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  1. ramskip

    Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.

    Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.

    The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.

    "It's exciting," says Ron Duman, a a psychiatarist and neurobiologist at Yale University. "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."

    Ketamine is an FDA-approved anesthetic. It's also a popular club drug that can produce out-of-body experiences. Not exactly the resume you'd expect for a depression drug.

    But a few years ago, researchers discovered that ketamine could help people with major depression who hadn't responded to other treatments. What's more, the relief came almost instantly.

    The discovery "represents maybe one of the biggest findings in the field over the last 50 years," Duman says.

    A rat neuron before (top) and after (bottom) ketamine treatment. The increased number of orange nodes are restored connections in the rat's brain.
    Ronald Duman/Yale University
    Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.

    The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to "rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress," Duman says.

    A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.

    It's possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

    A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. "What happens in depression is there's a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring."

    And there's also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.

    His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

    All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.

    Preliminary results suggest that "some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine," Zarate says.

    One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

    There is a bug that won't let me post links, you will have to search for the original source. Sorry, this problem remains unresolved


  1. imyourlittlebare
    This is an interesting find. I knew they were pushing forward with drugs similar to ketamine but a partial agonist at the glycine receptor? Just a few years ago they were investigating a drug that had more selectivity than ketamine in attaching to a subunit of the NMDA receptor called the NR2B subunit. This was animal research though.

    One thing that bothers me about this line of research is that while ketamine has been found to be effective, other NMDA antagonists fail to produce similar effects for depression (e.g. mementine). Maybe that is why this change in pharmacological focus has occurred. But there were a lot of unanswered questions regarding ketamine's action and whether it was specific to the NMDA receptor complex. Ketamine acts on GABA-A receptors, opiate receptors (activity on these, however, does not contribute to the antidepressant effect as a friend's thesis found out), muscarinic receptors, etc. Around the same time ketamine was becoming popular new treatment for depression, similar research findings regarding scopalamine were identified. I wonder if this is going to pan out or whether the research community needs to reread the original research on ketamine's therapeutic effects in animal models. Those researchers clearly stated that these other systems had to be tested for possible contributions to the overall effectiveness of ketamine. Scopalamine, acting similarly to ketamine as a muscarinic antagonist, has rapid antidepressant effects as well in human and non-human animal research.

    Interesting line of research. They have abandoned the neurotrophic hypothesis regarding ketamine's efficacy, reward pathway changes, monoamine hypothesis, and have moved into another domain. I hope they figure it out. But I hope they haven't gone so far they fail to consider research from 5 years ago regarding antimuscarinic activity or that the efficacy may be mediated through altered activity in a brain region known as the anterior cingulate cortex.

    Maura L. Furey, PhD; Wayne C. Drevets, MD Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine A Randomized, Placebo-Controlled Clinical Trial

    Wayne C. Drevets, Maura L. Furey. Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial

    Ronald S. Duman, , Nanxin Li, Rong-Jian Liu, Vanja Duric, George Aghajanian. Signaling pathways underlying the rapid antidepressant actions of ketamine

    Lêda S.B. Garcia et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

    Helen S. Mayberg et al. Deep Brain Stimulation for Treatment-Resistant Depression

    Laura M. Rowland, Ph.D et al. Effects of Ketamine on Anterior Cingulate Glutamate Metabolism in Healthy Humans: A 4-T Proton MRS Study

    Giacomo Salvadore et al. Increased Anterior Cingulate Cortical Activity in Response to Fearful Faces: A Neurophysiological Biomarker that Predicts Rapid Antidepressant Response to Ketamine
  2. enquirewithin
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