Clinical pharmacological innovation in the treatment of depression

ABSTRACT

Introduction

Deficiencies in standard of care antidepressants are driving novel drug discovery. A new age of antidepressant medications has emerged with the introduction of rapid-acting antidepressants with efficacy in treatment-resistant patients.

Areas covered

The newly approved medicines and those in clinical development for major depressive disorder (MDD) are documented in this scoping review of newly approved and emerging antidepressants. Compounds are evaluated for clinical efficacy, tolerability, and safety and compared to those of standard of care medicines.

Expert opinion

A new age of antidepressant discovery relies heavily on glutamatergic mechanisms. New medicines based upon the model of ketamine have been delivered and are in clinical development. Rapid onset and the ability to impact treatment-resistant depression, raises the question of the best first-line medicines for patients. Drugs with improvements in tolerability are being investigated (e.g. mGlu_2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators). Multiple companies are working toward the identification of novel psychedelic drugs where the requirement for psychedelic activity is not fully known. Gaps still exist – methods for matching patients with specific medicines are needed, and medicines for the prevention of MDD and its disease progression need research attention.

KEYWORDS:

• Antidepressant
• major depressive disorder
• treatment-resistant depression
• ketamine
• psychedelics
• NMDA receptors

Article highlights

• Novel antidepressants have been introduced for patient use: (S)-ketamine, brexanolone, dextromethorphan/bupropion.

• Newly emerging antidepressants are currently in clinical development including (R)- ketamine, (S)-methadone, and the novel NMDA receptor antagonists Gate-202 and 251.

• Other novel glutamate receptor modulators targeting mGlu and AMPA receptors are also in development.

• Psychedelic compounds including those without psychedelic effects are in clinical development by a plethora of biotech companies.

• Additional emerging pharmacological strategies have been identified including add on compounds and anti-inflammatory agents.

• It is our opinion that novel antidepressants will soon be approved for patients and that biomarkers to match antidepressants to specific patients are needed for best use.

Acknowledgments

We are grateful for the generous support of the Henry and Nellie Pence Foundation Trust. These funds enable our group to further our mission of finding improved medicines for those in need.

Declaration of interest

JL Smith occasionally receives funds from the Henry and Nellie Pence Foundation. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2023.2198703

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.