New investigational agents for the treatment of major depressive disorder

ABSTRACT

Introduction

Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression.

Areas covered

The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites. Furthermore, the antidepressant potential of psychedelics, non-hallucinogenic serotonergic modulators, and metabotropic glutamate receptor ligands was discussed.

Expert opinion

Recent data indicated that to achieve fast and long-acting antidepressant-like effects, compounds must induce durable effects on the architecture and density of dendritic spines in brain regions engaged in mood regulation. Such mechanisms underlie the actions of ketamine and psychedelics. These compounds trigger hallucinations; however, it is thought that these effects might be essential for their antidepressant action. Behavioral studies with serotonergic modulators affecting 5-HT1A (biased agonists), 5-HT4 (agonists), and 5-HT-7 (antagonists) receptors exert rapid antidepressant-like activity, but they seem to be devoid of these effects. Another way to avoid psychomimetic effects and achieve the desired rapid antidepressant-like effects is combined therapy. In this respect, ligands of metabotropic receptors show some potential.

KEYWORDS:

• depression
• NMDA
• Rapid-acting antidepressant
• ketamine
• serotonin
• psilocybin

Article highlights

• The rapid onset of action and long-lasting effects induced by a single dose of ketamine is a breakthrough in the modern pharmacotherapy of depression.

• Due to the promising preclinical results, 2R,6R-HNK, and R-ketamine should be tested in clinical trials.

• Classical psychedelics might be considered novel, fast-acting antidepressant drugs with long-lasting remission.

• Serotonergic receptor ligands, especially 5-HT1AR-biased agonists, 5-HT4R agonists, and 5-HT7R antagonists represent potential molecular targets for new antidepressant agents without hallucinogenic side effects.

• Drugs with multi-faceted mechanisms of action (e.g. vortioxetine) appear to have better antidepressant potential - a more substantial therapeutic effect, act on a broader range of symptoms and have fewer side effects.

• Metabotropic glutamate receptor ligands show potential as adjuncts that decrease the side effects of fast-acting antidepressants.

Acknowledgments

We would like to thank Agata Machaczka for her assistance in preparing Figures 1 and 2. All rights and ownership of BioRender content are reserved by BioRender.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer declares having received financial payment for contributing to ketamine training course for psychedelic support, received a provincial grant to conduct clinical research on ketamine for treatment-resistant depression (granting agency: RQSHA). One reviewer declares being the inventor of the patents of the use of R-ketamine in the treatment of psychiatric disorders such as depression. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by funds for statutory activity of the Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.