期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 28, 期 4, 页码 445-456出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2017.10.032
关键词
5-hydroxytryptamine (serotonin) receptors; Antidepressant drugs; Autoreceptors; Multi-target agents
资金
- Ministry of Economy, Industry and Competitiveness (MINECO) [SAF2015-68346-P, SAF2016-75797-R, RTC-2014-2812-1]
- European Regional Development Fund (ERDF), UE
- Instituto de Salud Carlos III [PI12/00156, PI13/01390, PI16/00287]
- European Regional Development Fund (ERDF), UE, A way to build Europe
- Instituto de Salud Carlos III, Centro de Investigation Biomedica en Red de Salud Mental, CIBERSAM
- Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya (Grup de Recerca Consolidat) [2014SGR798]
Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT1A, 5-HT1B, alpha(2)-adrenoceptors) and postsynaptic receptors (e.g., 5-HT3 ). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed beta-adrenoceptor/5-HT1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT3 receptors located in cortical and hippocampal GABA interneurons. 5-HT3 receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity. (C) 2017 Elsevier B.V. and ECNP. All rights reserved.
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