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Ketamine: a fast-acting antidepressant? Researchers identify a pathway associated with a faster onset of antidepressant effects.

A revolutionary break-through in the treatment of depression occurred in the late 1950s with the discovery of the monoamine oxidase inhibitors and tricyclic antidepressants. Since then, newer agents, starting with Prozac, were introduced. These newer antidepressants had fewer side effects and thus were easier to prescribe and manage in patients.

But there has always been one concern about antidepressant medications: Even when effective, they have a slow onset of action. Typically, they take nine to 14 days to have any impact, and perhaps weeks to deliver their full effects, even as patients continue to endure painful symptoms, diminished functioning, and an increased suicide risk. But what if an antidepressant could offer a more rapid onset, with sustained antidepressant effects?

Looking for a faster onset of action

Research initiated at Yale University and later extended to the National Institute of Mental Health (NIMH) has explored the use of ketamine to help understand and address the delayed-onset action of currently available antidepressants.

Ketamine, which has been employed as a human and animal anesthetic, has been found to act in the human brain by blocking the N-methyl-D-aspartic acid (NMDA) receptor, which receives nerve signals carried by the neurotransmitter glutamate. Studies have suggested that dysregulation in glutamate activity could be a causative factor in depression.


Ten years ago, investigators at Yale reported antidepressant effects of a single dose of intravenous (IV) ketamine in seven depressed patients. (1) Dr. John Krystal, who chairs the Department of Psychiatry at Yale University School of Medicine, has been studying ketamine since 1989 and was the senior author of that study. He found the antidepressant effect of ketamine extraordinary.

"It is simply striking to see someone who has struggled with long-standing treatment-resistant symptoms of depression get better overnight. It is a remarkable thing to see," Krystal says.

Six years following that Yale report, investigators at the NIMH replicated the results. (2) They reported "robust and rapid antidepressant effects" from a single intravenous dose of ketamine. The onset of action occurred within two hours after IV treatment and lasted one week. More recently, the NIMH investigators reported similar results when ketamine was added to lithium or valproate in bipolar depressed patients. (3) It appears that the rapid antidepressant effect of ketamine benefits about 70 percent of subjects who have participated in these studies.

Discovery: A "faster" neural pathway

Scientists know that antidepressants act on specific targets called "receptors" in the cell membrane of a neuron that "listen" for signals from other neurons that are sent via neurotransmitters such as glutamate. When a neurotransmitter signal is received, receptors trigger a specific cascade of biochemical reactions within the neuron that enable it to respond to the signal. This is called a "signal transduction reaction." Typical antidepressant medications trigger reactions that ultimately take nine to 14 days to produce the desired antidepressant effect.

However, as noted, ketamine produced an antidepressant effect in 24 hours or less. This led experts to assume that ketamine's antidepressant effects occurred through a different and faster signal transduction chain. They theorized that if this faster pathway could be identified and understood, it might open the door to a new, faster way to treat depression.

A recent Yale University study, detailed in the August issue of Science, has validated the experts' assumption and identified the exact mechanism of ketamine's action. (4) In studies with rats, basic researchers observed that ketamine rapidly activates the "mammalian target of rapamycin" (mTOR) pathway, one of many such pathways that perform signal transduction in neurons. When the mTOR pathway was activated in rats, the Yale investigators observed an increase in synaptic signaling proteins, the number of new spinal dendrites, and motor activity that appeared consistent with animal models developed in antidepressant studies. Convincingly, these ketamine-induced changes did not occur when mTOR signaling was blocked.

Clinical implications

These findings point to an exciting new direction for the treatment of depression: the potential for a 24-hour depression treatment. However, ketamine (or any other antidepressant that utilizes the mTOR pathway) would require a great deal of additional development before its use could be validated in routine clinical practice.

Ketamine is known to cause some undesirable cognitive and behavioral effects. Ravers in nightclubs abuse ketamine, or "Special K," to experience euphoria and perceptual distortions such as sounds and colors. Higher doses may produce outright hallucinations, delusions, and sometimes, paralysis. Recently, a study reported the occurrence of severe urinary tract dysfunction in long-term users of ketamine.

Despite these obstacles, Krystal feels that ketamine may yet be found feasible for clinical practice. "It may be that education, patient preparation, and initiation of other psychopharmacologic treatments to sustain remission will overcome these shortcomings, but this too has yet to be demonstrated," he says.

"At Yale," he adds, "we have conducted a preliminary open label study using ketamine for suicidal patients in a busy emergency room setting and it seemed quite feasible. The responses were encouraging." Krystal consults to several pharmaceutical companies and is a co-sponsor on two patent applications related to gluta-matergic treatments for mood and anxiety disorders, including one involving ketamine for depression.

Krystal points out that several issues suggest a high level of caution in incorporating ketamine into clinical practice:

* It is not clear how to transition someone from an acute antidepressant response lasting days to weeks to an extended remission. Ultimately, treatment is a long-term process and a rapid-onset antidepressant could play an important new role in inducing remission of depression that might help to reduce the impact of depression and avoid hospitalizations. "But, whether through repeated dosing or the initiation of other definitive treatments, it will be important to determine the best way to sustain the initial benefits," says Krystal.

* Some patients may not tolerate a rapid antidepressant treatment using ketamine.

* There is, at present, no way to determine which patients will be at higher risk for addiction to ketamine, given its prior history of abuse.

One more piece of the depression puzzle

Yale's ketamine research effort represents years of collaboration between bench scientists (a group knowledgeable about brain mechanisms in animals) and clinicians knowledgeable about human psychiatric disorders. While a Yale faculty member, I witnessed this rare alliance between neuroscience

and psychiatry and developed faith that knowledge about molecules will ultimately lead to the understanding and successful treatment of many psychiatric disorders. The work that went into the "ketamine story" has been a thing of beauty, and should be a source of hope to the millions who suffer from depression and the clinicians who treat them.

Now that activation of the mTOR pathway has been associated with the biochemical mechanism(s) of depression, scientists will be busy looking for simple blood tests to monitor mTOR activity and evaluating the antidepressant effects of other drugs that activate this pathway.


(1.) Berman RM, Cappiello A, Anand A, Oren D A, Heninger G R, Charney D S, Krystal J H. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15; 47(4):351-4.

(2.) Zarate C A, Singh J B, Carlson P J, et al. A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Arch Gen Psychiatry. 2006;63:856-864.

(3.) Diazgranados N, Ibrahim L, Brutsche N E, et al A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Arch Gen Psychiatry. 2010;67(8):793-802.

(4.) Li N, Lee B, Liu R J, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010 Aug 20;329(5994):959-64.


William M. Glazer, MD, is President of Glazer Medical Solutions ( of Key West, Fla., and Menemsha, Mass. He is a clinician, researcher, lecturer, and consultant, and has been a member of faculty of the departments of psychiatry at the Yale and Harvard schools of medicine.


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Title Annotation:RX RESOURCES
Author:Glazer, William M.
Publication:Behavioral Healthcare
Article Type:Report
Geographic Code:1USA
Date:Oct 1, 2010
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