Neuropsychiatric disorders affect one billion people worldwide and therefore constitute a major socio-economic burden for healthcare systems and societies. In many cases, the balance of neurotransmitters is disturbed; monoamine transporters are crucial in the regulation of neurotransmitter homeostasis. Transporters are involved in the re-uptake of neurotransmitters back into the terminal after quantal release. Different compounds target these transporters, including clinically relevant drugs like antidepressants but also drugs of abuse like psychostimulants including cocaine and amphetamines. Drugs inhibiting the serotonin transporter are largely used in the treatment of neuropsychiatric disorders, but they display a delayed onset of therapeutic effect and a relatively large number of non-responders. This effect may be due to feedback loop mechanisms involving the serotonergic pre-synaptic auto-receptors. We hypothesize that the use of agents acting to release serotonin in an exocytosis-independent manner and insensitive to auto-receptor feedback loops, may act as fast-acting SERT modulators and promise therapeutic advantages over classical antidepressants.