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Ketamine: Magic Antidepressant Or Illusion? Revisited

Neuroskeptic iconNeuroskeptic
By Neuroskeptic
Dec 18, 2012 10:54 PMNov 5, 2019 12:16 AM


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There's a lot of interest in the idea that ketamine provides unparalleled rapid, powerful antidepressant effects, even in people who haven't responded to conventional antidepressants.

Earlier this year, I asked:

Ketamine - Magic Antidepressant, or Expensive Illusion?

There have now been several studies finding dramatic antidepressant effects of ketamine, the "club drug" aka "horse-tranquilizer". Great news? If you believe it. But hold your, er, horses... there's a problem.

My concern was that although depressed patients certainly do report feeling better after an injection of ketamine, compared to people given placebo, that doesn't prove that the drug is actually an antidepressant.

Rather, patients might be experiencing an enhanced, 'active' placebo effect, because ketamine causes subjectively powerful hallucinogenic experiences. So the placebo-controlled trials weren't really blinded.

To settle the question, I suggested a three-way trial comparing it both to an inert placebo, and to some other hallucinogen; if ketamine has a specific antidepressant effect, it should produce more improvement than the comparison drug.

This has never been done.

Given this background, a new trial from NIMH's Ketamine King, Carlos Zarate, makes interesting reading:

A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression.

Zarate et al tried a novel drug, AZD6765 in depressed people. AZD6765 works much like ketamine in that it blocks brain NMDA receptors. But it is a less powerful trapping blocker than ketamine, meaning that AZD6765 causes less dramatic effects on the target receptors, in some respects.

In practice, this makes AZD6765, much less hallucinogenic than ketamine.

So it's interesting that, compared to placebo, the new drug only produced small benefits. On the MADRS depression symptom scale, patients felt a little better on AZD6765, but the boost only lasted a few hours.

The effect was far smaller than in an earlier ketamine trial as my crudely-mashed-up graph shows (although note that the patient populations were somewhat different, one bipolar and one unipolar depression, although their baseline severity was the same.)

While on ketamine people experienced significant subjective effects, with AZD6765 they didn't, and couldn't tell whether they got drug or placebo. Is that why they got a smaller benefit?

This is what we'd see if NMDA blockers do have a modest antidepressant effect but the dramatic improvements seen on ketamine are largely active placebo phenomena. Then again, it's also consistent with ketamine being a powerful antidepressant and AZD6765 just being less effective because it's a milder blocker of NMDA - effectively, a low dose of ketamine.

To tell the difference, we need... an active placebo controlled trial, like I've been banging on about for ages. But I wasn't the first one to suggest it - that was none other than Carlos Zarate et al in 2006.

Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, and Luckenbaugh DA (2012). A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. Biological psychiatry PMID: 23206319

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