Researchers have reported progress in the important effort to explain the rapid antidepressant action of ketamine, and in so doing, have gained insights that may inform the development of other rapidly acting antidepressant medicines.

An anesthetic, ketamine, when delivered at sub-anesthetic doses, can bring relief and even remission to patients with severe, treatment-resistant depression, often within hours. A chemical derivative of ketamine called esketamine was approved by the FDA in 2019 for use in refractory depression.

Ketamine's therapeutic benefits for some severely depressed patients is clearly established; but knowing why it produces this result is crucial for several reasons. The drug, at higher doses, has side effects that include dissociation, a disconcerting out-of-body sensation, as well as addiction risk. Additionally, its therapeutic effects, while dramatic and potentially valuable in "rescue" situations, are relatively short-lived, typically fading after 1 to 2 weeks in most patients.

Lisa M. Monteggia, Ph.D., and Ege T. Kavalali, Ph.D., senior faculty at Vanderbilt University's School of Medicine, have been trying to reverse-engineer ketamine's mechanism of action for several years. Success in this endeavor could open the way to development of other drugs that will have ketamine's rapid action, but with fewer side effects and perhaps longer therapeutic impact.

Dr. Monteggia is a member of BBRF's Scientific Council, and is a 2014 BBRF Distinguished Investigator, 2010 Independent Investigator, 2003 and 2001 Young Investigator, and 2005 BBRF Freedman Prize winner. Dr. Kavalali is a 2012 BBRF Distinguished Investigator.

Research Drs. Monteggia and Kavalali have published in recent years has reinforced the hypothesis that ketamine's target in the brain is the NMDA receptor, a type of receptor found on excitatory neurons that respond to the neurotransmitter glutamate.

The current understanding is that ketamine blocks NMDA receptors. This changes a neural biochemical pathway which increases levels of certain proteins, which, in turn, may contribute to or cause the rapid effects of ketamine in the brain.

The new research published by Drs. Monteggia and Kavalali in the journal Cell Reports takes this work an important step further, examining how changes in pathways "downstream" of the NMDA receptor— precipitated by ketamine's blockade of the receptor—may produce a form of neuronal plasticity called homeostatic plasticity.

Homeostatic plasticity refers to the capacity of neurons to regulate their own excitability relative to the activity of the larger networks which they, in large numbers, form. It is one of several types of neuronal plasticity—a more commonly discussed type is the acute strengthening or weaking of specific synaptic connections between neurons, which is centrally implicated in learning and memory.

Homeostatic plasticity has different functions, and Drs. Monteggia and Kavalali have proposed that it is this type of plasticity which is required for rapid antidepressant action like the kind generated by ketamine. Indeed, they suggest, it may be involved more generally in the action of other neuropsychiatric therapeutics.

The new research by Drs. Monteggia and Kavalali, and supported by the 2018 BBRF Young Investigator grant awarded to Kanzo Suzuki, Ph.D., first author of the new Cell Reports paper, focuses on the involvement of two chemical signaling pathways in a cascade of changes which, the team finds, is causally involved in generating homeostatic plasticity.

One of the two signaling pathways the team explored is associated with a protein called eEF2K. In experiments involving neurons sampled from the hippocampus of rodents, they show that acute inhibition of eEF2K signaling induces a chain of molecular events which results in what the researchers call "rapid synaptic scaling."

The team suggests that rapid synaptic scaling, an important mechanism in homeostatic plasticity, is something that must occur in order for rapid antidepressant action to occur. Ketamine, the researchers have shown, acutely inhibits eEF2K and its signaling; they have now established that this in turn causes changes in neurons that result in the rapid "scaling" of synapses—specifically in the hippocampus, one of the brain areas centrally involved in mood regulation.

The team also showed that a second signaling protein called retinoic acid, or RA, using an entirely independent molecular pathway, can have the same impact: it can induce rapid synaptic scaling in hippocampal neurons, and is associated, in rodents, with homeostatic plasticity changes that are causally involved in rapid antidepressant action.

One implication of the research concerns the importance of homeostatic plasticity, and its potential attractiveness as a target of new antidepressant drugs. Apart from its centrality in generating the rapid antidepressant effect, homeostatic plasticity has an important attribute which enhances its attractiveness as a target. It appears to modulate circuit function globally, and does not directly affect synaptic plasticity mechanisms that process and store information. Thus, drugs targeting homeostatic mechanisms may preserve memory and cognitive function.

The team's research also suggests the possibility of finding agents other than ketamine which can induce the kind of plasticity that they find is necessary in the rapid antidepressant action of ketamine. Although most drugs do have side effects, it would be the objective of such a search to find an agent which is as good or better than ketamine in relieving depression, with fewer or less serious potential side effects.