Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression

ABSTRACT

Introduction: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders.

Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States.

Expert commentary: Of these novel targets, the most promising – and the ones for whom the most evidence exists – appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders.

KEYWORDS:

• AMPA receptor
• bipolar disorder
• depression
• glutamate
• major depressive disorder (MDD)
• mood
• N-methyl-D-aspartate (NMDA)
• treatment

Acknowledgements

The authors thank the 7SE research unit and staff for their support.

Declaration of interest

CA Zarate is listed as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CA Zarate is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders; he has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. 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.

Additional information

Funding

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927), by a NARSAD Independent Investigator Award to CA Zarate, and by a Brain and Behavior Mood Disorders Research Award to CA Zarate.