Major depressive disorder (MDD) is a multifactorial psychiatric disorder with an obscure pathophysiology. Recent findings suggest that the mammalian target of rapamycin complex 1 (mTORC1) is impaired in MDD. However, no well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. Therefore, we aimed to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials of mTORC1 modulating ADs. To this purpose, we performed a PubMed-based narrative literature review of mTORC1 involvement in MDD. We summarized recent pre-clinical and clinical findings linking MDD to the impaired activity of several key biomarkers related to mTORC1, and summarized cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs. 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. Read the full review here.
