Jump to content


Photo

Tackling depression with ketamineMerged met: Ketamine als Reset-knop


  • Please log in to reply
15 replies to this topic

#1 mind

mind

    ?

  • Members
  • PipPipPipPipPipPip
  • 6850 posts

Posted 22 January 2007 - 12:39 AM

http://www.newscient...h-ketamine.html

Tackling depression with ketamine
20 January 2007
From New Scientist Print Edition
Maia Szalavitz


"FOR MANY, it was a huge, obvious effect," says psychiatrist John Krystal. "One of the patients said, 'Don't give me those old medications, I want this again'."

Krystal, a professor at Yale University, is talking about the time he gave seven severely depressed patients ketamine, a mind-blowing drug developed as an anaesthetic but better known as a club drug. It was a long shot, but the results were astonishing. Though most of the patients found the ketamine experience itself unpleasant, once it wore off they had a far better feeling: the disabling and suicidal depression they had lived with for years had vanished.

Krystal's pioneering experiment happened in the late 1990s, but now researchers at the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, have repeated the study and the results have got psychiatrists, neuroscientists and drug companies buzzing. An antidepressant that acts in hours rather than weeks would transform the treatment of depression, make a lot of money and change the way we understand the disease.

It's not just depression. Other studies suggest that ketamine might act with similar speed to help addiction, post-traumatic stress disorder (PTSD) and certain chronic pain conditions. Ketamine, researchers increasingly believe, may be a "reset button" for brains stuck in dysfunctional ruts.

Depression affects over 120 million people worldwide, making it the fourth largest contributor to the global burden of disease, according to the World Health Organization. At some point in their lives 13 per cent of Americans experience major depression, and globally 850,000 depressed people kill themselves every year.

Treatments are available, but they are slow to kick in and help only about 80 per cent of patients. Drugs such as Prozac and Lustral take between 10 days and six weeks to work; even electroconvulsive therapy (ECT), the fastest-acting treatment, takes at least a week. For 70 per cent of patients the first thing they try does not help. This means that many spend months trying different drugs before finding one that works for them - if they ever do.

That's why the ketamine results are creating such a stir. "This is a hot topic and people are very interested in it," says Lisa Monteggia, a neuroscientist specialising in depression at the University of Texas Southwestern Medical Center in Dallas. "The implications are huge." "It's very intriguing," agrees Lee Schechter, director of preclinical depression and anxiety research at Wyeth Pharmaceuticals in Princeton, New Jersey. Research on rapid antidepressants is now "an area of focus within the industry," he says.

The possibility that ketamine could lift depression was first mooted in the late 1990s, when Krystal and his colleagues were studying the drug as a way of understanding schizophrenia. Ketamine is classed as a "dissociative" because it produces feelings of disconnection from one's self and reality which are similar to some of the symptoms of schizophrenia; very high doses elicit complete depersonalisation and profoundly altered perception. Some have described this "k-hole" as similar to an out-of-body experience.

In the course of his work, Krystal had come across case reports from the 1950s and 1960s suggesting that depressed tuberculosis patients given a TB drug with pharmacological similarities to ketamine sometimes reported rapid release from their depression. He also found research showing that some existing antidepressants worked in a similar way.

Krystal's group put two and two together and decided to give ketamine a try as an antidepressant. They recruited seven patients with treatment-resistant depression - defined as disease so severe that two or more medications have failed - and gave each of them an infusion of either ketamine or a placebo. A week later the subjects were "crossed over" so those who had received ketamine got the placebo and vice versa.

The results, published in 2000, were dramatic: within three days of receiving the ketamine all seven had improved, some profoundly, and they remained so for at least a week. The placebo had little effect (Biological Psychiatry, vol 47, p 351).

Shortly after that experiment, Krystal's colleague Dennis Charney left Yale for NIMH, taking the depression work with him. Last year he and Carlos Zarate, head of the mood disorders research unit, published the results of a larger follow-up study (Archives of General Psychiatry, vol 63, p 856).

Zarate's results were not quite as dramatic as Krystal's but were impressive nevertheless. His team recruited 17 people who on average had failed to get relief from six different drugs; four had even tried ECT, the treatment of last resort. Of the 17, 12 experienced a strong antidepressant response within hours of receiving ketamine, and for six patients the response lasted a week or more. As Zarate describes it, the subjects reported that their depression "lifted".

Zarate's results make all the difference, Krystal says. "Replication is everything. One exciting finding is a footnote but a replication makes it much more interesting, particularly by a different group. It has opened up discussion about rapid-acting antidepressants."

As both researchers point out, the volunteers didn't feel better because they were on a "high" similar to a cocaine buzz, which some depressed people use to lift their mood. "I would really contrast ketamine's effects on depression to those of cocaine," says Krystal. "The hallmark of drugs of abuse is a transient euphoria followed by persistent dysphoria - the cocaine crash. Ketamine is fundamentally different. There may be brief euphoric effects but when those symptoms go away, instead of being dysphoric or hung-over, what we and Dr Zarate's group saw was remarkable."

Still, ketamine has a long way to go before it can prove itself as an antidepressant. Both Krystal and Zarate restricted their patients to a single infusion, so it remains unclear whether a second dose of ketamine would work; equally unclear is whether ketamine would carry on relieving depression if given regularly, or whether this would even be practical given the side effects and cost.

One intriguing possibility is that a single dose of ketamine might allow regular drugs to succeed where they have previously failed. After the trial, Zarate found that some of the volunteers responded better than expected to conventional antidepressants, suggesting that the ketamine had somehow cleared the way, or sensitised them to drugs they were previously immune to. Zarate's group is planning a second, larger trial, and he says there is "more interest than I could have imagined" in additional work.

Even if ketamine doesn't make it as an antidepressant in its own right, the trials make it clear that depression medications do not have to take weeks or months to start working - an excruciating time lag that can push patients already on the brink of suicide over the edge. The ketamine research suggests that it should be possible to develop other fast-acting antidepressants, as well as hinting that today's theories of depression are not the whole story.

The existence of the therapeutic time lag has long been seen as a critical part of an elegant theory of depression that has been coming together since the late 1990s. Before then, researchers saw depression as a result of a deficit in certain neurotransmitters, principally serotonin. That made sense when it turned out that drugs like Prozac, which raise serotonin levels, were effective antidepressants. However, medications that worked on other neurotransmitters often also worked and, most damagingly to this idea, even though drugs could change levels of their target neurotransmitter within hours, they still took weeks to elevate mood.

Enter the neurotrophic theory. Put simply, the idea is that extreme or prolonged stress can cause depression by damaging nerve cells in certain brain regions, particularly an area important for storing and consolidating memories called the hippocampus. Brain scans and autopsies find shrinkage in this area in depressed people.

There's even research suggesting exactly how stress could cause this damage. Under stress, the brain releases an excess of the excitatory neurotransmitter glutamate. Too much glutamate can damage or kill cells, a process known as excitotoxicity. The hippocampus is especially vulnerable.

So stress leads to nerve damage, which causes depression. Further evidence is that every drug known to help lift depression also seems to induce higher levels of peptides that encourage nerve growth, most notably BDNF, or brain-derived neurotrophic factor. This helps to repair injured cells and promotes the growth of new ones. Nerves take time to grow, though, hence the delay.

Ketamine, of course, isn't likely to be busy restoring or replacing damaged cells, so what is it doing? No one really knows, but there are some plausible ideas. Ketamine is known to work by blocking a glutamate receptor called the NMDA receptor, preventing glutamate from transmitting its message across the synapse. Faulty NMDA receptor function has recently been implicated in depression, and repeated doses of conventional antidepressants have been shown to slowly correct it in animal models. Perhaps ketamine does the job in one fell swoop. "One way of thinking about it is that the ketamine has reset the normal activity that was disturbed," says Monteggia. In other words, briefly blocking NMDA receptors with ketamine somehow reboots the system.

The reboot idea isn't the only possibility. Ketamine activates another glutamate receptor, known as AMPA, and this has been found to have antidepressant effects in animals; what is more, forthcoming research from NIMH appears to show that preventing AMPA activation blocks ketamine's antidepressant effect. Another possibility is that ketamine works by directly increasing levels of BDNF. That wouldn't account for ketamine's rapid action, of course, but it's possible that BDNF may act not just as a growth factor but as a neurotransmitter too. Some animal studies have found that infusing BDNF into the brain reverses depression-like symptoms in three days

Whatever the mechanism, most researchers in the area think it should be possible to produce a drug that selectively blocks the NMDA receptor without inducing ketamine-like hallucinations. In fact, at least one such drug already exists, developed by Merck and as yet unnamed. "In initial studies, we didn't see depersonalisation and psychosis-like side effects," says Husseini Manji of NIMH, which is collaborating with Merck to determine whether the compound works as an antidepressant.

Krystal isn't sure such drugs will do the trick. It is possible, he says, that ketamine's bizarre effects are an integral part of the process and not side effects that should be eliminated.

Other approaches to rapidly reversing depression are also attracting attention. Researchers at NIMH recently published a pilot study showing that scopolamine, which is normally used to treat motion sickness, appears to lift depression in three days (Archives of General Psychiatry, vol 63, p 1121).

Ketamine research - particularly the idea that manipulating NMDA receptors might reboot aberrant brain activity - also holds promise for chronic pain, addiction and post-traumatic stress disorder. While these are diverse conditions, researchers believe they may all be connected with abnormalities of the NMDA receptor, which is involved with learning and memory, or "neuroplasticity". In each case the brain may have learned a harmful pattern of responses "too well" and now cannot break free from it.

"The idea is that the [glutamate system] is very important to many forms of neuroplasticity. Many people are very interested in the idea of manipulating it so that acute stress doesn't produce chronic problems," says Krystal.

Take addiction, for example. Researchers know that one NMDA blocker, the herbal hallucinogen ibogaine, can help heroin addicts break their habit. Ketamine is a more potent NMDA blocker and seems to have similar effects in rat and human studies. Meanwhile, a group led by Evgeny Krupitsky at the Pavlov State Medical University of Saint Petersburg in Russia is studying ketamine as a treatment for alcoholism. Another illness in which memories seem to trap the brain in a dysfunctional rut is post-traumatic stress disorder. Ketamine may help, though nobody has tried it yet.

The drug may also be useful for treating some forms of chronic pain. Over the past few years neurologist Robert Schwartzman of Drexel University College of Medicine in Philadelphia and colleagues at the University of Tübingen in Germany have used ketamine to treat 41 patients with reflex sympathetic dystrophy (RSD). This is a rare, disabling pain disorder in which ordinary sensations such as touch, warmth and coolness are perceived as painful and minor knocks are agonising. RSD is associated with nerve injuries, after accidents or surgery, for example.

Schwartzman's methods are not for the faint-hearted. He gives RSD sufferers doses of ketamine high enough to put them in a coma for five days, accompanied by anti-anxiety medications to reduce the nightmare of the k-hole. But for many, the results are worth it. In 14 cases out of 41, according to Schwartzman, patients were completely cured. "We haven't cured the original injury," he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone."

"No one ever cured it before," he adds. "In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."

Results with six of these people have been presented at a meeting, and other peer-reviewed research by Schwartzman has shown that ketamine can help RSD pain, but the ketamine coma approach has yet to be subjected to a proper trial. The German group continues to offer the procedure and US researchers, including Schwartzman, are also collaborating with a research group in Mexico.

Realistically, with these complex and chronic conditions, it is unlikely that a one-time treatment will be a complete cure: with addiction, depression and RSD, it is already clear that many people either do not respond or relapse at some point after ketamine therapy. But understanding how the NMDA and glutamate systems drive memory and create responses that are resistant to change could offer insights well beyond these conditions in which the brain has got stuck in a rut and needs a reboot. Ketamine's mind-altering properties may be far more useful than any clubber ever imagined.


Maia Szalavitz is a writer based in New York City
From issue 2587 of New Scientist magazine, 20 January 2007, page 38-41
Letterlijk, spreekwoordelijk, dubbelzinnig.

>> Regels DHP << (klikbaar)
  • Geen links naar online RC-vendors/smartshops etc
  • Vragen om sources of online dealen is niet toegestaan, in het laatste geval wordt de overtreder ook meteen permanent verbannen.

#2 Lip

Lip

    Participation Mystique

  • Donateurs
  • PipPipPipPipPipPip
  • 1493 posts

Posted 22 January 2007 - 07:28 AM

^thnx nice stukje

#3 Dreadmanneke

Dreadmanneke

    bolle retoriek

  • Members
  • PipPipPipPipPipPip
  • 7617 posts

Posted 22 January 2007 - 08:56 AM

Thanks voor het stukje, zeer interessant!
Interweaving symbolic streams with the embroideries of life

#4 Lerez

Lerez

    Morosoof

  • Donateurs
  • PipPipPipPipPipPip
  • 5699 posts

Posted 22 January 2007 - 11:14 AM

Erg intressant artikel. Binnenkort mijn eigen brein maar weer eens resetten. :kneus:
"It is no measure of health to be well adjusted to a profoundly sick society." - Jiddu Krishnamurti -

"It's better to destroy peoples beliefs, than to give them beliefs." - Alan Watts -


Als Dreadmanneke een plant zou zijn; zou hij een vetplant zijn.

Niks overleeft het leven.

#5 ksi

ksi

    Totally Engaged

  • Members
  • PipPipPipPip
  • 680 posts

Posted 23 January 2007 - 12:55 AM

meer;
http://www.medpageto...ression/tb/3877
en
http://archpsyc.ama-...stract/63/8/856

#6 Bosgeest

Bosgeest

    held op sokken

  • Members
  • PipPipPipPipPipPip
  • 1519 posts

Posted 23 January 2007 - 11:07 PM

interessant... spectaculaire effecten. Nu nog grotere gerandomiseerde dubbelblind placebo gecontroleerde studies en dan kan je ook echt zeggen dat het werkt. In ieder geval weer een stukje van de puzzel van hoe depressie werkt en hoe je het aan kan pakken.

Ik vraag me trouwens af hoe ze de placebo groep hebben aangepakt. Ik bedoel, je zal patienten toch wel moeten informeren over dat ze gaan trippen, en als ze t niet doen, blijkt toch al vrij snel dat ze de placebo te pakken hebben, wat het placebo effect teniet doet.

Maar goed dat daargelaten... het lijkt me sowieso onmogelijk dat een placebo zo'n effect teweeg brengt.

Een ander iets wat al genoemd werd, het is eenmalig geprobeerd. Misschien nuttig om het ook bij meerdere malen te onderzoeken.

Sowieso veelbelovend allemaal, zeker voor die groep die op het punt staat zelfmoord te plegen zeg maar

#7 mike

mike

    Special (K) member

  • Members
  • PipPipPip
  • 434 posts

Posted 10 February 2007 - 11:06 PM

Hmmm. Iemand ooit nog iets gehoord van dat experiment in Rusland om (alcohol-?)verslaafden te laten afkicken met ketamine?
Drugs lead nowhere ... but it's the scenic route

#8 Bunzerr

Bunzerr

    kweenie

  • Admin
  • PipPipPipPipPipPip
  • 1851 posts

Posted 04 March 2007 - 01:51 PM

Daar plopt Mikieh even naar binnen :huh: Alles kits jongen? Nog steeds woonachtig in England?

Volgens mij heb ik wel eens iets gelezen over heroine verslaafden te laten afkicken met ketamine, alleen ik weet niet meer waar ik dat gelezen heb. Verder kan ik je niet helpen.
"Paradise is not a place..it's a state of mind"

Webshop blinkit >> kleding goodies woah

#9 iluminado

iluminado

    Participation Mystique

  • Members
  • PipPipPipPipPipPip
  • 1476 posts

Posted 02 July 2007 - 12:54 PM

Heeft er iemand zelf iets gemerkt van 'resetfunctie' van Ketamine? Ik heb er zelf weinig van moet ik zeggen, als het gaat om verandering van stemming. Eerder sufheid erbij dan een zonnetje dat harder straalt.

Is er iemand die uit eigen ervaring sprekend kan zeggen dat Ketamine een positieve bijdrage geleverd heeft aan zijn/ haar levensgeluk? Artikelen blijven ook maar artikelen anders.
Feest voor de baisseurs des fourmis, of de gouden medaille Chinenglish op de para-lympic?

2) The quality are topnotched .We 100% belive that you will satisfy with our quality.
4) We could dropship shoes to your customers which would save your domestic freight charge!
5) We will offer the lowest price you could ever have
宋体All order and payment from new clients with {imitatiewebsite} March 1st,2005 should be verified with Ms.zheng {e-mail} to avoid fraud from cheat not work for our company.


#10 mind

mind

    ?

  • Members
  • PipPipPipPipPipPip
  • 6850 posts

Posted 02 July 2007 - 02:46 PM

iemand op BL beweerde dat ie elke dag een beetje keta deed en dat hem dat goed deed... (hij gebruikte het dus als anti-depressiva).

Edited by mind, 02 July 2007 - 02:47 PM.

Letterlijk, spreekwoordelijk, dubbelzinnig.

>> Regels DHP << (klikbaar)
  • Geen links naar online RC-vendors/smartshops etc
  • Vragen om sources of online dealen is niet toegestaan, in het laatste geval wordt de overtreder ook meteen permanent verbannen.

#11 wolvenkind

wolvenkind

    BBB

  • Donateurs
  • PipPipPipPipPipPip
  • 5413 posts

Posted 02 July 2007 - 03:16 PM

twee keer heb ik gehad na een depressieve periode dat ik ket gebruikte low dose en me lange tijd goed voelde erna
'Den uitvreter, dien je in je bed vond liggen met zijn vuile schoenen, als je 's avonds laat thuis kwam. Den uitvreter, die je sigaren oprookte, en van je tabak stopte en je steenkolen verstookte en je kasten nakeek en geld van je leende en je schoenen opdroeg en een jas van je aantrok als-i in den regen naar huis moest. Den uitvreter, die altijd wat liet halen op den naam van een ander; die als een vorst jenever zat te drinken op 't terras 'Hollandais' voor de centen van de lui; die parapluies leende en nooit terugbracht; die een barst stookte in de tweedehandsch kachel van Bavink; die dubbele boorden droeg van zijn broer en de boeken uitleende van Appi, en buitenlansche reizen maakte als-i z'n ouwe heer weer had afgezet, en pakken droeg, die hij nooit betaalde.'

Mr.Toasted- wouldnt it be cool if one day you found out you were actually someone elses imagination.

#12 iluminado

iluminado

    Participation Mystique

  • Members
  • PipPipPipPipPipPip
  • 1476 posts

Posted 02 July 2007 - 03:44 PM

^Interessant, low dose heeft dergelijke effecten dus voor jou en die BL-er.
Dat is overigens wel hetgeen voor mij nog wel aardig is aan keta, die hoge afglijden-naar-gene-zijde effecten vind ik maar artificial en niet mindaltering.
Feest voor de baisseurs des fourmis, of de gouden medaille Chinenglish op de para-lympic?

2) The quality are topnotched .We 100% belive that you will satisfy with our quality.
4) We could dropship shoes to your customers which would save your domestic freight charge!
5) We will offer the lowest price you could ever have
宋体All order and payment from new clients with {imitatiewebsite} March 1st,2005 should be verified with Ms.zheng {e-mail} to avoid fraud from cheat not work for our company.


#13 Phlogiston

Phlogiston

    poelitie

  • Admin
  • PipPipPipPipPipPip
  • 6395 posts

Posted 25 July 2009 - 02:39 PM

[Poelster: Onder het motto; ken je eigen forum, even mijn post gemerged met dit bestaande topic, want volgens mij sluit het precies op elkaar aan]

Dat ketamine als een antidepressivum kan werken is al een tijde bekend en er zijn zelfs de nodige wetenschappelijke papers over verschenen.
Maar naar mijn mening kan/ doet ketamine meer dan alleen als een antidepressivum werken, ik heb nu al een aantal keer gemerkt, dat wanneer ik veel aan mijn hoofd heb. Dit kan verschillen tot veel afspraken of dingen onthouden tot veel nieuwe impressies en ervaringen en noem maar op, met andere woorden, het overzicht dus een beetje kwijt ben. En dan ketamine neem en hier ook tijdens de ervaring mee bezig ga, dat ik veel dingen op een rijtje kan zetten en de belangrijkere van de onbelangrijkere dingen weet te scheiden. Het het overzicht weer terug krijg. (Ik praat hier dan wel over dosissen om en nabij een K-hole)

Dus vandaar de vergelijking met een reset knop.

Bij andere psychedelica kan ik ook wel dingen helderder krijgen, maar met ketamine weet ik alles kristal helder te maken terwijl het bij de andere psychedelica meer aanwijzingen zijn over hoe ik dingen duidelijker kan maken. (ofzo)

Ik denk ook dat door deze eigenschap ketamine als een antidepressivum werkt, maar dit is dan ook niet echt meer de goede term, want in mijn ervaringen vlakt een antidepressivum emoties af, of deze nou negatief of positief zijn en dat is bij ketamine niet het geval.

Maar misschien is de reden dat alles eens zo helder wordt, gewoon dat tijdens de ketamine ervaring alles zo chaotisch is en alles erna geordend en helder lijkt.

Het blijft natuurlijk allemaal vaag gebrabbel, want ik weet niet precies hoe ik het onder woorden moet brengen, maar ik hoop dat het wel een beetje duidelijk is wat ik bedoel.
Ik vind het namelijk in ieder geval een discussie waardig.

Drugs against War



... R.I.P. Toasted ...


#14 Lµserg Diethel

Lµserg Diethel

    zonder (roet)filter

  • Members
  • PipPipPip
  • 424 posts

Posted 18 July 2010 - 07:07 AM

De vraag is; Wat voor dosis en welke route van administratie?

#15 Cad0

Cad0

    (ex-) koffie junk

  • Members
  • PipPipPipPip
  • 723 posts

Posted 11 September 2010 - 03:50 PM

De vraag is; Wat voor dosis en welke route van administratie?

Op de oude DHP Infobase staan een aantal artikelen en een topic die hierover gaan. De full articles had ik attached, IIRC. Waar ze nu zijn weet ik niet precies.

De studies van Zarate en co-workers uit 2006 en eentje van een Zwitserse groep uit 2007 luidden de glutamate/ketamine-BDNF-antidepressant hypothesis in. Zie alhier de belangrijkste refs:

Arch. Gen. Psychiatry. 2006, 63, 856-864.

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK.

CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.

OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.

DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.

SETTING: Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).

INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

http://archpsyc.ama-...t/full/63/8/856

Swiss Med. Wkly. 2007, 137, 234-236.

Intravenous ketamine therapy in a patient with a treatment-resistant major depression.

Liebrenz M, Borgeat A, Leisinger R, Stohler R.

BACKGROUND: Recently, reports from North America have indicated that the intravenous infusion of ketamine hydrochloride (an N-methyl-d-aspartate receptor antagonist) results in a sudden and robust improvement of depression symptoms.

OBJECTIVE: To corroborate antidepressant effectiveness of IV ketamine in a patient with a co-occurring substance use disorder for the first time in a European clinical setting.

DESIGN: Open label trial Methods: A 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence received an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes. Effects were assessed by means of a clinical interview, the 21-item Hamilton Depression Rating scale (HDRS), and the 21-item Beck Depression Inventory (BDI) at baseline, 1 hour, 1 day, 2 days, and 7 days after intervention.

RESULTS: Following the administration of ketamine the subject experienced a significant improvement of his symptoms peaking on the 2nd day post infusion (HDRS from 36 to 16; -56.6%, BDI from 26 to 9; -65.4%). The subject first reported improvements 25 min. into the infusion and continued to describe positive effects throughout the subsequent 7 days.

CONCLUSION: Ketamine not only seems to have strong antidepressant effects but also to act very swiftly. These actions were unaffected by an alcohol or benzodiazpine dependence.

http://www.smw.ch/do...5/smw-11852.pdf

Biol. Psychiatry 2009, 65, 181-184.

Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA Jr.

BACKGROUND: A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect.

METHODS: Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores.

RESULTS: Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence.

CONCLUSIONS: A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

http://dx.doi.org/10...ych.2008.09.029

Arch. Gen. Psychiatry 2010, 67, 793-802.

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.

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.

http://dx.doi.org/10...chiatry.2010.90

Tot slot een must-have voor de geïntresseerden:

Pharmacol. Ther. 2009, 123, 143-150.

Ketamine and the next generation of antidepressants with a rapid onset of action.

Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA Jr.

Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.

http://dx.doi.org/10...era.2009.02.010

-- Stay safe!
Cad0

Edited by Cad0, 11 September 2010 - 03:53 PM.


#16 Cad0

Cad0

    (ex-) koffie junk

  • Members
  • PipPipPipPip
  • 723 posts

Posted 11 September 2010 - 04:33 PM

ACK! :hartje: De belangrijkste en meest recente publicatie nog vergeten te adden:

Science 2010, 329, 959-964.

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.

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.

http://dx.doi.org/10...science.1190287

Op dit Science artikel kwam ook een response, een kleine review van Cryan en O'Leary in hetzelfde issue (http://dx.doi.org/10...science.1194313) en ook een editorial van Stern in Sci. Signal. 2010, 3, (136), ec259 (http://dx.doi.org/10...ignal.3136ec259).

Note: Aghajanian is coauthor van dit werk, dit is dé Aghajanian die (samen met Marek) in 1999 een zeer belangrijk artikel schreef met de titel: "Serotonin and hallucinogens", Neuropsychopharmacology 1999, 21, 16S-23S. Dit artikel is letterlijk honderde keren geciteerd in alle publicaties over hallucinogenen en de 5-HT2 receptors.




0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users