Ketamine - Magic Antidepressant, or Expensive Illusion?

Neuroskeptic iconNeuroskepticBy NeuroskepticMar 8, 2012 7:09 AM


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Not one but two new papers have appeared from the Carlos Zarate group at NIMH reporting that a single injection of the drug ketamine has rapid, powerful antidepressant effects.

One placebo-controlled study found a benefit in depressed bipolar patients who were already on mood stabilizers. The other found benefits in treatment-resistant major depression, though ketamine wasn't compared to placebo that time. Here's the bipolar trial:

There have now been several studies finding dramatic antidepressant effects of ketamine, a compound that all journalists seem contractually bound to call either a or a "club drug" or a "horse-tranquilizer". Great news?

If you believe it. But hold your, er, horses... there's a problem. As I said almost 3 years ago about one of the earlier ketamine trials:

In theory, the trial was double blind - neither the patients nor the doctors knew whether they were getting ketamine or placebo. But

you'll know when you've been injected with 0.5mg/kg ketamine.

You get high. That's why people take it [recreationally]. The study can't really be called double blind.

To their credit, Zarate et al did acknowledge this, and suggested that in future ketamine could be compared to another drug which produces noticeable effects. But they really should have done that to begin with.

It's now 2012, and there have still not been any published studies comparing ketamine to an active comparator i.e. a different drug that produces noticable psychoactive effects, to avoid unblinding. This means it's 12 years since the initial pilot report on ketamine in depression, and 6 years since the first large trial appeared.

The authors of the 2006 paper themselves wrote that "limitations in preserving study blind may have biased patient reporting... One potential study design in future studies with ketamine might be to include an active comparator" and suggested amphetamine for the big role.

Good idea. But six years later, we're still waiting. Which is really a bit silly. There have been dozens of papers written about the possible antidepressant effects of ketamine, from human trials to mouse work. That's a lot of research dollars (and dead mice) on something that might just be an active placebo.

Looking at the registered ketamine research on clinicaltrials.gov, I found that four active-comparator ketamine trials are in the pipeline (1,2,3,4), plus one cancelled (5). Only one is for depression though. The others being for OCD, cocaine dependence and suicidal ideation.

In all of these trials a benzodiazepine is the active comparator. Is that a good idea? Well, it's certainly better than nothing, but I wonder.

An active comparator has to "make an impression" on the patient equal to that produced by the real drug. The null hypothesis, remember, is that ketamine has no specific antidepressant effect. That means it produces improvement through a combination of a) the placebo effect (expectation) and b) non-specific psychoactive changes.

More on that second one: any psychoactive drug might relieve depression by "taking your mind off it" and a change in mental state, as provided by a drug, also provides a demonstration that "I won't always feel this way". By showing that states of consciousness are products of brain chemistry, almost any drug could therefore offer a "glimmer of hope" to the depressed. If all this sounds very subjective, it is, but that's the point. Psychiatry is.

Would a benzo make as big an impression as 0.5 mg/kg ketamine IV? It's impossible to predict, really; so we'd need to ask people about the subjective strength of the drug effect. Personally, I worry that a lot of people just get sleepy on benzos and don't really feel much, so I'd prefer they used something a bit more hard-hitting like amphetamine, but maybe that's just me.

There's a deeper problem though. Suppose our ketamine-benzo trial finds no difference between ketamine and benzo. A critic could say, ah, but maybe it was just a "failed trial", so it doesn't overturn the positive studies. The patients weren't properly diagnosed, or weren't depressed enough, or were too depressed, etc.

Nitpicking such differences between studies is a well-practiced art.

Critics could complain in other ways if the study did find a benefit of ketamine. As I see it, the only way to settle this once and for all is to do a three-way randomized controlled trial- inactive placebo vs. active comparator vs. ketamine.

That way, if it's a failed trial, we'd know: there'd be no difference between ketamine and the inactiveplacebo. If there was a difference, but the active comparator was just as good as ketamine, that means it was all about nonspecific effets. Finally, if ketamine was better than the other two conditions, we could be pretty confident it was really working.

Also important is the question of volunteer expertise; subjects shouldn't be able to tell what drug they're on, but people who'd taken ketamine and/or the comparator drug before might be able to do that, so you'd want naive volunteers.

In conclusion:

It's possible that ketamine has no specific antidepressant effects. To find out we ideally need a three-way trial, with both active and inactive comparators, careful monitoring of subjective drug effects and patient knowledge and expectations. Until that happens, I will be skeptical of ketamine in depression.

This is not because I just think it's impossible. Ketamine profoundly affects the brain in ways that we don't understand. I've suffered depression and I know it can come and go in a matter of minutes. So I think it's entirely possible that it works - but it's also possible that it's a nonspecific effect.

Look. I really want to know the answer to this. Both as a neuroscientist, and as a depression sufferer, this is very important to me. That's why we urgently need a good trial.

Link: See also the discussion and the comments over at The Neurocritic and this Scientific American piece which is pretty good except that it doesn't cover the active placebo issue.

Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, and Luckenbaugh DA (2012). Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological psychiatry PMID: 22297150

Ibrahim, L., et al. (2012). Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study Neuropsychopharmacology DOI: 10.1038/npp.2011.338

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