par Fabbri, Chiara;Kasper, Siegfried;Zohar, Joseph;Souery, Daniel ;Montgomery, Stuart;Albani, Diego;Forloni, GianLuigi Luigi G.;Ferentinos, Panagiotis;Rujescu, Dan;Mendlewicz, Julien ;De Ronchi, Diana;Riva, Marco Andrea;Lewis, Cathryn C.M.;Serretti, Alessandro
Référence Progress in neuro-psychopharmacology & biological psychiatry, 104, 110050
Publication Publié, 2021-01
Référence Progress in neuro-psychopharmacology & biological psychiatry, 104, 110050
Publication Publié, 2021-01
Article révisé par les pairs
Résumé : | About 20–30% of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) and finding new effective treatments for TRD has been a challenge. This study aimed to identify new possible pharmacological options for TRD. Genes in pathways included in predictive models of TRD in a previous whole exome sequence study were compared with those coding for targets of drugs in any phase of development, nutraceuticals, proteins and peptides from Drug repurposing Hub, Drug-Gene Interaction database and DrugBank database. We tested if known gene targets were enriched in TRD-associated genes by a hypergeometric test. Compounds enriched in TRD-associated genes after false-discovery rate (FDR) correction were annotated and compared with those showing enrichment in genes associated with MDD in the last Psychiatric Genomics Consortium genome-wide association study. Among a total of 15,475 compounds, 542 were enriched in TRD-associated genes (FDR p < .05). Significant results included drugs which are currently used in TRD (e.g. lithium and ketamine), confirming the rationale of this approach. Interesting molecules included modulators of inflammation, renin-angiotensin system, proliferator-activated receptor agonists, glycogen synthase kinase 3 beta inhibitors and the rho associated kinase inhibitor fasudil. Nutraceuticals, mostly antioxidant polyphenols, were also identified. Drugs showing enrichment for TRD-associated genes had a higher probability of enrichment for MDD-associated genes compared to those having no TRD-genes enrichment (p = 6.21e-55). This study suggested new potential treatments for TRD using a in silico approach. These analyses are exploratory only but can contribute to the identification of drugs to study in future clinical trials. |