Glutamatergic dysregulation in mood disorders: opportunities for the discovery of novel drug targets

ABSTRACT

Introduction

Recently, a considerable attention has been paid to glutamatergic conception of mood disorders. The development of new treatment strategies targeted at glutamate provides new opportunities for the treatment of mood disorders. It is expected that these novel therapeutic options will provide a fast and sustained antidepressant effect and will be better tolerated by patients than the currently available antidepressants.

Areas covered

This paper discusses glutamatergic abnormalities in mood disorders and reviews novel glutamate-based drugs developed for the treatment of these disorders. We have searched the PubMed and EMBASE databases, presented the results of relevant clinical studies and also describe novel glutamate-based agents that are under investigation.

Expert opinion

The glutamatergic system plays many important roles in energy metabolism of the brain and neurotransmission; therefore, any attempt to identify novel therapeutic targets within this system seems justified. The effective development of new glutamate-based drugs requires, among others, a more in-depth exploration and understanding of the anatomy, function, and localization of different glutamatergic receptors in the brain. In our opinion, novel glutamate-based antidepressants will find application in the treatment of mood disorders and present an option will be widely used in clinical practice in the future.

KEYWORDS:

• Depression
• mood disorders
• antidepressant
• glutamate
• glutamatergic system
• NMDA

Box 1. Drugs structure

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Article highlights

• The glutamatergic system is a superior brain-stimulating system. It is involved both in the regulation of the stress axis and in neuroplasticity of the brain; therefore, it can play an important role in neuroscience and the treatment of mood disorders.

• Dysregulation of the glutamatergic system causes neurotoxicity and negatively affects neurotransmission, neuroenergetics, and cell viability. Moreover, abnormalities of the glutamatergic system may be partially related to synaptic abnormalities in the course of mood disorders.

• Considering the increasing evidence for the key role of the glutamatergic system in the pathophysiology of mood disorders, the development of new strategies targeting glutamate provides new opportunities for the treatment of mood disorders. Glutamate-based antidepressants may not only improve the effectiveness of therapy but also positively affect the speed of therapeutic effects and treatment tolerance.

• The results of preliminary clinical trials have indicated significant antidepressant effects of some proposed therapies targeting the glutamatergic system, including mainly ketamine, esketamine, lanicemine, and AXS-05. On the other hand, several different studies have provided disappointing or inconclusive results for a number of agents, such as memantine, rislenemdaz, basimglurant, and decoglurant.

• Despite promising preliminary results, there are numerous issues that still require a more extensive research, such as the exact function of the glutamatergic system in mood disorders or the relationships between glutamatergic system abnormalities, astrocyte dysfunction, and altered energy metabolism in the brain. Moreover, populations that would benefit most from rapid-action glutamate-based antidepressants, relationships between the type of disorder and the response to treatment, and the exact mechanism of antidepressant action of these agents need to be identified and well described.

• In our opinion, glutamate-based antidepressants are an important and promising therapeutic option for brain disorders and offer hope for improved quality of life for patients in need of an effective treatment.

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

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.