Serotonin Reuptake Inhibitors: The Corner Stone in Treatment of Depression for Half a Century – A Medicinal Chemistry Survey

Abstract

Inhibition of serotonin (5-HT) reuptake has been a central theme in the therapy of depression for half a century. Through the years these therapies have improved, particularly with regard to side effects, and today's selective serotonin reuptake inhibitors (SSRIs) constitute a reasonably effective offer for the patients. However, there is still room for major improvement and considering that almost 20% of the population in the western world will experience a depressive period in their lifetime, there is a large need for improved therapies. A large spectrum of targets and strategies are currently being pursued, but so far none of these new approaches have been successful, mainly due to lack of a deeper understanding of the disease biology. Since inhibition of 5-HT reuptake ensures a certain degree of antidepressant efficacy, there has been a large interest in various combinations with serotonin reuptake inhibitors (SRIs) in order to improve on the shortcomings of treatment with SSRIs. Some of these approaches have resulted in marketed antidepressants, eg combinations of SRI with norepinephrine (NE) reuptake inhibition, whereas other approaches are still at an experimental stage. This review attempts to present the current status of these add-on/combination approaches with particular focus on the medicinal chemistry aspects.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…These endeavors have provided a plethora of ligands for these transporters, including compounds with high affinity and selectivity for each of the three transporters ( Table 3). The tricyclic antidepressants (TCAs), including imipramine and clomipramine, were developed in the 1950s as the first generation of monoamine transporter drugs (Moltzen and Bang-Andersen, 2006;Andersen et al, 2009a). However, the TCAs display activity across a variety of different receptors (Gillman, 2007), and new generations of monoamine transporter inhibitors with little or no affinity for other proteins have subsequently been developed.…”

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…Neuroprotective compounds that can slow down disease progression with few side effects have been studied for treating HD. For example, selective serotonin reuptake inhibitors (SSRIs), a class of drugs that is widely used for the treatment of patients with depression and severe anxiety disorders, have been shown to increase BDNF expression (19,20) and stimulate neurogenesis responsive to BDNF. Duan et al (21)(22)(23) have demonstrated that several SSRI compounds, including paroxetine and sertraline, elicited beneficial effects in HD mice.…”

Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease

“…Selective serotonin reuptake inhibitors (SSRIs), a class of drugs that is widely used for the treatment of patients with depression and severe anxiety disorders, has been shown to increase BDNF expression in brain (Nibuya et al, 1995;Nibuya et al, 1996;Moltzen and Bang-Andersen, 2006). SSRIs can also stimulate neurogenesis and protect neurons against metabolic/oxidative insults and processes known to be responsive to BDNF (Malberg and Blendy, 2005).…”