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Ketamine and depression

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Ketamine and depression

Postby rockyge » Tue Dec 13, 2011 5:44 pm

http://news.sciencemag.org/sciencenow/2 ... happy.html

by Sarah C.P. Williams on 15 June 2011
When psychiatrists write a prescription for a typical antidepressant such as Zoloft or Paxil, they don't expect their patients to show much improvement for a few weeks. Clinical trials, however, have shown that low doses of a drug known as ketamine, which is used at higher doses as an anesthetic and is taken recreationally as a hallucinogen (sometimes called "Special K"), can ease the symptoms of depression within hours. Now, scientists have figured out how ketamine works in the brain. In the process, they've uncovered a new molecular pathway involved in clinical depression.

Neuroscientist Lisa Monteggia and her colleagues at the University of Texas Southwestern Medical Center in Dallas began their work on ketamine by verifying what other scientists have shown: 30 minutes after receiving a dose of ketamine, mice prone to depression show an easing of their symptoms. When put in a tub of water, mice considered depressed quickly give up escape attempts and instead float motionless. After receiving ketamine treatment, such mice swim for a longer period of time in the water.

Monteggia's team then moved toward understanding how the drug affects the brain. Scientists already knew that ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects, so Monteggia's group used other compounds to block NMDARs in mice. As the water test revealed, the animals depression once again lessened, so the researchers knew that ketamine's antidepressant effects also depended on NMDAR. Next, the team studied how levels of certain proteins in the brain changed when mice were given ketamine. Blocking NMDARs with other compounds turns off production of some proteins, but ketamine causes the neurons to make more of a protein called BDNF (brain-derived neurotrophic factor), the researchers report online today in Nature. The findings suggest a new set of molecules that ketamine and NMDAR affects, and that means a new set of molecules involved in depression.

"There was no precedent for this," Monteggia says. "We had no idea why blocking an NMDAR would produce protein." There are two ways of activating NMDARs. Some turn on when the specific neurons fire to accomplish a task—be it learning, memorizing, or thinking. But other NMDARs are activated simply as background noise in the brain. Ketamine, the researchers showed, doesn't block the brain from activating NMDARs when it's using them to send a specific message. But it does block them from creating that background noise. Although scientists have long known about the brain's spontaneous level of background nerve firing, Monteggia's study is the first to suggest a link between such background noise and depression.

"What we're suggesting is that this background activity is important," Monteggia says. She says that the link between spontaneous nerve firing and depression could also explain why electroconvulsive therapy (also known as "electroshock therapy") eases depression--perhaps ECT and ketamine reset the background brain activity. Furthermore, Monteggia's group identified a new molecule that carries out NMDARs' effects on spontaneous brain activity. When the researchers activate this protein, called eEF2, in mice, they see the same fast-acting antidepressant action. A drug that targets eEF2 instead of NMDARs could treat depression, Monteggia says.

Carlos Zarate, a psychiatrist at the National Institute of Mental Health, in Bethesda, Maryland, who led many of the initials studies of ketamine as an antidepressant, says that the study goes far in uncovering a new pathway involved in depression. "It brings about a new series of targets for drugs that has not been pursued at all."

Although ketamine is used for short-term depression treatment in humans, its potential for abuse keeps doctors from prescribing it for the long term. A drug that targets the ketamine pathway in another way could offer antidepressants without the same potential for abuse. The next questions, Zarate says, are whether eEF2 is a safe drug target in humans and what other pathways are involved in depression.

-- Tue Dec 13, 2011 6:45 pm --

http://www.ncbi.nlm.nih.gov/pubmed/21677641

Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM.
Source

Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9111, USA.
Abstract

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

-- Tue Dec 13, 2011 6:46 pm --

http://www.ncbi.nlm.nih.gov/pubmed/20673547

2010 Dec; Epub 2010 Jul 13.
Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr.
Source

National Institute of Mental Health, and Department of Human Health Services, Bethesda, Maryland, USA.
Abstract
OBJECTIVE:

Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD).
METHOD:

Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009.
RESULTS:

Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001).
CONCLUSIONS:

Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health.

-

http://www.ncbi.nlm.nih.gov/pubmed/21466832

2011 Jun 1 Epub 2011 Apr 3.
Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression.
Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, Zarate CA Jr.
Source

Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, CRC Unit 7 Southeast, Room 7-3445, Bethesda, MD 20892, USA.
Abstract
BACKGROUND:

Ketamine rapidly improves depressive symptoms in patients with treatment-resistant major depressive disorder (MDD) who do not respond to multiple standard antidepressants. However, it remains unknown whether ketamine is equally effective in patients with MDD who previously also did not respond to electroconvulsive therapy (ECT).
METHODS:

This study compared 17 patients with treatment-resistant MDD who previously did not respond to ECT and 23 patients with treatment-resistant MDD who had not previously received ECT. All subjects received a single open-label infusion of ketamine (0.5 mg/kg). Patients were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (60 min before the infusion), as well as at 40, 80, 120, and 230 min after infusion.
RESULTS:

Depressive symptoms were significantly improved in the ECT-resistant group at 230 minutes with a moderate effect size (p < .001, d = 0.50, 95% C.I.: 0.21-0.80). At 230 minutes, the non-ECT exposed group showed significant improvement with a large effect size (p < .001, d=1.00, 95% C.I.: 0.71-1.29).
CONCLUSION:

Ketamine appears to improve depressive symptoms in patients with MDD who had previously not responded to ECT. These preliminary results encourage further investigation with a larger sample size to determine effectiveness compared to other treatment-resistant patients with MDD.

-- Tue Dec 13, 2011 6:49 pm --

http://www.ncbi.nlm.nih.gov/pubmed/20636166

2010 Jul
Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care.
Irwin SA, Iglewicz A.
Source

Institute for Palliative Medicine at San Diego Hospice, Palliative Care Psychiatry, San Diego, California 92103, USA. sirwin@sdhospice.org
Abstract

Depression is prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Here, two cases are reported in which a single oral dose of ketamine provided rapid and moderately sustained symptom relief for both depression and anxiety. In addition, no adverse effects were noted. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the effectiveness of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care. Ketamine may be a promising safe, effective, and cost-effective rapid treatment for depression and anxiety in this population.

-- Tue Dec 13, 2011 6:50 pm --

http://www.yalescientific.org/2011/02/uncovering-the-biology-of-depression/

Uncovering the Biology of Depression
By Jonathan Hwang – February 13, 2011

Professor of Psychiatry and Pharmacology Director at Yale University, Ronald Duman studies depression, a serious issue that affects approximately 17% of the U.S. population and is estimated to cost as much as $83.1 billion for our economy.

There is a general consensus in the scientific community that low levels of monoamine neurotransmitters are a major contributor of depression. From that belief, antidepressants are designed to increase levels of neurotransmitters in the brain. They block reuptake or breakdown of different types of neurotransmitters in order to maintain higher levels in the brain.

A diverse range of antidepressants exists. However, current antidepressants are still ineffective and have low response rates: only 1 in 3 respond to the first antidepressant treatment, and 2 in 3 ever respond after repeated treatments. Beyond knowing that antidepressants block or inhibit particular neurotransmitters, most scientists are still not sure which pathways these antidepressants influence and thus the types of mechanisms that contribute to depression. Duman’s work investigates these unknown pathways.

Neurotrophic Theory of Depression

The bulk of Professor Duman’s research has led to the formulation of the neurotrophic theory of depression, which states that neuronal growth factors contribute to the onset of depression. In 1995, Duman published a landmark paper relating increased brain derived neurotrophic factor (BDNF) levels with antidepressant effects, setting the foundation for the neurotrophic hypothesis of depression. Since then, subsequent research has clarified the pathways leading to the expression of BDNF. Professor Duman’s research suggests that BDNF is expressed through the cyclic adenosine monophosphate (cAMP) signal transduction pathway, which is regulated by serotonin. In this pathway, cAMP is first activated, and this leads to activation of cAMP dependent protein kinase, which regulates cAMP response to element-binding protein (CREB). Additionally, Duman found that long-term antidepressants increase levels of CREB mRNA and protein in the hippocampus, further supporting the link between antidepressants and the cAMP pathway. CREB seems to regulate a set of genes in the hippocampus producing antidepressant effects.

The Role of BDNF

BDNF is a vital neurotrophic factor in the brain. Previous studies have shown that exposure to BDNF in the hippocampus can lead to increased strength in some synaptic connections. BDNF’s role in neurogenesis was of particular interest. Duman discovered that upregulation of neurogenesis was the result of several antidepressants, suggesting that antidepressants reverse the atrophy of neurons that occur during depression. Other studies confirming Dr. Duman’s work have found that increasing levels of BDNF in specific areas of the brain, such as the hippocampus, leads to antidepressant effects. The hippocampus has been implicated in mood disorders and its connections to amygdala and the prefrontal cortex are important for the function of cognition and emotion. Additionally, studies by Duman also revealed the converse: loss of BDNF contributes to depression. Stress, a precursor of many mood disorders, also decreases expression of BDNF.

The approaches Professor Duman took to clarify BDNF’s role were varied. One was by using a viral vector to overexpress BDNF, which produced a behavioral phenotype typical of antidepressants. Antidepressant behavior was tested using the forced swim tests and learned helplessness models. Another approach involved infusing recombinant BDNF into the brain region, which also produced a similar antidepressant behavioral response. Duman also tested mice with a heterozygous deletion of the allele for BDNF. Although their phenotype appeared normal, they displayed a depressant-like phenotype once exposed to stress. This follows the widely held belief that a combination of environmental and genetic factors contributes to the onset of depression.

A Faster and More Efficient Pathway

In August 2010, Duman’s lab discovered a completely new pathway, a major breakthrough for the field of depression. In ketamine, Duman addresses a pressing need in the field for “a more rapid, more efficient drug” to treat depression. In his paper published in Science, Duman lays the foundation for further understanding of this novel pathway.

Ten years ago, ketamine was preliminarily tested at the Connecticut Mental Health Center as an antidepressant in low doses. The subjects were patients who previously resisted all other forms of treatment, but over two thirds responded positively to ketamine. These results were confirmed in later studies. Much more remarkable about ketamine’s use as an antidepressant was how quickly the patients responded; antidepressant effects took place within two hours of treatment and lasted more than seven days.

“The story is in the pathway,” Duman explained. Unlike traditional antidepressants, which are generally neurotransmitter inhibitors, ketamine is a N-methyl-D-aspartic acid (NMDA) receptor antagonist. It operates on an entirely different pathway from those of traditional neurotransmitters. Studies conducted by graduate student Nick Li demonstrate that ketamine activates the mammalian target of rapamycin (mTor) pathway. mTor is a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity in a process called synaptogenesis. Synaptogenesis restores the synapse connections in the brain that may deteriorate under stress and depression. The study also found increases in the levels of synapse proteins usually regulated by the mTor pathway. To physically confirm synapse formation, in collaboration with George Aghajanian, Professor of Psychiatry at Yale, two-photon imaging was used to observe increased spine density. Further supporting the link between the mTor pathway and antidepressant effects, Duman blocked the mTor pathway with rapamycin, leading to inhibition of ketamine’s antidepressant effects.

Ketamine is such a “magic drug” because it produces antidepressant effects in people who have resisted most other forms of treatment and its speed of response acts in days rather than weeks. However, the key disadvantages of directly using ketamine as an antidepressant are its use as a street drug and its toxicity from repeated dosages. Despite these shortcomings, knowing the mechanisms of ketamine’s antidepressant effects will further benefit drug designs for immediate antidepressant effects.

Duman’s lab continues to further investigate factors and pathways for depression. One future direction is to deepen understanding of what stress does on a molecular scale and its link to depression. Other directions include studies to reveal more details about the mechanisms underlying Duman’s neurotrophic theory of depression. Professor Duman’s discoveries today could be the basis of depression treatments tomorrow.

-- Tue Dec 13, 2011 6:51 pm --

http://counsellingcentral.com/ketamine-found-to-act-like-a-magic-drug-on-depression/


Ketamine Found To Act Like “A Magic Drug” On Depression

That’s according to the lead researcher of a team from Yale University in the US whose latest study suggests that ketamine, a drug normally used as an anesthetic, could be reformulated as an anti-depressant that takes effect in hours rather than the usual weeks and months of most available medications.

You can read how the researchers discovered this effect in a study they performed on rats which was published online on 20 August in the journal Science. Senior author Dr Ronald Duman, professor of psychiatry and pharmacology at Yale, told the media that just one dose of the drug can work rapidly and lasts for seven to ten days. This is the same ketamine that is used as a recreational drug, called “Special K”, or “K”.

He and his team found that the drug not only improved the rats’ depression-like behaviours, it also restored connections between neurons or brain cells that had been damaged by chronic stress. They called this “synaptogenesis”.

They hope their findings will help to speed up the development of a safe and easy to administer version of ketamine, which has already proved to be effective in severely depressed patients, they said. About ten years ago, scientists at Connecticut Mental Health Center found that in lower doses, ketamine, normally used as a general anesthetic for children, appeared to relieve patients with depression. Since then, other studies have shown that over two thirds of patients who don’t respond to all other types of anti-depressants improved hours after receiving ketamine, said Duman.

The problem with using ketamine more widely to treat depression has been the fact it has to be given intravenously under medical supervision, and it can also cause short-term psychotic symptoms. So Duman and colleagues decided to investigate the effect of ketamine on the brain to see if it might reveal suitable targets for other safer and easier to administer drugs.

They found that ketamine acts on a pathway that controls the formation of new synaptic links between neurons, encouraging synaptogenesis; they wrote that they observed: ” … increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats.”

Moreover, they found that a critical point on the pathway, involving the enzyme mTOR, controls production of proteins needed to form the new synapses. The researchers concluded that: “Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.”

Duman and colleagues told the press that they can already see ways to sustain the rapid effect of ketamine by intervening at other points downstream of this critical one. These could be additional targets for new drugs. This discovery not only brings new hope to the 40 per cent or so of patients with depression who don’t respond to medication, but to many others who only experience relief after months and sometimes years of treatment.

The researchers also noted that ketamine has already shown to be effective as a rapid way to treat people with suicidal thoughts, many such patients usually only respond weeks later with traditional drugs.

Catharine Paddock, PhD, Medical News Today

-- Tue Dec 13, 2011 6:52 pm --

http://blogs.scientificamerican.com/scicurious-brain/2011/07/14/ketamine-and-major-depressive-disorder-is-it-better-with-special-k/

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

By Scicurious | July 14, 2011

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.

-- Tue Dec 13, 2011 6:53 pm --

http://www.ncbi.nlm.nih.gov/pubmed/20679587

2010 Aug
A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr.
Source

Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Abstract
CONTEXT:

Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health.
OBJECTIVE:

To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression.
DESIGN:

A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009.
SETTING:

Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant).
INTERVENTIONS:

Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion.
MAIN OUTCOME MEASURES:

Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores.
RESULTS:

Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point.
CONCLUSION:

In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.
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Re: Ketamine and depression

Postby rockyge » Tue Dec 13, 2011 5:54 pm

http://www.dosenation.com/listing.php?id=8546

Ketamine depression relief linked to brain-derived neurotrophic factor

An article from Nature linking ketamine's fast antidepressant action to BDNF and neural growth hit the media this week. One small dose of ketamine is enough to promote neurogenesis for an entire week. If you do any more than that side effects may include intermittent paranoid psychosis and catatonia.

A new study sheds light on why the anesthetic and "club drug" ketamine can relieve depression rapidly -- in hours, instead of weeks or months.
The new study found that just one dose of ketamine produced [an antidepressant] effect in a half an hour -- compared with the weeks or months this can take with standard antidepressants, in mice as well as in humans. Further, the new study found that the antidepressant effect of a single dose of ketamine lasted for a week.

The researchers, led by Lisa Monteggia, an associate professor of psychiatry at the University of Texas Southwestern Medical Center, also measured brain changes after animals underwent behavioral tests. Monteggia and her colleagues found that ketamine acted by increasing synthesis of BDNF, a nerve growth factor that supports the health of brain cells, helps them grow and can promote the development of new neurons.

Digging further, Monteggia's group found that ketamine increases BDNF by deactivating a chemical called eEF2 kinase (also known as CAMKIII), which normally suppresses BDNF production. Consequently, when eEF2 kinase is inactivated, brain cells produce more BDNF.

Which leads to the question, if a little BDNF is a good thing, is too much BDNF a bad thing?

-- Tue Dec 13, 2011 6:55 pm --

http://thepsychguru.com/2011/12/what-is-mtor-and-why-its-a-hot-topic-in-psychiatry/

Ketamine is an antagonist at NMDA receptors. It works at the same site (inside the channel) where PCP also binds.

Hints about NMDA receptor antagonists causing improvement in depression existed since 1959 (reported by Crane).

In 2000 Berman et al. reported antidepressant effects from NMDA receptor antagonists.

More recently Carlos Zarate, at NIMH, reported in 2010 that “ robust and rapid antidepressant effects resulted from a single intravenous dose of ketamine”.

On August 30, 2010 Ron Duman from Yale identified cellular signaling pathway in rat prefrontal cortex activated by ketamine with a rapid and direct influence on behavior. This group reported that a single dose of ketamine activates the mammalian target of the rapamycin (mTOR) signaling pathway, resulting in increased synaptic protein expression within 2 hours and increased dendritic spine density and synaptic activity within 24 hours.

On the other hand inhibition of mTOR through infusion of rapamycin completely blocked ketamine’s influence on synaptic protein synthesis, synaptogenesis, and dendritic spine formation.

Depression seems to occur when dendritic spine formation is inhibited, while increased dendritic spine formation has been associated with euthymic states. Ketamine leads to increased dendritic spine density within minutes from infusion, by turning ON the mTOR switch to catabolism.



Dendritic spines grow within minutes from ketamine infusion causing improvement in depressive symptoms.

Aberant TOR activity was found not only in depression, but also in diabetes, obesity, heart disease, muscle degeneration and cancer.

Reason enough for excitement among many specialties.

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http://www.ncbi.nlm.nih.gov/pubmed/21397634

2011 Aug 1 Epub 2011 Mar 21.
Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain.
Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, Souza CT, Quevedo J.
Source

Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
Abstract

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.

-- Tue Dec 13, 2011 6:56 pm --

http://www.ncbi.nlm.nih.gov/pubmed/20724638

Science. 2010 Aug 20
mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS.
Source

Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Abstract

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

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http://www.ncbi.nlm.nih.gov/pubmed/21907221

2011 Sep 2.
Signaling pathways underlying the rapid antidepressant actions of ketamine.
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G.
Source

Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA. ronald.duman@yale.edu
Abstract

Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'.

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http://www.ncbi.nlm.nih.gov/pubmed/21996102

2011 Oct 11.
Cell atrophy and loss in depression: reversal by antidepressant treatment.
Banasr M, Dwyer JM, Duman RS.
Source

Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, United States.
Abstract

Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.

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http://www.ncbi.nlm.nih.gov/pubmed/22036038

2011 Oct 28.
Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex.
Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK.
Source

Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.
Abstract
BACKGROUND:

Knock-in mice with the common human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have impaired trafficking of BDNF messenger RNA to dendrites. It was hypothesized, given evidence that local synapse formation is dependent on dendritic translation of BDNF messenger RNA, that loss-of-function Met allele mice would show synaptic deficits both at baseline and in response to ketamine, an N-methyl-D-aspartate antagonist that stimulates synaptogenesis in prefrontal cortex (PFC).
METHODS:

Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were combined with two-photon laser scanning for analysis of wildtype, Val/Met, and Met/Met mice both at baseline and in response to a low dose of ketamine.
RESULTS:

Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical dendrites and decrements in apically targeted excitatory postsynaptic currents in layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased, indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met mice the synaptogenic effect of ketamine was markedly impaired, consistent with the idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In parallel behavioral studies, we found that the antidepressant response to ketamine in the forced swim test was blocked in Met/Met mice.
CONCLUSIONS:

The results demonstrate that expression of the BDNF Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in PFC, suggesting that the therapeutic response to this drug might be attenuated or blocked in depressed patients who carry the loss of function Met allele.

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http://www.ncbi.nlm.nih.gov/pubmed/22114864

2011 Nov 24
mTOR activation is required for the antidepressant effects of mGluR2/3 blockade.
Dwyer JM, Lepack AE, Duman RS.
Source

Yale University School of Medicine, New Haven, CT, USA.
Abstract

Recent studies demonstrate that ketamine, a fast-acting antidepressant, rapidly activates the mammalian target of rapamycin (mTOR) and increases synaptogenesis in the prefrontal cortex. Because of the side-effect and abuse potential of ketamine we are investigating alternative agents that produce similar effects. Here, we demonstrate that a single dose of LY 341495, an mGluR2/3 antagonist, produces ketamine-like biochemical and behavioural actions. LY 341495 administration rapidly (1 h) activates the mTOR pathway (mTOR, p70S6K, 4E-BP1) and subsequently (24 h later) increases levels of synaptic proteins (PSD-95, GluR1 and Synapsin I), similar to the effects of ketamine. Finally, the antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor, rapamycin. The results indicate that the antidepressant actions of LY 341495 are mediated by activation of mTOR and suggest that this and other mGluR2/3 antagonists could produce rapid antidepressant effects in depressed patients.
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Re: Ketamine and depression

Postby rockyge » Thu Dec 22, 2011 5:41 pm

http://www.ncbi.nlm.nih.gov/pubmed/19897179

2010 Jan 15
Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ.
Source

Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York. m.aan.het.rot@rug.nl
Abstract
BACKGROUND:

A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose.
METHODS:

On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score. If patients showed a > or =50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for > or =4 weeks or until relapse.
RESULTS:

Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days-45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months.
CONCLUSIONS:

These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.
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Re: Ketamine and depression

Postby rockyge » Fri Dec 23, 2011 10:29 am

http://www.ncbi.nlm.nih.gov/pubmed/22190250

Ann Pharmacother. 2011 Dec 20.
Intravenous Ketamine for Treatment-Resistant Major Depressive Disorder (January).
Covvey JR, Crawford AN, Lowe DK.
Source

< Richmond, Va.
Abstract
OBJECTIVE:

To evaluate the literature regarding the efficacy and safety of intravenousketamine for treatment-resistant major depressive disorder (MDD).
DATA SOURCES:

A MEDLINE search (1966-September 2011) was performed using the terms treatment-resistant depression and ketamine. The search was restricted to articles published in English and reporting on use of ketamine in humans.
STUDY SELECTION AND DATA EXTRACTION:

All English-language articles identified from the data search were evaluated. Data were eligible for inclusion if they wereprimary literature and evaluated the efficacy of ketamine for depressive symptoms in treatment-resistant MDD. One case report, 3 case series, 3 open-label trials, and 1 randomized crossover trial were included.
DATA SYNTHESIS:

Several medications are available for treatment-resistant MDD; however, they are often limited by a slow onset of therapeutic effect and tolerability. It has been suggested that ketamine, a rapid-acting, N-methyl-D-aspartate glutamatereceptor antagonist, may have antidepressant effects. Case reports, case series, and select trials evaluating ketamine use for depressive symptoms in treatment-resistant MDD have demonstrated a rapid effect for reductions of scores on a number of depression scales; however, its sustainability effect remains unknown. Several studies reported a large or moderate to large effect size for ketamine. Additionally, these studies showed that ketamine use in this patient population is associated with relatively well-tolerated adverse effects.
CONCLUSIONS:

Ketamine for treatment-resistant MDD requires further evaluation before it can be considered a viable treatment option.
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