Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

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.