TY - JOUR

T1 - Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy

AU - Kulikov, Alexander V.

AU - Gainetdinov, Raul R.

AU - Ponimaskin, Evgeni

AU - Kalueff, Allan V.

AU - Naumenko, Vladimir S.

AU - Popova, Nina K.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3-4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs. Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT1A receptor), (2) the effect of dimerization of 5-HT7 and 5-HT1A receptors on the internalization and functioning of 5-HT1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI. Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.

AB - INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3-4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs. Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT1A receptor), (2) the effect of dimerization of 5-HT7 and 5-HT1A receptors on the internalization and functioning of 5-HT1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI. Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.

KW - 5-HT

KW - 5-HT transporter

KW - 5-HT1A receptor

KW - 5-HT7 receptor

KW - gene knockout

KW - gene polymorphism

KW - SSRI resistance

KW - tryptophan hydroxylase 2

UR - http://www.scopus.com/inward/record.url?scp=85050541640&partnerID=8YFLogxK

U2 - 10.1080/14728222.2018.1452912

DO - 10.1080/14728222.2018.1452912

M3 - Review article

C2 - 29542343

AN - SCOPUS:85050541640

VL - 22

SP - 319

EP - 330

JO - Expert Opinion on Therapeutic Targets

JF - Expert Opinion on Therapeutic Targets

SN - 1472-8222

IS - 4

ER -