Tackling Depression With Ketamine
New Scientist 20 January 2007
"FOR MANY, it was a huge, obvious effect," says psychiatrist John Krystal. "One of the patients said, 'Don't give me those old medications, I want this again'."
Krystal, a professor at Yale University, is talking about the time he gave seven severely depressed patients ketamine, a mind-blowing drug developed as an anaesthetic but better known as a club drug. It was a long shot, but the results were astonishing. Though most of the patients found the ketamine experience itself unpleasant, once it wore off they had a far better feeling: the disabling and suicidal depression they had lived with for years had vanished.
Krystal's pioneering experiment happened in the late 1990s, but now researchers at the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, have repeated the study and the results have got psychiatrists, neuroscientists and drug companies buzzing. An antidepressant that acts in hours rather than weeks would transform the treatment of depression, make a lot of money and change the way we understand the disease.
It's not just depression. Other studies suggest that ketamine might act with similar speed to help addiction, post-traumatic stress disorder (PTSD) and certain chronic pain conditions. Ketamine, researchers increasingly believe, may be a "reset button" for brains stuck in dysfunctional ruts.
Depression affects over 120 million people worldwide, making it the fourth largest contributor to the global burden of disease, according to the World Health Organization. At some point in their lives 13 per cent of Americans experience major depression, and globally 850,000 depressed people kill themselves every year.
Treatments are available, but they are slow to kick in and help only about 80 per cent of patients. Drugs such as Prozac and Lustral take between 10 days and six weeks to work; even electroconvulsive therapy (ECT), the fastest-acting treatment, takes at least a week. For 70 per cent of patients the first thing they try does not help. This means that many spend months trying different drugs before finding one that works for them - if they ever do.
That's why the ketamine results are creating such a stir. "This is a hot topic and people are very interested in it," says Lisa Monteggia, a neuroscientist specialising in depression at the University of Texas Southwestern Medical Center in Dallas. "The implications are huge." "It's very intriguing," agrees Lee Schechter, director of preclinical depression and anxiety research at Wyeth Pharmaceuticals in Princeton, New Jersey. Research on rapid antidepressants is now "an area of focus within the industry," he says.
The possibility that ketamine could lift depression was first mooted in the late 1990s, when Krystal and his colleagues were studying the drug as a way of understanding schizophrenia. Ketamine is classed as a "dissociative" because it produces feelings of disconnection from one's self and reality which are similar to some of the symptoms of schizophrenia; very high doses elicit complete depersonalisation and profoundly altered perception. Some have described this "k-hole" as similar to an out-of-body experience.
In the course of his work, Krystal had come across case reports from the 1950s and 1960s suggesting that depressed tuberculosis patients given a TB drug with pharmacological similarities to ketamine sometimes reported rapid release from their depression. He also found research showing that some existing antidepressants worked in a similar way.
Krystal's group put two and two together and decided to give ketamine a try as an antidepressant. They recruited seven patients with treatment-resistant depression - defined as disease so severe that two or more medications have failed - and gave each of them an infusion of either ketamine or a placebo. A week later the subjects were "crossed over" so those who had received ketamine got the placebo and vice versa.
The results, published in 2000, were dramatic: within three days of receiving the ketamine all seven had improved, some profoundly, and they remained so for at least a week. The placebo had little effect (Biological Psychiatry, vol 47, p 351).
Shortly after that experiment, Krystal's colleague Dennis Charney left Yale for NIMH, taking the depression work with him. Last year he and Carlos Zarate, head of the mood disorders research unit, published the results of a larger follow-up study (Archives of General Psychiatry, vol 63, p 856).
Zarate's results were not quite as dramatic as Krystal's but were impressive nevertheless. His team recruited 17 people who on average had failed to get relief from six different drugs; four had even tried ECT, the treatment of last resort. Of the 17, 12 experienced a strong antidepressant response within hours of receiving ketamine, and for six patients the response lasted a week or more. As Zarate describes it, the subjects reported that their depression "lifted".
Zarate's results make all the difference, Krystal says. "Replication is everything. One exciting finding is a footnote but a replication makes it much more interesting, particularly by a different group. It has opened up discussion about rapid-acting antidepressants."
As both researchers point out, the volunteers didn't feel better because they were on a "high" similar to a cocaine buzz, which some depressed people use to lift their mood. "I would really contrast ketamine's effects on depression to those of cocaine," says Krystal. "The hallmark of drugs of abuse is a transient euphoria followed by persistent dysphoria - the cocaine crash. Ketamine is fundamentally different. There may be brief euphoric effects but when those symptoms go away, instead of being dysphoric or hung-over, what we and Dr Zarate's group saw was remarkable."
Still, ketamine has a long way to go before it can prove itself as an antidepressant. Both Krystal and Zarate restricted their patients to a single infusion, so it remains unclear whether a second dose of ketamine would work; equally unclear is whether ketamine would carry on relieving depression if given regularly, or whether this would even be practical given the side effects and cost.
One intriguing possibility is that a single dose of ketamine might allow regular drugs to succeed where they have previously failed. After the trial, Zarate found that some of the volunteers responded better than expected to conventional antidepressants, suggesting that the ketamine had somehow cleared the way, or sensitised them to drugs they were previously immune to. Zarate's group is planning a second, larger trial, and he says there is "more interest than I could have imagined" in additional work.
Even if ketamine doesn't make it as an antidepressant in its own right, the trials make it clear that depression medications do not have to take weeks or months to start working - an excruciating time lag that can push patients already on the brink of suicide over the edge. The ketamine research suggests that it should be possible to develop other fast-acting antidepressants, as well as hinting that today's theories of depression are not the whole story.
The existence of the therapeutic time lag has long been seen as a critical part of an elegant theory of depression that has been coming together since the late 1990s. Before then, researchers saw depression as a result of a deficit in certain neurotransmitters, principally serotonin. That made sense when it turned out that drugs like Prozac, which raise serotonin levels, were effective antidepressants. However, medications that worked on other neurotransmitters often also worked and, most damagingly to this idea, even though drugs could change levels of their target neurotransmitter within hours, they still took weeks to elevate mood.
Enter the neurotrophic theory. Put simply, the idea is that extreme or prolonged stress can cause depression by damaging nerve cells in certain brain regions, particularly an area important for storing and consolidating memories called the hippocampus. Brain scans and autopsies find shrinkage in this area in depressed people.
There's even research suggesting exactly how stress could cause this damage. Under stress, the brain releases an excess of the excitatory neurotransmitter glutamate. Too much glutamate can damage or kill cells, a process known as excitotoxicity. The hippocampus is especially vulnerable.
So stress leads to nerve damage, which causes depression. Further evidence is that every drug known to help lift depression also seems to induce higher levels of peptides that encourage nerve growth, most notably BDNF, or brain-derived neurotrophic factor. This helps to repair injured cells and promotes the growth of new ones. Nerves take time to grow, though, hence the delay.
Ketamine, of course, isn't likely to be busy restoring or replacing damaged cells, so what is it doing? No one really knows, but there are some plausible ideas. Ketamine is known to work by blocking a glutamate receptor called the NMDA receptor, preventing glutamate from transmitting its message across the synapse. Faulty NMDA receptor function has recently been implicated in depression, and repeated doses of conventional antidepressants have been shown to slowly correct it in animal models. Perhaps ketamine does the job in one fell swoop. "One way of thinking about it is that the ketamine has reset the normal activity that was disturbed," says Monteggia. In other words, briefly blocking NMDA receptors with ketamine somehow reboots the system.
“Ketamine somehow reboots the brain”. The reboot idea isn't the only possibility. Ketamine activates another glutamate receptor, known as AMPA, and this has been found to have antidepressant effects in animals; what is more, forthcoming research from NIMH appears to show that preventing AMPA activation blocks ketamine's antidepressant effect. Another possibility is that ketamine works by directly increasing levels of BDNF. That wouldn't account for ketamine's rapid action, of course, but it's possible that BDNF may act not just as a growth factor but as a neurotransmitter too. Some animal studies have found that infusing BDNF into the brain reverses depression-like symptoms in three days.
Whatever the mechanism, most researchers in the area think it should be possible to produce a drug that selectively blocks the NMDA receptor without inducing ketamine-like hallucinations. In fact, at least one such drug already exists, developed by Merck and as yet unnamed. "In initial studies, we didn't see depersonalisation and psychosis-like side effects," says Husseini Manji of NIMH, which is collaborating with Merck to determine whether the compound works as an antidepressant.
Krystal isn't sure such drugs will do the trick. It is possible, he says, that ketamine's bizarre effects are an integral part of the process and not side effects that should be eliminated.
Other approaches to rapidly reversing depression are also attracting attention. Researchers at NIMH recently published a pilot study showing that scopolamine, which is normally used to treat motion sickness, appears to lift depression in three days (Archives of General Psychiatry, vol 63, p 1121).
Ketamine research - particularly the idea that manipulating NMDA receptors might reboot aberrant brain activity - also holds promise for chronic pain, addiction and post-traumatic stress disorder. While these are diverse conditions, researchers believe they may all be connected with abnormalities of the NMDA receptor, which is involved with learning and memory, or "neuroplasticity". In each case the brain may have learned a harmful pattern of responses "too well" and now cannot break free from it.
Addiction and pain
"The idea is that the [glutamate system] is very important to many forms of neuroplasticity. Many people are very interested in the idea of manipulating it so that acute stress doesn't produce chronic problems," says Krystal.
Take addiction, for example. Researchers know that one NMDA blocker, the herbal hallucinogen ibogaine, can help heroin addicts break their habit. Ketamine is a more potent NMDA blocker and seems to have similar effects in rat and human studies. Meanwhile, a group led by Evgeny Krupitsky at the Pavlov State Medical University of Saint Petersburg in Russia is studying ketamine as a treatment for alcoholism. Another illness in which memories seem to trap the brain in a dysfunctional rut is post-traumatic stress disorder. Ketamine may help, though nobody has tried it yet.
The drug may also be useful for treating some forms of chronic pain. Over the past few years neurologist Robert Schwartzman of Drexel University College of Medicine in Philadelphia and colleagues at the University of Tübingen in Germany have used ketamine to treat 41 patients with reflex sympathetic dystrophy (RSD). This is a rare, disabling pain disorder in which ordinary sensations such as touch, warmth and coolness are perceived as painful and minor knocks are agonising. RSD is associated with nerve injuries, after accidents or surgery, for example.
Schwartzman's methods are not for the faint-hearted. He gives RSD sufferers doses of ketamine high enough to put them in a coma for five days, accompanied by anti-anxiety medications to reduce the nightmare of the k-hole. But for many, the results are worth it. In 14 cases out of 41, according to Schwartzman, patients were completely cured. "We haven't cured the original injury," he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone."
"No one ever cured it before," he adds. "In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."
Results with six of these people have been presented at a meeting, and other peer-reviewed research by Schwartzman has shown that ketamine can help RSD pain, but the ketamine coma approach has yet to be subjected to a proper trial. The German group continues to offer the procedure and US researchers, including Schwartzman, are also collaborating with a research group in Mexico.
Realistically, with these complex and chronic conditions, it is unlikely that a one-time treatment will be a complete cure: with addiction, depression and RSD, it is already clear that many people either do not respond or relapse at some point after ketamine therapy. But understanding how the NMDA and glutamate systems drive memory and create responses that are resistant to change could offer insights well beyond these conditions in which the brain has got stuck in a rut and needs a reboot. Ketamine's mind-altering properties may be far more useful than any clubber ever imagined.