Major depressive disorder (MDD) is a severe psychiatric syndrome with very high prevalence and socioeconomic impact. Monoamine-based antidepressant drugs (AD) display slow onset of action and limited efficacy. Preclinical studies show that ADs trigger a series of slow adaptive mechanisms that limit the clinical response. These mechanisms result from the pharmacological blockade of monoamine transporters (SERT, NET) and involve presynaptic, such as autoreceptor desensitization (e.g., 5-HT1A and 5-HT1B for serotonin neurons) as well as postsynaptic mechanisms, such as increased neurogenesis and expression of trophic factors, increased dendritic complexity, etc.

Given the strong homeostasis of serotonin and noradrenaline neurons, a way to improve antidepressant action is to prevent self-inhibitory presynaptic mechanisms mediated by auto- and heteroreceptors after reuptake blockade. This strategy was used in the past with the non-selective 5-HT1A antagonist pindolol and has been incorporated by two recently developed AD (vilazodone and vortioxetine). Likewise, new molecular strategies using RNA interference (RNAi) show that the modulation of gene expression in serotonin neurons offers a great potential. Hence, local or intrnasal administration of small interfering RNA (siRNA) molecules targeting SERT or 5-HT1A autoreceptors evokes rapid and robust antidepressant-like effects in rodents.

Moreover, glutamatergic drugs such as the non-competitive NMDA receptor antagonist ketmaine, offer a potential for the development of fast-acting AD due to its rapid and persistent antidepressant effects in treatment-resistant unipolar and bipolar patients after single i.v. infusion, an effect that likely involves the activation of AMPA receptors in ventral areas of the cingulate gyrus and the subsequent fast activation of serotonergic function.