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

被引:12
作者
Cholewinski, Tomasz [1 ]
Pereira, Diana [1 ]
Moerland, Matthijs [1 ]
Jacobs, Gabriel E. [1 ]
机构
[1] Ctr Human Drug Res, Zernikedreef 8, NL-2333 CL Leiden, Netherlands
关键词
rapid-acting antidepressants; pharmacological biomarkers; CNS drug development; biomarker-based drug development; major depressive disorder (MDD); mTORC1; NEUROTROPHIC FACTOR BDNF; TREATMENT-RESISTANT DEPRESSION; PREFRONTAL CORTEX; MAMMALIAN TARGET; DNA METHYLATION; SERUM BDNF; NMDA RECEPTOR; EPIGENETIC MODULATION; PERIPHERAL-BLOOD; HIPPOCAMPAL BDNF;
D O I
10.1177/20451253211036814
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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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页数:23
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