Scientists explain how ketamine vanquishes depression within hours

(Medical Xpress)—Many chronically depressed and treatment-resistant patients experience immediate relief from symptoms after taking small amounts of the drug ketamine. For a decade, scientists have been trying to explain the observation first made at Yale University.

Today, current evidence suggests that the pediatric anesthetic helps regenerate between damaged by stress and depression, according to a review of scientific research written by Yale School of Medicine researchers and published in the Oct. 5 issue of the journal Science.

Ketamine works on an entirely different type of neurotransmitter system than current antidepressants, which can take months to improve and do not work at all for one out of every three patients. Understanding how ketamine works in the brain could lead to the development of an entirely new class of antidepressants, offering relief for tens of millions of people suffering from .

"The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in a half century," said Ronald Duman, Elizabeth Mears and House Jameson Professor of Psychiatry and Professor of Neurobiology.

Duman and George K. Aghajanian, also professor of psychiatry at Yale, are co-authors of the review.

Understanding how ketamine works is crucial because of the drug's limitations. The improvement in symptoms, which are evident just hours after ketamine is administered, lasts only a week to 10 days. In large doses, ketamine can cause short-term symptoms of psychosis and is abused as the party drug "Special K."

In their research, Duman and others show that in a series of steps ketamine triggers release of neurotransmitter , which in turn stimulates growth of . Research at Yale has shown that damage of these synaptic connections caused by is rapidly reversed by a single dose of ketamine.

The original link between ketamine and relief of depression was made at the Connecticut Mental Health Center in New Haven by John Krystal, chair of the department of psychiatry at Yale, and Dennis Charney, now dean of Mt. Sinai School of Medicine, who helped launch clinical trials of ketamine while at the National Institute of Mental Health.

Efforts to develop drugs that replicate the effects of ketamine have produced some promising results, but they do not act as quickly as ketamine. Researchers are investigating alternatives they hope can duplicate the efficacy and rapid response of ketamine.

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More information:

Ketamine Timeline: A new model of rapid-acting antidepressant

1980's

Evidence emerges that the neurotransmitter glutamate and N-methyl-D-aspartate (NMDA) glutamate receptors play a key role in higher cortical functions.

1990's

Yale investigators at the VA Connecticut Healthcare System and Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center utilize ketamine as a probe to explore the underlying mechanisms of common psychiatric disorders including schizophrenia and alcoholism. A test of ketamine's effects on patients with major depression is initiated. Almost immediately, the scientists begin hearing evidence of the rapid-acting antidepressant effects of ketamine. These effects appeared within hours and lasted for several days.1, 2

2000

The results of the first placebo-controlled, double-blinded trial to assess the treatment effects of ketamine in patients with depression are published in Biological Psychiatry. The findings, by Yale researchers working at the VA Connecticut Healthcare System and the Connecticut Mental Health Center, outline the rapid antidepressant effects of the compound. The compelling results suggest a potential role for NMDA receptor modulating drugs in the treatment of depression.3

2006

The 2000 Yale findings are replicated by a team at the National Institute of Mental Health.4 The NIMH team includes a Yale Department of Psychiatry alumnus and co-author of the original Biological Psychiatry article.

2010

Yale research suggests an explanation for the rapid antidepressant effects of ketamine. Results published in Science demonstrate that a single dose of ketamine leads to an increased number and function of new synapses in the rodent prefrontal cortex. This restoration of connections between brain cells, a process called "synaptogenesis," is a much quicker process than forming entirely new neurons while accomplishing the same result of enhanced brain connectivity and circuit activity.5

2011

Yale-led study published in Biological Psychiatry demonstrates that the atrophy of dendrites caused by chronic stress in rodents may be reversed by administration of ketamine.6


References

1 Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R. Bremner, J.D., Heninger, G.R., Bowers, M.B. Jr, Charney, D.S. 1994 Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry 51, 199-214. www.ncbi.nlm.nih.gov/pubmed/8122957

2 Krystal, J.H., Petrakis, I.L., Webb, E., Cooney, N.L., Karper, L.P., Namanworth, S., Stetson, P., Trevisan, L.A, Charney, D.S. 1998 Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry 55, 354-360 www.ncbi.nlm.nih.gov/pubmed/9554431

3 Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., Krystal, J.H. 2000 Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47, 351–354. www.ncbi.nlm.nih.gov/pubmed/10686270

4 Zarate, C.A. Jr., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., Manji, H.K. 2006 A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63, 856–864. www.ncbi.nlm.nih.gov/pubmed/16894061

5 Li, N., Lee, B., Liu, R.J., Banasr, M., Dwyer, J.M., Iwata, M., Li, X.Y., Aghajanian, G., Duman, R.S. 2010 mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–64. www.ncbi.nlm.nih.gov/pubmed/20724638

6 Li, N., Liu, R.J., Dwyer, J.M., Banasr, M., Lee, B., Son, H., Li, X.Y., Aghajanian, G., Duman, R.S. 2011 Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69, 754–761. www.ncbi.nlm.nih.gov/pubmed/21292242

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User comments

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dirt
5 / 5 (7) Oct 04, 2012
Yet another potentially helpful substance made illegal because it's possible to be abused.... But alcohol and caffeine and nicotine.... it's impossible to abuse those, right? They don't have any adverse effects at all.
Newbeak
3.7 / 5 (3) Oct 04, 2012
Well,all the legal drugs enjoy wide social acceptance,whereas illegal drugs have the image of being used by down and out ne'er-do-wells..
Having said that,I firmly believe legalizing all drugs is the rational thing to do,and I am not alone in that belief: http://www.leap.cc/
Skepticus
3.7 / 5 (6) Oct 04, 2012
Welcome to another patchup. It is more profitable to treat the symptoms than the root causes of depression.
Neurons_At_Work
5 / 5 (5) Oct 04, 2012
Welcome to another patchup. It is more profitable to treat the symptoms than the root causes of depression.

I don't know if I would totally agree that growing new synapses is *just* treating a symptom; it sounds pretty interesting to me. On the other hand I totally agree with you--I mean they hint at root cause in the article: chronic stress. This is the ultimate culprit in many--I'll go so far as to say 90%--of life-shortening chronic diseases and beyond that creates a quality of life we wouldn't wish on our dog. THAT is what I'd like to see addressed in a serious and systematic way. I don't know what that way should be exactly, but I can tell you from personal experience that it just plain sucks.
Husky
3 / 5 (2) Oct 05, 2012
wrll its more than a patchup, because it makes the ehr "roots" grow , but only in small dose, problem remains its abusive potential. for an acute clinical situation/setting i think it could be used. Than there is another patcup called magnetic stimulation, to keep our neurons active, maybe superconductive materials will allow to make smaller helmet/cap versions of these that you can put on to your daily stressfull work or something....
vlaaing peerd
5 / 5 (3) Oct 05, 2012
What I would like to know is why they're searching for a Ketamine-like substance. Why not just use the real thing? Gives the patient a nice buzz too while they're at it.

@Husky,
Anything can be abused; drugs, a hammer, a pencil, an airplane. Denying access is not the way to prevent abusive behaviour. Teaching how to use or not use responsibly is the way.
Tausch
1.7 / 5 (3) Oct 05, 2012
Great comments.
So the single, ultimate, fail-safe, physical (characteristic) hallmark of depression is a reduction of structure with one of the many consequences a neurochemical imbalance among the pathways involved?

Playing devil's advocate:
Don't all humans start with a reduced(immature)structure at birth?

Are all newborns the most deprived, depleted, depressed, and stressed of all individuals or life forms - as compared to any other stage in life? And sleep to curcumvent this state of mind('depression'?)

What is Ketamine's neuronal morphology? Permanent or reversible?
What is the compliment compound/substance to Ketamine produced by one's own body?

The list of objects that make one happy, depressed, and stressed is long.
Too long. Mostly invented or created.
Lee_Lofgren
4.3 / 5 (3) Oct 05, 2012
If the drug looses it's ability to help depression, it might be because the body is adjusting to it. Has anyone tried administering single doses separated by long periods of time, such as every 10 days or twice a month? If it is functioning by stimulating new growth in the brain, I would think a stepped approach would be better.
Sinister1811
2.2 / 5 (6) Oct 06, 2012
What I would like to know is why they're searching for a Ketamine-like substance. Why not just use the real thing? Gives the patient a nice buzz too while they're at it.


Exactly. The buzz is probably partly responsible for the improvement in symptoms. The problem is that they try to produce synthetic versions of drugs (without the high/trip) and they just DON'T have the intended effect, or they're not quite the same (dramatically weaker). Why not just use the original drug, but place limits on its usage, to prevent abuse? It's amazing how many illegal drugs have a potential place within modern medicine, though.
Rohitasch
5 / 5 (1) Oct 07, 2012
Wow! I go through phases when I have to work really hard to get myself to do anything at all. And regular anti-depressants take a while to work. This seems to be a boon when one's gotta have to do something important when one's going through one of those low phases.
tnvt
5 / 5 (2) Oct 07, 2012
Let's not forget that every medicine has its side-effects. An instant happy pill sounds appealing but I would love to find out if, in the long run, the pros really outweigh the cons. I hope research on this continues.
ziphead
3 / 5 (4) Oct 08, 2012
"Welcome to another patchup... blah blah... Let's not forget that every medicine has its side-effects... "

People on this site sometimes really talk crap;

Doses needed to induce improvement of depression/anxiety with ketamine and other hallucinogens are generally much lower than dose required to induce psychological effect, and they do not need to be all that frequent either (for instance, effect of single dose of psilocybin can last months).

Given the really low dose needed to achieve effect, side-effects are minor concern in comparison to what SSRI/SNRI do to you for slightly better gain than placebo. IMHO, risk/benefit ratio here is much more favourable.

Due to this affliction, there are people out there who wish nothing but to die as we speak. To deny them treatment, "until more research is done" or "until safer alternative is found" (translate: until patentable alternative is found) is just plain criminal.
Tausch
1 / 5 (1) Oct 14, 2012
Well have that part of society with the highest risk and rate of suicide (psychiatrists and psychologists worldwide) self-administer the drug. And let the resulting drop in risk and rate in this group of society as far as suicide is concerned speak as clinical proof that the 'good' outweighs the 'bad'.

There is always the risk that this group will not let go of their conditions to commit suicide:
To preserve 'ethical' medical 'standards' (for lack of courage)
which dictates saving lives is paramount - even if this means saving their own lives

Schizophrenic 'pride'. Yes. Criminal.