Depression Breakthrough? The Many Faces of “Special K”
Recently, a 45-year-old anesthetic drug has been getting attention as a remarkably effective antidepressant. Ketamine is used for anesthesia in children as well as adults and animals, and sometimes for relief of chronic pain. It’s considered very safe. But it’s also known as Special K among people who use it as a hallucinogenic club drug.
What makes ketamine special in mental illness is that it is the first truly new potential drug treatment in more than 50 years. Exploratory studies going back 13 years have suggested that ketamine has some unique effects in people with depression, both unipolar major depressive disorder and bipolar depression.
So, what’s the big deal?
First, ketamine acts fast. Unlike most current antidepressants on the market, which can take 6-8 weeks to work, ketamine shows antidepressant effects within 24 hours, sometimes in just a couple of hours.
Second, ketamine works in people with treatment-resistant depression. A large percentage of people with depression—as many as half—don’t experience adequate relief with existing treatments. (In the large-scale, 7-year study called STAR*D, only about 50% of people with depression became symptom-free after 2 different treatments, and about 30% still had symptoms after 4 different treatments were tried.)
Third, ketamine decreases suicidal thoughts. People with depression are at increased risk for suicide (though most people with depression do not have suicidal thoughts or complete suicide). In particular, there is an increased risk of suicide in the first month of antidepressant therapy, perhaps because patients have unfulfilled hopes for immediate improvement.
Ketamine also opens up additional avenues for research on depression, because it doesn’t work in the same way as existing antidepressant medications. Current antidepressants all work on serotonin and norepinephrine (two neurotransmitters) in the brain, whereas ketamine works on several other neurotransmitters, particularly glutamate. The idea that adjusting the effects of glutamate in the brain could help depression has been around since the late 1980s, proposed by researchers such as Phil Skolnick at the National Institutes of Health. Various drugs were explored in animal models first, and then in 2000 John Krystal and Dennis Charney at Yale University were able to show rapid antidepressant effects of ketamine in humans.
This line of research suggests the possibility of a whole new class of antidepressant medications that could work for people who don’t respond to the existing ones. (For some technical reading on this, read the debate between two researchers about ketamine’s mechanisms of action and what these might mean for future treatments of depression.)
The promise of ketamine seems huge—given its fast-acting and anti-suicidal properties, it is not a stretch to say that ketamine could save lives.
So then, what’s the problem?
Why don’t we just start using ketamine to treat depression right away? There are a few reasons. The first is that it’s unclear how to maintain its antidepressant effect. Ketamine works fast, but it’s not known whether its antidepressant properties continue to work over the long term—in fact current data suggest that the antidepressant effect may wear off over time (even with repeated doses). Still, even a short-term effect is an advance, if it can prevent suicide and give other medications and psychotherapy a chance to gain a toehold.
More seriously, perhaps, it’s not clear whether long-term use of ketamine is safe. There is anecdotal evidence from ketamine’s off-label use to treat chronic pain that side effects are mild and not dangerous, but there are no hard data to establish ketamine’s long-term safety. It has also been suggested that ketamine could have opioid-like addictive qualities.
Another drawback is that ketamine is currently given as an intravenous injection, which needs to be done in a hospital or doctor’s office. Although there is also a pill version and a nasal spray, it remains to be seen whether these can be as effective as antidepressants. And a trade-off would be the wide availability of pills and nasal sprays that can reach the illegal drug market more easily than the intravenous form.
So, more research needs to be done. There is not likely to be much research coming from pharmaceutical companies, since the patent for ketamine expired long ago. Also, ketamine has to battle against its reputation as an illegal party drug, and heavy abuse does appear to produce some dangerous side effects. Given the current focus on preventing the abuse of prescription drugs like Oxycontin, Ritalin, or Xanax, government agencies will be very cautious in developing a drug like ketamine for use outside hospitals or doctor’s offices.
The FDA has given a “breakthrough therapy” designation to intranasal ketamine for depression, which means that reviews and approvals will be fast-tracked. Currently, there are also government-funded trials to determine the best doses for both efficacy and safety of intravenous infusion ketamine. This shows an understanding of the need and the hope, but it doesn’t automatically mean that all the necessary research will be funded, especially for a generic infusion version.
Perhaps the most interesting promise of ketamine is that if we could figure out how it’s actually working in the brain to decrease depression, we’d understand depression better, and have more possibilities for treatment. Though ketamine is known to work on the NMDA (N-methyl-D-aspartate) receptor for glutamate, it’s not clear that this is the only or even main cause of its antidepressant properties. Not all drugs that affect NMDA receptors work as antidepressants. And ketamine is known to be doing other things in the brain as well. Understanding all of its actions could help researchers understand depression’s actions in the brain better.
Pharmaceutical companies are currently testing medications with similar actions in the brain, but without the dissociative or hallucinogenic effects, the most promising of which may be GLYX-13.
Don’t do this
As a drug already approved for other uses, ketamine is currently available and being used by some psychiatrists to treat depression. For many people, it seems wrong to withhold it from patients who are desperate for relief from their symptoms, and not responding to other treatments, just because it is not approved for treatment of depression.
While this is understandable, it is a risky undertaking that we cannot recommend. Too much still needs to be known about the long-term effects of taking ketamine, including whether it can actually be effective in the long term as an antidepressant. One responsible option would be to find a clinical trial of the medication. You can find dozens of open trials listed at ClinicalTrials.gov.
In the meantime, we will be keeping an eye on ketamine studies and what they can tell us about depression and how to cure it.