Research Topic

Serotonin, Receptors and Transporters: Exploring New and Known Signaling Pathways to Improve the Efficacy of Antidepressant Treatment

About this Research Topic

Major depressive disorder (MDD) is one of the most common mental disorders worldwide. Currently about 350 million people suffer from MDD. According to projections of global mortality and burden of disease, MDD is going to have evolved into the second leading cause of burden of disease by 2030. The main therapeutic target for antidepressant treatment is to engage an impaired serotonin signaling, caused by diminished serotonin levels. Here, the most common treatment option in the pharmacotherapy of depression is the application of selective serotonin re-uptake inhibitors (SSRI).

The SSRI’s mode of action consists of two phases: during the first phase, SSRI inhibit the re-uptake of serotonin by the serotonin transporter (SERT). SERT is the key molecule in serotonin signaling as it precisely regulates the amount of bioactive, extracellular serotonin. Inhibition of SERT is assumed to ultimately prolong serotonin signaling via enhanced activation of postsynaptic serotonin receptors. The second phase of SSRI activity is delayed and comprises adaption processes, which include the desensizitation of serotonin receptors, the availability of functional SERT molecules at the cell surface of serotonergic neurons, and beneficial effects on the neuronal plasticity impaired or damaged during the progression of MDD. Although SSRIs share the same molecular target and result in elevated serotonin levels, SSRI treatments evoke varying efficacies in patients’ clinical responses to antidepressant treatment. Furthermore, about half of all patients suffering from MDD do not achieve full remission by or even do respond at all to SSRI pharmacotherapy. Currently, the number of MDD diagnoses increase, whereas the development of more efficient therapeutic treatment is stagnant. Up to now, many effects of known antidepressant-acting substances on serotonin release, re-uptake and signaling are still not well or even poorly understood. Therefore, one of the major goals to improve the efficacy of antidepressant treatments is to unravel in more detail how the basic cellular and molecular mechanisms in more detail how effective and promising classes of antidepressants modulate serotonergic neurotransmission.

Here, it is also necessary to look beyond serotonin autoregulation and anterograde serotonin signaling. Glutamatergic and GABAergic neurons are known to establish feedback mechanisms to control serotonin neuronal activity. For example, the interaction of dorsal raphe nuclei and prefrontal cortex neurons play an essential role in mood, stress resilience and antidepressant response. Gaining knowledge on these essential underlying molecular mechanisms requires a joint translational research effort, combining state-of-the-art in vitro- and in vivo-models, in silico as well as clinical studies, which will hopefully generate valuable insights in yet not fully understood aspects of serotonin signaling. This knowledge hopefully will bring forward new starting points for innovative therapeutic strategies and the development of novel classes of rapid-acting and clinically effective pharmacotherapies against MDD. Within this context, our Research Topic aims to provide a platform for discussion and presentation of new and established therapeutic strategies as well as recent findings on antidepressant research.


Keywords: Serotonin, Antidepressant Treatment, Serotonin Receptors, Serotonin Transporter, SSRI


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Major depressive disorder (MDD) is one of the most common mental disorders worldwide. Currently about 350 million people suffer from MDD. According to projections of global mortality and burden of disease, MDD is going to have evolved into the second leading cause of burden of disease by 2030. The main therapeutic target for antidepressant treatment is to engage an impaired serotonin signaling, caused by diminished serotonin levels. Here, the most common treatment option in the pharmacotherapy of depression is the application of selective serotonin re-uptake inhibitors (SSRI).

The SSRI’s mode of action consists of two phases: during the first phase, SSRI inhibit the re-uptake of serotonin by the serotonin transporter (SERT). SERT is the key molecule in serotonin signaling as it precisely regulates the amount of bioactive, extracellular serotonin. Inhibition of SERT is assumed to ultimately prolong serotonin signaling via enhanced activation of postsynaptic serotonin receptors. The second phase of SSRI activity is delayed and comprises adaption processes, which include the desensizitation of serotonin receptors, the availability of functional SERT molecules at the cell surface of serotonergic neurons, and beneficial effects on the neuronal plasticity impaired or damaged during the progression of MDD. Although SSRIs share the same molecular target and result in elevated serotonin levels, SSRI treatments evoke varying efficacies in patients’ clinical responses to antidepressant treatment. Furthermore, about half of all patients suffering from MDD do not achieve full remission by or even do respond at all to SSRI pharmacotherapy. Currently, the number of MDD diagnoses increase, whereas the development of more efficient therapeutic treatment is stagnant. Up to now, many effects of known antidepressant-acting substances on serotonin release, re-uptake and signaling are still not well or even poorly understood. Therefore, one of the major goals to improve the efficacy of antidepressant treatments is to unravel in more detail how the basic cellular and molecular mechanisms in more detail how effective and promising classes of antidepressants modulate serotonergic neurotransmission.

Here, it is also necessary to look beyond serotonin autoregulation and anterograde serotonin signaling. Glutamatergic and GABAergic neurons are known to establish feedback mechanisms to control serotonin neuronal activity. For example, the interaction of dorsal raphe nuclei and prefrontal cortex neurons play an essential role in mood, stress resilience and antidepressant response. Gaining knowledge on these essential underlying molecular mechanisms requires a joint translational research effort, combining state-of-the-art in vitro- and in vivo-models, in silico as well as clinical studies, which will hopefully generate valuable insights in yet not fully understood aspects of serotonin signaling. This knowledge hopefully will bring forward new starting points for innovative therapeutic strategies and the development of novel classes of rapid-acting and clinically effective pharmacotherapies against MDD. Within this context, our Research Topic aims to provide a platform for discussion and presentation of new and established therapeutic strategies as well as recent findings on antidepressant research.


Keywords: Serotonin, Antidepressant Treatment, Serotonin Receptors, Serotonin Transporter, SSRI


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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01 March 2018 Abstract
01 October 2018 Manuscript

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Topic Editors

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Submission Deadlines

01 March 2018 Abstract
01 October 2018 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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