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Ketamine and Rapid-Acting Antidepressants: A New Era in the Battle Against Depression and Suicide

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Review

Ketamine and Rapid-Acting Antidepressants: A New Era in the Battle Against Depression and Suicide

Ronald S Duman. F1000Res.

Abstract

Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.

Keywords: Ketamine; antidepressants; depression; mTOR; suicide.

Conflict of interest statement

Competing interests: The author has received consulting fees from Taisho, Johnson & Johnson, and Naurex and grant support from Taisho, Johnson & Johnson, Naurex, Allergan, Navitor, Lundbeck, Relmada, and Eli Lilly and Company.Competing interests: Sanjay J. Mathew receives research support from Janssen and NeuroRx, and consulting fees from Allergan, Alkermes, and Fortress Biotech.No competing interests were disclosed.Competing interests: Dr. Hashimoto is an inventor on a filed patent application on "The use of (R)-ketamine in the treatment of psychiatric diseases" by Chiba University.

Figures

Figure 1.
Figure 1.. Schematic model for the initial cellular target sites of rapid-acting antidepressants and subsequent synaptic changes.
Stress and depression cause neuronal atrophy and decreased synapse number in the medial prefrontal cortex (PFC) and hippocampus that is associated with the depressive symptoms and behaviors in rodent models. Conversely, fast-acting antidepressants like ketamine rapidly increase synapse number and function and reverse the synaptic deficits caused by chronic stress. The synaptic actions of ketamine, as well as several other agents (that is, esketamine, [2R,6R]-hydroxynorketamine, mGluR2/3 antagonists LY341,495 and MGS0039, and scopolamine acting at acetylcholine muscarinic 1 receptors), are activity-dependent and are thought to result from a burst of glutamate via blockade of receptors on tonic firing GABA interneurons, resulting in disinhibition of glutamate transmission. This burst of glutamate causes activity-dependent release of brain-derived neurotrophic factor (BDNF), stimulation of TrkB-Akt and mechanistic target of rapamycin complex 1 (mTORC1) signaling, and rapid increases in synaptic protein synthesis that underlie new synapse formation. Negative allosteric modulators, including CP-101,606, CERC-301, and Ro 25-6981 agents like rapastinel, may increase synapse formation by enhancing NMDA function and thereby increasing BDNF release and downstream mTORC1 signaling. A role for mTORC1 is further supported by evidence that an agent that increases mTORC1 activity also produces synaptic and rapid antidepressant responses. In addition to these sites, there is evidence that the GABA A-positive allosteric modulating agents brexanolone and SAGE-217 also produce rapid antidepressant responses. The intersection of these agents with the mechanisms underlying the rapid response to glutamatergic agents remains to be identified.
Figure 2.
Figure 2.. Model of the NMDA receptor complex and target sites of rapid-acting antidepressants.
The NMDA receptor is a complex of four subunits comprising four subunits that form a pore that is permeable to Ca 2+. At resting state, the pore is blocked by Mg 2+, but, upon depolarization, Mg 2+ is removed, allowing entry of Ca 2+. In the open state, the pore is also accessible by ketamine, which enters and blocks further Ca 2+ influx. The (S)-enantiomer esketamine binds to the same site to block the channel. There are several known sites for regulation of the NMDA receptor in addition to the ketamine and glutamate/NMDA binding sites. Glycine binds to the GluN1 subunit and enhances NMDA receptor function; AV-101 is an antagonist of the glycine B co-agonist site. Rapastinel has glycine-like enhancing properties, although it binds to an allosteric site on the complex. There are several GluN2B-selective allosteric modulators that have potential as rapid-acting agents, including CP-101,606, CERC-301, and Ro 25-6981. It is currently unknown what the initial target is for the metabolite (2R,6R)-hydroxynorketamine.

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