Major Depressive Disorders: Recent Developments and Clinical Application

Objectives

1. Provide an overview of the glutamate system in the brain and how it is impacted by ketamine;
2. Present clinical results establishing the rapid onset of action of ketamine in treatment-resistant major depressive episodes; and
3. Describe the clinical effectiveness of new emerging therapies in MDD.

Literature References

1. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC.Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):139-148. PMID: 29282469

2. Thase ME. New medications for treatment-resistant depression: a brief review of recent developments. CNS Spectr. 2017 Dec;22(S1):39-48. PMID: 29350129

3. Wilkinson ST, Sanacora G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2018 Nov 14. pii: S1359-6446(18)30376-3. doi: 10.1016/j.drudis.2018.11.007. [Epub ahead of print] PMID: 30447328

4. Zhang K, Hashimoto K. An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Rev Neurother. 2018 Dec 4:1-10. PMID: 30513009

Abstract

Although it is a coincidence that publication of the main findings of the seminal STAR*D study coincided with the 20^th anniversary of the introduction of fluoxetine, the “graying” of the second generation of antidepressants has been accompanied by recognition of many critical unmet needs. The relatively underwhelming results of the sequential stages of STAR*D underscored that there is a great need for therapies for depressed patients who do not respond to first- and second-line antidepressants. Perhaps the progressive decrement in remission rates observed across stages in STAR*D reflects the fact that all of the medications studied initiate antidepressant action through monoaminergic mechanisms. This talk will briefly overview of several alternate targets for novel medications, focusing primarily on the glutamatergic system. The rapid antidepressant effects of the dissociative anesthetic ketamine, initially observed serendipitously in the late 1990s, have now been widely replicated and set the stage for a new generation of drug discovery. Research pertaining to several other investigational antidepressants that modulate glutamatergic neurotransmission, including esketamine, raspastinel and lanicemine, will be summarized. There are several concerns and unanswered questions pertaining to durability of therapeutic effects and safety that warrant careful long-term study.  Nevertheless, for the first time since the discovery of imipramine and iproniazid in the mid-1950s, truly paradigm shifting antidepressant medications appear to be on the horizon.