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 Lewis; Alessandro Serretti

doi:10.1016/j.pnpbp.2020.110050

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 Lewis, Alessandro Serretti

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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 language	English
Article number	110050
Journal	Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume	104
DOIs	https://doi.org/10.1016/j.pnpbp.2020.110050
Publication status	E-pub ahead of print - 30 Jul 2020

Keywords

Drug repurposing
Major depression
Pharmacogenetics
Treatment-resistant depression

Access to Document

10.1016/j.pnpbp.2020.110050

Cite this

Fabbri, C., Kasper, S., Zohar, J., Souery, D., Montgomery, S., Albani, D., Forloni, G., Ferentinos, P., Rujescu, D., Mendlewicz, J., De Ronchi, D., Riva, M. A., Lewis, C., & Serretti, A. (2020). Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 104, Article 110050. Advance online publication. https://doi.org/10.1016/j.pnpbp.2020.110050

@article{b104656a79b04218af0c0ae10de9a610,

title = "Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study",

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.",

keywords = "Drug repurposing, Major depression, Pharmacogenetics, Treatment-resistant depression",

author = "Chiara Fabbri and Siegfried Kasper and Joseph Zohar and Daniel Souery and Stuart Montgomery and Diego Albani and Gianluigi Forloni and Panagiotis Ferentinos and Dan Rujescu and Julien Mendlewicz and {De Ronchi}, Diana and Riva, {Marco Andrea} and Cathryn Lewis and Alessandro Serretti",

year = "2020",

month = jul,

day = "30",

doi = "10.1016/j.pnpbp.2020.110050",

language = "English",

volume = "104",

journal = "Progress in Neuro-Psychopharmacology & Biological Psychiatry",

issn = "0278-5846",

publisher = "Elsevier Inc.",

}

Fabbri, C, Kasper, S, Zohar, J, Souery, D, Montgomery, S, Albani, D, Forloni, G, Ferentinos, P, Rujescu, D, Mendlewicz, J, De Ronchi, D, Riva, MA, Lewis, C & Serretti, A 2020, 'Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study', Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 104, 110050. https://doi.org/10.1016/j.pnpbp.2020.110050

TY - JOUR

T1 - Drug repositioning for treatment-resistant depression: 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

AU - Serretti, Alessandro

PY - 2020/7/30

Y1 - 2020/7/30

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

M3 - Article

SN - 0278-5846

VL - 104

JO - Progress in Neuro-Psychopharmacology & Biological Psychiatry

JF - Progress in Neuro-Psychopharmacology & Biological Psychiatry

M1 - 110050

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this