Molecular pathways linking the serotonin transporters (SERT) to depressive disorder: from mechanisms to treatments

Abstract

The serotonin transporter (SERT) plays a key role in the regulation of serotonin levels in synapses and is significantly involved in the pathophysiology of major depressive disorder (MDD). In this review, molecular pathways connecting SERT dysfunction associated with depression are defined, including genetic polymorphisms (e.g., 5-HTTLPR), epigenetics (e.g., SLC6A4 methylation), and environmental interactions through stress and inflammation. Using a serotonergic pharmacophore, oxidative/nitrosative stress, cytokines, and neuroendocrine factors act via the hypothalamic-pituitary-adrenal (HPA) axis on SERT, whereas the crosstalk between SERT and brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) signaling both bring about changes in mood and influence the response to treatment. Pharmacological treatments, such as SSRIs and SNRIs, aim at SERT; however, their effectiveness is limited due to interindividual variability. New treatments consist of allosteric modulators, multimodal antidepressants, and non-pharmacological treatments, involving exercise, diet, and microbiome manipulation. Tailor-made treatments involving the utilization of pharmacogenomics and neurobiological profiling can improve clinical outcomes. This review highlights SERT as a complex target in MDD and provides an argument in support of integrative, precision-focused interventions that aim to target the affective and cognitive symptoms of MDD.

Keywords: Depression; Molecular mechanisms; Pharmacological and non-pharmacological intervention; Serotonin; Serotonin transporter.