From The Quarterly, September 2016

“Imagine you had a compound that does what ketamine does, but without its side effects or risk of addiction,” says Carlos A. Zarate, M.D., a senior scientist at the National Institute of Mental Health. He’s referring to a drug that has been shown in recent years to almost miraculously relieve deep depression—the kind that resists other forms of treatment—within hours, and sometimes, though less frequently, in minutes. The problem is that it can generate serious side effects and is also addictive when misused.

This “improved” version of ketamine, Dr. Zarate explains, could similarly act rapidly to relieve treatment-resistant depression. It could help people in the midst of a suicidal crisis to stop thinking of ending their lives. Like ketamine, this new drug could also be effective in treating the depressive phase of bipolar disorder. And like ketamine, it could relieve anhedonia, the inability to experience pleasure that is seen in millions of depressed people, not only the most severely afflicted.

Indeed, says Dr. Zarate, “ketamine is an exciting drug” for all of these reasons, and he has been involved in some of the preclinical and clinical trials in animals and people that have documented its potential. Since 2009, when he founded the Experimental Therapeutics and Pathophysiology Branch (ETPB) at the Division of the Intramural Research Program at the NIMH, he and his colleagues have been trying to find out exactly how ketamine works, in the hope of learning how to engineer a safer alternative.

This alternative drug that would have all or even some of ketamine’s benefits but not cause its most troublesome side effect, dissociation (a variety of perceptions in which one feels detached from one’s immediate surroundings, or feels a distinct separation between one’s body and mind). A future ketamine substitute also would not be addictive. Indeed, ketamine, originally an anesthetic used in veterinary medicine, is also known on the street as a “party drug,” called Special K.

The wait for this improved ketamine may be nearing an end. On May 4, Dr. Zarate and colleagues at the NIH, along with a team at the University of Maryland led by Todd Gould, M.D., (a NARSAD 2013 Independent Investigator and 2004, 2010 Young Investigator) published a paper in the journal Nature that turned heads. They presented powerful evidence suggesting that ketamine did not work primarily as most scientists had previously postulated. Even more important, they showed that ketamine’s desirable effects are likely due to one of the chemicals generated when the drug is metabolized by the body.

This report shook the field because it suggested that it may be possible to administer the metabolite, called HNK (or “Hank”), separately as a drug in its own right. This metabolite, importantly, does not appear to be addictive or to generate dissociative effects. “If you have something without ketamine’s side effects and addictiveness, you could totally change how treatment is given for depression, suicidal thinking, and anhedonia,” Dr. Zarate says. “You could intervene very rapidly, and very early in the course of treatment.”

It could mean “rapidly and early” not only in the most severe cases of depression, he adds. If a safe drug based on HNK is as effective as hoped—“and we shouldn’t jump the gun, there’s plenty of work to do,” he stresses—it could be prescribed conceivably “for everybody” with life-impairing depression. He means the millions who currently take drugs in the Prozac class, called SSRIs, which affect the brain’s serotonin system. About half of those who take SSRIs are not helped by them, and those who are helped often must wait weeks or months to see any improvement in mood.

“We could decrease the length of every episode of depression, which ranges on average from three to nine months. So over the course of a lifespan one could significantly lessen the time spent ‘in depression’ and in this way decrease the harmful impact depression has on the brain and body. It could get people back to their normal lives very quickly, minimizing the disruption,” Dr. Zarate says of a drug with ketamine’s benefits and lacking its downsides.

A recipient of a Young Investigator grant in 1996, an Independent Investigator grant in 2005, and the Brain & Behavior Research Foundation’s Outstanding Achievement Award for Bipolar Mood Disorder Research in 2011, Dr. Zarate, an Argentinian by birth, came to the NIMH in 2001. He organized the ETPB precisely to work with drugs like ketamine that were already known to have a beneficial effect on psychiatric illnesses, but for one reason or another were not suitable for use in large numbers of patients. He likens his approach to reverse engineering, which has been very much in evidence in the years of work culminating in the new paper on ketamine and HNK.

He and his colleagues arrived at the new findings by trying to take apart or isolate different aspects of ketamine—ranging from what became of the compound once it entered the body to where it acted in brain cells to generate its beneficial antidepressant effects. An early clue was an experiment that tested the long-held theory that ketamine works by blocking docking ports called NMDA receptors on the surface of nerve cells. This blockade was thought to spur the release of a neurotransmitter called glutamate, which helps cells carry messages from one neuron to the next.

But when the team used a different compound to block NMDA receptors—one that did so much more powerfully than ketamine—they noticed very weak or no impact on depressive symptoms in mice. This led them to look for other mechanisms behind ketamine’s beneficial effects.

Knowing from their own work and that of others that ketamine generates stronger antidepressant responses in female mice than male mice, Dr. Zarate and colleagues looked closely at the drug’s metabolites. They noticed that one, HNK, was about three times more prevalent in the brains of female rodents given the drug compared with males, while other metabolite levels did not differ among the sexes. HNK thus seemed a good place to focus.

In meticulous experiments that can be compared, roughly, with taking a computer and subtracting parts until it malfunctions, the scientists tested a version of ketamine that did not break down into HNK. This version of ketamine was not effective in reducing depression in mice. They then tested two versions of HNK, and identified the one that most effectively and rapidly treated depressive symptoms and reversed the mouse equivalent of anhedonia.

The original questions about ketamine—how did it work and where did it act in the brain?—had to be applied to this desirable version of HNK. Perhaps it was HNK that blocked NMDA receptors, leading to a glutamate surge and accounting for ketamine’s effects. In a wonderful example of why a rigorous scientific approach is needed, the team demonstrated that HNK by itself does not block NMDA receptors. This experiment was important because it suggested that both ketamine and HNK administered alone rapidly relieved depression, but those benefits did not come from blocking NMDA receptors.

When the team blocked another type of glutamate receptor called AMPA in mice, HNK did not relieve depression-like symptoms. In other words, HNK’s rapid antidepressant action requires the vigorous activation of AMPA docking ports and a surge of glutamate signaling in nerve cells. Further experiments, using EEG brain-wave measurements and other methods, suggested to Dr. Zarate and the team that HNK relieves depression by causing more AMPA docking ports to appear at the synaptic junctions that connect nerve cells in the brain.

Will we see a drug based on HNK in the very near future? Not immediately. But Dr. Zarate says his team, in conjunction with the National Center for Advancing Translational Sciences (NCATS)—a section of the NIH created to assist in the development of therapeutics based on government- funded research—is already working hard to get to a drug that pharmaceutical companies would then test in large-scale human trials.

“Our results are very exciting, but we need to know more,” Dr. Zarate emphasizes. Since HNK is generated when ketamine is given to seriously ill patients, it is “proven” safe in at least limited dosages. But no one yet knows the dose to use to achieve the best results if HNK is given separately.

“We are conducting such tests right now,” says Zarate. “If we find that higher doses are needed than those generated naturally in ketamine administration, then we have to establish safety very carefully. We have to show how effective and how safe it is when taken over longer periods of time. We also have to test other metabolites of ketamine, repeating much of the same work with them, to see if any of them are important in ketamine’s ‘good’ effects. None of these steps can be skipped.”

The team hopes to move from preclinical tests in animals to Phase 1 and 2 trials in humans. If successful, then a partnering approach with the industry is possible in the near future, Dr. Zarate says.