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  1. Anna Thema
    (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 synaptic connections between brain cells 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 symptoms of depression 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 chronic depression.

    "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 glutamate, which in turn stimulates growth of synapses. Research at Yale has shown that damage of these synaptic connections caused by chronic stress 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.

    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.g… bmed/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.g… bmed/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.g… med/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.g… med/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.g… med/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.g… med/21292242

    http://medicalxpress.com/news/2012-1...ssion.html#jCp

Comments

  1. hookedonhelping
    'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    The most intriguing way of putting it is that a notoriously unpredictable and dangerous club drug may be the solution to depression.

    Perhaps unsurprisingly, this isn't the entire story.

    So why, in a review published late last week in Science, have researchers declared that findings on the effects of ketamine -- what the kids call "Special K" -- on the depressed brain are "the biggest breakthrough in depression research in a half century"?

    Anyone who's experienced major depressive disorder, either personally or through a loved one, would understandably be excited about the news that taking ketamine can lift depression in mere hours, and in patients who are resistant to typical antidepressants. The commonly prescribed serotonin selective reuptake inhibitors (SSRIs) take weeks to kick in, if they end up working at all (they don't, for more than a third of depressed patients). It is during this painfully long waiting period that suicide, for two to twelve percent of patients, can begin to be seen as the quickest way out of the darkest depressions.

    So yes, ketamine's potent and rapid effects seem downright miraculous, even though the relief it provides from depression onlys last seven to ten days. But researchers at the Yale School of Medicine have known this for a decade now. And the drug actually been approved by the FDA for use as an injected anesthetic, albeit one with short-term, but psychologically intense

    What is new -- and legitimately exciting -- about all this is that scientists are beginning to realize that we may have been thinking about the depressed brain in the wrong way. The effects seen with ketamine suggest that the common explanations for depression -- that it's caused by a "chemical imbalance" in the brain, or by low levels of serotonin -- may not be what's really causing the disorder after all.

    Instead, the studies reviewed here support a different theory, one which suggests that depression is the result of damage to the brain cells responsible for controlling mood. In mice, at least, this atrophy of neurons occurred in response to stress. Although the reasons for why stress causes this to happen are unclear, the weakening of synaptic connections appears to be at the root of depression and other stress-related disorders.

    SSRIs are intended to increase brain levels of serotonin, but they do also, eventually, restore neurons. Ketamine is able to repair these synaptic connections in mice with near-miraculous speed. Indirect evidence from brain imaging supports the theory that this "synaptogensis" is the mechanism allowing for ketamine's rapid effects in humans as well.

    For the most extreme and SSRI-resistant cases of depression, an emergency dose of ketamine just might be an actual treatment option. But it's no miracle cure, and it certainly couldn't be prescribed as a long-term solution. The abuse potential for ketamine in its current form is high, and the drug is also associated with damage to the bladder and kidneys.

    Ron Duman, who co-authored the review with George Aghajanian, told NPR" The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression."

    There have been some preliminary results for drugs that work like ketamine without producing hallucinations and other side effects, but they don't work as rapidly.

    But if what these findings suggest turns out to be true, and if further studies, as the authors predict, "define the neuronal and synaptic alterations underlying depression and ... contribute to the development of safer, more efficacious antidepressants that last longer and act faster," the claims about ketamine may turn out to be just as promising as they sound.

    http://www.theatlantic.com/health/a...sion-research-in-50-years-is-ketamine/263400/
  2. kumar420
    Re: 'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    good that they mentioned the potential bladder and kidney damage, which takes a while to reverse (if it isn't too serious: there are K users out there with bladders like thimbles and wrecked kidneys)
    amazing how something previously thought to be a mere anaesthetic turns out to be a breakthrough in the treatment of depression. I can testify as to the hit and miss nature of SSRI's; in my experience they made me feel a hell of a lot worse and made me want to drink pretty much constantly. hopefully they will be able to figure out the specific mechanism of ketamine and tailor it to treat depression without the risk of addiction and physical harm from use.
  3. hookedonhelping
    Re: 'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    I am of the same thought. I can easily see where some of these dissociatives could be used in a patient who is strong enough to avoid addiction. They are addictive, but in my opinion they are not as physically addicting as SSRI's are. Mentally, perhaps, but physically speaking, SSRI's are a bitch.

    When I prescribed Effexor, I gave it a fair shake, loyally taking me dose as prescribed. After a month of prescribed use, I decided it made me feel weird, and not like myself. My depression was situational and situations change over time. Using a drug like Effexor was not the answer. Drugs were not the answer, I needed to understand that life is long and that things would get better if I put in the work.

    To make a long story short, Effexor left me with severe dizziness and vertigo for days after going turkey with it. That constitutes as a physical withdrawal symptom that I was glad to free myself from in a weeks time.
  4. kumar420
    Re: 'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    i agree, i'm coming off fluoxetine myself and haven't taken a dose in about 2.5 weeks now, and i'm still getting those damn brain zaps (as well as mega trouble sleeping+waking up)
    unfortunately i don't think i could use ketamine medicinally effectively, i'm too fond of its intoxicating effects for it to be a medicine as it is. if they found a way to remove the psychoactive effects i'd definitely consider it; however the intranasal/oral dosing methods negatively impact bladder and kidney function, so that wouldn't be the ideal way to take it. and obviously IM/IV injections would be a quick way to get hooked without the willpower to stay off it.
  5. profesor
    Re: 'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    I'd like to do a little self-experimentation with methoxetamine or NEK and my depression, but my previously reliable sources are dried up. I'm not good at making connections. :(
    I could really use occasional short term relief, as well as long term medication treatment, like an asthma inhaler for my brain.
  6. enquirewithin
    Re: 'The Biggest Breakthrough in Depression Research' in 50 Years Is... Ketamine?

    This avenue or research is referred to in David Jay Brown's Psychedelic Drug Research: A Comprehensive Review. For a review:

    http://www.drugs-forum.com/forum/showthread.php?t=196653

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