Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning

TY - JOUR

T1 - Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning

AU - Powell, Timothy

AU - Lee, Sang H.

AU - Murphy, Tytus

AU - Price, Jack

AU - Thuret, Sandrine

AU - Breen, Gerome

N1 - ♯Corresponding Author: Dr Sandrine Thuret, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK Telephone number: +44 (0)20 7848 5405 Email: [email protected] Gerome Breen and Sandrine Thuret contributed equally to this paper and should be considered as equal contributors.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. ‘Connectivity mapping’ is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an ‘antidepressant mRNA signature’. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD.

AB - Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. ‘Connectivity mapping’ is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an ‘antidepressant mRNA signature’. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD.

U2 - 10.1177/0269881117691467

DO - 10.1177/0269881117691467

M3 - Article

SN - 0269-8811

VL - 31

SP - 338

EP - 345

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

IS - 3

ER -