A large amount of the data gathered in the last 50 years support the hypothesis that alterations of the serotonin
(5-HT) neurotransmission play a crucial role in the pathophysiology of not only major depression (MD), but also of different
neuropsychiatric disorders. Research in this field has been substantially promoted by the evidence that the reuptake
protein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in the
synaptic cleft. For this reason, it was specifically targeted for the development of second-generation antidepressants, in
particular of selective 5-HT reuptake inhibitors (SSRIs), with the aim of increasing the intrasynaptic 5-HT concentrations.
Moreover, since a lot of studies showed that circulating platelets and, more recently, lymphocytes possess functional
SERT proteins, they have been widely used as peripheral mirrors of the same structures located in the central nervous system.
The presence of functional SERT in blood cells suggests strict relationships between the nervous and the immune
system that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by different
This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possible
role of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosological
involvement of this structure in different conditions spanning from normality to pathology.