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Ketamine lifts mood quickly in bipolar disorder

By Spucky, Aug 4, 2010 | | |
  1. Spucky
    Ketamine lifts mood quickly in bipolar disorder

    (Reuters Health) - An infusion of the anesthetic ketamine can lift mood within minutes in patients suffering from severe bipolar depression, according to a small study out this month in the Archives of General Psychiatry.

    The 18 patients in the study had tried an average of seven different drugs for treating their bipolar illness, and were still severely depressed; 55 percent had failed electroconvulsive therapy (ECT), or shock treatment. But within 40 minutes of receiving a ketamine injection, their depressive symptoms improved; the effect persisted for at least three days.

    Right now, medications available for treating either major depression or bipolar illness can take weeks, or even months, to work, notes Dr. Carlos A. Zarate Jr. of the National Institutes of Health in Bethesda, Maryland, one of the researchers on the study.

    And as a person waits for their medications to kick in, he added, they will continue to have difficulty working and coping with social and family life; they may even be having thoughts of suicide. "We want to alleviate the suffering and get them back to their life," he said.

    Zarate and his colleagues had previously demonstrated that ketamine shots helped some patients with treatment-resistant unipolar depression, meaning they did not cycle through manic episodes. In the new study, they gave patients with bipolar illness ketamine or a placebo on two test days two weeks apart.

    All of the patients were on lithium or valproate - two drugs commonly used for bipolar illness - but had not responded to treatment. Nearly all were unemployed, Zarate and his team note, and two-thirds were on psychiatric disability.
    Compared to placebo, patients showed significant improvement in mood within 40 minutes of receiving the ketamine infusion, using a common depression rating scale. Symptom improvement peaked two days after the injection, but remained significantly greater than for placebo for three days.
    Seventy-one percent of the patients responded to ketamine, meaning they had at least a 50 percent improvement in their depressive symptoms. Six percent responded to placebo.

    Side effects included anxiety, "feeling woozy or loopy," headache, and dissociative symptoms, meaning a temporary sense of disconnection from reality, although there were no serious adverse events. By developing more specifically targeted drugs, Zarate noted, it may be possible to treat patients effectively while avoiding these symptoms.
    Ketamine appears to work by "resetting" the way nerve cells process glutamate, a brain chemical key for learning, memory, and other functions, according to Zarate. The problem in bipolar illness and depression, he explains, doesn't appear to be that a person has too much or too little glutamate; instead, it's likely that the way their neurons release and take up the chemical is out of whack.

    First introduced in 1962, ketamine is used legally in both human and veterinary medicine as an anesthetic. It's also a drug of abuse, at much higher doses than those used in Zarate's research; while patients in the current study received about 50 milligrams during a 40-minute period, a dose too low to induce anesthesia, recreational users of ketamine, known as "Special K," may take hundreds of milligrams per week.
    In 1999, US regulators classified ketamine as a Schedule III controlled substance, meaning it has the potential for abuse but is also useful medically.

    Ketamine could improve treatment of bipolar illness and depression in a variety of ways, Zarate said; for example, as a means to jump-start standard drug treatment, or as an anesthetic before ECT. "It's opened the floodgate of many different directions of research, and all of them are quite encouraging," said Zarate, who along with a co-author has filed for a patent on the use of ketamine in depression. Those rights would be assigned to his employer, the National Institutes of Health.
    Efforts are already underway in Europe to develop guidelines for how ketamine should be used and prescribed to treat bipolar illness and depression, the researcher said.

    In the US, research is continuing on the drug, he added, and some physicians are likely trying the drug in their patients with bipolar illness or depression who aren't helped by standard treatments. But, according to Zarate, more research is needed on how to use the drug in the safest and most effective way.

    SOURCE: link.reuters.com/wek23n Archives of General Psychiatry, August 2010.


  1. Spucky
    AW: Ketamine lifts mood quickly in bipolar disorder

    Ketamine Cuts Depression in Bipolar Illness

    The anesthetic ketamine (sometimes illicitly used as a recreational drug) produced rapid alleviation of severe depression in patients with treatment-resistant bipolar illness in a small clinic trial.

    In an 18-patient randomized trial, a single infusion of intravenous ketamine knocked 10 points off Montgomery-Asberg Depression Rating Scale (MADRS) scores in 40 minutes compared with a placebo treatment, reported Carlos Zarate Jr., MD, of the National Institute of Mental Health in Bethesda, Md., and colleagues.

    The difference between ketamine and placebo groups in mean MADRS scores grew to more than 13 points on the second day after the ketamine infusion, the researchers wrote in the August issue of Archives of General Psychiatry.

    "To our knowledge, this is the first article detailing the rapid antidepressant effects of a single infusion of an NMDA [N-methyl-D-aspartate] antagonist in patients with treatment-resistant bipolar depression," Zarate and colleagues wrote.
    Zarate had led an earlier randomized trial of ketamine in patients with severe unipolar depression that also found rapid and pronounced benefits.
    Numerous other researchers have reported similar findings in case reports and in small, uncontrolled series.

    Conventional antidepressants all require several weeks of treatment before effects are apparent. Adherence can suffer in the meantime, as patients lose interest in taking a drug that doesn't seem to be working.

    Nevertheless, even though ketamine is an approved prescription drug, it does not appear to have caught on clinically -- perhaps because its label includes a boxed warning for "vivid imagery, hallucinations, or emergence delirium" when used as an anesthetic. This effect has led to the illicit use of ketamine as a "rave" party drug, dubbed "Special K."

    Quasi-psychedelic reactions were not uncommon in the new study. Zarate and colleagues indicated that at least 10% of participants reported "feeling woozy or loopy" or having "odd sensations," as well as more mundane effects such as drowsiness, cognitive impairment, nausea, blurred vision, and headache.

    On the other hand, given the severe and disabling depression seen in study participants, such effects -- which Zarate and colleagues described as nonserious -- may be a small price to pay.

    The researchers noted that their patients had failed to respond to a mean of seven previous antidepressant drugs, and 55% had not responded to electroconvulsive therapy.

    "The toll of this protracted and refractory illness on the subjects was evident, in that two-thirds of participants were on psychiatric disability and nearly all were unemployed," Zarate and colleagues noted.
    Patients in the study remained on bipolar illness medications including lithium or valproate. They were hospitalized for an average of nine weeks prior to starting the randomized treatment, during which their responses to these mood stabilizers were assessed and stability of depression symptoms could be monitored in a relatively controlled setting.

    MADRS scores averaged about 31 in the treatment group and 33 in the control group at the start of the randomized treatment phase.
    Just 40 minutes after a ketamine infusion of 0.5 mg/kg -- the standard anesthetic dose is 1 to 4.5 mg/kg -- mean MADRS scores in the active treatment group dropped to 18, whereas scores in the placebo group declined to 28.

    Scores in the ketamine group remained stable through the second day after infusion, then returned to near baseline levels (not significantly different from the placebo group) by day seven.
    Very similar patterns were seen in scores on the standard Hamilton and Beck depression evaluations.

    Zarate and colleagues noted that the onset of significant relief was even faster in this sample than in the earlier trial with unipolar depressed patients -- in which relief took 110 minutes. They suggested that this discrepancy may reflect concomitant treatment with lithium or valproate, and the more severe depression in the current study's sample.
    The researchers cited several limitations to their study. One of the most important may be the hallucinogenic side effects of ketamine, which might have clued patients to whether they had received the active drug as opposed to placebo.

    Zarate and colleagues noted that a significant number of placebo patients experienced similar adverse effects, and there was no apparent relationship between adverse effects and treatment efficacy in the ketamine group. Nevertheless, the researchers conceded that blinding could have been compromised, "potentially confounding the results."
    "Future studies using ketamine will have to address the limitation of blinding and may include an active comparator with central nervous system effects," they suggested.

    Zarate and colleagues also noted that the trial was small and that their patients were very severely depressed -- with a mean duration of illness of nearly 30 years -- which is not representative of most patients with bipolar depression.

    In addition, they emphasized that it is still unknown whether the improvements in symptoms of severe depression seen with ketamine can be maintained -- or if so, how.

    Zarate is currently leading what would be the first large trial of ketamine for treating depression. The 164-patient study in unipolar depression, which began recruitment in 2004, is expected to be completed in 2014, according to its listing on Clinicaltrials.gov.

    source: http://www.medpagetoday.com/Psychiatry/Depression/21499
  2. abuseforapie
    This is fantastic! I really hope Ketamine can surface to the mainstream, it has major potential. Both for spiritual enlightenment and medicinal benifits. Thanks for the find ;D
  3. Spucky
    AW: Re: Ketamine lifts mood quickly in bipolar disorder

    They work already a few Years with Ketamin in Israel for Post-Traumatic Stress Disorders, if you use the search engine you can find more Info.,
    the Dosage is always very, very low, but it works well!

    I am sure that sometimes a Doc prescribe something like Keta.
    for PTSD. off-label even in the "Western World"!
  4. Terrapinzflyer
    Anesthetic Said to Aid Depression

    A new study suggests that a 50-year-old drug commonly used as an anesthetic for humans and animals — and abused, as the drug called Special K — may deliver almost instant relief in some of the most troublesome cases of bipolar depression.

    It has been known for several years that small doses of the drug, ketamine, can relieve major depression. But this study, done by researchers at the National Institute of Mental Health, is the first to demonstrate efficacy in patients with treatment-resistant bipolar depression.

    Indeed, the researchers said, the effect on this group appeared to be even stronger. Although the study was small, with just 18 patients, it was conducted under the highest standards for a drug study: it was randomized, placebo-controlled and double-blinded.

    In bipolar disorder, sometimes called manic-depressive illness, patients cycle between periods of elation and severe depression, and the depressive phase carries a high risk of suicide. It is commonly treated with mood stabilizers, including lithium, anticonvulsants and some antipsychotics, often in complex combinations.

    Both mania and depression usually improve on these drugs. But when the depression remains, it is notoriously difficult to treat, so a fast-acting medicine with lasting effects would have obvious advantages. Ketamine probably acts by limiting the action of one type of brain receptor that moves nerve signals between neurons.

    The treatment is still experimental, said Dr. Carlos A. Zarate Jr., the senior author of the study, published in the August issue of The Archives of General Psychiatry.

    Because ketamine is already approved as an anesthetic, physicians could use it off label for other purposes. But Dr. Zarate, a clinical investigator with the Centers for Disease Control and Prevention, warns against it.

    “I’m not encouraging it for clinical use at this time,” he said. “We need more knowledge about safety, and long-term data on efficacy and how it interacts with other antidepressants.”

    The 18 patients in the study had taken lithium or the anticonvulsant valproate for at least six weeks without getting better. They were randomly assigned to receive an intravenous infusion of either ketamine or a placebo saline solution two weeks apart, with each receiving the drug on one occasion and the saline solution on the other. Neither the patients nor the experimenters were told which solution was being delivered.

    Tests showed that the ketamine patients had significantly fewer depressive symptoms than those who received the placebo — beginning 40 minutes after the infusion and lasting three days. After that, the effect of the ketamine began to fade, and within two weeks those who had received the medicine had about the same symptoms of depression as those who had taken the placebo.

    There were no serious side effects, although about 10 percent of both those receiving ketamine and those taking the placebo got a headache or nausea, or reported feeling woozy or lethargic after the infusions. The adverse effects associated only with ketamine included feeling strange, having a dry mouth, increased blood pressure or faster heartbeat. After about 80 minutes, there were no differences in side effects between the ketamine and placebo groups.

    The scientists view these findings as highly significant, because the patients had failed an average of seven antidepressant trials, and more than half had failed to respond to electroconvulsive therapy. But they also emphasized the study’s limitations. The number of patients was small, all were late in the course of their illness, and all were also taking valproate or lithium, which may have affected the results. Finally, there was a small but insignificant placebo effect.

    Dr. Dost Ongur, an assistant professor of psychiatry at Harvard, doubted that the experiment could be truly double-blinded — the vivid effects of injected ketamine can be easy to perceive, both by the patient and by the person giving the injection.

    Still, he was impressed. “This is a solid piece of work that really has the potential for being a true advance,” he said. “There is real hope, there is real excitement around this, even though there is skepticism from some quarters.”

    Published: August 9, 2010


    Original paper added to the Archives
  5. Rachelle Unwell
    I am suffering from major bi-polar depression and PTSD and am desperate to have this done. It's a last resort, I am unable to tolerate any anti-psychotics, SSRI's do not work for me, over the last 12 years there has been no relief. I am unable to work and am suicidal most days. I live in Ontario, Canada and my psychiatrist is trying to find me somewhere to get ketamine infusions or a nasal spray with no luck at all. If anyone knows of any doctors or clinical trials accepting people, I would be ever so grateful
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