TY - JOUR
T1 - Drug repositioning for treatment-resistant depression
T2 - Hypotheses from a pharmacogenomic study
AU - Fabbri, Chiara
AU - Kasper, Siegfried
AU - Zohar, Joseph
AU - Souery, Daniel
AU - Montgomery, Stuart
AU - Albani, Diego
AU - Forloni, Gianluigi
AU - Ferentinos, Panagiotis
AU - Rujescu, Dan
AU - Mendlewicz, Julien
AU - De Ronchi, Diana
AU - Riva, Marco Andrea
AU - Lewis, Cathryn M.
AU - Serretti, Alessandro
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1/10
Y1 - 2021/1/10
N2 - 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.
AB - 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.
KW - Drug repurposing
KW - Major depression
KW - Pharmacogenetics
KW - Treatment-resistant depression
UR - http://www.scopus.com/inward/record.url?scp=85088973537&partnerID=8YFLogxK
U2 - 10.1016/j.pnpbp.2020.110050
DO - 10.1016/j.pnpbp.2020.110050
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C2 - 32738352
AN - SCOPUS:85088973537
SN - 0278-5846
VL - 104
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
M1 - 110050
ER -