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      Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression

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          Abstract

          Decreased serotonergic activity has been implicated in anxiety and major depression, and antidepressants directly or indirectly increase the long-term activity of the serotonin system. A key component of serotonin circuitry is the 5-HT1A autoreceptor, which functions as the major somatodendritic autoreceptor to negatively regulate the “gain” of the serotonin system. In addition, 5-HT1A heteroreceptors are abundantly expressed post-synaptically in the prefrontal cortex (PFC), amygdala, and hippocampus to mediate serotonin actions on fear, anxiety, stress, and cognition. Importantly, in the PFC 5-HT1A heteroreceptors are expressed on at least two antagonist neuronal populations: excitatory pyramidal neurons and inhibitory interneurons. Rodent models implicate the 5-HT1A receptor in anxiety- and depression-like phenotypes with distinct roles for pre- and post-synaptic 5-HT1A receptors. In this review, we present a model of serotonin-PFC circuitry that integrates evidence from mouse genetic models of anxiety and depression involving knockout, suppression, over-expression, or mutation of genes of the serotonin system including 5-HT1A receptors. The model postulates that behavioral phenotype shifts as serotonin activity increases from none (depressed/aggressive not anxious) to low (anxious/depressed) to high (anxious, not depressed). We identify a set of conserved transcription factors including Deaf1, Freud-1/CC2D1A, Freud-2/CC2D1B and glucocorticoid receptors that may confer deleterious regional changes in 5-HT1A receptors in depression, and how future treatments could target these mechanisms. Further studies to specifically test the roles and regulation of pyramidal vs. interneuronal populations of 5-HT receptors are needed better understand the role of serotonin in anxiety and depression and to devise more effective targeted therapeutic approaches.

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          Most cited references 139

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          Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.

          We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs). For each of the 20 mental and substance use disorders included in GBD 2010, we systematically reviewed epidemiological data and used a Bayesian meta-regression tool, DisMod-MR, to model prevalence by age, sex, country, region, and year. We obtained disability weights from representative community surveys and an internet-based survey to calculate YLDs. We calculated premature mortality as YLLs from cause of death estimates for 1980-2010 for 20 age groups, both sexes, and 187 countries. We derived DALYs from the sum of YLDs and YLLs. We adjusted burden estimates for comorbidity and present them with 95% uncertainty intervals. In 2010, mental and substance use disorders accounted for 183·9 million DALYs (95% UI 153·5 million-216·7 million), or 7·4% (6·2-8·6) of all DALYs worldwide. Such disorders accounted for 8·6 million YLLs (6·5 million-12·1 million; 0·5% [0·4-0·7] of all YLLs) and 175·3 million YLDs (144·5 million-207·8 million; 22·9% [18·6-27·2] of all YLDs). Mental and substance use disorders were the leading cause of YLDs worldwide. Depressive disorders accounted for 40·5% (31·7-49·2) of DALYs caused by mental and substance use disorders, with anxiety disorders accounting for 14·6% (11·2-18·4), illicit drug use disorders for 10·9% (8·9-13·2), alcohol use disorders for 9·6% (7·7-11·8), schizophrenia for 7·4% (5·0-9·8), bipolar disorder for 7·0% (4·4-10·3), pervasive developmental disorders for 4·2% (3·2-5·3), childhood behavioural disorders for 3·4% (2·2-4·7), and eating disorders for 1·2% (0·9-1·5). DALYs varied by age and sex, with the highest proportion of total DALYs occurring in people aged 10-29 years. The burden of mental and substance use disorders increased by 37·6% between 1990 and 2010, which for most disorders was driven by population growth and ageing. Despite the apparently small contribution of YLLs--with deaths in people with mental disorders coded to the physical cause of death and suicide coded to the category of injuries under self-harm--our findings show the striking and growing challenge that these disorders pose for health systems in developed and developing regions. In view of the magnitude of their contribution, improvement in population health is only possible if countries make the prevention and treatment of mental and substance use disorders a public health priority. Queensland Department of Health, National Health and Medical Research Council of Australia, National Drug and Alcohol Research Centre-University of New South Wales, Bill & Melinda Gates Foundation, University of Toronto, Technische Universität, Ontario Ministry of Health and Long Term Care, and the US National Institute of Alcohol Abuse and Alcoholism. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.

            Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
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              Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.

              Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder. This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care "real world" settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of or=50% in baseline QIDS-SR score. Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates. The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.
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                Author and article information

                Contributors
                Journal
                Front Behav Neurosci
                Front Behav Neurosci
                Front. Behav. Neurosci.
                Frontiers in Behavioral Neuroscience
                Frontiers Media S.A.
                1662-5153
                06 June 2014
                2014
                : 8
                Affiliations
                1Neuroscience, Ottawa Hospital Research Institute, University of Ottawa Ottawa, ON, Canada
                2Department of Cellular and Molecular Medicine, University of Ottawa Ottawa ON, Canada
                Author notes

                Edited by: Zoe R. Donaldson, Columbia University, USA

                Reviewed by: Eduardo David Leonardo, Columbia University, USA; Orna Issler, Weizmann Institute of Science, Israel; Alvaro L. Garcia-Garcia, Columbia Univeristy, USA

                *Correspondence: Paul R. Albert, Neuroscience, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H-8M5, Canada e-mail: palbert@ 123456uottawa.ca

                This article was submitted to the journal Frontiers in Behavioral Neuroscience.

                Article
                10.3389/fnbeh.2014.00199
                4047678
                Copyright © 2014 Albert, Vahid-Ansari and Luckhart.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 139, Pages: 13, Words: 11220
                Categories
                Neuroscience
                Review Article

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