.025) and by 42% in the raphe (P<.02) in depression. The magnitudes of these reductions in 5-HT1AR binding were similar to those found postmortem in 5-HT1AR mRNA concentrations in the hippocampus in MDD [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT1AR-binding capacity in the raphe in depressed suicide victims [Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25(6):892-903]. There exists disagreement within the literature, however, regarding the presence and direction of 5-HT1AR-binding abnormalities in depression, which may be explained in some cases by differences in anatomical location (e.g., [Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression--postmortem evidence for decreased serotonin activity. J Neurosci 1998;18(18):7394-401]) and in other cases by pathophysiological heterogeneity within MDD (e.g., some depressives hypersecrete cortisol, which would be expected to down-regulate 5-HT1AR expression [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73]). Antidepressant drug treatment does not alter these abnormalities in 5-HT1AR binding [Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57(2):174-80; Moses-Kolko EL, Price JC, Thase ME, Meltzer CC, Kupfer DJ, Mathis CA, Bogers WD, Berman SR, Houck PR, Schneider TN, Drevets WC. Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635. Synapse 2007;61(7):523-30] but may compensate for blunted 5-HT1AR function by increasing post-synaptic 5-HT1AR transmission [Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991;5(4):219-29].

Crawley JN. · Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892-3730. USA. · Brain Pathol. · Pubmed #17919130 No free full text.

Abstract: While the cause of autism remains unknown, the high concordance between monozygotic twins supports a strong genetic component. The importance of genetic factors in autism encourages the development of mutant mouse models, to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (i) face validity (resemblance to the human symptoms) (ii) construct validity (similarity to the underlying causes of the disease) and (iii) predictive validity (expected responses to treatments that are effective in the human disease). There is a growing need for mouse behavioral tasks with all three types of validity, to define robust phenotypes in mouse models of autism. Ideal mouse models will incorporate analogies to the three diagnostic symptoms of autism: abnormal social interactions, deficits in communication and high levels of repetitive behaviors. Social approach is tested in an automated three chambered apparatus that offers the subject a choice between spending time with another mouse, with a novel object, or remaining in an empty familiar environment. Reciprocal social interaction is scored from videotapes of interactions between pairs of unfamiliar mice. Communication is evaluated by measuring emission and responses to vocalizations and olfactory cues. Repetitive behaviors are scored for measures of grooming, jumping, or stereotyped sniffing of one location or object. Insistence on sameness is modeled by scoring a change in habit, for example, reversal of the spatial location of a reinforcer in the Morris water maze or T-maze. Associated features of autism, for example, mouse phenotypes relevant to anxiety, seizures, sleep disturbances and sensory hypersensitivity, may be useful to include in a mouse model that meets some of the core diagnostic criteria. Applications of these assays include (i) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism; (ii) characterization of inbred strains of mice; (iii) evaluation of environmental toxins; (iv) comparison of behavioral phenotypes with genetic factors, such as unusual expression patterns of genes or unusual single nucleotide polymorphisms; and (v) evaluation of proposed therapeutics for the treatment of autism.

Schloesser RJ, Huang J, Klein PS, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. · Neuropsychopharmacology. · Pubmed #17912251 links to  free full text

Abstract: Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood-stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder.

Martinowich K, Lu B. · Mood and Anxiety Disorders Program (MAP), NIMH, National Institutes of Health, Bethesda, MD 20892-3714, USA. · Neuropsychopharmacology. · Pubmed #17882234 links to  free full text

Abstract: Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are two seemingly distinct signaling systems that play regulatory roles in many neuronal functions including survival, neurogenesis, and synaptic plasticity. A common feature of the two systems is their ability to regulate the development and plasticity of neural circuits involved in mood disorders such as depression and anxiety. BDNF promotes the survival and differentiation of 5-HT neurons. Conversely, administration of antidepressant selective serotonin reuptake inhibitors (SSRIs) enhances BDNF gene expression. There is also evidence for synergism between the two systems in affective behaviors and genetic epitasis between BDNF and the serotonin transporter genes.

Shippenberg TS, Zapata A, Chefer VI. · Integrative Neuroscience Section, NIH/NIDA Intramural Research Program, 333 Cassell Drive, Baltimore, MD 21224, USA. · Pharmacol Ther. · Pubmed #17868902 No free full text.

Abstract: Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/kappa-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.

Kalueff AV, Ishikawa K, Griffith AJ. · Laboratory of Clinical Science, Building 10, Room 3D41, National Institute of Mental Health, 10 Center Dr. MSC 1264, NIH, Bethesda, MD 20892-1264, USA. · Behav Brain Res. · Pubmed #17822783 No free full text.

Abstract: Human anxiety and vestibular disorders have long been known to co-occur. Paralleling human clinical and non-clinical data, mounting genetic, pharmacological and behavioral evidence confirms that animal anxiety interplays and co-exists with vestibular/balance deficits. However, relatively few animal models have addressed the nature of this relationship. This paper examines side-by-side human psychiatric and otovestibular phenotypes with animal experimentation data, and outlines future directions of translational research in this field. Discussed here are recently developed specific animal models targeting this interplay, other traditional animal tests sensitive to altered anxiety and vestibular domains, and the existing problems with translation of animal data into human phenotypes. The role of hearing deficits and their contribution to anxiety and vestibular phenotypes are also outlined. Overall, the overlap between anxiety and balance disorders emerges as an important phenomenon in both animal and clinical studies, and may contribute markedly to the complexity of behavioral and physiological phenotypes. Animal experimental models that focus on the interplay between anxiety and vestibular disorders are needed to improve our understanding of this important biomedical problem.

Martinowich K, Manji H, Lu B. · Mood and Anxiety Program, National Institute of Mental Health, Building 35, Room 1C1004, 35 Convent Drive, MSC 3714, Bethesda, Maryland 20892-3714, USA. · Nat Neurosci. · Pubmed #17726474 No free full text.

Abstract: The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.

Leibenluft E, Rich BA. · Section on Bipolar Spectrum Disorders, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda MD, USA. · Annu Rev Clin Psychol. · Pubmed #17716034 No free full text.

Abstract: In the past decade, interest in and research on pediatric bipolar disorder (BD) has increased substantially. Prevalence rates of the disorder have doubled in outpatient settings, while twice as many research articles on pediatric BD were published in the past five years as in the prior decade. This review focuses on recent developments in the study of pediatric BD. We examine current research on the diagnostic boundaries of BD in youths, in particular the issues of episodicity and irritability, and provide assessment guidelines. We review data elucidating the pathophysiology of pediatric BD, with a focus on how these results may inform diagnosis. Finally, we discuss treatment approaches for pediatric BD, particularly psychotherapeutic interventions. Throughout the review, we pay particular attention to youths with severe chronic irritability, hyperarousal, and hyperreactivity, who reflect the population in whom the diagnosis of BD is most debated.

Pine DS. · Section on Development and Affective Neuroscience, National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA. · J Child Psychol Psychiatry. · Pubmed #17593144 No free full text.

Abstract: Across a range of mammalian species, early developmental variations in fear-related behaviors constrain patterns of anxious behavior throughout life. Individual differences in anxiety among rodents and non-human primates have been shown to reflect early-life influences of genes and the environment on brain circuitry. However, in humans, the manner in which genes and the environment developmentally shape individual differences in anxiety and associated brain circuitry remains poorly specified. The current review presents a conceptual framework that facilitates clinical research examining developmental influences on brain circuitry and anxiety. Research using threat-exposure paradigms might most directly integrate basic and clinical perspectives on pediatric anxiety.

Chuang DM, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA. · Biol Psychiatry. · Pubmed #17572175 links to  free full text

This publication has no abstract.

Murthy RS. · National Institute of Mental Health and Neurosciences, Bangalore, India. · Int Rev Psychiatry. · Pubmed #17566896 No free full text.

Abstract: There is growing awareness of the mental health impact of all types of mass violence. The exposure of large population groups, mostly having no mental health problems prior to the exposure, and the subsequent development, in a significant proportion of the population, of a variety of psychiatric symptoms and disorders represent both a challenge and an opportunity for psychiatrists. There is sufficient evidence from the variety of mass violence/conflict situations, that a significant proportion of the exposed population develop different mental disorders. There are vulnerable groups like women, children, widows, orphans, elderly, disabled, those exposed to severe pain and loss of body parts. There is also a consistent finding of the dose-response to the amount of trauma and the prevalence of mental disorders. There is growing recognition that there is need to consider a variety of syndromes, in addition to post-traumatic stress disorder (PTSD) like acute stress disorder (ASD), depression, complicated bereavement reactions, substance use disorders, poor physical health, fear, anxiety, physiological arousal, somatisation, anger control, functional disability and arrest or regression of childhood developmental progression. The challenge is to reach all of the ill persons and provide mental health services. The opportunity provided by this field is to develop a better understanding of issues of resilience, recovery and effectiveness of public health approaches to mental health care.

Merikangas KR, Kalaydjian A. · National Institute of Mental Health, Bethesda, Maryland 20892, USA. · Curr Opin Psychiatry. · Pubmed #17551350 No free full text.

Abstract: PURPOSE OF REVIEW: To consider comorbidity across multiple classes of disorders in data derived from recent large-scale community surveys. RECENT FINDINGS: There has been substantial recent progress in our understanding of patterns and implications of comorbidity of mental disorders. There is now converging evidence on the magnitude and specific patterns of comorbidity in international studies worldwide. There is increasing recognition of comorbidity of mental and physical disorders. Comorbidity of mental disorders and substance abuse has now been recognized universally, and the results of treatment and prevention studies incorporating comorbidity are now beginning to emerge. SUMMARY: Comorbidity has been shown to be an index of more severe course and outcome of mental disorders. Systematic inclusion of comorbidity into clinical evaluation and treatment will enhance the effectiveness of intervention with these conditions. Prevention of the development of secondary conditions as a consequence of primary disorders should reduce the impact of these conditions on both the individual and society.

O'Donnell KC, Gould TD. · The Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bldg 35, Rm 1C-912, 35 Convent Drive, Bethesda, MD 20892 3711, USA. · Neurosci Biobehav Rev. · Pubmed #17532044 links to  free full text

Abstract: For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.

Chrousos GP, Kino T. · First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece. · Stress. · Pubmed #17514590 No free full text.

Abstract: Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. These hormones influence a large percentage of the expressed human genome and their effects spare almost no organs or tissues. Glucocorticoids influence many functions of the central nervous system, such as arousal, cognition, mood and sleep, the activity and direction of intermediary metabolism, the maintenance of a normal cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, as well as growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems. The presence of multiple GR monomers and dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic. Based on ample evidence, we present our conception that glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common psychiatric and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid component.

Saavedra JM, Benicky J. · Section on Pharmacology, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Stress. · Pubmed #17514587 No free full text.

Abstract: Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT(1) receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT(1) receptors increase during stress. Blockade of peripheral and brain AT(1) receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF(1) and benzodiazepine receptors, part of the GABA(A) complex, and reduced anxiety in rodents. AT(1) receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT(1) receptors could be proposed as a potentially useful therapy for stress-induced disorders.

Daly JW. · Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892-0820, USA. · Cell Mol Life Sci. · Pubmed #17514358 No free full text.

Abstract: Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.

Math SB, Janardhan Reddy YC. · OCD clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India. · Int J Clin Pract. · Pubmed #17511795 No free full text.

Abstract: AIMS: Obsessive-compulsive disorder (OCD) preferentially responds to a class of antidepressants called serotonin reuptake inhibitors (SRI). This review discusses certain issues unique to pharmacological treatment of OCD: choice of SRI, dose and duration of treatment, options after first failed SRI trial and treatment of SRI non-responders. METHODS: We performed a MEDLINE search for pharmacotherapy studies published until December 2006. In addition, the reference sections of major articles, and reviews were also screened. We also considered clinical guidelines and narrative reviews in writing this review. RESULTS: The SRIs are equally effective in treating OCD. Meta-analyses suggest that clomipramine may be superior to other SRIs. OCD tends to respond to higher doses of SRIs than that used to treat depression. Response to treatment is usually delayed and may take up to 8-12 weeks. Atypical antipsychotics are the only proven augmenting agents in SRI non-responders. Cognitive behaviour therapy (CBT) is an effective treatment strategy in treating OCD and possibly has a role in treating SRI non-responders. DISCUSSION: Side effect profile and drug-drug interactions largely determine the choice of SRI. Those who fail to respond to one SRI trial may well respond to another SRI trial. Clomipramine is recommended if 2-3 trials of SRIs fail to produce response. Atypical antipsychotics are the first-line augmenting agents in SRI non-responders. CBT should be considered in all patients with OCD and is a potential option in SRI non-responders. CONCLUSION: OCD is a chronic and debilitating disorder. In responders, SRIs have to be continued in the same doses (if possible) for a minimum of 1-2 years and may be lifelong in those with persistent symptoms and in those with multiple relapses. CBT has to be offered in combination with SRIs wherever facilities for CBT exist.

Gould TD, Dow ER, O'Donnell KC, Chen G, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, Maryland 20892-3711, USA. · CNS Neurol Disord Drug Targets. · Pubmed #17511616 No free full text.

Abstract: Regulation of complex signaling pathways plays a critical role in higher-order brain functions including the regulation of mood, cognition, appetite, sexual arousal, sleep patterns, and weight, all of which are altered in mood disorders, suggesting the involvement of signaling pathways in mood disorder pathogenesis and pathophysiology. Most existing medications used to treat mood disorders take many weeks to exert their full clinical effects, a fact which implicates changes in gene and protein expression, as well as neuroplasticity, in their mechanism of action. Modulation of signaling pathways has many downstream effects on gene expression and protein function, causing changes in synaptic function, plasticity, and response to various inputs such as neurohormones. The Wnt signaling pathway has recently been linked to the therapeutically relevant actions of available treatments of mood disorders. We provide a brief introduction to signaling cascades and their potential roles in mood disorder pathophysiology and treatment. Subsequently, we describe the Wnt signaling pathway, and glycogen synthase kinase-3 (GSK-3) and beta-catenin specifically, discussing studies that have implicated these proteins as relevant to the pathophysiology and treatment of mood disorders. Future directions, aimed at understanding mood disorders and developing more efficacious treatments, are also discussed.

Rowe MK, Wiest C, Chuang DM. · Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Building 10, Room 4C206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363, USA. · Neurosci Biobehav Rev. · Pubmed #17499358 links to  free full text

Abstract: Bipolar disorder is a serious psychiatric condition that has been treated for over 50 years with lithium. Lithium is a well established glycogen synthase kinase-3 (GSK-3) inhibitor, suggesting that manipulating GSK-3 may have therapeutic value in treating bipolar disorder. GSK-3 is regulated by a wide variety of mechanisms including phosphorylation, binding with protein complexes, phosphorylation state of its substrates, cellular localization and autoregulation, thus providing a wide number of potential therapeutic mechanisms. Mounting evidence suggests that GSK-3 regulation can be used to manage bipolar disorder symptoms. Although GSK-3 mutations have not been detected amongst the general bipolar population, they have been correlated with females with bipolar II and most of the drugs used for successful bipolar disorder treatment regulate GSK-3. These drugs produce a weak anti-depressant-like and a strong anti-mania-like effect in a wide range of animal models tested, mirroring their utility in treating bipolar disorder symptoms. Taken together, the evidence suggests that targeting GSK-3 may be a means to control the symptoms of bipolar disorder.

Nakajima S, Shirai A. · National Center of Neurology and Psychiatry, National Institute of Mental Health, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan. · Nihon Arukoru Yakubutsu Igakkai Zasshi. · Pubmed #17447467 No free full text.

Abstract: Since the Crime Victims Act became enforced in 2005, the mental health recovery of crime victims has become an important issue among national government and local authorities. A high prevalence of psychiatric disorders, such as PTSD, among crime victims has been reported in domestic and foreign studies. However, little is known about the percentage of victims of crime who actually attend mental health services. The prevalence of mental health service usage varied from one study to another and is thought to be higher among victims of severe crimes, such as sexual assault. Several factors associated with seeking mental health care, including the presence of psychopathology, appear to be common among the studies. To offer suitable mental health services for crime victims, various organizations or agencies must cooperate with each other, including the police and prosecution, private victim support groups, and medical departments like emergency medical care centers and gynecology clinics. This report summarizes mental health problems and the use of mental health services among crime victims, and discusses how crime victims who require medical treatment may actually receive adequate mental health care.