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Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy |
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| Authors: | Alexander V Kulikov Raul R Gainetdinov Evgeni Ponimaskin Allan V Kalueff Vladimir S Naumenko |
| Institution: | 1. Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia;2. Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia;3. Skolkovo Institute of Science and Technology, Moscow, Russia;4. Cellular Neurophysiology, Hannover Medical School, Hannover, Germany;5. School of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China;6. Laboratory of Biological Psychiatry, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia;7. Ural Federal University, Ekaterinburg 620002, Russia;8. Research Institute of Physiology and Basic Medicine, Novosibirsk 630117, Russia;9. Russian Research Center for Radiology and Surgical Technologies, Pesochny 197758, Russia;10. Institute of Experimental Medicine, Almazov National Medical Research Centre, St. Petersburg 197341, Russia;11. ZENEREI Research Center, Slidell 70458, LA, USA |
| Abstract: | 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. |
| Keywords: | SSRI resistance 5-HT tryptophan hydroxylase 2 5-HT transporter 5-HT1A receptor 5-HT7 receptor gene polymorphism gene knockout |