...and no. I don't mean the cereal.

My eye was caught last week by a piece in Scientific American proper asking "is ketamine the next big depression drug?" It's a good piece, and I appreciate the balance in the article, but I was also kind of surprised that...it took so long.

There have been previous media rumblings (and blog) about ketamine through the years, so I'm rather curious as to why the article came out now (maybe there's another new paper out? I didn't see any referenced and couldn't find anything). To be honest, while yes, ketamine has a lot of interesting potential, it's not really quite as "new" as you might think. The first major clinical reports of ketamine as an effective antidepressant actually date back to 2000. Since then, scientists have been spending a lot of time trying to figure out WHY a drug usually used to knock out horses, or abused for its perception-changing qualities, acts as an antidepressant.

And not just any antidepressant, but an almost miracle drug (maybe), helping people who respond to no other treatment, and with effects of a single dose occurring within hours (currently antidepressants take weeks), and lasting for weeks. And for all that...they don't know how it works.

So I saw the article, and I wanted to write a bit of follow-up. Because yes, while we don't know QUITE how ketamine works...we have some ideas. And here is one of them.

Autry et al. "NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses" Nature, 2011.


Ketamine isn't like the current drugs used as antidepressants. Current drugs, like Prozac affect chemical neurotransmitters like serotonin. Neurotransmitters are chemical messengers, released from one neuron and signaling to another. They have have extremely different effects depending on where in the brain you are, what neurotransmitter is released, and what "flavors" of receptors it hits. But while the current drugs hit dopamine, serotonin, and norepinephrine, ketamine interacts with glutamate, the main excitatory neurotransmitter in the brain. And instead of increasing neurotransmitter concentrations (like other antidepressants do to serotonin or dopamine), ketamine acts as an ANTAGONIST at what of the glutamate receptor types, NMDA, preventing glutamate from binding to the receptor. But that's not all, ketamine is also involved in the opioid system (which has its own receptors), and can inhibit nitric oxide from being synthesized.

This gives ketamine several properties. First, it's a drug powerful enough to knock out a horse at the right doses. It can also do things like increase blood pressure. And it means that ketamine has the effects for which it is most famous: hallucinations and "dissociation" (which basically results in a feeling of detachment from your surroundings). And now, an antidepressant, too.

The authors of this study were interested in what aspects of ketamine made it an effect antidepressants. Was it the effects of the NMDA receptor? And WHY would those effects help fight depression?

They started by trying to isolate the NMDA receptor effects, working in mice (the C57 strain of mouse, which is usually resistant to normal antidepressants*). Sure enough, ketamine showed antidepressant properties in things like the forced swim test (where antidepressants make mice swim more instead of floating), sucrose preference (where stressed or "depressed" mice drink less sugar water, which can be reversed with antidepressants), and others. These effects could be isolated to the NMDA effects of ketamine, an NMDA blocker alone (with no other properties, unlike ketamine itself), still produced the antidepressant effects, and unlike the reference drugs (normal antidepressants), it only took one dose, and the effects lasted more than 24 hours.

Why did the effects last so long? After all, ketamine itself doesn't last 24 hours, it only lasts 2-3. It had to be having effects while it was active that persisted after the drug was gone.

The scientists then looked to neuroplasticity, the ability of neurons to grow and change connections. Neuroplasticity has been an active focus of antidepressant research for a while now, long term antidepressant use (3-6 weeks) increases neuroplasticity and the birth of new neurons, and this is on a timeline with its antidepressant effects. Inducing neuroplasticity can help animal models fight off stress, which otherwise can produce depressive behaviors.

But normal drugs take 3-6 weeks. Ketamine takes 3 hours. Was ketamine causing rapid neuroplasticity?

To examine this the authors looked at brain-derived neurotrophic factor (BDNF). This is a protein that can stimulate neuron growth and the formation of new connections. Long term antidepressant treatment with current antidepressants can slower increase BDNF. But as the authors found, ketamine increases BDNF immediately.

(Figure 2 from the paper)

What you can see here is that ketamine and MK-801 (the second and third two bars from the left), an NMDA drug that blocks the channel of the receptor, both increased BDNF only 30 minutes after administration. This effect, and the behavioral antidepressant effects, were completely gone if you genetically knocked out BDNF, showing that the antidepressant effects of ketamine depended on BDNF increasing.

And after ketamine, the authors found that the strength of the neuronal connections in the hippocampus (where neuroplasticity can be incredibly important in mood), was much stronger than before. Again, this depended on BDNF. It appears that the administration of ketamine or an NMDA blocker like MK-801 produces neuroplasticity, resulting in stronger synapses, and that these may be the cause of the antidepressant effects.

This is a new mechanism for antidepressants, and it's a lot faster than the current drugs on the market. So it could be a new avenue for making new drugs, that act faster than the old ones (though whether they treat all depression or are better in most patients is still up for debate).

There are important things to note here. First is that, yes, ketamine has a new, and different, mechanism of action than the antidepressants currently on the market. But it is NOT the only new mechanism that is being investigated to treat depression. Another mechanism under investigation is the idea of using opiate receptors, specifically kappa, to treat depression. And both of these, I think, will end up being good things for antidepressants. Even if ketamine itself is never approved for use, knowing these other potential mechanisms is a great avenue for developing new drugs, that may be effective in hard-to-treat patients.

Another important thing to note is that, for ketamine (and other drugs like it), it's going to be very important to conduct very good clinical studies. When you've gotten ketamine, you KNOW you've gotten ketamine (those dissociative effects kind of give it away), and so the question becomes how do you conduct a study with a placebo that will give people that dissociative feeling, without, you know, being ketamine, in order to accurately compare the drug to the placebo. I don't doubt the potential effects, but with the complications of knowing you have ketamine or not, it's tough to tell just HOW big the effects are.

But it's definitely something worth looking into , both to find newer, and hopefully better, antidepressants...and to learn about mechanism. All previous antidepressants have acted on the monoamine neurotransmitters, like serotonin, norepinephrine, and dopamine. These are, like glutamate, signaling chemicals between neurons. And in the long run, these antidepressants ALSO increase neurogenesis. Are they working through the same mechanism as ketamine, just on a slower time frame? Is there another pathway? What is it? And if the end result is an increase in neurogenesis no matter what...why does ketamine work in patients where nothing else works? What makes the difference? Looking deeper into drugs like ketamine could end up telling us a lot about how antidepressants work, and hopefully, in turn, end up telling us what may cause depression in some people.

*Full disclosure, I have an authorship on that paper, but several other labs have shown similar findings.

Autry, A., Adachi, M., Nosyreva, E., Na, E., Los, M., Cheng, P., Kavalali, E., & Monteggia, L. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses Nature, 475 (7354), 91-95 DOI: 10.1038/nature10130