title: Monoamine neurocircuitry in depression and strategies for new treatments.
abstract: Extensive studies showed that monoaminergic neurotransmission that involves serotonin (5-HT), norepinephrine (NE) and dopamine (DA) exerts major influence on brain circuits concerned by the regulation of mood, reactivity to psychological stress, self-control, motivation, drive, and cognitive performance. Antidepressants targeting monoamines directly affect the functional tone of these circuits, notably in limbic and frontocortical areas, and evidence has been provided that this action plays a key role in their therapeutic efficacy. Indeed, at least some of functional changes detected by functional magnetic resonance imaging in emotion- and cognitive-related circuits such as the one involving limbic-cortical-striatal-pallidal-thalamic connections in depressed patients can be reversed by monoamine-targeted antidepressants. However, antidepressants acting selectively on only one monoamine, such as selective inhibitors of 5-HT or NE reuptake, alleviate depression symptoms in a limited percentage of patients, and are poorly effective to prevent recurrence. Thorough investigations for the last 30 years allowed the demonstration of the existence of functional interactions between 5-HT, NE and DA systems, and the identification of the specific receptors involved. In particular, 5-HT systems were shown to exert negative influence on NE and DA systems through 5-HT2A and 5-HT2C receptor- mediated mechanisms, respectively. On the other hand, complex positive and negative influences of NE system on 5-HT neurotransmission are mediated through α1- and α2-adrenergic receptors, respectively. These data provided a rationale for the design of new, multimodal, therapeutic strategies involving drugs acting not only at the "historical" targets such as the 5-HT and/or the NE transporter, but also at other molecular targets to improve their efficacy and their tolerability.
authors.affiliation: INSERM U894, Centre of Psychiatry and Neurosciences, Paris, France. michel.hamon@upmc.fr
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D015306:Biogenic Monoamines / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D059907:Functional Neuroimaging; D006801:Humans; D008959:Models, Neurological; D058990:Molecular Targeted Therapy / Q000379:methods; D009434:Neural Pathways / Q000187:drug effects* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines
keywords: 5-HT; 5-hydroxytryptamine, serotonin; BDNF; CA; CNS; CO-MED; CRH; Cg25; Combining Medications to Enhance Depression Outcomes; DA; DAT; DRN; HAM-D; HPA; Hamilton Depression rating scale; LCSPT; MADRS; MAOIs; MDD; MRI; Major depressive disorder; Monoamine neurocircuitry; Montgomery-Åsberg Depression Rating Scale; Multimodal antidepressants; N-methyl-D-aspartate; NE; NET; NMDA; NRIs; OFC; PET; PRL; QIDS-SR; Quick Inventory of Depressive Symptomatology: Self Rated; ROI; ReHo; SERT; SNP; SNRIs; SR; SSRIs; Serotonin receptors; TCAs; Tph2; VTA; brain derived neurotrophic factor; catecholamines; central nervous system; corticotropin-releasing hormone; dopamine; dopamine transporter; dorsal raphe nucleus; fMRI; functional magnetic resonance imaging; hypothalamo-pituitary-adrenal (axis); limbic-cortical-striatal-pallidal-thalamic (circuits); magnetic resonance imaging; major depressive disorder; mixed serotonin and norepinephrine reuptake inhibitors; monoamine oxidase inhibitors; norepinephrine; norepinephrine transporter; orbitofrontal cortex; positron emission tomography; prolactin; regional homogeneity; regions of interest; selective norepinephrine reuptake inhibitors; selective serotonin reuptake inhibitors; serotonin transporter; single nucleotide polymorphism; subgenual cingulate (Brodmann area 25); sustained release; tricyclic antidepressants; tryptophan hydroxylase-2; ventral tegmentum area