Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies
| Autor: | Analía Bortolozzi, Francesc Artigas, Pau Celada |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Salud Mental (España), Generalitat de Catalunya |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Antidepressant drugs
Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Postsynaptic potential Vilazodone Medicine Animals Humans Pharmacology (medical) Biogenic Monoamines Receptor Biological Psychiatry Autoreceptors Vortioxetine Depressive Disorder Major Neurotransmitter Agents business.industry Multi-target agents Antidepressive Agents 030227 psychiatry Psychiatry and Mental health 5-hydroxytryptamine (serotonin) receptors Monoamine neurotransmitter Neurology chemistry Antidepressant Neurology (clinical) Serotonin business Reuptake inhibitor 030217 neurology & neurosurgery |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 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, α2-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 ß-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. Support from the following grants is acknowledged: grants SAF2015-68346-P, SAF2016-75797-R and Retos-Colaboración Subprogram RTC-2014-2812-1, Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; grants PI12/00156, PI13/01390 and PI16/00287, Instituto de Salud Carlos III, co-financed by European Regional Development Fund (ERDF), UE, “A way to build Europe”; the Instituto de Salud Carlos III, Centro de Investigación Biomédica 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|