Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study

Chiara Fabbri*, Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu, Julien Mendlewicz, Diana De Ronchi, Marco Andrea Riva, Cathryn M. Lewis, Alessandro Serretti

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Article number110050
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume104
DOIs
StatePublished - 10 Jan 2021

Funding

FundersFunder number
AOP Orphan Pharmaceuticals AG
Celegne GmbH
Janssen-Cilag Pharma GmbH
Lundbeck International Neuroscience Foundation
Myriad Neuroscience
Abbott Laboratories
Eli Lilly and Company
AstraZeneca
GlaxoSmithKline
AbbVie
Shire
Pfizer UK
South London and Maudsley NHS Foundation Trust
Roche Products
National Institute for Health and Care Research
King's College London
Dainippon Sumitomo Pharma
Fondazione Umberto Veronesi
Angelini Pharma
Servier
H. Lundbeck A/S

    Keywords

    • Drug repurposing
    • Major depression
    • Pharmacogenetics
    • Treatment-resistant depression

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