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| Ketamine: from the dealer or from the doctor? (image source) |
The possibility that it might have near immediate anti-depressant effects on humans has been around for a little while, but the concept is picking up steam as new research finds mechanisms for how it might actually work in depressed patients. (I briefly mention one new study in an SfN neuroblogging post. )
An emerging theory is that depression is not so much a chemical imbalance as it is a loss of neurons. Thus the cure for depression is not restoring the balance of serotonin or dopamine, but restoring the growth of new neurons. Some suggest that this is how classic anti-depressants (like Zoloft) work, by fixing the neuron atrophy problem. This could also explain why these anti-depressants take so long to work, though I have expressed skepticism about this hypothesis.
So the question is: Does ketamine cause the growth of new neurons, help in their maturation, or prevent neuronal atrophy? Ketamine is an NMDA receptor antagonist, so it inhibits synaptic transmission. It doesn't inhibit all synaptic transmission like deadly poisons do (tetrodotoxin for example), but enough of it to change something in the brain. Knowing something about NMDA receptors, it was still hard for me to conceive of a connection between blocking them and neuronal growth.
A nice review by Duman and Li (2012) spells it out for me, explaining new research that links ketamine with the growth of new synapses.
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| Duman and Li 2012 figure 3 |
The authors cite their previous Li et al., 2010 Science paper explaining that when they block mTOR with the drug rapamycin, the effects of ketamine on new spine growth disappear and its anti-depressant effects disappear. However, this is a study in rats and assessing the depressed state of a rat is as tricky as assessing a rat's post-traumatic stress. So the claim here isn't so much that ketamine causes neurogenesis, but that it could help new neurons become synaptically mature, and thus functionally useful. (Carter et al. is investigating this further)
As shiny and interesting as this is, I am not quite sold on it. I don't see how the NMDA antagonist is going to inhibit the inhibitory neurons more than the excitatory neurons, and I would love to see research showing how ketamine causes glutamate accumulation.
And as far as actually using it as a treatment for depression, there are some serious side-effects. Ketamine is a hallucinagenic street drug which can cause a schizophrenia-like state. Therefore, it seems unlikely that ketamine itself will ever be prescribed as an anti-depressant, but new research could reveal (or synthesize) other molecules that activate mTOR directly or somehow bypass the hallucinogenic aspect of ketamine.
For more, see some skeptical and critical analyses of human ketamine studies.
© TheCellularScale
Duman RS, & Li N (2012). A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367 (1601), 2475-84 PMID: 22826346
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, & Duman RS (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, N.Y.), 329 (5994), 959-64 PMID: 20724638
I get why ketamine might not be any physician's first choice, but I think the *immediacy* aspect is a huge advantage. It doesn't have to be more effective at treating mild depression than Zoloft, it has to be less destructive at treating severe depression than ECT. That's the clinical application that makes sense.
ReplyDeleteGood point, becca, but maybe a comparison between ketamine and DBS would be better. Both promise fast relief from depression, but the safety and long term efficacy is not clear yet for either.
ReplyDeleteare there any people out there who have had success with the .5mg ketamine injections, and who once the effects wore off, just continued gettting more injections. i realize the financial cost is generally outrageous, and this keeps most from being able to do this. but are there any out there with chronic major depression and/or anxiety, ptsd etc, who have regualrly had the injections for a year or more? and if so, has the ketamine (at the same dose, and at the same frequency of injection) maintained its efficacy? perhaps there's someone out there who either can financially afford this, or who has special circumstances allowing for regular injections, who could answer this? my example would be that say if ketamine injection works well for 10 days, but by day 11 it generally starts losing its effectiveness for someone, and so then the person uses this as their schedule of injection (.5mg injection every 10 days); does the drug tend to maintain its efficacy? or do people generally need higher doses or more frequent shots over time? or perhaps the opposite; as synapses form and neurons repair (and whatever else the apparrent NMDA antagonism /glutamate modulation etc does), perhaps people over time began to build sustainable lasting benefits from the ketamine, and can then began spacing out injections/titrating off until it's no longer needed? this would of course be the ideal. does anyone know of cases where the drug atleast maintains its efficacy over a year or longer with regular scheduled injections? i am told by a very reputable psychiatrist that this can very well be the case. and that it's only the cost, inconvenience, and potential discomfort (hallucinatory etc) of the injection administration that keeps this from being performed. he tells me that at this dosage and at no closer than 10 days between shots, there is NO reported lab abnormalities, bladder or kidney problems,,,and that the drug generally keeps its efficacy indefinitely (for those who it works for initially). is there anyone out there who could confirm this, or provide any info of known cases that supports this line of thinking? i already know that of course ketamine doesnt work for everyone, but for those who it does help......any data on above questions? any patients recieving regular longterm injections out there??
ReplyDeleteI don't know. I haven't seen any long-term study on Ketamine and depression. My guess is that if Ketamine is ever to be used in a clinical setting, it will be used as an acute dose for someone who is on the brink of suicide. It seems like regular antidepressants, like ssris, are effective in the long run, but they take weeks to work.
DeleteYour idea of titrating off the drug is interesting, and again I don't know of any studies testing the 'permanency' of these synaptic changes with ketamine. Ketamine may eventually have a place bridging the gap between treatment onset and the anti-depressant effects of traditional medications.
It is important to remember that this study is on rats and that ketamine is a street drug, NOT a prescribed antidepressant. It is a possibility for the future, but not enough is known about it yet.
are there any people out there who have had success with the .5mg ketamine injections, and who once the effects wore off, just continued gettting more injections. i realize the financial cost is generally outrageous, and this keeps most from being able to do this. but are there any out there with chronic major depression and/or anxiety, ptsd etc, who have regualrly had the injections for a year or more? and if so, has the ketamine (at the same dose, and at the same frequency of injection) maintained its efficacy? perhaps there's someone out there who either can financially afford this, or who has special circumstances allowing for regular injections, who could answer this? my example would be that say if ketamine injection works well for 10 days, but by day 11 it generally starts losing its effectiveness for someone, and so then the person uses this as their schedule of injection (.5mg injection every 10 days); does the drug tend to maintain its efficacy? or do people generally need higher doses or more frequent shots over time? or perhaps the opposite; as synapses form and neurons repair (and whatever else the apparrent NMDA antagonism /glutamate modulation etc does), perhaps people over time began to build sustainable lasting benefits from the ketamine, and can then began spacing out injections/titrating off until it's no longer needed? this would of course be the ideal. does anyone know of cases where the drug atleast maintains its efficacy over a year or longer with regular scheduled injections? i am told by a very reputable psychiatrist that this can very well be the case. and that it's only the cost, inconvenience, and potential discomfort (hallucinatory etc) of the injection administration that keeps this from being performed. he tells me that at this dosage and at no closer than 10 days between shots, there is NO reported lab abnormalities, bladder or kidney problems,,,and that the drug generally keeps its efficacy indefinitely (for those who it works for initially). is there anyone out there who could confirm this, or provide any info of known cases that supports this line of thinking? i already know that of course ketamine doesnt work for everyone, but for those who it does help......any data on above questions? any patients recieving regular longterm injections out there??
ReplyDeleteHere I am, USA legally certified experimental ketamine therapy subject! Regular intervals and still at it for over a year, but I don't remember how long ago I started getting dosed. I'm dosed (intramuscular injection, now at 125 mg, where my dose is finally fixed to work) every two-three (sometimes four) weeks now to maintain my progress in mood. Works damn well for my depression, but I have read that too many experiences will leave the ketamine user with a feeling not unlike a mix of booze and opiates and ruin the magic. It's when you get to "too many" doses that ketamine is most addictive. How many is too many is not a set number. But you need to be WELL-FUCKING-INFORMED to even experience this drug at its true potential (without putting tons of powdered K up the nose). JUST SAY "KNOW" TO DRUGS, NOT JUST "NO"!!!!!
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ReplyDeleteExcellent Sharing! Yes, It's true that, Depression is a common but serious illness, and most who experience depression need treatment to get better, But there are a variety of strategies to help you cope with depression. It's vital that you do so and don't try to go through this alone. ......exercise and depression
ReplyDeleteClinical Depression is the most horrible state of a human mind. If I was to describe it I would use the words: PURE EVIL. Being unable to do anything about it makes it even more EVIL. Imagine being stuck in the middle of African dessert with a mind warping, throbbing tooth infection. No dentist, no pain killers, no way of pulling the tooth out. No way of stopping it. Wouldn't you wish you were dead? So, ketamine is good, it is your pain killer that will pull you out and let you come to the part where you are taking vitamins, nutritions, exercising etc.....
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