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August 9, 2006

BehindTheMedspeak: Ketamine for depression?

Depression1_1

Two days ago Dr. Carlos A. Zarate and his research group published a paper entitled "A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression."

Sounds impenetrable, eh?

That's why you pay me the big bucks, to deconstruct these verbal firewalls and tell you about what's behind them in plain English.

Long story short: the scientists used ketamine, an anesthetic drug with a long, colorful and checkered history, to treat major depression.

The results: many of the patients improved, some in a matter of hours after receiving the drug.

Even more profound: they remained significantly better for one week following drug administration.

The importance of these findings, preliminary as they may be and in a group of only 18 individuals, cannot be overstated.

Depression kills.

Anything that can reverse it quickly — hours as opposed to the weeks or months required with current state-of-the-art antidepressants — marks a tremendous advance.

Zarate is chief of the mood disorders unit at the National Institute of Mental Health: this is no wacked-out guy trying something at Elsewhere General in a Third-World country.

Here's Shankar Vedantam's article about the study, from yesterday's Washington Post.

    Injection May Treat Depression Much Faster

    Government researchers announced yesterday that they have had striking success in treating depression in a matter of hours, using an experimental injectable drug that acts much more quickly than conventional antidepressants.

    The study, based on a small sample, is part of a push by researchers to develop treatments that can bring quick relief to patients with mental disorders. Patients and their doctors report that it often takes weeks or months for most available medications to improve symptoms.

    Much more work needs to be done before patients can see benefits from the breakthrough, the researchers said. Among the unanswered questions are whether patients will be able to tolerate the drug for long periods, and whether it will continue to be effective. Researchers said they hope the finding will prompt the pharmaceutical industry to develop similar compounds with fewer side effects that can then be tested on a large scale.

    "Psychiatrists have gotten used to the idea we have to wait weeks or months, but we can break the sound barrier and get an antidepressant effect within hours," said Carlos Zarate Jr., chief of the mood disorders research unit at the National Institute of Mental Health.

    Zarate and his colleagues published a paper about their findings in yesterday's issue of the Archives of General Psychiatry.

    In the study, 18 patients were injected with a drug called ketamine, which has been used for a long time as an anesthetic. Patients briefly experienced a well-known side effect of the drug -- a mild feeling of dissociation, where they felt disconnected or found it difficult to put thoughts into words.

    Ketamine is a controlled substance and can produce mild euphoria.

    But the dissociative symptoms disappeared within a couple of hours, and shortly afterward patients and physicians reported a dramatic improvement in mood. Half the patients had a 50 percent decline in depression symptoms after two hours, and by the end of the first day, 71 percent reported a similar improvement. More than a third continued to report such a benefit after seven days, and nearly a third reported a complete end of symptoms. Conventional antidepressants approach those kinds of numbers only after eight to 10 weeks of treatment.

    "We can truly raise the bar on what we can expect of antidepressant treatments," said Thomas Insel, director of the National Institute of Mental Health. "A modest response after six weeks is what we used to define as success. What I love about this project is it redefines success not in terms of weeks, but in terms of hours."

    Rather than go after the conventional targets of serotonin and norepinephrine, the new drug targets an entirely different neurotransmitter in the brain called glutamate.

    "This is not a subtle change," Insel added. "It is almost like rebooting a computer. It is a chemical reboot, and the striking thing is the effect lasts for about a week."

....................

You want more?

How about the abstract of Zarate et al's paper?

It follows.

    A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

    Carlos A. Zarate, Jr, MD; Jaskaran B. Singh, MD; Paul J. Carlson, MD; Nancy E. Brutsche, MSN; Rezvan Ameli, PhD; David A. Luckenbaugh, MA; Dennis S. Charney, MD; Husseini K. Manji, MD, FRCPC

    Arch Gen Psychiatry. 2006;63:856-864.

    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.

    Trial Registration clinicaltrials.gov Identifier: NCT00088699.

    Author Affiliations: Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Md.

....................

Now you're really intrigued, huh?

I mean, you made it this far: you should get something for your trouble, if there's any justice in the world.

OK, then: how about the details of the NIH clinical trial?

They follow.

    Rapid Antidepressant Effects of Ketamine

    This study is currently recruiting patients.

    Verified by National Institutes of Health Clinical Center (CC) May 2006

    Sponsored by: National Institute of Mental Health (NIMH)

    Information provided by: National Institutes of Health Clinical Center (CC)

    ClinicalTrials.gov Identifier: NCT00088699

    Purpose:

    This study will test whether a single dose of ketamine - a drug that blocks a brain receptor called NMDA - can cause a rapid (next day) antidepressant effect in patients with major depression. Several medications are effective for treating depression; however, they take weeks or months to achieve their full effects. A more rapidly acting antidepressant would have a significant impact on the treatment of depression. In a previous study, ketamine produced a rapid antidepressant effect within hours, but the effect lasted less than 1 week. Understanding how ketamine works may lead to a better understanding of the causes of depression and the design of a longer lasting rapidly acting antidepressant.

    Patients between 18 and 65 years of age who are currently experiencing an episode of major depression of at least 4 weeks duration and have not responded to two treatment trials may be eligible for this study. Candidates are screened with a medical and psychiatric history, physical examination, and blood and urine tests.

    Participants undergo the following tests and procedures:

    • Medication tapering: Patients who are taking medications for depression are tapered off the drugs over a 1- to 2-week period.

    • Ketamine/placebo trial: Patients are given a single dose of either ketamine or placebo (an inactive substance), administered intravenously (through a vein) over 40 minutes. After 7 days, patients are given another dose of study drug in crossover fashion; that is, those who previously took ketamine are switched to receive placebo, and those who took placebo are switched to ketamine. Oximetry (measurement of blood oxygen), pulse, and blood pressure are measured continuously for 1 hour before and 4 hours after each ketamine or placebo dose to monitor safety.

    • Interviews and rating scales: Patients complete a series of psychiatric rating scales to assess the effects of the study drug on mood and thinking. The rating scales are repeated up to 18 times during the study, with each time taking about 15 to 20 minutes.
    Physical examination and laboratory tests: Patients have a physical examination, blood tests, weight measure, and electrocardiogram (ECG) at the beginning and end of the study.

    Official Title: Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist

    Total Enrollment: 101

    Study start: July 2004

    Last follow-up: May 2006

    Data entry closure: May 2006

    Bipolar affective disorder (manic-depressive illness) and unipolar depression are common, severe, chronic and often life-threatening illnesses. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. In two separate trials, we tested riluzole (an inhibitor of glutamate release) and found it to have antidepressant properties in patients with unipolar and bipolar depression (Zarate et al. 2004, 2005). In another study, we found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week (Zarate et al in press). The current protocol consists of 3 studies designed to address 3 major questions:

    Study 1 (Rapid improvement research in unipolar depression):

    Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? Patients, ages 18 to 65 years with treatment-resistant major (unipolar) depression will in a double-blind crossover study receive either intravenous ketamine or saline solution.

    Study 2 (Rapid improvement research in bipolar depression):

    Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients, ages 18 to 65 years with treatment-resistant bipolar depression will in a double-blind crossover study receive either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate).

    Study 3 (Rapid and sustained improvement research in unipolar depression):

    Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients, ages 18 to 65 years, with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine will in a double-blind study receive either riluzole or placebo to determine if the rapid response obtained can be sustained.

    Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression.

    Eligibility

    Ages Eligible for Study: 18 Years-65 Years; Genders Eligible for Study: Both

    INCLUSION CRITERIA:

    1. Male or female subjects, 18 to 65 years of age.
    2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
    3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
    4. Subjects must fulfill DSM-IV criteria for Major Depression (296.3) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
    5. Subjects must have an initial score of at least 22 on the MADRS at screen and at baseline of study phase I.
    6. Subjects with a greater than a 25% decrease in the MADRS total scores between screen and baseline of study phase I will be dropped from the study.
    7. Current or past history of lack of response to two adequate antidepressant trials (may be from the same chemical class) operationally defined using the Antidepressant Treatment History Form (ATHF).
    8. Current major depressive episode of at least 4 weeks duration.

    EXCLUSION CRITERIA:

    9. Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
    10. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (excluding nicotine or caffeine) within the preceding 3 months.
    11. Female subjects who are either pregnant or nursing.
    12. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
    13. Subjects with uncorrected hypothyroidism or hyperthyroidism.
    14. Subjects with one or more seizures without a clear and resolved etiology.
    15. Previous treatment with riluzole or hypersensitivity to it or to amantadine.
    16. Previous lack of response to ketamine for depression.
    17. Treatment with a reversible MAOI within 2 weeks prior to study phase I.
    18. Treatment with fluoxetine within 5 weeks prior to study phase I.
    19. Treatment with any other concomitant medication not allowed 14 days prior to study phase I.
    20. No structured psychotherapy will be permitted during the study.

    Please refer to this study by ClinicalTrials.gov identifier NCT00088699

    prpl@mail.cc.nih.gov

    National Institute of Mental Health (NIMH), Bethesda, Maryland, 20892, United States of America

....................

I daresay I know as much about using ketamine in people as anyone on the planet.

Why?

Because even after ketamine was essentially abandoned as an anesthetic due to side effects like hallucinations, flashbacks and in rare cases respiratory obstruction and death, I kept it in the back of my drug drawer "just in case."

Just in case I had a patient coming to the OR bleeding out, for example: ketamine acts like adrenaline, increasing blood pressure and heart rate and supporting a bottoming-out circulatory system.

That's because its mechanism of action peripherally involves the release of epinephrine.

Oh, and did I mention that it improves airway function and respiratory status?

So why isn't it used more?

Because given in large doses without ancillary drugs, it can cause all manner of unpleasant psychiatric side effects.

For example, patients under ketamine anesthesia may start talking or yelling or singing.

Sometimes it's so bizarre or off-color that nurses and surgeons beg me to give the patient something to make them stop.

If they ask nicely I comply.

But I digress.

The dose used by the psychiatrists in their study (0.5 mg/kg IV) isn't enough to provide surgical anesthesia.

I use an initial dose of 1-2 mg/kg IV to induce a patient, with subsequent doses of 0.5-1.0 mg/kg as needed (about every 20-30 minutes in most cases).

I add IV fentanyl, propofol, Versed or other drugs as needed.

Perhaps I should add a surcharge for psychotherapy for those of my patients receiving ketamine.

Ya think?

August 9, 2006 at 04:01 PM | Permalink


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Comments

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Posted by: Pippo Link | Jul 18, 2008 1:03:26 PM

garbage has an appropriate screen name: what (s)he is spouting is, indeed, garbage. Saying glibly that depression can be treated by "making changes for the better" and dismissing the exploration of new drugs for treating it as an attempt by "the powers that be" to "neutralise dissent" display callow ignorance. Obviously,(s)he knows nothing about depression.

I was one of the participants in this study. It's not in the least about "replacing depression with addiction." A single dose of ketamine (much smaller than recreational users take) was given in a hospital setting by an anesthesiologist, with the intent not to develop a market for ketamine as a depression drug, but to do basic research that could someday lead to new drugs for rapid relief from depression.

No one would dream of suggesting that leukemia or TB has a "real role to play" and therefore shouldn't be treated. There is nothing ennobling about the suffering of depression. Anything - ANYTHING - that might cut short the exhausting struggle to keep from killing one's self during the weeks of waiting for today's antidepressant medications to become effective (assuming they ever do) is worth investigating.

Posted by: anonymous | Aug 12, 2006 11:07:37 PM

"Yesterday, today, and tomorrow are so close together that they might as well be the same moment"

Now this sounds like something Joe would say. After all, time is so,
so.............................now.

Posted by: meg | Aug 11, 2006 1:51:35 PM

It's also a large (or small) animal tranquilizer. I used some once to free a cat who had impaled himself on a barbecue spit and then wound himself around it trying to get free. Worked great.

Posted by: cat | Aug 11, 2006 10:01:14 AM

As far as I know, there is a REASON why Ketamine is a controlled substance. It's supposed to be addictive.

So we're going to replace a depression problem with an addiction problem? Great...

Besides, there are reasons why people experience depression, and it's usually something internal with the way one's mind works or with something external, from pressure from work, environment, family, whatever. By pumping people with depression with ketamine, you are going to remove all rationale for changing themselves or their environment. So instead of trying to make changes for the better, we are just going to pump them with Ketamine. It feels too much like Huxley's "A brave new world" where people where pumped with medication in order to keep them complacent.

Depression has a real role to play in forcing people to change or to at least express dissatisfaction with the powers that be. Now the powers that be have a potent weapon to neutralise dissent.

Posted by: garbage | Aug 10, 2006 3:36:11 AM

This reminds me of the trials of MDMA for PTSD. Sometimes just a few hours of realization can alter one's perspective enough to impart longer-termed changes. It's like CBT, but with instant results. I would be greatly surprised if the drug itself caused any measurable, clinically significant changes in neurochemistry.

I have used IM Ketamine recreationally a number of times. In Mexico, you see, it can be bought over the counter in sealed ampules of controlled concentration at the appropriate type of store (and no, it's not the pharmacy, you'll have to figure that out on your own).

Anywhoo, in my experience the disassociative effect is so profound as to completely obliterate the concept of short-term time. Ketamine makes everything feel like it's happening on universe time. The shifting of plates, the birth and death of stars, it all seems so quick and fleeting. Yesterday, today, and tomorrow are so close together that they might as well be the same moment.

I think it's something about this perspective--that any individual's life and experiences are just a tiny, almost unnoticeable blip on the universe's radar--that allows one to step back and realize that whatever their troubles, they don't really matter in the big scheme of things.

Dust in the wind, that's what we are.

Posted by: Marc | Aug 9, 2006 11:59:51 PM

Having suffered depression as my mother did and as my daughter does I think this is great news. Unless you have suffered through depression most people just don't get it. I've been on a very low maintenance dose of anti depressant since 85.Before I was hospitalized in 85 I had friends say just snap out of it, as if that was a choice.

Posted by: Jackie | Aug 9, 2006 8:59:05 PM

But, as the lame-but-true joke says:

How many psychologists does it take to change a light bulb?

Doesn't matter, since the light bulb must want to change.

Posted by: Mb | Aug 9, 2006 5:10:58 PM

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