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MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants

Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of t...

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Autores principales: Cholewinski, Tomasz, Pereira, Diana, Moerland, Matthijs, Jacobs, Gabriel E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558816/
https://www.ncbi.nlm.nih.gov/pubmed/34733478
http://dx.doi.org/10.1177/20451253211036814
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author Cholewinski, Tomasz
Pereira, Diana
Moerland, Matthijs
Jacobs, Gabriel E.
author_facet Cholewinski, Tomasz
Pereira, Diana
Moerland, Matthijs
Jacobs, Gabriel E.
author_sort Cholewinski, Tomasz
collection PubMed
description Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an ex vivo model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs.
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spelling pubmed-85588162021-11-02 MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants Cholewinski, Tomasz Pereira, Diana Moerland, Matthijs Jacobs, Gabriel E. Ther Adv Psychopharmacol Review Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an ex vivo model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs. SAGE Publications 2021-10-28 /pmc/articles/PMC8558816/ /pubmed/34733478 http://dx.doi.org/10.1177/20451253211036814 Text en © The Author(s), 2021 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Review
Cholewinski, Tomasz
Pereira, Diana
Moerland, Matthijs
Jacobs, Gabriel E.
MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title_full MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title_fullStr MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title_full_unstemmed MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title_short MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
title_sort mtorc1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558816/
https://www.ncbi.nlm.nih.gov/pubmed/34733478
http://dx.doi.org/10.1177/20451253211036814
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