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      Mechanisms of antidepressant resistance

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          Depression is one of the most frequent and severe mental disorder. Since the discovery of antidepressant (AD) properties of the imipramine and then after of other tricyclic compounds, several classes of psychotropic drugs have shown be effective in treating major depressive disorder (MDD). However, there is a wide range of variability in response to ADs that might lead to non response or partial response or in increased rate of relapse or recurrence. The mechanisms of response to AD therapy are poorly understood, and few biomarkers are available than can predict response to pharmacotherapy. Here, we will first review markers that can be used to predict response to pharmacotherapy, such as markers of drug metabolism or blood-brain barrier (BBB) function, the activity of specific brain areas or neurotransmitter systems, hormonal dysregulations or plasticity, and related molecular targets. We will describe both clinical and preclinical studies and describe factors that might affect the expression of these markers, including environmental or genetic factors and comorbidities. This information will permit us to suggest practical recommendations and innovative treatment strategies to improve therapeutic outcomes.

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            A new depression scale designed to be sensitive to change

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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.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                22 November 2013
                : 4
                1INSERM 930, Faculté de Sciences et Techniques, Université François Rabelais Tours, France
                2Centre Hospitalier Régional Universitaire de Tours, Centre Expert Dépression Résistante, Fondation FondaMental Tours, France
                Author notes

                Edited by: Thibault Renoir, Florey Institute of Neuroscience and Mental Health, Australia

                Reviewed by: Jean-Philippe Guilloux, Université Paris Sud, France; Andre Carvalho, Federal University of Ceara, Brazil

                *Correspondence: Catherine Belzung, INSERM 930, Faculté de Sciences et Techniques, Université François Rabelais, Parc Grandmont, F-37200 Tours, France e-mail: catherine.belzung@

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology.

                Copyright © 2013 El-Hage, Leman, Camus and Belzung.

                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: 1, Tables: 1, Equations: 0, References: 321, Pages: 23, Words: 23355
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