Are adult neurogenesis and glucocorticoid signaling missing links between stress and depression?

Abstract

Depression contributes substantially to disease burden worldwide; however despite of this, the progress in understanding its pathophysiology has been extremely slow and the discovery of new therapeutic mechanisms is at a near standstill. The molecular targets of current major classes of antidepressants were all reverse engineered from drugs previously discovered by serendipitous clinical observations. Since the existence of adult-born neurons was unequivocally documented, adult neurogenesis became a very promising, but also very hyped target for antidepressant drugs. Introduction of corticotrophin releasing hormone inhibitors aimed to exploit a prospective reduction of glucocorticoid-mediated inhibition of adult neurogenesis with the aim to produce antidepressant effect. Although these drugs failed to demonstrate efficiency in phase three clinical trials, they provided the following valuable lesions for the future: (1) Inter-species differences between animals and humans should be considered very carefully, (2) Animal model phenotypes mimicking depression should be more robust, preferably shown by multiple behavioral paradigms, and (3) variability between different subgroups of depression should be taken into consideration because of the pronounced heterogeneity of the disease.

Iako depresija značajno doprinosi morbiditetu na globalnom nivou, napredak u razumevanju patofiziologije ove bolesti je izuzetno spor, pa su posledično, otkrića novih terapeutskih mehanizama praktično u zastoju. Ciljni molekuli preko kojih deluju antidepresivi koji su danas u upotrebi identifikovani su reverznim inženjeringom lekova otkrivenih empirijski, kliničkim zapažanjima. Otkad je jasno pokazano postojanje novonastalih neurona, adultna neurogeneza je postala izuzetno atraktivna potencijalna meta delovanja kandidata za antidepresivne lekove. Uvođenje inhibitora kortikotropin-oslobađajućeg hormona imalo je za cilj da se iskoristi činjenica da glukokortikoidni hormoni inhibiraju adultnu neurogenezu i time doprinose antisdepresivnom efektu. Iako su se ovi lekovi pokazali kao neefikasni u trećoj fazi kliničkih studija, naučene su sledeće važne lekcije za budućnost: (1) razlike u funkcionisanju mozga ljudi i životinja moraju biti pažljivo razmotrene, (2) da bi se zaključilo da animalni model ima depresivni fenotip, isti je potrebno ubedljivo demonstrirati, po mogućstvu korišćenjem većeg broja bihejvioralnih testova i (3) varijacije u simptomima između različitih podklasa depresije treba uzeti u obzir imajući u vidu heterogenost oboljenja.