CLE-100 as an Oral Therapy in Addition to Standard Antidepressant Drug for Major Depressive Disorder - CLEO Study

Author(s):  
2021 ◽  
Vol 11 ◽  
pp. 204512532110368
Author(s):  
Tomasz Cholewinski ◽  
Diana Pereira ◽  
Matthijs Moerland ◽  
Gabriel E. Jacobs

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.


2019 ◽  
Vol 26 (20) ◽  
pp. 3775-3791 ◽  
Author(s):  
Denis Sarrouilhe ◽  
Marc Mesnil ◽  
Catherine Dejean

Background:Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments for this disease are not effective in all patients showing the need to find new therapeutic targets.Objective:This review aims to update our knowledge on the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology.Methods:The method applied in this review includes a systematic compilation of the relevant literature.Results and Conclusion:The use of rodent models of depression, gene analysis of hippocampal tissues of MDD patients and post-mortem studies on the brains from MDD patients suggest that astrocytic gap junction dysfunction may be a part of MDD etiologies. Chronic antidepressant treatments of rats, rat cultured cortical astrocytes and human astrocytoma cell lines support the hypothesis that the up-regulation of gap junctional coupling between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants. However, two recent functional studies suggest that connexin43 hemichannel activity is a part of several antidepressants’ mode of action and that astrocyte gap junctional intercellular communication and hemichannels exert different effects on antidepressant drug response. Even if they emerge as new therapeutic targets for new and more active treatments, further studies are needed to decipher the sophisticated and respective role of astrocytic gap junctions and hemichannels in MDD.


CNS Spectrums ◽  
2014 ◽  
Vol 19 (6) ◽  
pp. 496-508 ◽  
Author(s):  
Gioia Mura ◽  
Maria Francesca Moro ◽  
Scott B. Patten ◽  
Mauro G. Carta

Antidepressants are currently the treatment of choice for major depressive disorder (MDD). Nevertheless, a high percentage of patients do not respond to a first-line antidepressant drug, and combination treatments and augmentation strategies increase the risk of side effects. Moreover, a significant proportion of patients are treatment-resistant. In the last 30 years, a number of studies have sought to establish whether exercise could be regarded as an alternative to antidepressants, but so far no specific analysis has examined the efficacy of exercise as an adjunctive treatment in combination with antidepressants. We carried out a systematic review to evaluate the effectiveness of exercise as an adjunctive treatment with antidepressants on depression.A search of relevant papers was carried out in PubMed/Medline, Google Scholar, and Scopus with the following keywords: “exercise,” “physical activity,” “physical fitness,” “depressive disorder,” “depression,” “depressive symptoms,” “add-on,” “augmentation,” “adjunction,” and “combined therapy.” Twenty-two full-text articles were retrieved by the search. Among the 13 papers that fulfilled our inclusion criteria, we found methodological weaknesses in the majority. However, the included studies showed a strong effectiveness of exercise combined with antidepressants.Further analyses and higher quality studies are needed; nevertheless, as we have focused on a particular intervention (exercise in adjunction to antidepressants) that better reflects clinical practice, we can hypothesize that this strategy could be appropriately and safely translated into real-world practice.


2009 ◽  
Vol 59 (4) ◽  
pp. 227-233 ◽  
Author(s):  
Jay D. Amsterdam ◽  
David Williams ◽  
David Michelson ◽  
Lenard A. Adler ◽  
David L. Dunner ◽  
...  

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