Abstract
Progress toward new antidepressant therapies has been relatively slow over the past few decades, with the result that individuals suffering from depression often struggle to find an effective treatment – a process often requiring months. Furthermore, the neural factors that contribute to depression remain poorly understood, and there are many open questions regarding the mechanism of action of existing antidepressants. A better understanding of the molecular processes that underlie depression and contribute to antidepressant efficacy is therefore badly needed. In this review we highlight research investigating the role of G-proteins and the regulators of G-protein signaling (RGS) proteins, two protein families that are intimately involved in both the genesis of depressive states and the action of antidepressant drugs. Many antidepressants are known to indirectly affect the function of these proteins. Conversely, dysfunction of the G-protein and RGS systems can affect antidepressant efficacy. However, a great deal remains unknown about how these proteins interact with antidepressants. Findings pertinent to each individual G-protein and RGS protein are summarized from in vitro, in vivo, and clinical studies.
Highlights
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders with over 16% of adults in the US experiencing a depressive event within their lifetime, and over half of these events leading to severe or very severe role impairment (Kessler et al, 2003; García-Velázquez et al, 2017)
These results suggest that 5-HT1A receptor stimulated GIRK activity in the hippocampus is detrimental to antidepressant activity, and that agonists which preferentially couple to 5-HT1A/fibroblast growth factor receptor 1 (FGFR1) heterodimers would be superior to unbiased ligands
Preclinical studies provide multiple hypotheses for how these proteins behave in depressed populations in the clinic, only a handful of these theories have been addressed in humans
Summary
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders with over 16% of adults in the US experiencing a depressive event within their lifetime, and over half of these events leading to severe or very severe role impairment (Kessler et al, 2003; García-Velázquez et al, 2017). While a multitude of antidepressant drugs are available, no one treatment is fully effective in all patients, with about one third failing to remit even after 4th line treatments (Insel and Wang, 2009). In this review we highlight the role of G-proteins and their signaling partners, especially the Regulators of G-protein Signaling (RGS) proteins, in both the etiology and treatment of depression
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