Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs

SummaryThe past decade of efforts to find improved treatment for major depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT1A, 5-HT1B and possibly 5-HT5A and 5-HT7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT4 and 5-HT6). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT2C antagonist) has clinically proven activity in major depression. Dual neurokinin1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H3 antagonists/SRIs, GABAB antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3β, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual- and triple-acting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

[1]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[2]  G. Gessa,et al.  Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex. , 2004, European journal of pharmacology.

[3]  H. Manji,et al.  Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs , 2005, Neuropsychopharmacology.

[4]  L. Agüera,et al.  Potentiation strategies for treatment‐resistant depression , 2005, Acta psychiatrica Scandinavica. Supplementum.

[5]  Csaba Böde,et al.  Stress‐induced rearrangements of cellular networks: Consequences for protection and drug design , 2007, FEBS letters.

[6]  K. Lawson.  Pharmacological treatments of fibromyalgia: do complex conditions need complex therapies? , 2008, Drug discovery today.

[7]  L. Schneider,et al.  Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials , 2007, The Lancet Neurology.

[8]  Trevor R. Norman,et al.  Emerging treatments for major depression , 2007, Expert review of neurotherapeutics.

[9]  Charles A. Marsden,et al.  A role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory , 2008 .

[10]  J. Hagan,et al.  SB‐656104‐A, a novel selective 5‐HT7 receptor antagonist, modulates REM sleep in rats , 2003, British journal of pharmacology.

[11]  I. Anderson,et al.  Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. , 2000, Journal of affective disorders.

[12]  L. Cipak,et al.  Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells , 2003, The Journal of pharmacy and pharmacology.

[13]  Abbas F. Sadikot,et al.  Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action , 2007, Neuron.

[14]  O. Wiborg,et al.  Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests , 2009, Journal of psychopharmacology.

[15]  M. Millan,et al.  Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. , 2008, Trends in pharmacological sciences.

[16]  A. Arai,et al.  Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. , 2007, Current drug targets.

[17]  D. Evrard.  Recent Strategies for the Development of New Antidepressant Drugs , 2006 .

[18]  P. Bork,et al.  Drug Target Identification Using Side-Effect Similarity , 2008, Science.

[19]  Olaf Sporns,et al.  Networks analysis, complexity, and brain function , 2002 .

[20]  Ceri H. Davies,et al.  SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain , 2006, Neuropharmacology.

[21]  Alan C. Evans,et al.  Small-world anatomical networks in the human brain revealed by cortical thickness from MRI. , 2007, Cerebral cortex.

[22]  M. Hotopf,et al.  Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials , 2001, British Journal of Psychiatry.

[23]  J. Lehár,et al.  Multi-target therapeutics: when the whole is greater than the sum of the parts. , 2007, Drug discovery today.

[24]  M. Millan,et al.  Cognitive impairment in schizophrenia: a review of developmental and genetic models, and pro-cognitive profile of the optimised D(3) > D(2) antagonist, S33138. , 2008, Therapie.

[25]  F Tisserand,et al.  Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade , 2001, International Journal of Obesity.

[26]  C. Gambarana,et al.  Study of mirtazapine antidepressant effects in rats. , 2005, The international journal of neuropsychopharmacology.

[27]  M. Martina,et al.  The sigma‐1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus , 2007, The Journal of physiology.

[28]  R. Kishony,et al.  Functional classification of drugs by properties of their pairwise interactions , 2006, Nature Genetics.

[29]  Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms , 2007, Psychopharmacology.

[30]  Franz X Vollenweider,et al.  Serotonin research: contributions to understanding psychoses. , 2008, Trends in pharmacological sciences.

[31]  A. Wesołowska,et al.  The selective 5-HT(6) receptor antagonist SB-399885 enhances anti-immobility action of antidepressants in rats. , 2008, European journal of pharmacology.

[32]  David R. Thomas,et al.  5-ht5A receptors as a therapeutic target. , 2006, Pharmacology & therapeutics.

[33]  M. Millan.  The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review. , 2004, European journal of pharmacology.

[34]  D. Charney,et al.  Addition of the α2-Antagonist Yohimbine to Fluoxetine: Effects on Rate of Antidepressant Response , 2004, Neuropsychopharmacology.

[35]  J. Doyle,et al.  Bow Ties, Metabolism and Disease , 2022 .

[36]  J. Rojo,et al.  Combined antidepressants: clinical experience , 2005, Acta psychiatrica Scandinavica. Supplementum.

[37]  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.

[38]  D. Quartermain,et al.  Central α1-adrenergic system in behavioral activity and depression , 2007 .

[39]  A. Rex,et al.  In vivo/ex vivo and behavioural study on central effects of 5-HT1B/1D and 5-HT1A antagonists in guinea pigs , 2008, Pharmacology Biochemistry and Behavior.

[40]  M. Meegan,et al.  Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter. , 2008, Current medicinal chemistry.

[41]  J. Forn,et al.  Effect of chronic lithium treatment on the turnover of α2-adrenoceptors after chemical inactivation in rats , 2004, European Neuropsychopharmacology.

[42]  G. Geisslinger,et al.  Cardiovascular risk with cyclooxygenase inhibitors: general problem with substance specific differences? , 2006, Naunyn-Schmiedeberg's Archives of Pharmacology.

[43]  D. Chuang,et al.  GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder , 2007, Neuroscience & Biobehavioral Reviews.

[44]  R. Sharan,et al.  Protein networks in disease. , 2008, Genome research.

[45]  M. Radhakrishnan,et al.  Antidepressant-like effects of serotonin type-3 antagonist, ondansetron: an investigation in behaviour-based rodent models , 2008, Behavioural pharmacology.

[46]  N. Volkow,et al.  The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects , 2005, Biological Psychiatry.

[47]  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.

[48]  B. Czéh,et al.  NK1 receptor antagonists under investigation for the treatment of affective disorders , 2006, Expert opinion on investigational drugs.

[49]  P. Celada,et al.  Pindolol augmentation of antidepressant response. , 2006, Current drug targets.

[50]  Robert M May,et al.  Network structure and the biology of populations. , 2006, Trends in ecology & evolution.

[51]  Helen S Mayberg,et al.  Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. , 2007, The American journal of psychiatry.

[52]  M. Joëls,et al.  Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress , 2007, The European journal of neuroscience.

[53]  M. Millan.  Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. , 2006, Pharmacology & therapeutics.

[54]  S. Korte.  Corticosteroids in relation to fear, anxiety and psychopathology , 2001, Neuroscience & Biobehavioral Reviews.

[55]  R. Landgraf.  The involvement of the vasopressin system in stress-related disorders. , 2006, CNS & neurological disorders drug targets.

[56]  A. Young,et al.  Antiglucocorticoid treatments for mood disorders. , 2015, The Cochrane database of systematic reviews.

[57]  Mary Sano,et al.  Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , 2008, The Lancet.

[58]  E. Bullmore,et al.  A Resilient, Low-Frequency, Small-World Human Brain Functional Network with Highly Connected Association Cortical Hubs , 2006, The Journal of Neuroscience.

[59]  Shigeyoshi Fujisawa,et al.  Single neurons can induce phase transitions of cortical recurrent networks with multiple internal States. , 2006, Cerebral cortex.

[60]  Timothy Edward John Behrens,et al.  Cerebral Cortex doi:10.1093/cercor/bhm167 Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression , 2007 .

[61]  S. Giordano,et al.  From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. , 2008, Current medicinal chemistry.

[62]  Afshin Ghavami,et al.  Selective Phosphodiesterase (PDE)-4 Inhibitors , 2006, Drugs in R&D.

[63]  M. Millan,et al.  The neurobiology and control of anxious states , 2003, Progress in Neurobiology.

[64]  David E Tupper,et al.  Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression. , 2003, Bioorganic & medicinal chemistry letters.

[65]  C. Guilleminault,et al.  Agomelatine , 2006, CNS drugs.

[66]  F. Kiefer,et al.  Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. , 2004, Archives of general psychiatry.

[67]  P. Celada,et al.  The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. , 2004, Journal of psychiatry & neuroscience : JPN.

[68]  S. Stahl,et al.  Stimulation of the β3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders , 2008, Neuropsychopharmacology.

[69]  L. Zimmer,et al.  5-HT7 receptor antagonists as a new class of antidepressants. , 2007, Drug news & perspectives.

[70]  P. Bonaventure,et al.  Selective Blockade of 5-Hydroxytryptamine (5-HT)7 Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents , 2007, Journal of Pharmacology and Experimental Therapeutics.

[71]  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.

[72]  Moussa B. H. Youdim,et al.  Iron dysregulation in Alzheimer's disease: Multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents , 2007, Progress in Neurobiology.

[73]  B. Costall,et al.  5-HT3 receptors. , 2004, Current drug targets. CNS and neurological disorders.

[74]  J. Herman,et al.  Organization and regulation of paraventricular nucleus glutamate signaling systems: N‐methyl‐D‐aspartate receptors , 2005, The Journal of comparative neurology.

[75]  Neil Upton,et al.  SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test , 2007, Neuropsychopharmacology.

[76]  André Schrattenholz,et al.  What does systems biology mean for drug development? , 2008, Current medicinal chemistry.

[77]  R. Jaffard,et al.  The Serotonin1A Receptor Partial Agonist S15535 [4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine] Enhances Cholinergic Transmission and Cognitive Function in Rodents: A Combined Neurochemical and Behavioral Analysis , 2004, Journal of Pharmacology and Experimental Therapeutics.

[78]  Janet A. Clark,et al.  Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus , 2005, Biological Psychiatry.

[79]  Richard Morphy,et al.  Fragments, network biology and designing multiple ligands. , 2007, Drug discovery today.

[80]  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.

[81]  R. Emsley,et al.  Placebo-controlled trial of agomelatine in the treatment of major depressive disorder , 2006, European Neuropsychopharmacology.

[82]  C. Altar,et al.  Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523 , 2001, Neuropharmacology.

[83]  J. Krystal,et al.  Clinical Studies Implementing Glutamate Neurotransmission in Mood Disorders , 2003, Annals of the New York Academy of Sciences.

[84]  M. Shahid,et al.  Multi- and single-target agents for major psychiatric diseases: therapeutic opportunities and challenges. , 2008, Current opinion in investigational drugs.

[85]  Thomas Ryckmans,et al.  First dual NK(1) antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. , 2002, Bioorganic & medicinal chemistry letters.

[86]  M. Millan,et al.  Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization , 2009, Neuropsychopharmacology.

[87]  E. Castrén,et al.  Is mood chemistry? , 2005, Nature Reviews Neuroscience.

[88]  J. Hellewell,et al.  A review of the efficacy and tolerability of agomelatine in the treatment of major depression , 2007, Expert opinion on investigational drugs.

[89]  Abraham Weizman,et al.  Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on β-catenin in mouse hippocampus , 2004, Biological Psychiatry.

[90]  Silvio Garattini,et al.  Role of presynaptic α2-adrenoceptors in antidepressant action: recent findings from microdialysis studies , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[91]  S. Rasmussen,et al.  Allosteric effects of R- and S-citalopram on the human 5-HT transporter: evidence for distinct high- and low-affinity binding sites. , 2007, European journal of pharmacology.

[92]  S. Bromidge,et al.  5-HT1 receptor augmentation strategies as enhanced efficacy: therapeutics for psychiatric disorders. , 2008, Current topics in medicinal chemistry.

[93]  M. Gallagher,et al.  SGS742: the first GABA(B) receptor antagonist in clinical trials. , 2004, Biochemical pharmacology.

[94]  S. E. Gartside,et al.  Glucocorticoid Receptor Antagonists Hasten and Augment Neurochemical Responses to a Selective Serotonin Reuptake Inhibitor Antidepressant , 2007, Biological Psychiatry.

[95]  G. Skuza,et al.  Effects of combined treatment with imipramine and metyrapone in the forced swimming test in rats. Behavioral and pharmacokinetic studies. , 2003, Polish journal of pharmacology.

[96]  M. Millan,et al.  Modulation of Dialysate Levels of Dopamine, Noradrenaline, and Serotonin (5-HT) in the Frontal Cortex of Freely-Moving Rats by (-)-Pindolol Alone and in Association with 5-HT Reuptake Inhibitors: Comparative Roles of β-Adrenergic, 5-HT1A, and 5-HT1B Receptors , 1999, Neuropsychopharmacology.

[97]  Jiajia Wang,et al.  Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice , 2007, European Neuropsychopharmacology.

[98]  K. Lesch,et al.  GABAB receptors in 5‐HT transporter‐ and 5‐HT1A receptor‐knock‐out mice: further evidence of a transduction pathway shared with 5‐HT1A receptors , 2004 .

[99]  J. Kehne.  The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. , 2007, CNS & neurological disorders drug targets.

[100]  R. Nelson,et al.  Melatonin receptor (MT1) knockout mice display depression-like behaviors and deficits in sensorimotor gating , 2006, Brain Research Bulletin.

[101]  P. Cowen,et al.  5HT3 antagonism abolishes the emotion potentiated startle effect in humans , 2006, Psychopharmacology.

[102]  Michael J. Keiser,et al.  Relating protein pharmacology by ligand chemistry , 2007, Nature Biotechnology.

[103]  B. Lebowitz,et al.  Medication augmentation after the failure of SSRIs for depression. , 2006, The New England journal of medicine.

[104]  E. Smeraldi,et al.  Chronotherapeutics in a psychiatric ward. , 2007, Sleep medicine reviews.

[105]  B. Lerer,et al.  Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities , 2006, Dialogues in clinical neuroscience.

[106]  J. O'Donnell,et al.  Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats , 2005, Psychopharmacology.

[107]  B. O'dowd,et al.  Insights into the Role of Dopamine Receptor Systems in Learning and Memory , 2007, Reviews in the neurosciences.

[108]  William W. McDonald,et al.  Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial , 2007, Biological Psychiatry.

[109]  R. Shelton,et al.  Are Antidepressant Drugs That Combine Serotonergic and Noradrenergic Mechanisms of Action More Effective Than the Selective Serotonin Reuptake Inhibitors in Treating Major Depressive Disorder? A Meta-analysis of Studies of Newer Agents , 2007, Biological Psychiatry.

[110]  E. Nestler,et al.  The Mesolimbic Dopamine Reward Circuit in Depression , 2006, Biological Psychiatry.

[111]  M. Millan,et al.  Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties. , 2001, Journal of medicinal chemistry.

[112]  F. Holsboer.  How can we realize the promise of personalized antidepressant medicines? , 2008, Nature Reviews Neuroscience.

[113]  M. Decker.  Recent advances in the development of hybrid molecules/designed multiple compounds with antiamnesic properties. , 2007, Mini reviews in medicinal chemistry.

[114]  S. Preskorn,et al.  Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression , 2004, Neuropsychopharmacology.

[115]  C. Stam,et al.  Small-world networks and functional connectivity in Alzheimer's disease. , 2006, Cerebral cortex.

[116]  G. V. Paolini,et al.  Global mapping of pharmacological space , 2006, Nature Biotechnology.

[117]  F. Bymaster,et al.  New approaches to developing antidepressants by enhancing monoaminergic neurotransmission , 2003, Expert opinion on investigational drugs.

[118]  Peter Andras,et al.  Simulation of robustness against lesions of cortical networks , 2007, The European journal of neuroscience.

[119]  T. Imanishi,et al.  Possible involvement of peripheral serotonin 5‐HT3 receptors in fluvoxamine‐induced emesis in Suncus murinus , 2003, The Journal of pharmacy and pharmacology.

[120]  E. Petricoin,et al.  Proteins, drug targets and the mechanisms they control: the simple truth about complex networks , 2007, Nature Reviews Drug Discovery.

[121]  F. Drago,et al.  Behavioral effects of saredutant, a tachykinin NK2 receptor antagonist, in experimental models of mood disorders under basal and stress-related conditions , 2008, Pharmacology Biochemistry and Behavior.

[122]  J. Hagan,et al.  Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B , 2007, Psychopharmacology.

[123]  Joel K. Elmquist,et al.  Serotonin Activates the Hypothalamic–Pituitary–Adrenal Axis via Serotonin 2C Receptor Stimulation , 2007, The Journal of Neuroscience.

[124]  P. Skolnick,et al.  Triple reuptake inhibitors as antidepressants , 2006 .

[125]  D. Giuliani,et al.  Effects of chronic desipramine treatment on α2-adrenoceptors and μ-opioid receptors in the guinea pig cortex and hippocampus , 2008 .

[126]  Ram Samudrala,et al.  Novel paradigms for drug discovery: computational multitarget screening. , 2008, Trends in pharmacological sciences.

[127]  D. Cardinali,et al.  Melatonin in mood disorders , 2006, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[128]  A. Cavalli,et al.  Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. , 2008, Bioorganic & medicinal chemistry letters.

[129]  P. Czobor,et al.  Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor. , 2006, CNS drug reviews.

[130]  A. Hancock,et al.  Assessment of pharmacology and potential anti-obesity properties of H3 receptor antagonists/inverse agonists , 2005, Expert opinion on investigational drugs.

[131]  M. Millan.  The Discovery and Development of Pharmacotherapy for Psychiatric Disorders: A Critical Survey of Animal and Translational Models and Perspectives for Their Improvement , 2008 .

[132]  S. Potkin,et al.  Circadian abnormalities, molecular clock genes and chronobiological treatments in depression. , 2008, British medical bulletin.

[133]  F. López-Muñoz,et al.  Reboxetine Combination in Treatment-resistant Depression to Selective Serotonin Reuptake Inhibitors , 2007, Pharmacopsychiatry.

[134]  F. Colpaert,et al.  High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity. , 2007, Journal of medicinal chemistry.

[135]  M. Millan,et al.  Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: A comparison to other agents , 2008, European Neuropsychopharmacology.

[136]  D. Schoepp,et al.  Metabotropic glutamate receptor targets for neuropsychiatric disorders , 2006 .

[137]  Chris G. Parsons,et al.  Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse , 2007, Neuropharmacology.

[138]  M. Millan,et al.  Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity , 2007, Proceedings of the National Academy of Sciences.

[139]  M. Millan,et al.  The melanin-concentrating hormone1 receptor antagonists, SNAP-7941 and GW3430, enhance social recognition and dialysate levels of acetylcholine in the frontal cortex of rats. , 2008, International Journal of Neuropsychopharmacology.

[140]  M. Black.  Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data , 2005, Psychopharmacology.

[141]  S. Hollon,et al.  Enduring effects for cognitive behavior therapy in the treatment of depression and anxiety. , 2006, Annual review of psychology.

[142]  Ruoyan Chen,et al.  In vitro profile of the antidepressant candidate OPC-14523 at rat and human 5-HT1A receptors. , 2005, European journal of pharmacology.

[143]  M. Millan,et al.  Selective blockade of neurokinin (NK)1 receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats , 2001, Journal of neurochemistry.

[144]  C. Stam,et al.  Small-world networks and disturbed functional connectivity in schizophrenia , 2006, Schizophrenia Research.

[145]  D. Middlemiss,et al.  8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands. , 2005, Bioorganic & medicinal chemistry letters.

[146]  Mark E. J. Newman,et al.  The Structure and Function of Complex Networks , 2003, SIAM Rev..

[147]  D. Overstreet,et al.  Confirmation of antidepressant potential of the selective β3 adrenoceptor agonist amibegron in an animal model of depression , 2008, Pharmacology Biochemistry and Behavior.

[148]  A. Wesołowska,et al.  Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression , 2006, Neuropharmacology.

[149]  Y. Gomita,et al.  Neuronal nicotinic receptor and psychiatric disorders: functional and behavioral effects of nicotine. , 2002, Japanese journal of pharmacology.

[150]  M. Roh,et al.  Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. , 2006, Current drug targets.

[151]  M. Picciotto,et al.  The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice , 2006, Psychopharmacology.

[152]  John P. Overington,et al.  Can we rationally design promiscuous drugs? , 2006, Current opinion in structural biology.

[153]  L. F. Alguacil,et al.  Effects of histamine H3 receptor ligands in experimental models of anxiety and depression , 1999, Psychopharmacology.

[154]  A. Szegedi,et al.  Mirtazapine: a review of its clinical efficacy and tolerability , 2005, Expert opinion on pharmacotherapy.

[155]  Darin D Dougherty,et al.  Neuroimaging and the functional neuroanatomy of psychotherapy , 2005, Psychological Medicine.

[156]  M. Bakker,et al.  Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism. , 2007, Bioorganic & medicinal chemistry.

[157]  Sylvain Crochet,et al.  The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. , 2004, Trends in pharmacological sciences.

[158]  P. Skolnick,et al.  Enhancement of Antidepressant Potency by a Potentiator of AMPA Receptors , 2003, Cellular and Molecular Neurobiology.

[159]  J. Belanoff,et al.  The use of mifepristone in the treatment of neuropsychiatric disorders , 2006, Trends in Endocrinology & Metabolism.

[160]  Philippe A. Chouinard,et al.  Mechanisms of Action Underlying the Effect of Repetitive Transcranial Magnetic Stimulation on Mood: Behavioral and Brain Imaging Studies , 2004, Neuropsychopharmacology.

[161]  Marcin Siwek,et al.  Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. , 2003, Polish journal of pharmacology.

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

[163]  A. Di Stefano,et al.  Synthesis and study of L-dopa-glutathione codrugs as new anti-Parkinson agents with free radical scavenging properties. , 2007, Journal of medicinal chemistry.

[164]  N. Singewald,et al.  5-HT receptor subtypes involved in the anxiogenic-like action and associated Fos response of acute fluoxetine treatment in rats , 2006, Psychopharmacology.

[165]  A. Schatzberg,et al.  Glucocorticoid antagonists in neuropsychiatric [corrected] disorders. , 2008, European journal of pharmacology.

[166]  D. Morilak,et al.  Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability , 2006, Neuroscience.

[167]  A. Iguchi,et al.  Stimulation of the hippocampal glutamate receptor systems induces stress-like responses. , 2006, Neuro endocrinology letters.

[168]  B. Lerer,et al.  Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. , 2008, The international journal of neuropsychopharmacology.

[169]  L. Tecott,et al.  Serotonin 5‐HT2C receptors regulate anxiety‐like behavior , 2007 .

[170]  D. Luckenbaugh,et al.  A double-blind, placebo-controlled study of memantine in the treatment of major depression. , 2006, The American journal of psychiatry.

[171]  T. George,et al.  Nicotinic Antagonist Augmentation of Selective Serotonin Reuptake Inhibitor-Refractory Major Depressive Disorder: A Preliminary Study , 2008, Journal of clinical psychopharmacology.

[172]  D. Slattery,et al.  The role of GABAB receptors in depression and antidepressant‐related behavioural responses , 2006 .

[173]  S Schenone,et al.  Last findings on dual inhibitors of abl and SRC tyrosine-kinases. , 2007, Mini reviews in medicinal chemistry.

[174]  Jeffrey W. Clark,et al.  Targeted Agents: The Rules of Combination , 2007, Clinical Cancer Research.

[175]  P. Joyce,et al.  Randomised controlled trial of interpersonal psychotherapy and cognitive–behavioural therapy for depression , 2007, British Journal of Psychiatry.

[176]  J. O'Donnell,et al.  Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B) , 2008, Neuropsychopharmacology.

[177]  Michael A. Briggs,et al.  GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models , 2007, Journal of Pharmacology and Experimental Therapeutics.

[178]  Paul W Smith,et al.  Discovery of potent, orally bioavailable, selective 5-HT1A/B/D receptor antagonists. , 2008, Journal of medicinal chemistry.

[179]  M. Millan,et al.  The Novel Melatonin Agonist Agomelatine (S20098) Is an Antagonist at 5-Hydroxytryptamine2C Receptors, Blockade of Which Enhances the Activity of Frontocortical Dopaminergic and Adrenergic Pathways , 2003, Journal of Pharmacology and Experimental Therapeutics.

[180]  M. Kaster,et al.  Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[181]  Jarmo Hietala,et al.  Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder , 2006, Biological Psychiatry.

[182]  F. Nicoletti,et al.  Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication? , 2007, Molecular Psychiatry.

[183]  Emanuel F. Petricoin,et al.  Network-targeted combination therapy : a new concept in cancer treatment , 2004 .

[184]  S. Shibata,et al.  Facilitation of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor transmission in the suprachiasmatic nucleus by aniracetam enhances photic responses of the biological clock in rodents , 2003, Journal of neurochemistry.

[185]  R. Hodgson,et al.  Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression , 2007, Pharmacology Biochemistry and Behavior.

[186]  M. Roh,et al.  In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. , 2004, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[187]  Teruo Hayashi,et al.  Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival , 2007, Cell.

[188]  N. Zisapel,et al.  Prolonged‐release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects , 2007, Journal of sleep research.

[189]  R. Jakus,et al.  Despite Similar Anxiolytic Potential, the 5-Hydroxytryptamine 2C Receptor Antagonist SB-242084 [6-Chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl Carbamoyl] Indoline] and Chlordiazepoxide Produced Differential Effects on Electroencephalogram Power Spectra , 2005, Journal of Pharmacology and Experimental Therapeutics.

[190]  D. Cussac,et al.  The novel antidepressant, S35966, is a mixed serotonin and noradrenaline reuptake inhibitor and an antagonist at α2-adrenoceptors , 2002, European Neuropsychopharmacology.

[191]  Shigeru Okuyama,et al.  MCL0042: A nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity , 2005, Pharmacology Biochemistry and Behavior.

[192]  N. Crossley,et al.  Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. , 2007, The Journal of clinical psychiatry.

[193]  J. Watson,et al.  Characterization of the potent 5-HT(1A/B) receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy. , 2007, CNS drug reviews.

[194]  T. Matsuda,et al.  Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression , 2008, Neuropharmacology.

[195]  T. Robinson,et al.  Why does the rapid delivery of drugs to the brain promote addiction? , 2005, Trends in pharmacological sciences.

[196]  T. Stiger,et al.  A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. , 2008, The American journal of psychiatry.

[197]  Y. Lamberty,et al.  First Dual NK1 Antagonists—Serotonin Reuptake Inhibitors: Synthesis and SAR of a New Class of Potential Antidepressants. , 2002 .

[198]  M. Bourin,et al.  Antidepressant-like activity of selective serotonin reuptake inhibitors combined with a NK1 receptor antagonist in the mouse forced swimming test , 2006, Behavioural Brain Research.

[199]  B. Harrison,et al.  Synthesis and biological evaluation of novel compounds within a class of 3-aminochroman derivatives with dual 5-HT1A receptor and serotonin transporter affinity. , 2006, Journal of medicinal chemistry.

[200]  Kazuo Koyama,et al.  A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. , 2003, Bioorganic & medicinal chemistry.

[201]  M. Millan,et al.  Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of α2‐adrenergic and serotonin2C receptors: a comparison with citalopram , 2000, The European journal of neuroscience.

[202]  G. Griebel,et al.  Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models , 2008, Pharmacology Biochemistry and Behavior.

[203]  F. Holsboer,et al.  Stress and the brain: from adaptation to disease , 2005, Nature Reviews Neuroscience.

[204]  M. Millan,et al.  The selective neurokinin (NK)1 antagonist, GR205,171, stereospecifically enhances mesocortical dopaminergic transmission in the rat: a combined dialysis and electrophysiological study , 2002, Brain Research.

[205]  G. Chrousos,et al.  Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states , 2002, Molecular Psychiatry.

[206]  RW Lam.  Addressing circadian rhythm disturbances in depressed patients , 2008 .

[207]  Pal Pacher,et al.  Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? , 2004, Current pharmaceutical design.

[208]  J. Kehr,et al.  Reciprocal effects of combined administration of serotonin, noradrenaline and dopamine reuptake inhibitors on serotonin and dopamine levels in the rat prefrontal cortex: the role of 5-HT1A receptors , 2007, Journal of psychopharmacology.

[209]  P. Csermely.  Strong links are important, but weak links stabilize them. , 2004, Trends in biochemical sciences.

[210]  Marc K Hellerstein,et al.  Exploiting Complexity and the Robustness of Network Architecture for Drug Discovery , 2008, Journal of Pharmacology and Experimental Therapeutics.

[211]  J. Deschamps,et al.  Further structural exploration of trisubstituted asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S,6S) pyran derivatives: a proposed pharmacophore model for high-affinity interaction with the dopamine, serotonin, and nor , 2006, Journal of medicinal chemistry.

[212]  J. Lönnqvist,et al.  Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. , 2008, The Journal of clinical psychiatry.

[213]  Manuela G. López,et al.  Evidence for the involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of memantine in mice , 2006, Behavioural Brain Research.

[214]  R. Hauser,et al.  Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[215]  W. Danysz,et al.  Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats , 2002, Neuropharmacology.

[216]  M. Millan,et al.  Citalopram reduces social interaction in rats by activation of serotonin (5-HT)2C receptors , 2000, Neuropharmacology.

[217]  Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. , 2004, Polish journal of pharmacology.

[218]  G. Parker,et al.  Structural and functional models of depression: from sub‐types to substrates , 2005, Acta psychiatrica Scandinavica.

[219]  Patrick C Phillips,et al.  Network thinking in ecology and evolution. , 2005, Trends in ecology & evolution.

[220]  T. Depaulis.  Drug evaluation: Vilazodone--a combined SSRI and 5-HT1A partial agonist for the treatment of depression. , 2007 .

[221]  T. Hökfelt,et al.  Galanin Receptor Antagonists , 2006, CNS drugs.

[222]  Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition. , 2007, The international journal of neuropsychopharmacology.

[223]  Richard Morphy,et al.  The physicochemical challenges of designing multiple ligands. , 2006, Journal of medicinal chemistry.

[224]  R. Schoevers,et al.  Relative efficacy of psychotherapy and combined therapy in the treatment of depression: A meta-analysis , 2007, European Psychiatry.

[225]  M. Héry,et al.  Agomelatine, a New Antidepressant, Induces Regional Changes in Hippocampal Neurogenesis , 2006, Biological Psychiatry.

[226]  M. Millan.  N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives , 2005, Psychopharmacology.

[227]  M. Millan,et al.  Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis , 2007, Journal of neurochemistry.

[228]  P. Carlier,et al.  Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. , 2007, European journal of pharmacology.

[229]  Sandy J. Wilson,et al.  Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[230]  A. Schatzberg,et al.  Corrigendum to: Glucocorticoid antagonists in neuropsychiatric disorders [European Journal of Pharmacology 583 (2008) 358–364] , 2008 .

[231]  D. Morilak,et al.  Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. , 2004, The international journal of neuropsychopharmacology.

[232]  M. Papp,et al.  S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models , 2008, Psychopharmacology.

[233]  S. Marumoto,et al.  Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease. , 2003, Journal of pharmacological sciences.

[234]  C. Lindley,et al.  Aprepitant – a novel NK1-receptor antagonist , 2003, Expert opinion on pharmacotherapy.

[235]  P. Greengard,et al.  Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6 Receptor Stimulation , 2007, The Journal of Neuroscience.

[236]  M. Bergeron,et al.  Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus , 2003, Neuropharmacology.

[237]  Jiang-Ning Zhou,et al.  Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression , 2007, Neuropsychopharmacology.

[238]  W. Geldenhuys,et al.  Multifunctional neuroprotective–neurorescue drugs for Parkinson’s disease , 2007 .

[239]  M. Millan,et al.  Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokinin1 (NK1) receptor antagonists , 2002, Neuropharmacology.

[240]  M. Millan,et al.  Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. , 2005, Therapie.

[241]  Kieran Rea,et al.  Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies , 2007, Neuropsychopharmacology.

[242]  D. Nutt,et al.  Role of GABA in anxiety and depression. , 2007, Depression and anxiety.

[243]  C. Höschl,et al.  Escitalopram for the treatment of major depression and anxiety disorders , 2008, Expert review of neurotherapeutics.

[244]  S. Tam,et al.  Yohimbine: a clinical review. , 2001, Pharmacology & therapeutics.

[245]  W. Drevets,et al.  Discovering Endophenotypes for Major Depression , 2004, Neuropsychopharmacology.

[246]  M. Millan,et al.  Reciprocal Autoreceptor and Heteroreceptor Control of Serotonergic, Dopaminergic and Noradrenergic on Behalf Of: British Association for Psychopharmacology , 2022 .

[247]  E. Hull,et al.  Dopamine and serotonin: influences on male sexual behavior , 2004, Physiology & Behavior.

[248]  Sui Huang.  Rational drug discovery: what can we learn from regulatory networks? , 2002, Drug discovery today.

[249]  H. Manji,et al.  Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test , 2008, Neuropharmacology.

[250]  S. Hemrick-Luecke,et al.  Comparison of the potency of MDL 100,907 and SB 242084 in blocking the serotonin (5-HT)2 receptor agonist-induced increases in rat serum corticosterone concentrations: evidence for 5-HT2A receptor mediation of the HPA axis , 2002, Neuropharmacology.

[251]  J. O'Donnell,et al.  Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus , 2004, Neuropsychopharmacology.

[252]  M. Millan,et al.  Blockade of dopamine D3 receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: Similar actions of D1 receptor agonists, but not of D2 antagonists , 2009, European Neuropsychopharmacology.

[253]  Brian Lord,et al.  In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor. , 2008, European journal of pharmacology.

[254]  L. Yatham,et al.  Polytherapy in Bipolar Disorder , 2006, CNS drugs.

[255]  M. Millan,et al.  Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade , 2005, Psychopharmacology.

[256]  J. Kornhuber,et al.  BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation , 2007, Journal of Neural Transmission.

[257]  K. Rasmussen.  Creating more effective antidepressants: clues from the clinic. , 2006, Drug discovery today.

[258]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[259]  G. Griebel,et al.  An overview of SSR149415, a selective nonpeptide vasopressin V(1b) receptor antagonist for the treatment of stress-related disorders. , 2006, CNS drug reviews.

[260]  M. Millan,et al.  The selective tachykinin neurokinin 1 (NK1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms. , 2005, European journal of pharmacology.

[261]  Maurizio Recanatini,et al.  Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. , 2007, Journal of medicinal chemistry.

[262]  A. Wesołowska,et al.  Enhancement of the anti-immobility action of antidepressants by a selective 5-HT7 receptor antagonist in the forced swimming test in mice. , 2007, European journal of pharmacology.

[263]  Naomi A. Fineberg,et al.  Which antidepressants have demonstrated superior efficacy? A review of the evidence , 2007, International clinical psychopharmacology.

[264]  C. Sánchez,et al.  P.2.b.015 Lu AA21004: a novel potential treatment for mood disorders , 2008, European Neuropsychopharmacology.

[265]  M. Bourin,et al.  Is co-administration of bupropion with SSRIs and SNRIs in forced swimming test in mice, predictive of efficacy in resistant depression? , 2008, Behavioural Brain Research.

[266]  C. McClung,et al.  Circadian genes, rhythms and the biology of mood disorders. , 2007, Pharmacology & therapeutics.

[267]  P. Bonaventure,et al.  Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor. , 2007, European journal of pharmacology.

[268]  Y. Mineur,et al.  Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice , 2007, Neuropharmacology.

[269]  R. Hen,et al.  Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function , 2007, European Neuropsychopharmacology.

[270]  O. Sporns.  Network Analysis , Complexity , and Brain Function , 2002 .

[271]  M. Millan,et al.  Piribedil Enhances Frontocortical and Hippocampal Release of Acetylcholine in Freely Moving Rats by Blockade of α2A-Adrenoceptors: A Dialysis Comparison to Talipexole and Quinelorane in the Absence of Acetylcholinesterase Inhibitors , 2003, Journal of Pharmacology and Experimental Therapeutics.

[272]  J. C. Lodder,et al.  Reduced 5-HT1A- and GABAB receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats. , 2007, Journal of neurophysiology.

[273]  M. Millan,et al.  Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of α2-adrenergic receptors underlie its actions , 1999, Neuroscience.

[274]  S. Hunt,et al.  Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex , 2007, Molecular Pharmacology.