Cellular and molecular mechanisms in the long-term action of antidepressants.

The hypotheses on the pathophysiology of depression /mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the “hypothesis of neuroplasticity. ” In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.

[1]  R. Anwyl,et al.  Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. , 2009, The international journal of neuropsychopharmacology.

[2]  T. Jay,et al.  Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation , 2009, Neuropharmacology.

[3]  R. Emsley,et al.  P.2.c.025 Long-term treatment with agomelatine: prevention of relapse in patients with Major Depressive Disorder over 10 months , 2008, European Neuropsychopharmacology.

[4]  M. Popoli,et al.  Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells , 2008, BMC Neuroscience.

[5]  S. Kennedy,et al.  A Double-Blind Comparison of Sexual Functioning, Antidepressant Efficacy, and Tolerability Between Agomelatine and Venlafaxine XR , 2008, Journal of clinical psychopharmacology.

[6]  I. Lucki,et al.  Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments , 2008, Brain Research.

[7]  K. Lesch,et al.  Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter × Environment Risk Factor for Anxiety and Depression , 2008, Biological Psychiatry.

[8]  Carlos A. Zarate,et al.  Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders , 2008, Nature Reviews Drug Discovery.

[9]  L. Maffei,et al.  The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex , 2008, Science.

[10]  R. Hen,et al.  The When and Where of BDNF and the Antidepressant Response , 2008, Biological Psychiatry.

[11]  M. Barrot,et al.  Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy , 2008, Biological Psychiatry.

[12]  T. Shimazaki,et al.  [Mammalian neural stem cells]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[13]  Guang Chen,et al.  Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors , 2008, Biological Psychiatry.

[14]  L. Rønn,et al.  Temporal expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat hippocampus after treatment with selective and mixed monoaminergic antidepressants. , 2008, European journal of pharmacology.

[15]  K. Hashimoto,et al.  Increased Levels of Glutamate in Brains from Patients with Mood Disorders , 2007, Biological Psychiatry.

[16]  J. Lieberman,et al.  Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based on a review of evidence. , 2007, The international journal of neuropsychopharmacology.

[17]  P. Greengard,et al.  Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine , 2007, The European journal of neuroscience.

[18]  C. Guilleminault,et al.  Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. , 2007, The Journal of clinical psychiatry.

[19]  C. Guilleminault,et al.  Major depressive disorder, sleep EEG and agomelatine: an open-label study. , 2007, The international journal of neuropsychopharmacology.

[20]  S. Kasper,et al.  Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. , 2007, The international journal of neuropsychopharmacology.

[21]  H. Manji,et al.  New insights into BDNF function in depression and anxiety , 2007, Nature Neuroscience.

[22]  Rene Hen,et al.  Adult hippocampal neurogenesis in depression , 2007, Nature Neuroscience.

[23]  J. Groves,et al.  Is it time to reassess the BDNF hypothesis of depression? , 2007, Molecular Psychiatry.

[24]  J. Kasahara,et al.  Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus. , 2007, The international journal of neuropsychopharmacology.

[25]  B. Dias,et al.  Stressor-Specific Regulation of Distinct Brain-Derived Neurotrophic Factor Transcripts and Cyclic AMP Response Element-Binding Protein Expression in the Postnatal and Adult Rat Hippocampus , 2007, Neuropsychopharmacology.

[26]  M. Raiteri,et al.  Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus , 2007, Neuropharmacology.

[27]  B. McEwen,et al.  Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala. , 2007, European journal of pharmacology.

[28]  J. Fadel,et al.  Acute stress‐mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment , 2007, The European journal of neuroscience.

[29]  Dan J Stein,et al.  Early maternal separation alters the response to traumatization: resulting in increased levels of hippocampal neurotrophic factors , 2007, Metabolic Brain Disease.

[30]  György Buzsáki,et al.  How can drug discovery for psychiatric disorders be improved? , 2007, Nature Reviews Drug Discovery.

[31]  Kaia Palm,et al.  Mouse and rat BDNF gene structure and expression revisited , 2006, Journal of neuroscience research.

[32]  H. Manji,et al.  Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action. , 2006, Drug discovery today. Therapeutic strategies.

[33]  C. Siao,et al.  Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior , 2006, Science.

[34]  A. Khundakar,et al.  Biphasic change in BDNF gene expression following antidepressant drug treatment explained by differential transcript regulation , 2006, Brain Research.

[35]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[36]  R. Duman,et al.  A Neurotrophic Model for Stress-Related Mood Disorders , 2006, Biological Psychiatry.

[37]  E. Nestler,et al.  Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action , 2006, Nature Neuroscience.

[38]  M. Popoli,et al.  Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview , 2006, Pharmacological Reviews.

[39]  C. Sánchez,et al.  Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity , 2006, Neuroscience Letters.

[40]  Danielle L. Graham,et al.  Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress , 2006, Science.

[41]  E. Tongiorgi,et al.  What is the biological significance of BDNF mRNA targeting in the dendrites? , 2006, Molecular Neurobiology.

[42]  Anna Wirz-Justice,et al.  Biological rhythm disturbances in mood disorders , 2006, International clinical psychopharmacology.

[43]  Eric J. Nestler,et al.  New approaches to antidepressant drug discovery: beyond monoamines , 2006, Nature Reviews Neuroscience.

[44]  J. Blendy,et al.  Antidepressant action: to the nucleus and beyond. , 2005, Trends in pharmacological sciences.

[45]  E. Nestler,et al.  The many faces of CREB , 2005, Trends in Neurosciences.

[46]  Russo-Neustadt Aa,et al.  Brain-derived neurotrophic factor and antidepressant activity. , 2005, Current pharmaceutical design.

[47]  M. Yoshioka,et al.  Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress , 2005, Psychopharmacology.

[48]  P. Celada,et al.  Strategies for producing faster acting antidepressants. , 2005, Drug discovery today.

[49]  M. Raiteri,et al.  Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus , 2005, The Journal of Neuroscience.

[50]  T. Bolwig,et al.  Increased adult hippocampal brain‐derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats , 2005, Journal of neuroscience research.

[51]  E. Tongiorgi,et al.  Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo , 2005, Molecular and Cellular Neuroscience.

[52]  Greg Q Butcher,et al.  Activity-Dependent Neuroprotection and cAMP Response Element-Binding Protein (CREB): Kinase Coupling, Stimulus Intensity, and Temporal Regulation of CREB Phosphorylation at Serine 133 , 2005, The Journal of Neuroscience.

[53]  C. Swanson,et al.  Metabotropic glutamate receptors as novel targets for anxiety and stress disorders , 2005, Nature Reviews Drug Discovery.

[54]  U. Moens,et al.  What turns CREB on? , 2004, Cellular signalling.

[55]  G. MacQueen,et al.  The role of the hippocampus in the pathophysiology of major depression. , 2004, Journal of psychiatry & neuroscience : JPN.

[56]  J. Kasahara,et al.  Selective Phosphorylation of Nuclear CREB by Fluoxetine is Linked to Activation of CaM Kinase IV and MAP Kinase Cascades , 2004, Neuropsychopharmacology.

[57]  Graeme Eisenhofer,et al.  Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine , 2004, Pharmacological Reviews.

[58]  S. Kennedy,et al.  Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study , 2004, International clinical psychopharmacology.

[59]  R. Duman Depression: a case of neuronal life and death? , 2004, Biological Psychiatry.

[60]  P. Riederer,et al.  Clinical applications of MAO-inhibitors. , 2004, Current medicinal chemistry.

[61]  H. Manji,et al.  Modulation of Synaptic Plasticity by Antimanic Agents: The Role of AMPA Glutamate Receptor Subunit 1 Synaptic Expression , 2004, The Journal of Neuroscience.

[62]  John H Krystal,et al.  Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. , 2004, Archives of general psychiatry.

[63]  Guosong Liu,et al.  Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites , 2004, Nature Neuroscience.

[64]  M. Riva,et al.  Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions , 2004, Biological Psychiatry.

[65]  O. Kemmotsu,et al.  Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and α1-adrenoceptors , 2004, Neuroscience Letters.

[66]  T. Jay,et al.  Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. , 2004, Cerebral cortex.

[67]  K. Denicoff,et al.  Regulation of Cellular Plasticity Cascades in the Pathophysiology and Treatment of Mood Disorders , 2003, Annals of the New York Academy of Sciences.

[68]  P. Skolnick,et al.  Glutamate and Depression , 2003 .

[69]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[70]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[71]  C. Holden Excited by Glutamate , 2003, Science.

[72]  O. Kemmotsu,et al.  Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors , 2003, Brain Research.

[73]  Eric C. Griffith,et al.  Regulation of transcription factors by neuronal activity , 2002, Nature Reviews Neuroscience.

[74]  Rebeca Martínez-Turrillas,et al.  Chronic antidepressant treatment increases the membrane expression of AMPA receptors in rat hippocampus , 2002, Neuropharmacology.

[75]  René Garcia Stress, metaplasticity, and antidepressants. , 2002, Current molecular medicine.

[76]  E. Gould,et al.  Preclinical models: status of basic research in depression , 2002, Biological Psychiatry.

[77]  M. Yoshioka,et al.  Changes in synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway induced by repeated treatments with fluvoxamine , 2002, Brain Research.

[78]  E. Fuchs,et al.  The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats , 2002, The European journal of neuroscience.

[79]  D. Ginty,et al.  Function and Regulation of CREB Family Transcription Factors in the Nervous System , 2002, Neuron.

[80]  David M. Diamond,et al.  The stressed hippocampus, synaptic plasticity and lost memories , 2002, Nature Reviews Neuroscience.

[81]  M. Popoli,et al.  Modulation of synaptic plasticity by stress and antidepressants. , 2002, Bipolar disorders.

[82]  R. Anwyl,et al.  Overcoming the Effects of Stress on Synaptic Plasticity in the Intact Hippocampus: Rapid Actions of Serotonergic and Antidepressant Agents , 2002, The Journal of Neuroscience.

[83]  K. Deisseroth,et al.  Dynamic Multiphosphorylation Passwords for Activity-Dependent Gene Expression , 2002, Neuron.

[84]  A. West,et al.  Calcium regulation of neuronal gene expression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[85]  B. Spruijt,et al.  Chronic imipramine treatment partially reverses the long-term changes of hippocampal synaptic plasticity in socially stressed rats , 2001, Neuroscience Letters.

[86]  Marc Montminy,et al.  Transcriptional regulation by the phosphorylation-dependent factor CREB , 2001, Nature Reviews Molecular Cell Biology.

[87]  B. Vollmayr,et al.  Learned helplessness in the rat: improvements in validity and reliability. , 2001, Brain research. Brain research protocols.

[88]  R. McKay,et al.  Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus , 2001, The Journal of comparative neurology.

[89]  K. Fukunaga,et al.  Activation of Calcium/Calmodulin-dependent Protein Kinase IV in Long Term Potentiation in the Rat Hippocampal CA1 Region* , 2001, The Journal of Biological Chemistry.

[90]  R. Sapolsky,et al.  The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death , 2000, Biological Psychiatry.

[91]  W. Drevets Neuroimaging studies of mood disorders , 2000, Biological Psychiatry.

[92]  C. Mathers,et al.  The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors , 2000, The Medical journal of Australia.

[93]  F. Gage,et al.  Mammalian neural stem cells. , 2000, Science.

[94]  John H Krystal,et al.  Antidepressant effects of ketamine in depressed patients , 2000, Biological Psychiatry.

[95]  C. Stewart,et al.  Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity , 2000, Psychopharmacology.

[96]  G Lynch,et al.  Positive Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal and Cortical Neurons , 2000, The Journal of Neuroscience.

[97]  P. Sassone-Corsi,et al.  Signaling routes to CREM and CREB: plasticity in transcriptional activation. , 1999, Trends in biochemical sciences.

[98]  C. Venero,et al.  Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats , 1999, The European journal of neuroscience.

[99]  P. Skolnick,et al.  Antidepressants for the new millennium. , 1999, European journal of pharmacology.

[100]  Yvette I. Sheline,et al.  Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression , 1999, The Journal of Neuroscience.

[101]  J. Chatton,et al.  Acute application of the tricyclic antidepressant desipramine presynaptically stimulates the exocytosis of glutamate in the hippocampus , 1999, Neuroscience.

[102]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[103]  E Gould,et al.  Hippocampal neurogenesis in adult Old World primates. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[104]  R. Morris,et al.  Impaired spatial learning after saturation of long-term potentiation. , 1998, Science.

[105]  P. Skolnick,et al.  Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain , 1998, Journal of Molecular Neuroscience.

[106]  S. Stahl,et al.  Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. , 1998, The Journal of clinical psychiatry.

[107]  B. Westerink,et al.  Brain microdialysis of GABA and glutamate: What does it signify? , 1997, Synapse.

[108]  A. L. Bemmel The link between sleep and depression: The effects of antidepressants on EEG sleep , 1997 .

[109]  M. Raichle,et al.  Subgenual prefrontal cortex abnormalities in mood disorders , 1997, Nature.

[110]  B. Moghaddam,et al.  Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam , 1997, Neuroscience.

[111]  K. Deisseroth,et al.  CREB Phosphorylation and Dephosphorylation: A Ca2+- and Stimulus Duration–Dependent Switch for Hippocampal Gene Expression , 1996, Cell.

[112]  Richard F. Thompson,et al.  Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[113]  S. Hyman,et al.  Initiation and adaptation: a paradigm for understanding psychotropic drug action. , 1996, The American journal of psychiatry.

[114]  C. Montigny,et al.  Current advances and trends in the treatment of depression. , 1994, Trends in pharmacological sciences.

[115]  M E Greenberg,et al.  Calcium regulation of gene expression in neuronal cells. , 1994, Journal of neurobiology.

[116]  M. Mauri,et al.  Plasma and platelet excitatory amino acids in psychiatric disorders. , 1993, The American journal of psychiatry.

[117]  B. Moghaddam,et al.  Stress Preferentially Increases Extraneuronal Levels of Excitatory Amino Acids in the Prefrontal Cortex: Comparison to Hippocampus and Basal Ganglia , 1993, Journal of neurochemistry.

[118]  Bruce S. McEwen,et al.  Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons , 1992, Brain Research.

[119]  L. S. Kung,et al.  Development of β-adrenergic receptor subsensitivity by antidepressants , 1977, Nature.

[120]  R. Malenka,et al.  Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms , 2008, Neuropsychopharmacology.

[121]  C. Pittenger,et al.  Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms , 2008, Neuropsychopharmacology.

[122]  C. McClung,et al.  Neuroplasticity Mediated by Altered Gene Expression , 2008, Neuropsychopharmacology.

[123]  K. Hsu,et al.  Do stress and long-term potentiation share the same molecular mechanisms? , 2007, Molecular Neurobiology.

[124]  F. Sulser New perspectives on the molecular pharmacology of affective disorders , 2004, European archives of psychiatry and neurological sciences.

[125]  C. Holden Psychiatric drugs. Excited by glutamate. , 2003, Science.

[126]  P. Skolnick,et al.  Glutamate and depression: clinical and preclinical studies. , 2003, Annals of the New York Academy of Sciences.

[127]  A. V. van Bemmel The link between sleep and depression: the effects of antidepressants on EEG sleep. , 1997, Journal of psychosomatic research.

[128]  D. Charney,et al.  The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. , 1996, Pharmacopsychiatry.

[129]  L. S. Kung,et al.  Development of beta-adrenergic receptor subsensitivity by antidepressants. , 1977, Nature.