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Ketamine and Major Depressive Disorder: Is it Better with Special K?


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Most people have heard of ketamine. Originally invented in 1962 to be used as an anesthetic, it is still used for children and in some topical anesthetics, but mostly when you hear of ketamine used clinically now, it’s actually used in combination with xylazine as a veterinary anesthetic (side note: SciCat coming to after a visit to the vet from a Ketamine/Xylazine combo is…hilarious. Hilarious and full of ANGER).

But of course, the medical uses of ketamine are not what people have heard about. Instead, people hear about the recreational uses of ketamine (aka Special K), where street users describe hallucinations and a sense of dissociation from the world. It’s achieved widespread fame as a drug of abuse, and that’s how most people know it nowadays.

But there may be more to it than that. There are currently trials underway to look at how ketamine treatment might help with depression and other psychiatric disorders in humans.

Of course, you can do clinical trials in humans and get subjective reports from the patients. But if you want to see what’s REALLY going down with how ketamine is WORKING, you need a brain. And for brains, you need rats.

Li et al. “Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure” Biological Psychiatry, 2011.

Ketamine does not behave like many other drugs that are known to be drugs of abuse. Unlike the benzodiazepines, it doesn’t act on GABA. It doesn’t act directly on dopamine like the stimulants, or on serotonin like the hallucinogens. Instead, ketamine acts on the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain. But not DIRECTLY. Instead, it acts on a specific type of glutamate RECEPTOR, the N-methyl-D-aspartate (NMDA) receptor type. Ketamine acts at NMDA receptors as an antagonist, blocking the ability of glutamate to bind to the receptor and do its job.

And this is an aspect of the brain that has been relatively ignored in studies of depression. Often, scientists who study depression focus on serotonin, and on the birth of new neurons in the brain. Many believe that the increases in serotonin produced by traditional antidepressants such as Prozac lead to the increases in neurogenesis in the hippocampus which may help symptoms of depression. But serotonin doesn’t have to be the ONLY neurotransmitter involved. There could be other mechanisms that mediate how depression occurs, and thus other potential drug targets.

And we NEED some other drug targets. Major Depressive Disorder is widespread, and in a large number of cases, the available antidepressants never work. So recently scientists have begun to look at glutamate, and at ketamine. Clinical trials have shown that low doses of ketamine (which still can produce some dissociative symptoms, but no hallucinations) can produce a rapid antidepressant response in severely depressed or bipolar patients. The studies are still very small and limited. And so far, it’s unknown HOW ketamine is acting to relieve depression in these patients.

Bring on the rats.

For this study, the authors took rats, and induced a depression-like state (we say “depression-like” because you can’t ever ASK a rat how it feels about life) using a method called Chronic Unpredictable Stress. Kind of like exposing a rat to the equivalent of grad school. The stresses could be anything, and the rats get two stressors per day. But instead of experimental equipment breaking or their advisor yelling at them or running out of beer money, the rats get stressors like being placed in a chilly room, leaving the lights on overnight, bad smells, being put on a shaker plate or having their cages tilted at weird angles, or leaving the radio on loud. After 21 days of this, you get some stressed out unhappy rats. You can tell by giving them a test to see how much sugar water they want to drink. Happy rats LOVE sugar water, but unhappy rats will drink less of the sugar water.

Here you can see the results for the sucrose drinking rats exposed to chronic stress. The rats showed a decrease in sucrose preference, as well an increase in how long it took them to eat food in a novel environment (called Novelty Suppressed Feeding). BUT, when they gave the rats a single dose of either ketamine or a similar NMDA antagonist RO-256981, 24 hours before they began testing, the rats didn’t have these symptoms. They drank as much sucrose water and ate as much food as animals that had never been exposed to stress at all. And in the bottom two panels of the figure you can see that this effect of a single dose of ketamine or RU-256981 lasted for up to 7 days after the drug was given to the stressed animals.

But of course, if you want to determine a mechanism of how something is acting in the body, you have to BLOCK it. In this case, the authors gave a drug called rapamycin, which is a bacterial produce that inhibits…”the mammalian target of rapamycin”, otherwise called mTOR (you know that you know NOTHING about a protein when you call it “oh, you know, that target of that one drug we have…”). Luckily, we do NOW know a good bit about mTOR, which is a kinase that regulates things like cell growth and proliferation, as well as transcription of DNA. IT also lies downstream of NMDA receptor signaling, so is probably stimulated by drugs which hit the NMDA receptor. So IF ketamine is relieving anhedonia in these rats via mTOR, blocking mTOR will block the effects of ketamine.

So they gave rapamycin right before giving ketamine in the stressed out rats, and rapamycin blocked the effects of ketamine on sucrose preference and suppressed feeding. The rats looked as stressed as ever when mTOR was blocked, which suggests that ketamine was producing the behavioral effects via mTOR.

The authors then looked for various proteins that could be involved. They found that proteins that are associated with synapses, like glutamate receptors and proteins like synapsin 1 are reduced during stress in the rats, and that ketamine can increase these proteins again.

But what are these proteins DOING? It looks like they may be involved in difference spine densities in the stressed rat brains. They authors looked at neurons in the prefrontal cortex, looking specifically at an area called the apical tuft, which is where the tuft of dendrites comes out at the end of the axon (more on basic neuron anatomy here). This is because depressive symptoms in animals are associated with something called dendritic atrophy, where you get a decrease in the numbers of dendritic spines in areas like the apical tuft.

You can see here the photos of the dendritic spines from the rat prefrontal cortex (yup, we can take pictures of tiny parts of tiny neurons. Sometimes, that STILL blows my mind). The stressed rats have decreases in the number of little spines coming off the dendrites, and this can be reversed with ketamine.

But finally, we want to know how stress, and then ketamine, changes the way the neurons BEHAVE. To figure that out, we have to do electrophysiology, which is a technique where you take a REEEAAAALLY TEEEENY end of a glass tip, and suck a REAAAALLLLLY TEEEENY bit of cell membrane into it. If you do this in a live brain slice (which you can keep alive for a few hours outside of the rat’s head), you can get a live cell, and you’ve got something patched into it. You can then get recordings of what the cell is doing electrically (how it is firing, action potentials, etc), kind of like using peephole into a room.

In this case, they were interested two specific TYPES of neurons, those receiving the neurotransmitter serotonin, and those received the relatively new transmitter hypocretin/orexin (so new they are still arguing about the name). Those receiving serotonin are involved in signaling within the cortex, while those receiving hypocretin are involved in signaling which goes outside the cortex to the thalamus.

So they put serotonin and hypocretin on their slices and looked at how the neurons behaved.

You can see the little traces there, which show the neurons experiencing little postsynaptic currents. In the stressed rats (center) the currents were reduced in both cases, but when you gave ketamine, they were increased again. This may mean that the lack of dendritic spines seen in the stressed animals has functional effects on how well the neurons can make their little postsynaptic currents, which is a big effect on functionality.

What I find to be most interesting about this study is that there was only ONE DOSE of ketamine given here. ONE. The effects lasted up to a week. We don’t know if we’d get similar effects in humans (or whether the rats were experiencing hallucinations, for that matter, tough to ask them about that), but if we did, it’s possible that the mechanism through which ketamine works could be used to find new and effective antidepressant drugs. Or, if the effects of ketamine are mostly temporary and it’s not feasible to give it as a long term drug (and it may not be due to legal issues and the potential for abuse and thus possibly the selling of it to other people), we may be able to give it in the clinic, and use it to “kickstart” the effects of more traditional antidepressants like Prozac, where the ketamine may be able to bridge the gap while the Prozac is working (though no results yet on whether the ketamine increases neurogenesis like other antidepressants do, but knowing the work of this laboratory, I bet they’re on it). Or maybe we’ll get both. I don’t know if it’s a magic bullet (I doubt it), but I think it’s got potential as a new mechanism to pursue when looking for antidepressant drugs.

Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, & Duman RS (2011). Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biological psychiatry, 69 (8), 754-61 PMID: 21292242

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.





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  1. 1. Tom Michael 11:32 am 07/14/2011

    Great post Scicurious – your articles are helpful as its hard to keep up with the papers on these subjects, and you do a better job of communicating the science. You’re not overly technical and not too dumbed down either.

    As a neuropsychologist, I’d like to understand what these rat brain findings might imply for cognition in depressed humans. Previously I’ve interpreted the serotonin hypothesis of depression in terms of SSRIs and the like reducing *stress* rather than depression, hence treating a cause of depression and possibly preventing the reduced neurogenesis in the hippocampus. This fits in nicely with the neurogenesis hypothesis of depression, hippocampal atrophy, and the fact that the SSRIs take a couple weeks to make people feel better. It also fits in with the fact that depressed people have trouble getting over painful old memories and moving on (if we remember that the hippocampus is critical to new memory formation). Its always good if the neuroscience explanations match up with psychological or common sense ones.

    I guess my question is, if the Ketamine is working almost immmediately, what is it doing psychologically? In the rats (who we can’t ask, unless we had a good rat neuropsychologist who spoke English) the removal of the decrease in sucrose preference implies that the Ketamine is reducing anhedonia (at least, I think thats what it means right?). And of course anhedonia is a key aspect of depression, particularly atypical depression (which actually might be the more common type).

    But what does the prevention of the decrease in dendritic spines in the rat PFC mean? Does this mean depression causes a decrease in synaptic plasticity in the rat PFC (it looks like it) and that Ketamine treats this? Also, do we know what part of the rat PFC this is happening in (is it all of the rat PFC?) because as you of course know, the human PFC is massive and incredibly specialised in comparison with our rat mammal cousins.

    Might the reduction in PFC neurons explain why rats give up earlier in forced swim tests? (especially if its the rat orbitofrontal cortex equivalent), how about rat executive function? (which I guess we have to test with mazes)

    You post makes me want to become a rat neuropsychologist, but I’ll stick to humans for now. Unfortunately, the ethics committee won’t let me feed ketamine to depressed humans, but other people are doing this research at least…..

    Link to this
  2. 2. Alchemystress 12:13 pm 07/14/2011

    Great article and well written. I did not know this about ketamine

    Link to this
  3. 3. jdjentsch 10:02 pm 07/14/2011

    Effective for otherwise treatment refractory patients? Rapid onset of efficacy? Post-treatment delirium? Somewhat unknown mechanism of action?

    Could be special K (ketamine). Could be ECT (electroconvulsive therapy).

    Several other things spring to mind when imagining the comparison. For example, both produce lingering changes in psychological and cognitive function that impair function in the post-treatment period. Both have the risk for a bit of retrograde amnesia. Both may need occasional redosing to maintain their effects.

    So, is ketamine a pharmacological ECT? It’s hard to say since no one really knows why ECT works the way it does. But, in a sense, both ketamine and ECT are the most general types of manipulations, acting across the CNS in a way that typical antidepressant drugs do not.

    These are just speculations, but I think it might be worthwhile to explore common neural mechanisms of action of ECT and ketamine in order to try and understand what these special, rapid-acting manipulations do.

    But given their side effects, they will always be last lines of defense…

    [PS. Ketamine is a channel blocker, so technically, it does not prevent glutamate from binding to the NMDA channel to achieve its effect. Instead, it blocks ion flux across the channel once glutamate has opened the channel. It is also use dependent in the sense that NMDA receptors must be active and opening in order for ketamine to gain access to and occupy the channel].

    Link to this
  4. 4. Horrible Clarity 12:13 am 07/15/2011

    Interesting that you suggested the link between ECT and ketamine. This has been looked at (Fumagalli 2010 Int. J Neuropsychopharmacology), finding that ECT affected the phosphorylation of NMDA and AMPA receptors, effectivley altering their function. I’m not sure about ketamine but I know that MK-801 also effects the phosphorylation of NMDA receptor levels and would presumably have similar anti-deppresant effects as ketamine.

    So this provides some preliminary evidence that NMDA antagonists and ECT do work in similar ways, effecting neuronal excitability and then potentially downstream synapse formation.

    We’re a long way from understanding it but it sure is interesting stuff.

    Link to this
  5. 5. sciliz 6:50 pm 07/24/2011

    Woo! I’m so glad you blogged this. I’ve been following this story for a few years now, since I had to do my comps (we had to write a proposal on a topic unrelated to our thesis work. One of the two proposals with specific aims I sent to my committee was on NMDA and ketamine.)
    On this paper- I’m really uncomfortable with the lack of the control for what just ketamine (in control/unstressed rats) does to the electrophysiology. And I’d really, really like to see the results with the rapamycin variable as well.

    For the record, my understanding is that ketamine is a channel blocker, and that the dissociative effects (which occur relatively rapidly, e.g. 2 hours) are thought to be attributable to that mode of action. However, the mood-improvement effects occur on a different time scale (e.g. peak at 24h and last up to 7 days), and may in fact relate to a difference in the gene expression patterns of the NMDA receptors.

    And, Sci? “Kind of like exposing a rat to the equivalent of grad school.”
    Seriously, that’s just unsettlingly accurate as a description of my life. I mean, there was a reason I got all interested in this right before comps…

    Link to this

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